On the Action of 5-Amino-Salicylic Acid and Sulfapyridine on M. avium including Subspecies paratuberculosis

BACKGROUND: Introduced in 1942, sulfasalazine (a conjugate of 5-aminosalicylic acid (5-ASA) and sulfapyridine) is the most prescribed medication used to treat "inflammatory" bowel disease (IBD.) Although controversial, there are increasingly compelling data that Mycobacterium avium subspecies paratuberculosis (MAP) may be an etiological agent in some or all of IBD. We have shown that two other agents used in the therapy of IBD (methotrexate and 6-MP) profoundly inhibit MAP growth. We concluded that their most plausible mechanism of action is as antiMAP antibiotics. We herein hypothesize that the mechanism of action of 5-ASA and/or sulfapyridine may also simply be to inhibit MAP growth. METHODOLOGY: The effect on MAP growth kinetics by sulfasalazine and its components were evaluated in bacterial culture of two strains each of MAP and M. avium, using a radiometric ((14)CO(2) BACTEC(R)) detection system that quantifies mycobacterial growth as arbitrary "growth index units" (GI). Efficacy data are presented as "percent decrease in cumulative GI" (%-DeltacGI). PRINCIPAL FINDINGS: There are disparate responses to 5-ASA and sulfapyridine in the two subspecies. Against MAP, 5-ASA is inhibitory in a dose-dependent manner (MAP ATCC 19698 46%-DeltacGI at 64 microg/ml), whereas sulfapyridine has virtually no effect. In contrast, against M. avium ATCC 25291, 5-ASA has no effect, whereas sulfapyridine (88%-DeltacGI at 4 microg/ml) is as effective as methotrexate, our positive control (88%-DeltacGI at 4 microg/ml). CONCLUSIONS: 5-ASA inhibits MAP growth in culture. We posit that, unknowingly, the medical profession has been treating MAP infections since sulfasalazine's introduction in 1942. These observations may explain, in part, why MAP has not previously been identified as a human pathogen. We conclude that henceforth in clinical trials evaluating antiMAP agents in IBD, if considered ethical, the use of 5-ASA (as well as methotrexate and 6-MP) should be excluded from control groups

Oral 5-aminosalicylic acid for maintenance of surgically-induced remission in Crohn's disease

Background Crohn’s disease (CD) is a chronic inflammatory disorder that can involve any part of the gastrointestinal tract. 5‐Aminosalicylates (5‐ASAs) are locally acting, anti‐inflammatory compounds that reduce inflammation of the colonic mucosa with release profiles that vary among various commercially available formulations. This updated Cochrane review summarizes current evidence on the use of 5‐ASA formulations for maintenance of surgically‐induced remission in CD. Objectives To assess the efficacy and safety of 5‐ASA agents for the maintenance of surgically‐induced remission in CD. Search methods We searched MEDLINE, Embase, CENTRAL, the Cochrane IBD Group Specialized Register from inception to 16 July 2018. We also searched references, conference abstracts, and trials registers. Selection criteria Randomised controlled trials (RCTs) that included participants with CD in remission following surgery and compared 5‐ASAs to no treatment, placebo or any other active intervention with duration of at least three months were considered for inclusion. Data collection and analysis We used standard methodological procedures expected by Cochrane. The primary outcome was clinical relapse. Secondary outcomes included endoscopic recurrence, radiologic and surgical relapse, adverse events, serious adverse events and withdrawal due to adverse events. Main results Fourteen RCTs (1867 participants) were included in the review. Participants (15 to 70 years) were recruited from gastroenterology hospitals and medical clinics in Europe and North America and followed up between 3 and 72 months. The risk of bias was assessed as 'low' in one study, 'unclear' in seven and as 'high' in six. At 12 months, 36% (20/55) of participants in the 5‐ASA group experienced clinical relapse compared to 51% (28/55) in the no treatment control group (RR 0.71, 95% CI 0.46 to 1.10; low certainty evidence). Moderate certainty evidence suggests that 5‐ASAs are more effective for preventing clinical relapse than placebo. During a follow‐up period of 12 to 72 months, 36% (131/361) of 5‐ASA participants relapsed compared to 43% (160/369) of placebo participants (RR 0.83, 95% CI 0.72 to 0.96; I² = 0%; moderate certainty evidence). At 12 months, 17% (17/101) of the 4 g/day mesalamine group relapsed compared to 26% (27/105) of the 2.4 g/day group (RR 0.65, 95% CI 0.38 to 1.13; moderate certainty evidence). There was no evidence of a difference in clinical relapse rates when 5‐ASA compounds were compared to purine antimetabolites. At 24 months, 61% (103/170) of mesalamine participants relapsed compared to 67% (119/177) of azathioprine participants (RR 0.90, 95% CI 0.76 to 1.07; I² = 28%; low certainty evidence). During 24 months, 50% (9/18) of 5‐ASA participants had clinical relapse compared to 13% (2/16) of adalimumab participants (RR 4.0, 95% CI 1.01 to 15.84; low certainty evidence). The effects of sulphasalazine compared to placebo on clinical relapse rate is uncertain. After 18 to 36 months, 66% (95/143) of participants treated with sulphasalazine relapsed compared to 71% (110/155) in the placebo group (RR 0.88, 95% CI 0.56 to 1.38; I² = 38%; low certainty evidence). The effect of 5‐ASA drugs on safety was uncertain. During 24 months follow‐up, 4% (2/55) of 5‐ASA participants experienced adverse events compared to none (0/55) in the no treatment control group (RR 5.00, 95% CI 0.25 to 101.81; very low certainty evidence). An equal proportion of 5‐ASA participants (10%; 23/241) and placebo (9%; 20/225) groups experienced an adverse event during a follow‐up of 3 to 72 months (RR 1.07, 95% CI 0.60 to 1.91; I² = 0%; low certainty evidence). Adverse event rates were similar in the 5‐ASA and purine analogues groups. However, serious adverse events and withdrawals due to adverse events were more common in participants who received purine analogues than 5‐ASA. At 52 weeks to 24 months, 52% (107/207) of 5‐ASA participants had an adverse event compared to 47% (102/218) of purine analogue participants (RR 1.11, 95% CI 0.97 to 1.27, I² = 0%; low certainty evidence). Four per cent (6/152) of 5‐ASA participants had a serious adverse event compared to 17% (27/159) of purine analogue participants (RR 0.30, 95% CI 0.11 to 0.80; very low certainty evidence). Eight per cent (17/207) of 5‐ASA participants withdrew due to an adverse event compared to 19% (42/218) of purine analogue participants (RR 0.48, 95% CI 0.28 to 0.83; low certainty evidence). Adverse event rates were similar in high and low dose mesalamine participants. After 12 months, 2% (2/101) of 4 g/day mesalamine participants had an adverse event compared to 2% (2/105) of 2.4 g/day participants (RR 1.04, 95% CI 0.15 to 7.24; low certainty evidence). The proportion of participants who experienced adverse events over a 24 month follow‐up in the mesalamine group was 78% (14/18) compared to 69% (11/16) of adalimumab participants (RR 1.13, 95% CI 0.75 to 1.71; very low certainty evidence). None (0/32) of the sulphasalazine participants had an adverse event at 18 months follow‐up compared to 3% (1/34) of the placebo group (RR 0.35, 95% CI 0.01 to 8.38; very low certainty evidence). Commonly reported adverse events in the included studies were diarrhoea, nausea, increased liver function tests, pancreatitis, and abdominal pain. Authors' conclusions 5‐ASA preparations are superior to placebo for the maintenance of surgically‐induced clinical remission in patients with CD (moderate certainty). The number needed to treat to prevent one relapse was 13 patients. The evidence for endoscopic remission is uncertain. The sulphasalazine class of 5‐ASA agents failed to demonstrate superiority against placebo, 5‐ASAs failed to demonstrate superiority compared to no treatment (very low and low certainty). The efficacy of two different doses of the same 5‐ASA and the efficacy of 5‐ASA compared to purine antimetabolites (azathioprine or 6‐mercaptopurine) in maintaining surgically‐induced remission of CD remains unclear. However, purine analogues lead to more serious adverse events and discontinuation due to adverse events. There is a low certainty that 5‐ASA is inferior for maintaining surgically‐induced remission of CD compared to biologics (anti TNF‐ɑ). 5‐ASA formulations appear to be safe with no difference in the occurrence of adverse events or withdrawal when compared with placebo, no treatment or biologics