Abstract
Background
Two major types of 5-aminosalicylic acid (5-ASA)-containing preparations, namely, mesalazine/5-ASA and sulfasalazine (SASP), are currently used as first-line therapy for ulcerative colitis. Recent reports show that optimization of 5-ASA therapy is beneficial for both patient outcomes and healthcare costs. Although 5-ASA and SASP have good efficacy and safety profiles, clinicians occasionally encounter patients who develop 5-ASA intolerance.
Summary
The most common symptoms of acute 5-ASA intolerance syndrome are exacerbation of diarrhea, fever, and abdominal pain. Patients who discontinue 5-ASA therapy because of intolerance have a higher risk of adverse clinical outcomes, such as hospital admission, colectomy, need for advanced therapies, and loss of response to anti-tumor necrosis factor (TNF) biologics. When patients develop symptoms of 5-ASA intolerance, the clinician should consider changing the type of 5-ASA preparation. Recent genome-wide association studies and meta-analyses have shown that 5-ASA allergy is associated with certain single-nucleotide polymorphisms. Although there are no modalities or biomarkers for diagnosing 5-ASA intolerance, the drug-induced lymphocyte stimulation test can be used to assist in the diagnosis of acute 5-ASA intolerance syndrome with high specificity and low sensitivity. This review presents a general overview of 5-ASA and SASP in the treatment of inflammatory bowel disease and discusses the latest insights into 5-ASA intolerance.
Key Messages
5-ASA is used as first-line therapy for ulcerative colitis. Optimization of 5-ASA may be beneficial for patient outcomes and healthcare systems. Acute 5-ASA intolerance syndrome is characterized by diarrhea, fever, and abdominal pain. Periodic renal function monitoring is recommended for patients receiving 5-ASA.
Keywords: Inflammatory bowel disease, Ulcerative colitis, 5-Aminosalicylic acid intolerance, 5-Aminosalicylic acid, Mesalazine
Introduction: Overview of Treatment of Ulcerative Colitis by 5-Aminosalicyclic Acid
Ulcerative colitis (UC) is a remitting and relapsing inflammatory condition that affects the rectum and colon [1]. UC is usually classified by its disease severity (mild, moderate, or severe) and disease location (proctitis, left-sided colitis, or extensive colitis) [2, 3]. The first-line option for induction and maintenance therapy in patients with mild to moderate UC is a 5-aminosalicylic acid (5-ASA)-containing preparation [3, 4, 5, 6]. Two main types of 5-ASA-containing therapies, namely, mesalazine (5-ASA) and sulfasalazine (SASP), are currently available in clinical practice. In addition, 5-ASA-containing therapies such as SASP are used for arthritis accompanied by UC [3]. Recommendations for 5-ASA induction and maintenance therapy in patients with Crohn's disease vary across countries because of the limited evidence compared with that for UC [3, 7, 8]. SASP is used to treat UC as well as some cases of Crohn's disease, particularly active Crohn's colitis [3]. SASP is metabolized to 5-ASA and sulfapyridine and has anti-inflammatory effects in the colon. Because 5-ASA is the active ingredient in SASP, the efficacy of SASP is similar to that of 5-ASA in the treatment of inflammatory bowel disease (IBD). However, sulfapyridine, a metabolite of SASP, sometimes causes adverse events, such as headache and vomiting [9] (Fig. 1). These SASP-specific adverse events may contribute to the tolerability of SASP being lower than that of 5-ASA (risk ratio: 0.48; 95% confidence interval: 0.36–0.63) [10].
Fig. 1.
Intestinal anti-inflammatory effects of 5-ASA. SASP and 5-ASA are two types of 5-ASA-containing therapies used to treat IBD. SASP is metabolized by bacterial enzymes, and sulfapyridine and 5-ASA are released. Most SASP-related adverse events, such as headache, dizziness, and fever, are considered to be associated with sulfapyridine. Although 5-ASA is effective, several rare but clinically significant adverse events, such as nephrotoxicity, pancreatitis, and pericarditis, have been documented. After ingestion, 5-ASA is rapidly acetylated to N-acetyl-5-ASA in intestinal epithelial cells and to a lesser extent in the liver and is excreted mostly in the feces and to a lesser extent in the urine. 5-ASA, 5-aminosalicylic acid; PPARγ, proliferator-activated receptor gamma; ROS, reactive oxygen species; SASP, sulfasalazine.
5-ASA is administered in patients with UC as an oral formulation in addition to topical 5-ASA-containing enemas and suppositories. An appropriate formulation of 5-ASA should be chosen according to disease location and patient adherence. A suppository formulation of 5-ASA should be considered as first-line therapy for patients with mild to moderately active proctitis and an enema formulation for those with distal colitis. Oral 5-ASA alone is also effective for induction of remission in patients with active proctitis and distal disease [3]. In patients with left-sided or extensive colitis, administration of oral 5-ASA alone or in combination with an enema formulation is recommended for induction of remission [2, 9]. Daily oral 5-ASA doses of ≥2 g are more effective than lower doses for induction and maintenance of remission [11]. When remission has not been achieved on oral or topical 5-ASA alone, a combination of oral and topical 5-ASA is recommended [3]. One study showed that the local concentration of 5-ASA and its acetylated form, N-acetyl-5-ASA, in the sigmoid colon was significantly correlated with endoscopic remission in patients with UC regardless of the formulation of 5-ASA used [12], suggesting the importance of optimizing the local concentration of 5-ASA. Indeed, a subsequent study showed that optimization of 5-ASA therapy by maximizing the oral dose and/or combining oral and topical formulations of 5-ASA had clinically beneficial effects in terms of reducing the dose of systemic corticosteroids and the need for advanced therapies [13]. Therefore, optimization of 5-ASA therapy is considered beneficial in terms of both patient outcomes and health care costs in the treatment of UC by minimizing unnecessary introduction of various molecular targeted immunosuppressive agents and the adverse events associated with their use.
Mesalazine/5-ASA is available in several oral formulations. The time-dependent release formulation of 5-ASA contains microgranules covered by a semipermeable ethyl cellulose membrane [14]. This formulation slowly releases 5-ASA from the duodenum to the ileum in a time-dependent manner and is absorbed by the ileal and colonic mucosa [15]. Therefore, this formulation is used for both UC and Crohn's disease. In contrast, the pH-dependent release formulation releases 5-ASA when the threshold pH value is exceeded during gastrointestinal transition from the small intestine to the large intestine [16]. In the terminal ileum, where the pH is > 7, the pH-dependent release formulation of 5-ASA starts to dissolve and exerts its effect mainly in the large intestine. The Multi-Matrix System 5-ASA formulation also begins dissolution in the terminal ileum and has advantages in terms of efficacy and tolerability [17].
Although it remains unclear whether high doses of 5-ASA or N-acetyl-5-ASA in the local mucosa exert a therapeutic effect in patients in remission or whether absorption and metabolism are higher in healthy colonic epithelia than in inflammatory epithelia [12, 18], it is reasonable to speculate that an adequate amount of 5-ASA in the colonic mucosa contributes to therapeutic effects in patients with colitis. This notion is supported by previous studies showing that poor adherence is a risk factor for flares [19]. There is no significant difference in the long-term risk of flares between patients with a low or high average daily dose of 5-ASA [20], suggesting that the requirement of high-dose 5-ASA may need to be stratified by disease behavior, biomarkers, and endoscopic findings. Indeed, optimization of 5-ASA results in better clinical outcomes [13]. It is important to improve adherence by selecting the appropriate drugs for individual patients and optimizing the dose and preparation of 5-ASA according to disease activity.
Definition of 5-ASA Intolerance
SASP and 5-ASA are prescribed worldwide for the treatment of mild to moderate UC. However, adverse events occur in a small but substantial number of patients with IBD, especially UC. Mild adverse events include headache, skin rash, and gastrointestinal symptoms, such as nausea, abdominal pain, and diarrhea. More severe adverse events include nephrotoxicity, hepatic dysfunction, pancreatitis, pericarditis, pneumonitis, severe skin reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute gastroenteropathy, often referred to as “acute 5-ASA intolerance syndrome” or “acute mesalazine intolerance syndrome” [21].
There is no clear definition of or diagnostic criteria for acute 5-ASA intolerance syndrome; it is commonly diagnosed by its clinical features (e.g., fever, diarrhea, and abdominal pain), which typically occur 1–3 weeks after starting 5-ASA and resolve within a few days after discontinuation of the drug or administration of systemic corticosteroids [22, 23, 24]. Therefore, it is better to define such clinical manifestations as acute 5-ASA intolerance syndrome to distinguish them from other adverse events, such as nephrotoxicity, which are usually observed within the first year of treatment with 5-ASA but sometimes even several years later [25]. Adverse events associated with acute 5-ASA intolerance syndrome are observed in about 5–10% of patients with UC [23, 24, 26]. Acute 5-ASA intolerance syndrome has been reported as an allergic reaction that appears a few weeks after starting the medication, but precise diagnosis is difficult because the symptoms and endoscopic findings are similar to those of exacerbation of UC [22]. A more recent study found that adverse effects appeared approximately 10 ± 5 days after the start of 5-ASA and that the second and subsequent attacks occurred 2 ± 1 days later [26]. Symptoms of acute 5-ASA intolerance syndrome are diverse; fever, diarrhea, abdominal pain, headache, arthralgia, and fatigue have been reported, but the most common are fever, diarrhea, abdominal pain, and bloody stool [24]. Thus, the symptoms of acute 5-ASA intolerance syndrome and exacerbation of UC are very similar, and it is difficult to distinguish whether they are caused by acute 5-ASA intolerance, a flare of the primary disease, or insufficient therapeutic effects of 5-ASA. However, it is important to be able to recognize acute 5-ASA intolerance syndrome so that discontinuation of 5-ASA is not delayed. Fever (>38°C) and an elevated C-reactive protein concentration (>30 mg/L) appear in most patients with acute 5-ASA intolerance, even if the UC is mild. Considering that fever and an elevated C-reactive protein level are hallmarks of moderate to severe UC, the presence of fever despite only mild disease activity might be a useful clue to distinguish acute 5-ASA intolerance syndrome from exacerbation of the primary disease [26].
Diagnosis of 5-ASA Intolerance and Biomarkers
There is no perfect test that can confirm or rule out acute 5-ASA intolerance; therefore, it is important for the attending physician or surgeon to keep in mind the possibility of acute 5-ASA intolerance syndrome to ensure timely diagnosis. There are no significant differences in the history of drug allergy, disease activity, or concomitant medications between patients with and without acute 5-ASA intolerance. However, female sex, age younger than 60 years, and pancolitis have been reported to be risk factors for acute 5-ASA intolerance syndrome [23]. Patients who discontinue 5-ASA drugs because of intolerance are at higher risk of hospital admission, refractoriness to TNF inhibitor therapy [27], and colectomy [28].
The drug-induced lymphocyte stimulation test (DLST), traditionally used to diagnose type IV allergy, has also been used in an attempt to diagnose acute 5-ASA intolerance syndrome based on the hypothesis that reactivation of T cells is also involved in allergic reactions [29]. In some hospitals and clinics, the DLST and lymphocyte transformation test are used as auxiliary methods for diagnosis of acute 5-ASA intolerance. In the DLST, purified peripheral blood mononuclear cells from the patient are cultured with the culprit drugs, and 3H-thymidine uptake by proliferating lymphocytes is measured. If T cells that have been sensitized to a specific antigen are present, cell proliferation in the drug-stimulated samples is upregulated when compared with unstimulated samples [30]. The precise mechanisms via which acute 5-ASA intolerance syndrome develops have not been fully clarified; however, this syndrome is thought to be an immune response to 5-ASA, sulfapyridine, and other drug excipients. It has been suggested that acute 5-ASA intolerance syndrome is caused by povidone, which is an excipient in all 5-ASA preparations other than the Multi-Matrix System [31]. Therefore, the discrepancies in the results obtained using different preparations of 5-ASA and SASP can be explained by reactions to the drug derivatives or excipients of a specific preparation of 5-ASA or merely by limited sensitivity of the DLST.
Some issues remain to be resolved in terms of the use of DLST as a biomarker for acute 5-ASA intolerance syndrome, despite it having some advantages in the clinical setting. First, the most appropriate time point at which to perform this examination is controversial. The timing of the test has not been consistent in the reported studies and has varied from patient to patient. Second, the sensitivity of the test decreases after administering corticosteroids because T-cell activation is suppressed. Third, the best cutoff point for diagnosing acute 5-ASA intolerance syndrome should be explored because the results differ depending on the culprit drug. Finally, obtaining the results of the test takes a few weeks in many hospitals. If acute 5-ASA intolerance syndrome is suspected, we usually stop 5-ASA without waiting for the DLST result.
The reported sensitivity of DLST for acute 5-ASA intolerance syndrome is 0.24, the specificity is 0.81, the false-positive rate is 0.195, and the false-negative rate is 0.76 [32]. These results suggest that a positive 5-ASA DLST result indicates a high probability of acute 5-ASA intolerance syndrome but that a negative result does not rule it out. Therefore, the DLST can be used to assist in making a definite diagnosis of acute 5-ASA intolerance if positive but not to exclude it if negative. Although the DLST provides clinically significant information when deciding whether or not to resume treatment with 5-ASA, further research is needed to optimize the application of the DLST for acute 5-ASA intolerance syndrome. At present, the diagnosis of acute 5-ASA intolerance syndrome is based on a detailed review of the patient's medical history.
Treatment of Patients with UC and 5-ASA Intolerance
When acute 5-ASA intolerance syndrome is suspected clinically within a few weeks of starting 5-ASA as treatment for UC, discontinuation should be considered. The symptoms of this syndrome usually resolve promptly after cessation of the drug. However, acute aggravation, progression to toxic megacolon, and complications of enteropathogenic bacteria, Clostridioides difficile, and cytomegalovirus should be considered in patients with an unfavorable disease course after withdrawal of 5-ASA (Fig. 2). Such patients may require advanced induction therapies, such as systemic corticosteroids and/or antibacterial or antiviral treatment.
Fig. 2.
Proposed algorithm for treating patients with 5-ASA. Suspected symptoms of acute 5-ASA intolerance syndrome (diarrhea, fever, and abdominal pain) are typically recognized 1–2 weeks after initiation of 5-ASA-containing therapy. If acute 5-ASA intolerance syndrome or a skin disorder is suspected, induction/maintenance treatment should be reconsidered after timely discontinuation of 5-ASA. 5-ASA, 5-aminosalicylic acid; SASP, sulfasalazine; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis.
When the symptoms of acute 5-ASA intolerance syndrome have improved, there are three possible options for maintenance treatment: “5-ASA switching,” alternative treatment, and desensitization to 5-ASA. The 5-ASA switching strategy entails changing from one preparation to another in an effort to improve clinical outcomes or avoid adverse reactions, including acute 5-ASA intolerance syndrome. In our cohort of 59 patients with UC, 44% (n = 26) who were intolerant to one or more 5-ASA preparations could be maintained by another, whereas 19% (n = 11) were intolerant to two 5-ASA preparations and 3% (n = 2) were intolerant to three [27]. Although larger -scale clinical studies are needed to confirm the efficacy and safety of using second or third preparation, our data suggest that this switching strategy may allow patients with UC to be maintained on 5-ASA therapy. Sometimes, 5-ASA switching is considered from the perspectives of the efficacy, safety, cost-effectiveness, and non-immunosuppressive properties of 5-ASA. Notably, patients may experience recurrent symptoms of 5-ASA intolerance, especially when systemic corticosteroid therapy is used and the dose is weaned. Therefore, patients in whom 5-ASA therapy is resumed should be monitored carefully, particularly those receiving concomitant systemic corticosteroids. Another option to consider is use of an alternative treatment. Patients with IBD generally require treatment for both induction and maintenance of remission, and therapies for maintenance of remission should be carefully selected. Importantly, corticosteroids should not be used as maintenance treatment for UC even if they are required for induction of remission [33]. Desensitization to 5-ASA has also been attempted, and several protocols similar to those used for desensitization to other salicylate drugs have been proposed. Although there is no well-established strategy for safe 5-ASA desensitization in patients who are intolerant to 5-ASA, there has been a report of a desensitization protocol with readministration of 5-ASA that had a success rate of up to 60% [23]. Allergic disease experts may consider readministration of 5-ASA using only a small amount with the patient's informed consent regarding its efficacy and possible allergic reactions and adverse events, including anaphylaxis. However, there is no standardized protocol for 5-ASA desensitization therapy, with daily doses ranging from less than 1 mg–500 mg and treatment durations ranging from a few days to 6 months. Most gastroenterologists and general practitioners do not consider 5-ASA desensitization as a first-line therapy for patients with UC who are intolerant to 5-ASA in view of the availability of other treatment options and the difficulty of implementing a protocol that starts with micro-doses of 5-ASA and takes several weeks, sometimes resulting in serious adverse effects (Fig. 2).
In addition to acute intolerance, several other adverse events, including nephrotoxicity, pancreatitis, pericarditis, and pneumonitis, have been documented as rare but clinically significant disorders associated with 5-ASA [22, 25]. Two British studies reported a very low incidence of 5-ASA-induced renal impairment (1.0 per 4,000 or 1.7 per 1,000 person-years). Furthermore, nephrotoxicity has been reported in animals treated with 5-ASA and in patients treated with drugs chemically similar to 5-ASA, such as acetylsalicylic acid. Therefore, a causal association between 5-ASA and nephrotoxicity is likely, although this issue remains controversial in view of a recent large-scale cohort study, also performed in the UK, that showed no significant association between use of 5-ASA and nephrotoxicity [34]. Furthermore, IBD itself is a risk factor for interstitial nephritis. However, most cases of renal impairment characterized by elevated creatinine are resolved by timely drug discontinuation [25]. Periodic renal monitoring of patients on 5-ASA therapy for UC may help with early diagnosis of renal dysfunction and allow timely cessation of 5-ASA, thereby preventing progression to renal failure, which may occur even after discontinuation. The serum creatinine concentration and estimated glomerular filtration rate are reliable indices of renal impairment and the most commonly measured. Although there is no evidence-based method or protocol that can be used to monitor for nephrotoxicity in patients with UC on treatment with 5-ASA, measuring the serum creatinine concentration before starting treatment and periodically thereafter has been proposed in previous studies [25] (Fig. 2).
Latest Insights into Acute 5-ASA Intolerance Syndrome
5-ASA is absorbed by cells in the intestinal epithelium and has anti-inflammatory effects on the intestinal mucosa. Although its mechanism of action remains unclear, 5-ASA is thought to scavenge free oxygen radicals produced by macrophages and neutrophils that damage the intestinal epithelium and suppress synthesis of leukotrienes, thereby inhibiting migration of inflammatory cells [35]. In epithelial cells in the colon, a large proportion of 5-ASA is acetylated to N-acetyl-5-ASA by the N-acetyltransferase 1 (NAT1) enzyme and excreted in feces. The remainder of the 5-ASA is converted to N-acetyl-5-ASA by NAT1 in the liver and excreted into urine. Some variants of NAT1 and its isozyme, NAT2, have been reported, and these variants may contribute to the efficiency of acetylation. Although an association between NAT2 variants and SASP-related adverse events has been reported [36], NAT2 genes are irrelevant to the metabolism of 5-ASA, and whether NAT1 is associated with acute or chronic 5-ASA intolerance remains unclear. A recent study revealed an association between genotypes of rs144384547 and 5-ASA-induced fever and diarrhea [24]. rs144384547 is located upstream of the regulator of G protein signaling 17 gene (RGS17) and encodes the RGS17 protein, which binds directly to G protein α-subunits and attenuates signaling activity. Patients with IBD and the rs144384547-G allele were found to have a higher risk of developing 5-ASA-induced fever and diarrhea (n = 9/41, 22.0%) than those who were homozygous for the common allele rs144384547-C (n = 53/2,269, 2.34%) [24]. Notably, the rs144384547-G allele contributed to the risk of developing concomitant fever and diarrhea but not to developing either fever or diarrhea alone. It is also interesting that a single-nucleotide polymorphism located in the ADRA1A gene, which encodes a G protein-coupled α1 adrenergic receptor, was found to be a candidate allele, although this finding did not reach statistical significance [24]. Further studies are expected to establish genomic tests that will help predict the occurrence of 5-ASA intolerance and allow selection of the most appropriate 5-ASA therapy for specific patients.
Although the precise mechanisms underlying the development of acute 5-ASA intolerance syndrome have not been fully clarified, this syndrome is attributed to an allergic reaction to preparations containing 5-ASA. Thymus and activation-regulated chemokine and serum-specific immunoglobulin E antibody are used as diagnostic biomarkers for type I allergic diseases, such as atopic dermatitis, asthma, and allergic rhinitis. However, their value for diagnosing acute 5-ASA intolerance syndrome has not been demonstrated [37].
There is a growing body of evidence showing that the intestinal microbiota contributes to the development and persistence of IBD [38, 39]. We have investigated the relationship between 5-ASA intolerance and the gut microbiota by analyzing the fecal microbiota in 124 patients with UC in remission (12 with previous acute 5-ASA intolerance syndrome and 112 who were 5-ASA-tolerant). Although there was no significant difference in the diversity of the gut microbiota between the two groups, the taxonomic profile showed more abundance of the phylum Firmicutes and less abundance of the phylum Bacteroidetes in the patients with previous acute 5-ASA intolerance syndrome. This suggests that alteration in the gut microbiota or gut dysbiosis may be involved in acute 5-ASA intolerance syndrome and may be associated with a worse clinical outcome, including early discontinuation of TNF inhibitor therapy [27] or colectomy [28].
Conclusion
Despite recent therapeutic advances, 5-ASA-containing preparations remain the first-line therapy for UC, and optimization of 5-ASA therapy is a safe and efficacious treatment option. However, recent reports indicate that a substantial proportion of patients (up to 10%) who are treated with these therapies experience symptoms of acute 5-ASA intolerance. It has been suggested that acute 5-ASA intolerance syndrome is associated with a poor prognosis in patients with UC, but it remains unclear whether the occurrence of this syndrome is in itself an independent poor prognostic factor or whether there are as yet unknown shared mechanisms that provoke both acute 5-ASA syndrome and difficult-to-treat disease subtypes. Furthermore, there is a lack of high-quality evidence as a result of a lack of consensus regarding the definition of 5-ASA intolerance. Therefore, it is difficult to diagnose acute 5-ASA intolerance syndrome because of its similarity to worsening UC. Although the prediction and diagnosis of acute 5-ASA intolerance syndrome is difficult, recent studies have produced some promising results with respect to genetic background [24] and bacterial composition in the colon [27]. In this regard, combinatorial approaches that include genomic and metagenomic profiling may shed light on how to predict 5-ASA intolerance when prescribing 5-ASA-containing therapy. Finally, the mechanisms underlying the development of 5-ASA intolerance and how 5-ASA exerts its therapeutic effect on intestinal inflammation are not fully understood. Further research to clarify the whole picture of 5-ASA therapy may improve its safety and efficacy.
Conflict of Interest Statement
No potential conflicts of interest were disclosed regarding this review paper.
Funding Sources
This research was funded by the Japan Society for the Promotion of Science (JSPS) KAKENHI (A) 20H00536 for T.K., (B) 20H03666 for Y.M., and a Grant-in-Aid for Early Career Scientists (22K16005 to H.K.); Advanced Research and Development Programs for Medical Innovation (the Practical Research Project for Rare/Intractable Disease; 21ek0109556h0001 to Y.M.); and the Keio University Medical Fund.
Author Contributions
Yohei Mikami wrote the manuscript and prepared the figures. Junya Tsunoda, Shohei Suzuki, and Ichiro Mizushima performed the literature review and drafted the manuscript. Hiroki Kiyohara was responsible for intellectual input and critically revised the manuscript. Takanori Kanai provided supervision and gave final approval of the article.
Acknowledgments
We thank all the members of the Division of Gastroenterology and Hepatology for their constructive suggestions and discussions. We also thank Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.
Funding Statement
This research was funded by the Japan Society for the Promotion of Science (JSPS) KAKENHI (A) 20H00536 for T.K., (B) 20H03666 for Y.M., and a Grant-in-Aid for Early Career Scientists (22K16005 to H.K.); Advanced Research and Development Programs for Medical Innovation (the Practical Research Project for Rare/Intractable Disease; 21ek0109556h0001 to Y.M.); and the Keio University Medical Fund.
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