Novel desensitization therapy of mesalamine intolerance in patients with ulcerative colitis

Abstract

Background

Mesalamine is the first-line drug for treating mild-to-moderate ulcerative colitis (UC); however, some patients develop symptoms of intolerance. Although several desensitization methods have been reported, these desensitization regimens were rather complicated for physicians to prescribe in daily clinical practice; therefore, it has not yet become a major therapeutic option for intolerance patients. Thus, we developed an alternative desensitization protocol.

Methods

We performed a single-center, retrospective study of patients with UC, who were intolerant to mesalamine and had undergone desensitization therapy. Desensitization starts with 50 mg of granule mesalamine, with an increase in the dose by 50 mg every week up to 200 mg, followed by incremental doses of 100 mg every week. After patients received dosages of more than 1000 mg, the dose was increased by 200 mg every week up to the target dose. Concomitant medications such as oral prednisolone or budesonide rectal foam were allowed during the protocol but were withdrawn before the end of desensitization. We evaluated the success rate of our mesalamine desensitization method and performed safety assessments during the protocol.

Results

Of 115 patients, 17 were intolerant to mesalamine. We excluded six patients who had severe disease or organ disorders. Overall, 11 patients received desensitization therapy without hospitalization. All 11 patients successfully underwent desensitization therapy and received the target dose of mesalamine (3000–4000 mg/day) at the end of the protocol. No serious adverse events were observed during this protocol.

Conclusions

This retrospective study reports a successful and safe desensitization method for UC patients with mesalamine intolerance.

Resumen

Antecedentes

La mesalamina es el fármaco de primera línea para el tratamiento de la colitis ulcerosa (CU) leve a moderada; sin embargo, algunos pacientes desarrollan síntomas de intolerancia. Aunque se han descrito varios métodos de desensibilización, estos regímenes de desensibilización eran bastante complicados de prescribir para los médicos en la práctica clínica diaria; por lo tanto, aún no se ha convertido en una opción terapéutica importante para los pacientes con intolerancia. Por lo tanto, desarrollamos un protocolo de desensibilización alternativo.

Métodos

Realizamos un estudio retrospectivo de un solo centro de pacientes con CU, que eran intolerantes a la mesalamina y se habían sometido a terapia de desensibilización. La desensibilización comienza con 50 mg de mesalamina en gránulos, con un aumento de la dosis de 50 mg/cada semana hasta 200 mg, seguido de dosis incrementales de 100 mg/cada semana. Después de que los pacientes recibieron dosis de más de 1000 mg, la dosis se aumentó en 200 mg cada semana hasta la dosis objetivo. Evaluamos la tasa de éxito de nuestro método de desensibilización con mesalamina y realizamos evaluaciones de seguridad durante el protocolo.

Resultados

De 115 pacientes, 11 pacientes recibieron terapia de desensibilización sin hospitalización. Todos los pacientes tuvieron una terapia de desensibilización exitosa y recibieron la dosis objetivo (3.000-4.000 mg) al final del protocolo. No se observaron eventos adversos graves durante este protocolo.

Conclusiones

Este estudio retrospectivo informa sobre un método de desensibilización exitoso y seguro para los pacientes con CU y con intolerancia a la mesalamina.

Introduction

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by alternating periods of remission and relapse that cause frequent bowel movements and bloody diarrhea leading to an impaired quality of life.¹ Mesalamine, the first-line drug for the induction and maintenance treatment of mild-to-moderate UC, is generally well tolerated compared with sulfasalazine (SASP).^2,3 Mesalamine consists of three different types of mesalamine formulations (time-dependent, pH-dependent, or multimatrix system). Time-dependent mesalamine has a granular formulation, which is more acceptable for UC patients compared with tablets.⁴ However, some patients develop symptoms of mesalamine intolerance, such as high fever, skin rash, and exacerbation of abdominal symptoms including abdominal pain or bloody diarrhea.^5,6 Usually, these intolerance symptoms resolve after discontinuation of the drug; however, subsequent maintenance treatments are needed. Especially for mild disease or distal UC patients, there are concerns about over treatment with immunosuppressants or biologics, which are expensive and can lead to an increased risk of infection and malignancy.^7,8 Several studies have shown that the administration of different mesalamine formulations or SASP is useful for the subsequent treatment, although nearly half of the patients still had recurrent symptoms related to mesalamine intolerance.^9–13

To overcome mesalamine intolerance, a desensitization method that induces tolerance to drugs by slowly increasing the drug dose, has been reported. Although the success rate of this method is high, there is no standardized protocol for desensitization and it is difficult to prepare low doses of mesalamine using tablets or solutions.^14–17 Previous studies reported a successful desensitization method using mesalamine granules, starting with 50 mg followed by increasing amounts of granules by 50–100 mg every 1–3 days, up to 4000 mg.^18,19 This method allows the simple preparation of exact dose fractions of mesalamine and provides a safe desensitization procedure without needing hospitalization. However, this regimen is complicated, which makes physicians reluctant to offer desensitization, and thus, it is not commonly performed in daily clinical practice. Therefore, an alternative desensitization protocol that is reliable and easy for UC patients with mesalamine intolerance as well as physicians is needed.

Patients and methods

Patients

UC patients treated with mesalamine were recruited retrospectively at Hakodate Municipal Hospital between 2019 and December 2023. Among them, patients who were diagnosed with mesalamine intolerance were eligible. Patients were excluded from this desensitization study if they had serious adverse events including pancreatitis, pericarditis, pneumonitis, or other organ failures. Severe UC patients were also excluded. Patients who were already treated with immunosuppressants or biological treatments because of mesalamine intolerance were included in this study if they accepted desensitization. All data were collected from medical records.

This single-center retrospective study was approved by the research ethics committee and the institutional review board of Hakodate Municipal Hospital, and there were no conflicts of interest or sponsors of this study (IRB approval number: 2023-165). The clinical procedures were conducted in accordance with the ethical principles established in the Declaration of Helsinki, the Ministerial Ordinance on Good Clinical Practice for Drugs, and other relevant laws, regulations, and standards. Because of the retrospective nature of this study, the requirement for informed consent was waived by the Ethics Committee of our hospital.

Definition of mesalamine intolerance

We defined mesalamine intolerance as the exacerbation of diarrhea, abdominal pain, fever, or other clinical symptoms including skin rash or joint pain, which were immediately relieved after the discontinuation of mesalamine therapy.

Desensitization protocol

Mesalamine intolerance patients underwent desensitization therapy. Due to the complexity of implementing a dose up protocol every 1–3 days in daily clinical practice, we developed a new protocol with reference to previous studies (Table 1).^18,19 This method starts with 50 mg of granule mesalamine, followed by an increase in the dose by 50 mg every week up to 200 mg, followed by incremental doses of 100 mg every week. After patients received dosages of more than 1000 mg, the dose was increased by 200 mg every week up to 2000 mg. According to the patients’ disease severity, dosages could be increased up to 4000 mg. Topical mesalamine therapy was not allowed during the desensitization protocol. Concomitant medications such as oral prednisolone or budesonide rectal foam were allowed during desensitization therapy but were withdrawn before reaching the final target dose of mesalamine. Patients were instructed that if any intolerance symptoms occurred, the dose should not be increased and the same amount of dosage could be continued until the symptoms had settled down. After the symptoms disappeared, mesalamine could be increased to the target dose following the protocol. If the symptoms continued or worsened, the desensitization was stopped and an alternative treatment was considered.

Table 1.

Desensitization protocol with mesalamine granules.

Day	Dose (mg)	Day	Dose (mg)	Day	Dose (mg)
1–7	50	71–77	900	141–147	2800
8–15	100	78–85	1000	148–155	3000
16–21	150	86–91	1200	156–161	3200
22–28	200	92–98	1400	162–168	3400
29–35	300	99–105	1600	169–175	3600
36–42	400	106–112	1800	176–182	3800
43–49	500	113–119	2000	183–189	4000
50–56	600	120–126	2200
57–63	700	127–133	2400
64–70	800	134–140	2600

Evaluated outcomes

Covariates including age, sex, disease duration, disease severity, disease extent according to the Montreal classification, laboratory parameters, and concomitant medications were obtained. Clinical disease activity at the time of diagnosis was assessed by the Mayo score (0–5 = mild disease; 6–10 = moderate disease; ≥11 = severe disease).²⁰ The Partial Mayo score (excluding the sigmoidoscopy subscore; range, 0–9, with higher scores indicating more active disease) was calculated before and after the mesalamine desensitization. The drug-induced lymphocyte stimulation test (DLST), which is commonly used for the diagnosis of drug allergies, was performed.

Our primary outcome was to evaluate the success rate of the mesalamine desensitization protocol. Clinical efficacy was assessed by comparing changes in the data for the Partial Mayo score, serum C-reactive protein (CRP), albumin (Alb), and hemoglobin (Hb) levels before and after the mesalamine desensitization. Safety assessments (concomitant medications, adverse events, serious adverse events) were performed during the desensitization therapy as a secondary outcome. Clinical courses after mesalamine desensitization were also investigated. Relapse was defined as new steroids or biologics required after desensitization therapy, and the time to relapse was evaluated.

Statistical analyses

Continuous data were described as medians and interquartile ranges or percentages. The changes in scores and laboratory results were evaluated by the Mann–Whitney U test. We used the Kaplan–Meier method to estimate the time to relapse after mesalamine desensitization. All statistical analyses were performed using SPSS software (version 23.0; SPSS Inc., Chicago, IL, USA). Two-sided P-values were considered statistically significant at a level of <0.05.

Results

Patient characteristics

During the study period, 115 patients with UC were initially enrolled in this study. Among them, 17 (14.7%) were intolerant to mesalamine. We excluded six patients, of which three had severe disease, and another had pericarditis, interstitial nephritis, and liver dysfunction. Overall, 11 patients received desensitization therapy.

The patients’ baseline characteristics of this study are shown in Table 2. Eight patients were diagnosed for the first time with mild-to-moderate UC, and prescribed oral mesalamine without concomitant medications. None of the patients received topical mesalamine therapy before undergoing desensitization therapy. Three patients who were already diagnosed with mesalamine intolerance and had undergone an alternative treatment, accepted desensitization. The purpose of readministering mesalamine was for the additional effects of mesalamine in two patients and for planning the discontinuation of anti-TNF after desensitization therapy succeeded in one patient.

Table 2.

Baseline characteristics of patients (n = 11).

Sex, male/female, n	4/7
Age, years, median (IQR)	37 (24–67)
Duration of disease, months, median (IQR)	3 (2–146)
Disease location of UC
E1 (Proctitis)/E2 (Left sided)/E3 (Extensive)	1/5/5
Clinical disease activity, mild/moderate	5/6
CRP concentration, mg/dl, median (IQR)	0.14 (0.09–1.24)
Albumin concentration, g/dl, median (IQR)	3.9 (3.8–4.6)
Hemoglobin concentration, g/dl, median (IQR)	13.5 (11.5–14.5)
Oral formulations when starting oral mesalamine
Time-dependent/pH-dependent/MMX	5/2/4
Dose of mesalamine, mg/day, median (IQR)	4000 (2000–4800)
Concomitant medications, n
Thiopurine	2
Anti-TNF	1
Symptoms of intolerance, n (%)
Fever	9 (81.8)
Exacerbation of abdominal pain	6 (54.5)
Exacerbation of diarrhea and/or bloody stool	5 (45.4)
Joint or muscle pain	4 (36.3)
Headache	1 (0.9)
Dermopathy	1 (0.9)
Nausea	1 (0.9)
Period from start of administration to onset of symptoms, days, median (IQR)	10 (9–1968)

MMX, multimatrix system; IQR, interquartile range.

Details of symptoms of intolerance and time to onset of the symptoms

The common symptoms of intolerance were fever, exacerbation of abdominal pain, diarrhea, and bloody stools (Table 2). Ten out of 11 patients developed symptoms within 18 days from the start of mesalamine treatment, and one patient suddenly developed joint pain 5 years after the administration of pH-dependent mesalamine, which disappeared after the discontinuation of mesalamine.

DLST

The DLST test was performed in 72% of patients (8/11), half of which (4/8) were DLST-positive.

Desensitization therapy

Desensitization therapy with granule mesalamine was performed and all patients were desensitized successfully, achieving continuous mesalamine administration. The Partial Mayo score significantly improved from a median of 2 to 0 (P = 0.03). Although there were no significant changes in the serum concentrations of CRP, Alb, and Hb, these concentrations tended to improve from 0.14 mg/dl to 0.06 mg/dl (P = 0.35), from 3.9 g/dl to 4.0 g/dl (P = 0.79), and from 13.5 g/dl to 13.7 g/dl (P = 0.20), respectively. During the desensitization, one patient (9%) developed fever and the increase in the dosage of mesalamine was stopped. This patient resumed the desensitization therapy after the fever had passed. No serious adverse events were observed with this protocol. Clinical courses during and after mesalamine desensitization are shown in Table 3. Oral corticosteroids (18%) and budesonide rectal foam (82%) were used during the desensitization and all were withdrawn by the end of the protocol. After the desensitization therapy, 9 out of 11 patients had sustained remission, whereas two patients (18%) relapsed and were treated with other medications (Fig. 1). One patient had a relapse 3 months after the desensitization and required oral corticosteroids (Case 2). She subsequently achieved sustained remission with oral and topical mesalamine. Another patient (Case 7) who had received 4000 mg mesalamine, did not achieve clinical remission with the desensitization therapy and failed to respond to corticosteroids. She was eventually treated with upadacitinib.

Table 3.

Clinical courses during and after mesalamine desensitization.

Case	Sex	Age	Disease duration (month)	Disease location	Clinical disease activity	DLST	p-Mayo (before DT)	Efficacy of DT	Adverse events	Duration of DT (month)	Concomitant medication during DT	Final dose of mesalamine	p-Mayo (after DT)	Concomitant medication at the end of DT	Relapse after DT
1	F	64	5	E3	Moderate	Positive	4	Success	None	6	BUD	4000	0	None	No
2	F	24	3	E2	Moderate	Negative	1	Success	None	6	BUD	4000	0	None	Yes
3	F	37	2	E1	Mild	Positive	2	Success	None	6	BUD	4000	1	None	No
4	F	35	4	E2	Moderate	Negative	1	Success	None	6	BUD	4000	0	None	No
5	F	55	19	E2	Mild	Negative	3	Success	None	5	BUD	3000	0	None	No
6	F	48	166	E2	Moderate	Positive	0	Success	None	6	IFX	4000	0	IFX	No
7	F	27	2	E3	Moderate	Positive	4	Success	Fever	6	CS, BUD	4000	6	None	Yes
8	M	67	2	E3	Mild	Negative	1	Success	None	6	CS, BUD	4000	0	None	No
9	M	52	68	E3	Mild	–	1	Success	None	6	IM	4000	0	IM	No
10	M	32	29	E3	Moderate	–	1	Success	None	6	BUD, IM	4000	0	IM	No
11	M	47	2	E2	Moderate	–	4	Success	None	6	BUD	4000	1	None	No

p-Mayo, partial Mayo score; DT, desensitization therapy; E1, proctitis; E2, left sided; E3, extensive; BUD, budesonide rectal foam; CS, corticosteroids; IM, immunosuppressants; IFX, infliximab.

Figure 1.

Survival curve of the remission rate after desensitization therapy.

Discussion

It has been reported that mesalamine intolerance occurs in up to 16.2% of UC patients, with an incidence has been increasing in recent years.^3,6,9,21 There is no established strategy for intolerance patients after mesalamine has been withdrawn. For the subsequent medical treatment, immunosuppressants or advanced therapies such as biologics/small molecule agents are considered. However, these medicines are associated with risks of infections, certain malignancies, and are extremely expensive compared with mesalamine.^7,8 There have been several reports of challenge by the administration of another mesalamine compound or SASP, which led to approximately half of the patients experiencing recurrent symptoms of mesalamine intolerance.^9,10 It is well known that SASP causes more frequent adverse events than mesalamine.^3,22 When physicians start a patient on mesalamine, most such patients are newly diagnosed with UC and are being prescribed the medicine for the first time. The occurrence of recurrent adverse events negatively affects the doctor–patient relationship and make it difficult for physicians to share the decision-making for the next treatment strategy with their patients. Thus, other treatment options are required for patients with mesalamine intolerance.

The first report of a desensitization method for UC patients was by Holdsworth using SASP in 1981.²³ Few case reports have shown effective desensitization using mesalamine tablets, which need to be crushed and made into a solution or placed in a capsule when preparing tiny doses of mesalamine.^15–17 In 2011, Oustamanolakis et al. developed a new desensitization protocol using mesalamine granules,¹⁸ which can easily be prepared for exact dose fractions of mesalamine, providing a preferable method for mesalamine desensitization. Recent studies also reported good outcomes with mesalamine granule desensitization.^19,24 However, desensitization has not yet become a general treatment option for intolerance patients, because incremental dosing regimens have not been established. In addition, the desensitization protocol used in previous reports, which increased the dose every 1–3 days, makes it difficult to apply in daily clinical practice. Thus, we developed “an every week dose up” protocol, which is preferable in outpatient settings.

In this retrospective study, we demonstrated the effective and safe desensitization method for UC patients with mesalamine intolerance. Although the number of cases was limited, all were successfully desensitized without any serious adverse events. Only one patient (9%) had fever for a short period and after the fever had passed, the dose of mesalamine was gradually increased to 4000 mg. Most patients who responded to desensitization achieved clinical remission, and all patients received the desensitization therapy without the need for hospitalization. Thus, this protocol appears to be an effective and safe desensitization method, which can easily be administered in outpatient settings.

This regimen provides a rather slow procedure for a median of 6 months (range, 5–6). Eight patients, who were newly diagnosed with UC for the first time, required oral corticosteroids and/or budesonide rectal foam at the beginning of this desensitization, which were withdrawn at the end of the protocol. In the present study, 9 out of 11 patients (82%) had sustained remission with oral and/or topical mesalamine; however, two patients relapsed after desensitization within the observation period for a median of 6 months (range, 11 days to 28 months). Previous studies reported a worse prognosis for patients with mesalamine intolerance who required advanced therapies and had a high risk of colectomy.^14,21 Therefore, patients should be monitored carefully for mesalamine intolerance, even after successful desensitization.

There are several advantages of mesalamine desensitization. First, intolerant patients might avoid taking immunosuppressants or advanced therapies, which can cause infections and malignancies, especially in older patients.⁷ Second, the desensitization method may contribute to reducing the healthcare costs of UC patients, which are becoming an economic burden with the increasing use of advanced therapies.⁸ Moreover, recent research has shown that mesalamine has a protective effect against colorectal cancer or neoplasia in patients with UC.^25,26 In the present study, three intolerant patients who had already been treated with immunosuppressants or biologics achieved successful mesalamine desensitization, indicating the potential benefit of the additional effects of mesalamine or the possibility of discontinuing biologics in the future.

As the mechanisms of mesalamine intolerance have not yet been elucidated, there is no test that can definitively confirm or rule out mesalamine intolerance. The DLST, which measures 3H-thymidine uptake by proliferating lymphocytes following stimulation with the drug of interest, is used for the auxiliary diagnosis of type IV drug allergies.²⁷ It has been reported as a diagnostic test for mesalamine allergy with low sensitivity and high specificity.²⁸ In our study, the DLST was performed in 8 of 11 patients with mesalamine intolerance, and positivity was found in four cases. Regardless of the DLST positivity, all patients with mesalamine intolerance achieved safe and successful desensitization. This result indicates that our desensitization protocol can be safely used for DLST positive mesalamine intolerance patients.

In this study, we excluded patients who had severe disease activity or adverse events such as pancreatitis, pericarditis, and pneumonitis. A search of the literature revealed no previous reports of successful desensitization in patients with these severe adverse effects. We consider that desensitization therapy should be performed for patients with mild-to-moderate disease activity without organ disorders. In addition, we did not evaluate SASP for desensitization, because it causes more frequent adverse events than mesalamine.²²

This study had several limitations. First, this was a single-center retrospective study with a small number of patients. Second, the small sample size may limit the ability to differentiate between tolerance and effectiveness in patients with positive versus negative DLST results. Third, we did not evaluate the long-term prognoses of the mesalamine intolerant patients after the desensitization. A prospective, multicenter study is needed to confirm the usefulness and safety of our desensitization protocol. Furthermore, evaluating the intolerant patients’ clinical course for a longer period after desensitization is an important agenda for future study.

In conclusion, our retrospective study reports a useful and safe desensitization method for mesalamine intolerant patients, which can easily be used in day-to-day clinical practice. Mesalamine desensitization might be a viable therapeutic option for intolerant patients with mild-to-moderate clinical activity without organ disorders. A larger, prospective study to clarify which patients may benefit from desensitization and might avoid receiving immunosuppressants or advanced therapies is required.

Conflict of interest

The authors declare that they have no conflict of interest.