“For Hospitalized Patients With ASUC, 5-ASA Adds No Value to Steroids”

From Gastroenterology and Endoscopy News (4/25/22): Open Access: For Hospitalized Patients With ASUC, 5-ASA Adds No Value to Steroids

In the first prospective randomized study, presented at the 2022 Crohn’s & Colitis Congress and published in Inflammatory Bowel Dis (S Ben-Horin et al 2022;28 [suppl 1]:S14 CORTICOSTEROIDS AND 5ASA VERSUS CORTICOSTEROIDS ALONE FOR ACUTE SEVERE ULCERATIVE COLITIS: A RANDOMIZED CONTROLLED TRIAL), investigators at 10 centers in six countries randomly assigned 149 patients hospitalized for ASUC to receive daily doses of 300 mg of hydrocortisone (or equivalent methylprednisolone) alone or in combination with 4 g of mesalamine.

Key findings:

  • 72.6% of patients receiving combination corticosteroids with 5-ASA responded to treatment at one week compared with 76.3% of responders in the group receiving corticosteroids alone
  • “There were no differences in hospital length of stay between groups (median, 10 vs. nine days for the combination and monotherapy groups, respectively), the proportion of patients whose C-reactive protein level normalized (34.2% vs. 34.3%, respectively), or the proportion requiring colectomy within 90 days (4.9% vs. 4.5%, respectively).”
  • While 5-ASAs did not alter the trajectory of acute colitis, one other finding was a lower rate of biologic use (27% vs 47%, P=.07) at 90 days in those who continued to receive 5-ASA therapy at 90 days.

My take: 5-ASAs do not appear to be helpful during hospitalization for ASUC but may be beneficial as a maintenance therapy in some patients.

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Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  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

Another Obscure Medication Effect: Mesalamine Staining Cleaned Toilet

D Zeef et al. JPGN ReportsFebruary 2022 – Volume 3 – Issue 1 – p e167 Open Access: Urine Discoloration After Voiding in a Boy With Ulcerative Colitis Using Mesalamine

“The boy noticed the colorization only when he urinated in the toilet at home and this phenomenon was most pronounced after the toilet had been cleaned.” He had a normal urinalysis. “Discoloration of urine by a chemical reaction between mesalamine and sodium hypochlorite bleach has been widely reported in online patient forums, we only found 2 related case reports.”

“Mesalamine and its metabolite, N-acetyl-5-aminosalicylic acid, have structural similarity to methyldopa, which is metabolized to melanin-like compounds. In an alkaline environment (the pH of bleach is 11–13), polymerization of these melanin-like metabolites causes a brownish/red discoloration of urine after methyldopa ingestion.”

IBD Update -July 2020

X Roblin et al. Gut 2020; DOI: 10.1136/gutjnl-2019-319758 Addition of azathioprine to the switch of anti-TNF in patients with IBD in clinical relapse with undetectable anti-TNF trough levels and antidrug antibodies: a prospective randomised trial. Key Findings:

  • Rates of clinical failure and occurrence of unfavourable pharmacokinetics were higher in monotherapy compared with combination therapy
  • At 24 months, survival rates without clinical failure and without appearance of unfavourable pharmacokinetics were respectively 22% versus 77% and 22% versus 78% (p<0.001 for both) in monotherapy versus combination therapy

RC Ungaro et al. Clin Gastroenterol Hepatol 2020; 18: 1152-60.  The authors retrospectively analyzed 3178 patients with Crohn’s disease and found that stopping mesalamine therapy in individuals who were starting biologic therapy did NOT increase their risk of adverse clinical events.  They caution that their findings should be validated in a prospective study.

J Wang et al. AP&T. https://doi.org/10.1111/apt.15766. Full Text: Risk factors and treatment outcomes of peristomal pyoderma gangrenosum in patients with inflammatory bowel disease Key finding: “Complete resolution with topical corticosteroids and calcineurin inhibitors alone were low (14% and 13% respectively). Higher rates of complete resolution were reported with anti‐tumour necrosis factor (TNF) agents (63%) and surgical interventions (80%).”

B Verstockt et al. Clin Gastroenterol Hepatol 2020; 18: 1142-51. The authors found that expression of 4 genes in colon tissue could be used to predict which patients will enter endoscopic remission with vedolizumab therapy.  Given the increasing number of expensive therapies for IBD, the ability to predict likely success with treatment rather than selecting empirically would be a huge advance.

ST Leach et al. JPGN 2020; 70: 580-5. The authors found that fecal calprotectin was overall the best fecal biomarker for pediatric Crohn’s disease (=156 patients); however, FA12  (aka S100A12) at 5 mcg/g predicted mucosal healing with greater specificity (87% vs 70%) –though this is related in part to the cut-off values. For calprotectin to have greater specificity (>90%), a cut-off of <100 mcg/g lowered the sensitivity to 63%. FA12 also performs better in younger children as calprotectin levels are higher in this age group in healthy children.

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.

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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.

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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.