Tag Archives: Methotrexate

Methotrexate –First Choice Immunomodulator?

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In pediatric inflammatory bowel disease (IBD), there has been an uptick in the usage of methotrexate (MTX) over the last 10 years.  This coincides with malignancy concerns, particularly hepatosplenic T-cell lymphoma, with thiopurine use.  Recently, a retrospective study examines the use of MTX in a cohort of 290 patients from 19 centers. 172 received monotherapy with MTX for >3 months and had at least one year of followup.

Key findings:

  • 81 of these 172 used MTX as their first immunomodulator (IMM) (monotherapy) and this had become more prevalent towards the end of the study period (60% in 2010).  Among these 81, 27% achieved a sustained clinical remission –based on physician global assessment.
  • 35% who used MTX as their second IMM achieved a sustained clinical remission.
  • Among MTX users, 15% had increased ALT (>60 IU/L) and 12% had white blood cells <4000 cells/mL.
  • There was wide variation in usage of MTX therapy among different pediatric centers.
  • According to Figure 2, there was little difference in the usage of MTX between males and females.  Given the well-recognized teratogenicity with MTX, it is interesting that the authors did not elaborate on this finding.

One limitation of this study was the absence of data regarding route of MTX administration. Oral bioavailability is likely a little lower than with parental dosing.  Another limitation was reliance on physician global assessment without correlating a marker for mucosal healing.

Take-home message: Methotrexate is being used more frequently as a first-line IMM.  As there are no head-to-head comparison studies with thiopurines, one can only speculate whether its efficacy and safety are good enough to chosen as the first immunomodulator.

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Tofacitinib -Risks and Benefits in Rheumatoid Arthritis

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Previously Tofacitnib, an oral Janus kinase inhibitor, has shown promise as an emerging treatment for inflammatory bowel disease (Tofacitinib –a JAK Inhibitor for UC | gutsandgrowth).  So, a recent large study in tofacitinib use in rheumatoid arthritis caught my attention, specifically with regards to the potential risks of treatment (NEJM 2014; 370: 2377-86).

This double-blind study randomly assigned 958 patients (mean age ~49 years) to receive 5 mg or 10 mg of tofacitinib twice daily or weekly methotrexate.  This study, called ORAL Start, examined the effectiveness of these drugs over a 24 month period in patients with active moderate-to-severe rheumatoid arthritis naive to therapeutic doses of methotrexate.

Key findings:

  • Among tofacitinib patients, 25.5% (5 mg group) and 37.7% (10 mg group) had an ACR 70 response at 6 months compared with 12.0% of methotrexate patients.  Results at 12 and 24 months were similar (Figure 1)
  • Adverse effects:
  1. 4% of tofacitinib patients developed herpes zoster compared with 1.1% of methotrexate patients
  2. 5 tofacitinib patients developed cases of cancer (three cases of lymphoma) compared with 1 case among patients receiving methotrexate
  3. Tofacitinib was associated with decreases in neutrophil/lymphoctye counts, increases in creatinine levels, increases in aminotransferases, and increases (16-22%) in LDL/HDL cholesterol levels
  4. Four deaths were noted among patients treated with tofacitinib compared with none in the methotrexate patients.

Related blog post: Source Article: Methotrexate Safety | gutsandgrowth

Source Article: Methotrexate Safety

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A recent post (Monotherapy or Combination Therapy with Adalimumab) referenced an article indicating some potential concern for malignancy potential with methotrexate (Semin Arthritis Rheum 2014; 43: 489-97). Here’s a link to the source article/abstract:  Comparative cancer risk associated with methotrexate, other…

The authors conducted a comparative effectiveness study with cancer as an outcome in patients with rheumatoid arthritis (RA).  The final sample size was 6806 patients.  The most common drugs examined included methotrexate (n=1566) and TNF antagonists (n=3761). Other disease-modifying anti-rheumatic drugs (DMARDs) included other non-biologics (n=904), rituximab (n=167), and abatacept (n=408).

The authors note that with “the advent of newer DMARDs and combination therapy (this) has allowed more RA patients to lead more functional lives.  With this improvement in therapy, more attention is focused on the comparative risks and benefits of treatment.”

Key findings/discussion:

  • TNF antagonists were associated “with a reduced overall cancer risk versus methotrexate.” (HR 0.29).  Figure 2B, shows a plot with specific HR for various malignancies.  TNF antagonists had a HR of 0.15 for lymphoma.
  • Oncogenic potential of methotrexate was described almost 20 years ago, however, “its obvious clinical benefits have overshadowed malignancy concerns.”
  • “Our findings suggest that when examining the cancer risk associated with other DMARDs, combined methotrexate use must be factor into adjusted analyses.”

How does this translate to inflammatory bowel disease (IBD)?  While RA and IBD patients may have different risks for malignancy, this study suggests that patients receiving methotrexate therapy may have a low risk of malignancy.  The potential benefits of methotrexate therapy along with alternatives need to be weighed against this possible risk. Perhaps, this article may help reduce the concerns regarding anti-TNF therapy with regard to relative risk.

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How Long Will Infliximab Work?

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Given the limited therapeutic options, the question of infliximab (IFX) durability in pediatrics is quite important.  One center has published its 10-year retrospective experience (Inflamm Bowel Dis 2014; 20: 606-13).

Inclusion criteria for the 188 patients included initiating IFX prior to age 21 years and patients who had a minimum of 1-year followup.

Demographics: Median age at diagnosis was 11 years for Crohn’s disease (CD) and 12 years for ulcerative colitis (UC). Indication for IFX due to steroid refractory disease was present in 42% of UC patients compared with 14% of CD patients.  Monotherapy was more common in UC patients, 65%, compared to 35% of CD patients.

Methotrexate was administered in 69 (44%) of CD patients at time of IFX with the majority (n=56) as oral treatment (low-dose <10 mg every week).  In addition, MTX was initiated after IFX induction in another 38 (24%).  Only 36 (23%) remained on IFX mono therapy throughout the duration of treatment in CD patients.

Key findings:

  • 88% of CD patients remained on IFX at 1 year, 80% at 2 years, and 72% at 5 years.
  • Only 7 of 157 CD patients were primary nonresponders.
  • 65 of 89 CD patients who did not achieve a sustained durable remission underwent dose escalation. 40 of 65 responded to dose escalation.
  • Of those who lost response to IFX, the majority were transitioned to adalimumab (ADA) and among this group, 82% remained on ADA treatment at last followup.
  • Among UC patients (n=31), 9 were primary nonresponders. At last followup, 41% (9) remained in a durable sustained response at last followup.
  • While the authors used MTX due to favorable effects on IFX pharmacokinetics (Arthritis Rheum 1998; 41: 1552-63), there was “not a significant difference in IFX durability or efficacy between this group and patients with CD on IFX monotherapy”
  • Availability of antibodies to infliximab (ATIs) and IFX trough levels were only assessed in a subset.  However, “we did see a significant difference in those that responded to dose intensification when ATIs were undetectable.”

Bottomline: The majority of CD patients can remain on IFX for >5 years.  Among those who lose response, adalimumab was a durable alternative.  A much lower durable response was evident with the subset of patients with UC.

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Also noted:

Inflamm Bowel Dis 2014; 20: 614-21. In this study of 78 youth with IBD, depressive symptoms warranting additional evaluation were present in 13% which was lower than in the community comparison group.  Disease severity was noted to be inactive in 63% and mild in another 18%.

Inflamm Bowel Dis 2014; 20: 495-501. This study showed that 25 children exposed to anti-TNFs prenatally for maternal IBD seemed to show good safety.  Immunologic investigation undertaken in 17 of the children was normal.  No control group limited the ability to determine if increased infections were present.

And, here’s a link to Mar-April Circle Newsletter from ImproveCareNow -topics include group medical appointments, parent working group, dieting with IBD, and includes link to self management handbook.

 

 

Digging into the COMMIT Study

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“Lies, damned lies, and statistics” –Mark Twain (who attributed this quote to Benjamin Disraeli)

Using statistics, the recent COMMIT study (Gastroenterol 2014; 146: 681-88) showed that the combination therapy of methotrexate (MTX) and infliximab (IFX) was not more effective than IFX alone. Does this result makes sense? No.

Before getting back to that question, here’s the background: this 50-week study was a randomized, double-blind, placebo-controlled trial with patients assigned to either methotrexate at dose escalated gradually to 25 mg/week (n=63) or placebo (n=62); both groups received a prednisone induction (with tapering starting at week 1) along with IFX (5 mg/kg) at weeks 1, 3, 7, 14, 22, 30, 38, and 46.  Remission was considered to be a CD Activity Index (CDAI) of <150 in individuals off prednisone.  The patients enrolled in this study were on average about 40 years of age and had similar baseline characteristics, including disease duration of more 9 years.

Amazing to me was the fact that nearly 40% of both the treatment and control group included current smokers (since smoking clearly worsens CD).

Key Results:

  • Combination therapy resulted in fewer antibodies to IFX (ATIs): 4% vs. 20% (P=.01)
  • Combination therapy resulted in higher IFX trough levels: 6.35 mcg/mL vs. 3.75 mcg/mL (P=.08); the proportion with detectable trough levels was also higher in the combination group: 52% compared with 46%.
  • Safety was similar.  “No clinically relevant hepatotoxicity was identified.” However, 14 patients did experience an increase in liver enzymes. Infusion-related reactions were infrequent: 1 in combination group, and 3 in IFX monotherapy.
  • At week 14, 76% of combination group achieved prednisone-free remission and 78% of IFX monotherapy.  At week 50, these numbers were 56% and 57% respectively.

Getting back to the question about why this does not add up as a negative study –the combination group had lower ATIs and better IFX drug levels, this usually translates into better response.  As such, the limitations of this study deserve to be scrutinized:

  • Relatively small numbers of patients
  • Objective markers like colonoscopy were not included
  • Short duration of study period.  While a 1 year study is not really all that short, some benefits of medications can take a longer time to appreciate
  • Prednisone induction may have obscured MTX benefit
  • Treatment group had long duration of disease.  Those with shorter disease duration may have a more inflammatory component to their disease and respond more favorably.

Bottomline: this study showed that the combination of MTX/IFX was not statistically-superior to IFX alone.  Given the favorable benefit on ATIs and IFX drug levels, MTX combination may still be useful, particularly in those with more recent onset of IBD.

Plus One More Reference:

Clin Gastroenterol Hepatol 2014; 12: 434-42.  This retrospective study of 425 patients (1975-2012) examined features associated with failure of medical treatment. “Patients prescribed thiopurine or anti-TNF therapy when they have a complicated stage of CD are more likely to require surgery.  Better patient outcomes are achieved by treating CD at early inflammation stages.”

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Teaching an Old Drug New Tricks

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A couple recent articles focused on the new uses of methotrexate (MTX) and how to handle potential hepatotoxicity:

  1. J Pediatr 2014; 164: 231-36
  2. Inflamm Bowel Dis 2014; 20: 47-59

In the first medical review article, the authors note the efficacy of MTX for the following:

  • Juvenile idiopathic arthritis
  • Uveitis
  • Psoriasis
  • Crohn disease
  • Juvenile dermatomyositis
  • Localized scleroderma
  • Vasculitis

This review article discusses mechanism of action which is poorly understood along with pharmacogenomics and practical issues in usage.  The latter includes the need for supplemental folic acid.  Other points:

  • “The long-term safety of MTX is remarkable”
  • “The issue of nausea and vomiting…can be especially disturbing.”  They note that one study demonstrated that ondansetron 1 hour prior to MTX from the first injection prevented nausea, which was often difficult to treat once developed.
  • “Liver enzyme abnormalities occur frequently (up to 30% of patients) but are usually of minimal clinical significance.”  Best to draw blood tests 1-2 days before MTX dosing.
  • “In children, unlike adults, MTX-related pulmonary adverse events are very rare.”
  • “In recent years it was shown that live vaccine boosters are effective and safe during MTX use (caution may be needed if MTX is used with other immunosuppression medications)” Ref: JAMA 2013; 309: 2449–56.
  • “Use during pregnancy or within 3 months of planning pregnancy is contraindicated”

The second article was a systemic review which identified 12 high-quality studies which focused on MTX hepatotoxicity in children.  Key findings:

  • 57 of 457 developed some degree of abnormal liver biochemistries.
  • Due to hepatotoxicity, dose reductions were undertaken in 6.4% and 4.5% discontinued MTX.

The authors note that studies of MTX in adults with IBD have not demonstrated cumulative liver toxicity from MTX.  In addition, many of the patients with hepatotoxicity may have had  other reasons for abnormal liver biochemistries including other medications (eg. glucocorticoids).  “Confirmation of MTX hepatotoxicity with a liver biopsy is seldom performed in children;” as a consequence, the exact rate of MTX hepatotoxicity is unknown.

The authors propose that liver biochemistry monitoring occur at baseline, biweekly x 2, then every 2-3 months.  Also, the authors recommend:

  • If ALT < 2 times upper limit of normal (ULN), check liver biochemistries every 2 weeks
  • If persistent abnormalities, the authors recommend an ultrasound
  • If ALT ≥ 2 times ULN, repeat testing should be obtained and consider consultation with a hepatologist

Bottomline: Methotrexate is an important medication for Crohn disease –there are not very many available.  If there are persistent liver enzyme elevations, dose reduction of MTX (or cessation) may be necessary.  As a practical matter, it is advisable to obtain blood draws 1-2 days prior to MTX rather than afterwards. Nausea can be minimized with ondansetron and weekend dosing.

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AGA Guidelines for the Use of Thiopurines and Anti-TNF Agents for Crohn’s

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The link (from KT Park’s twitter feed): gastrojournal.org/article/S0016-5085(13)01521-7/fulltext …

Some of the key points/recommendations for adults with Crohn’s disease:

  • In clinical practice, CD of moderate severity is defined as disease requiring systemic corticosteroids for symptom control.

For Induction of Remission:

  • We Suggest Against Using Thiopurine Monotherapy to Induce Remission in Patients With Moderately Severe CD (Weak Recommendation, Moderate-Quality Evidence)
  • We Suggest Against Using Methotrexate to Induce Remission in Patients With Moderately Severe CD (Weak Recommendation, Low-Quality Evidence)
  • We Recommend Using Anti–TNF-α Drugs to Induce Remission in Patients With Moderately Severe CD (Strong Recommendation, Moderate-Quality Evidence)
  • We Suggest Using Anti–TNF-α Drugs in Combination With Thiopurines Over Anti–TNF-α Drug Monotherapy to Induce Remission in Patients Who Have Moderately Severe CD (Weak Recommendation, Moderate-Quality Evidence)

Maintenance of Remission:

  • We Recommend Using Thiopurines Over No Immunomodulator Therapy to Maintain a Corticosteroid-Induced Remission in Patients With CD (Strong Recommendation, Moderate-Quality Evidence)
  • We Suggest Using Methotrexate Over No Immunomodulator Therapy to Maintain Corticosteroid-Induced Remission in Patients With CD (Weak Recommendation, Low-Quality Evidence)
  • We Recommend Using Anti–TNF-α Drugs Over No Anti–TNF-α Drugs to Maintain Corticosteroid- or Anti–TNF-α—Induced Remission in Patients With CD (Strong Recommendation, High-Quality Evidence)
  • We Make No Recommendation for or Against the Combination of an Anti–TNF-α Drug and a Thiopurine Versus an Anti–TNF-α Drug Alone to Maintain Remission Induced by a Combination of These Drugs in Patients With CD (No Recommendation, Low-Quality Evidence)

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Switching from Thiopurines to Methotrexate

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Data regarding methotrexate treatment for Crohn’s disease (CD) is limited.  A fairly large retrospective study provides a better idea about its effectiveness over a five-year period (Clin Gastroenterol Hepatol 2013; 11: 667-72).

In total 174 consecutive CD patients (age 35 ±12 y) from 3 hospitals were analyzed.  All of these patients received methotrexate (MTX) after thiopurine therapy. 23% had not responded to an anti-TNF agent.  Most of the patients who had failed thiopurine treatment had an intolerance to thiopurine rather than loss of clinical response.  Data on patient characteristics including smoking status, disease behavior/location, previous treatments, and indication for MTX are detailed in Table 2.  Interestingly, 113 patients were female.  The authors noted that 90% of their patients received MTX parenterally.

Key findings:

  • Patients with sustained clinical benefits from methotrexate monotherapy:  98 (86%) at 6 months, 50 (63%) at 12 months, 27 (47%) at 24 months, and 3 (20%) at 60 months.
  • 45 (26%) discontinue methotrexate due to intolerance, mostly within the first 6 months.  However, adverse effects were generally mild.  Only one patient required hospital admission for an infection (cytomegalovirus).

There are many limitations of this retrospective study.  Nevertheless, a significant portion of patients derived clinical benefit for at least 2 years.

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PPI Side Effects: “Dissecting the Evidence”

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While proton pump inhibitors (PPIs) are used extensively for acid-related diseases and have been around for nearly 25 years, there have been a number of reports about potential side effects.  As a drug class, PPIs have a very good safety profile.  A recent article reviews some controversial adverse effects and summarizes the evidence for and against (Clin Gastroenterol Hepatol 2013; 11: 458-64).

I. Calcium/bone effects.  After reviewing a number of studies, the authors conclude: “There is no good evidence to establish that PPI use has a significant risk for bone density loss or osteroporotic-related fractures….Supplemental calcium is not recommended or justified solely because of PPI use.”

II. Iron. “Although it is conceivable that PPI therapy may reduce absorption of nonheme iron and retard iron pool replenishment, this effect has not been well-studied or evident from widespread use in clinical practice.

III.  Magnesium.  “The FDA recommendation to consider checking magnesium levels before starting is not practical, in particular for the over-the-counter market. In patients who may be predisposed to …ongoing magnesium loss…it may be reasonable to follow…Given the rarity of the reports and no controlled studies to delineate the mechanisms, it is important for health care providers to be aware of this” (rare reports of profound hypomagnesemia).

IV. Pneumonia. “Small relative risk associated with short-term and high-dose PPI use.  These relationships, however, do not offer a definitive explanation for the relative risk” due to the studies and confounding factors.

V. Clostridium difficile.  “To date, there is insufficient evidence to conclude that there is a definitive relationship between PPI use and C difficile infection…clinicians should be aware of this potential relationship.”

VI. Traveler’s diarrhea.  “The data…were overall supportive of no associated risk, albeit there were a few specific case reports suggesting a remote causal association.”

VII. Small intestinal bacterial overgrowth. “The relationship between PPI use and the development of SIBO is still not understood.”

VIII. Interstitial nephritis.  Extremely rare. “Investigators…did not find enough evidence to support a causative relationship.”

IX. Methotrexate.  “Coadministration of PPIs with high-dose methotrexate appears to be correlated with delayed methotrexate elimination.”

Also discussed: Vitamin B12, Clopidogrel, Spontaneous bacterial peritonitis

The authors conclude that the above reported associations have received considerable attention.  “Because PPIs are overprescribed in many patients, …the clinical effects always should be reviewed and attempts should be justified to stop any therapy that may not be needed.”

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Overcoming ATIs

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Usually, when antibodies to infliximab (ATI) develop in combination with a loss of clinical response in an individual with inflammatory bowel disease (IBD), this often indicates a need to switch treatments.  A recent study suggests that some patients can eliminate ATIs with the addition of immunomodulators (Clin Gastroenterol Hepatol 2013; 11: 444-47).

In this small retrospective study, 5 patients (18-37 years of age) who developed ATIs were able to continue infliximab therapy after instituting immunomodulator treatment (3 with thiopurines, and 2 with methotrexate).  What makes this report interesting, was that these ATIs (prior to immunomodulator use) were identified multiple times and were associated with undetectable infliximab levels.  None of these patients had dose intensification of infliximab.  After instituting immunomodulator therapy, detectable infliximab was evident and the ATIs disappeared.  According to Figure 1, the timeframe for return of response was about 10 weeks in some of these patients.

The authors note that the addition of immunomodulators can gradually eliminate a preformed memory response to infliximab antigen.  They also note that ATIs can sometimes disappear spontaneously, though this had not been noted to occur previously when mulitple ATIs levels have been identified.

While these observations are important, a larger prospective study is needed to inform how frequently this strategy could be successful.

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