Is There Renal Toxicity with Mesalamine Therapy for IBD?

A recent study (V Jairath et al. AP&T 2019; https://doi.org/10.1111/apt.15408) provides evidence that 5-aminosalicylic acid therapy for IBD does NOT increase the risk of nephrotoxicity.  This paper’s findings run counter to more than thirty years of teaching on this medication.

Full Free Link: No increased risk of nephrotoxicity associated with 5‐aminosalicylic acid in IBD: a population‐based cohort and nested case‐control study

Abstract (bold highlighted by blog author):

Background

There is conflicting evidence about nephrotoxicity risk associated with 5‐aminosalicylates for treatment of IBD.

Methods

Retrospective cohort and nested case‐control study, using the Health Improvement Network primary care database linked to hospital discharge coding for patients in England, 1996‐2017. Nephrotoxicity risk analysis was a first recorded renal impairment diagnosis adjusted for key variables and was assessed between 2008 and 2017.

Results

A total of 35 601 patients with prevalent UC or CD were included. The proportion of patients prescribed 5‐aminosalicylates fell from 83% in 1996‐1999 to 71% in 2012‐2015 for UC patients and 64% to 45% for CD patients. Thirty per cent of patients had prolonged 5‐aminosalicylate use. Between 2008 and 2017, the incident rate of nephrotoxicity was similar and stable for UC (12.6/1000 person‐years) and CD (10.9/1000 person‐years) patients. Multivariate analysis showed no evidence for association between current prescription of 5‐aminosalicylate and nephrotoxicity in UC or CD patients, comparing ≤ 30 days prescription prior to index vs 31‐≤180 days. However, active disease, disease duration, concomitant cardiovascular disease or diabetes and nephrotoxic drug use were independently associated with development of nephrotoxicity in UC and CD.

Conclusions

Despite the paucity of evidence for their benefit, 5‐aminosalicylates were prescribed to approximately half of CD patients (30% prolonged therapy). Nephrotoxicity was rare in this patient cohort, and was not associated with 5‐aminosalicylate use, but rather with disease status, comorbidity and use of nephrotoxic drugs.

Related blog posts:

Park Guell, Barcelona

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition

 

New Normal for Ulcerative Colitis

A recent study (Clin Gastroenterol Hepatol 2014; 12: 1887-93) shows that patients with ulcerative colitis (UC) with subclinical activity, based on fecal calprotectin levels, improve with mesalamine escalation.  DEAR, the acronym for this study,  stands for Dose Escalation And Remission.

Methods: The researchers screened 119 patients with UC who were considered to be in remission based on the Simple Clinical Colitis Activity Index score. 52 patients who had calprotectin > 50 mcg/g and were receiving no more that  3 g/day of mesalamine were identified and switched to a mesalamine  MMX 2.4 g/day dose for 6 weeks.  Then the group was divided into an escalation group (4.8 g/day) or control group (continued with 2.4 g/day) for an additional 6 weeks.

Key findings:

  • 26.9% of the escalation group and 3.8% of the control group achieved a calprotectin <50 mcg/g.
  • 52.6% of the escalation group and 15.8% of the control group achieved a calprotectin <100 mcg/g.
  • 76.9% of the escalation group and 16.7% of the control group achieved a calprotectin <200 mcg/g.

This study shows that higher doses of mesalamine were more effective in improving the calprotectin biomarker; however, the exact target value for calprotectin is not entirely clear.  This study is in agreement with several others which have suggested a dose-response relationship with mesalamine therapy. This study suggests that a “quiescent” ulcerative colitis by scoring indices may overestimate the extent of colitis control.  However, the associated editorial (pg 1894) cautions that “the current data are not sufficient to warrant the use of mesalamine dose escalation in patients with UC in clinical remission who have an increased FC (fecal calprotectin) concentration greater than 50 mcg/kg.”

Also noted: Clin Gastroenterol Hepatol 2014; 12: 1865-70.  Prospective study of 59 patients with UC with clinical and endoscopic remission.  18 (30.5%) had histologic inflammation which correlated with elevated fecal calprotectin: median 278 mcg/g compared with 68 mcg/g for those without histologic inflammation.

Take-away message: If histologic inflammation is important, then fecal calprotectin can help identify this in patients otherwise considered to be in remission.

Related blog posts:

How effective are aminosalicylates for pediatric UC?

In a prospective, multicenter, inception cohort study (JPGN 2013; 56: 12-18) with 213 newly diagnosed ulcerative colitis (UC) patients, oral aminosalicylate (5-ASA) therapy was effective in 86 (40%).  That is, 40% were considered to be in corticosteroid-free remission at 1 year using 5-ASA as primary maintenance therapy.

This study took place between 2002-2010.  Of 1669 children enrolled in the registry from 32 sites, 440 (26%) were diagnosed with UC.  Of this group, 353 had followup >1 year and 213 met inclusion/exclusion criteria; all patients had to be treated with only 5-ASA or corticosteroids in the initial 30 days following diagnosis.  Most of those excluded had other therapies.  Among those with primary oral 5-ASA treatment, only 98 started treatment without a steroid induction.

Some interesting aspects of the study group:

  • 82% had pancolitis
  • 62% had moderate/severe disease at diagnosis based on physician global assessment
  • No laboratory or clinical features were associated with a higher likelihood of response
  • Mean daily dosage of 5-ASA was 52 mg/kg/day; 23% had a dose >60 mg/kg/day

The authors note that improved patient adherence and possibly higher 5-ASA dosing schedules may improve response to 5-ASA treatment.

Related blog entry:

Once daily Mesalamine | gutsandgrowth

Once daily Mesalamine

Based on the literature, it is not clear that there is any need to give melamine more than once a day; this is often in contrast to labeling for many of these products:

  1. Inflamm Bowel Dis 2012; 18: 1785-94 
  2. Inflamm Bowel Dis 2012; 18: 1885-93

The 1st study identified 11 relevant randomized studies, after excluding 6870 that were considered irrelevant. Five of these studies were single blind and one was open-label; the remainder were double-blind randomized trials. In total, these studies examined 4070 patients.

Mesalamine products studied: Mesalazine (Salofalk), MMX mesalamine, Asacol, and Pentasa

Summary of findings:

  • Failure to induce clinical remission: relative risk (RR) with once daily 0.95; absolute risk 421 per 1000 in once daily group
  • Failure to induce clinical improvement: RR 0.87; absolute risk 398 per 1000
  • Failure to maintain clinical remission at 12 months: RR 0.92; absolute risk 286 per 1000
  • Failure to adhere to study medication regimen: RR 1.21; absolute risk 128 per 1000

Thus, this meta-analysis indicates that once daily dosing is as effective as conventional dosing for both induction and maintenance, at least with the formulations that were tested. Also, in this meta-analysis, adherence was not improved with once daily therapy, though some previous studies have indicated that once daily therapy may be helpful particularly in the first few months of treatment.

The 2nd study examined 213 patients for maintenance of UC remission; patients were randomized to receive either Asacol 2.4 g once a day (QD) or 800 mg three times a day (TID). Patients were treated at 32 UK centers and had an average age of 50 years. Relapse rates were 31% for QD therapy and 45% for TID over 1 year.  This study showed that QD was noninferior to TID and possibly superior, perhaps due to improved adherence.

Perhaps it is time to give all mesalamine products once a day.