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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Development of a scoring system for critical review of published and submitted case reports of drug-induced MC
  5. Review of the literature
  6. Suggestions for clinical management of individual patients suspected of having drug-induced MC according to the level of evidence in the literature that the drug may cause colitis
  7. References

The pathophysiology of microscopic colitis is unknown, although it is thought to be because of an abnormal immune reaction to luminal antigens in predisposed hosts. Specific antigens have not been proved, although various infectious triggers and drugs have been proposed. The responsibility of several drugs has been questioned, some with strong clinical and/or histological evidence suggesting causality. The issue of drug-induced microscopic colitis is important because of the burden of this disease. Thus, any case that can be cured by withdrawal of a drug must be identified. In this report, we propose a scoring system for drug-induced microscopic colitis, adapting existing criteria of drug causality, and review the literature using this framework. Based on this review, several drugs are identified with intermediate or high likelihood of inducing microscopic colitis. Finally, we suggest how to treat individual patients suspected of having drug-induced colitis according to the level of evidence for that particular drug.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Development of a scoring system for critical review of published and submitted case reports of drug-induced MC
  5. Review of the literature
  6. Suggestions for clinical management of individual patients suspected of having drug-induced MC according to the level of evidence in the literature that the drug may cause colitis
  7. References

Microscopic colitis (MC) is a diagnosis based upon histological abnormalities of the colonic mucosa encountered in patients with chronic watery diarrhoea and macroscopically normal or near-normal colonic mucosa.1 There are two main subsets of MC, collagenous colitis (CC) and lymphocytic colitis (LC), described in 19762 and 19893 respectively. Epithelial damage, such as flattening and detachment, and inflammation in the lamina propria with mainly mononuclear cells are observed in both diseases. In LC, the intraepithelial lymphocyte count must be ≥20/100 epithelial cells and the subepithelial collagen layer <10 μm thick. In CC, the intraepithelial lymphocyte count may be increased, but a thickening of the subepithelial collagen layer ≥10 μm is necessary for the diagnosis.

The most recent population-based epidemiological studies from the Europe,4, 5 Iceland6 and the United States7 suggest that the incidence of both LC and CC have become similar to those of Crohn's disease or ulcerative colitis.8

It is generally accepted that MC is secondary to an abnormal immune reaction to luminal antigens in predisposed hosts, but the primary cause of the immune dysfunction remains unknown. The question of environmental agents as causative or triggering factors in selected cases of MC has been raised. The role of various infectious triggers, such as Yersinia species,9Clostridium difficile10,11 and the agent of ‘Brainerd colitis’12 (a condition histologically similar to LC), has been hypothesized, but not proved.

The concept that some drugs could cause or worsen MC was proposed in the early 1990s.13, 14 After some anecdotal clinical observations of possible drug-induced MC,15, 16 the first well-documented case was published in 1994.17 In this report, a woman treated with Cyclo3 Fort developed histologically proven LC. Diarrhoea ceased with drug withdrawal and recurred with drug rechallenge. Immunopathological abnormalities, namely CD25 expression in lamina propria mononuclear cells and increased HLA-DR expression on epithelial cells, were only present after drug rechallenge. Thus, this clinical and histological sequence first demonstrated with a high level of evidence that MC could be drug-induced.

To date, the involvement of several molecules has been questioned, either with strong clinical and/or histological evidence after rechallenge or from pure chronological and/or frequency arguments. It is important to clarify the issue of drug-induced MC, because MC may require the use of expensive or potentially toxic treatments, often impacts on quality of life and can occasionally be life-threatening (e.g. hypokalaemia). Thus, any case of MC that can be cured by withdrawal of a drug must be identified.

The aims of this work were to: (i) propose a scoring system for drug-induced MC, adapting existing criteria of drug causality; (ii) review the literature using this framework; and (iii) suggest recommendations for specific drugs or drug classes based on individual evidence levels of potential responsibility.

Development of a scoring system for critical review of published and submitted case reports of drug-induced MC

  1. Top of page
  2. Summary
  3. Introduction
  4. Development of a scoring system for critical review of published and submitted case reports of drug-induced MC
  5. Review of the literature
  6. Suggestions for clinical management of individual patients suspected of having drug-induced MC according to the level of evidence in the literature that the drug may cause colitis
  7. References

To date, there is no international consensus about one particular drug causality assessment method.18 We developed a scoring system specific for drug-induced MC from the method proposed by Begaud et al.19 This method is the standard tool used in pharmacovigilance studies in France for assessing the causal relationship between adverse events and drugs.20 This method, recently used in a safety report in gastroenterology,21 is based on chronological and causality criteria. Begaud's score comprises seven criteria divided into two groups: chronological and causality criteria. Chronological criteria (Table 1) refer to the time elapsed between exposure to a drug and an adverse event, the evolution of the adverse event when the therapy is discontinued, and the evolution if the therapy is resumed. For the adaptation of the score to the case of MC, we arbitrarily considered as time intervals suggestive of drug responsibility those included in the range of times reported in published cases of MC related to drugs (Table 2) fulfilling at least one of the following criteria: (i) at least one report with a positive test for drug responsibility after rechallenge; or (ii) a literature score of 3 (see below). Drugs that fulfilled these criteria were acarbose, aspirin, carbamazepine, lansoprazole, non-steroidal anti-inflammatory drugs (NSAIDs), ranitidine, ticlopidine, and the French phlebotonic drugs (cyclo3 fort and cirkan, combinations of vegetable extract from Ruscus aculeatus, hesperidine methylchalcone and ascorbic acid).

Table 1.  Scoring system for suspected cases of drug-induced microscopic colitis: chronological scoring*
Drug rechallenge (R)Time between drug onset and onset of diarrhoea
SuggestiveCompatibleNot compatible
R+R0R−R+R0R− 
  1. R+, recurrence of diarrhoea; R0, rechallenge test not performed or impossible to assess; R−, no recurrence of diarrhoea; Ch3, probable chronology; Ch2, plausible chronology; Ch1, doubtful chronology; Ch0, drug responsibility seems to be ruled-out.

  2. * Adapted from Begaud et al.19

Suggestive evolution: diarrhoea resolution after drug withdrawalCh3Ch3Ch1Ch3Ch2Ch1Ch0
Non-conclusive evolution: incomplete or late resolution of diarrhoeaCh3Ch2Ch1Ch3Ch1Ch1Ch0
Non-suggestive evolution: no significant change after drug withdrawalCh1Ch1Ch1Ch1Ch1Ch1Ch0
Table 2.  Ranges of time intervals suggestive of drug responsibility in suspected cases of drug-induced microscopic colitis
Time interval (days)Range of suggestive time intervals (median)Total number of casesReferences
  1. From published detailed clinical cases of MC related to drugs fulfilling at least one of the two following criteria: (i) at least one published report with positive test for drug responsibility and (ii) literature score of 3 (see Methods section).

Time between drug onset and the onset of diarrhoea1–112 (4)2516, 17, 23, 26, 31, 32, 37, 40, 41, 43, 45, 48, 50, 56, 57, 59, 61
Time between drug withdrawal and cessation of diarrhoea2–30 (5)2116, 17, 23, 26, 32, 37, 40, 41, 43, 45, 48, 50, 56, 61, 65
Time between drug rechallenge and recurrence of diarrhoea0.3–7 (2)717, 23, 45, 57, 59
Time between the end of rechallenge period and cessation of diarrhoea1–10 (1)517, 23, 59

For the purpose of the adaptation of Begaud's criteria to the case of MC, the likelihood that a given drug causes MC (the causality score) was based on the exclusion of other potential causes of diarrhoea and histological (presence of apoptosis) or immunopathological (HLA-DR expression on epithelial cells or CD25 expression on lamina propria mononuclear cells) findings specifically suggesting responsibility (Table 3). We considered bacterial infections as possible non-drug-related causes of MC that could only be excluded by negative stool cultures.

Table 3.  Scoring system for suspected cases of drug-induced microscopic colitis (MC): causality scoring*
 Test suggestive of drug responsibility (T)†
T+T0T−
  1. T+, positive test; T0, test not performed; T−, negative test; Ca3, probable causality; Ca2, possible causality; Ca1, doubtful causality.

  2. * Adapted from Begaud's causality score19 by the authors (L.B., D.P.) for establishing the list (see†) of tests suggestive of drug responsibility in the case of MC, the list of non-drug-related possible causes of MC (see‡) and the appropriate work-up (see§).

  3. † Colonic histological (apoptosis) or immunopathological changes (HLA-DR expression of epithelial cells, CD25 expression of mononuclear cells of the lamina propria) induced by a brief period of drug rechallenge.

  4. ‡ Intestinal bacterial infection at the onset of diarrhoea.

  5. § Stool culture.

Non-drug-related possible cause‡
 Absent after appropriate work-up§Ca3Ca2Ca1
 Possible (present or not tested)Ca3Ca1Ca1

The chronological score and the causality score are combined to determine the likelihood of responsibility (R score) of a given drug in a given patient, ranging 0–4: 0, not related; 1, doubtful; 2, possible; 3, likely and 4, almost definite (Table 4).

Table 4.  Scoring system for suspected cases of drug-induced microscopic colitis: resulting scoring*
Chronology scoreCausality score
Ca1Ca2Ca3
  1. Ca, causality score; Ch, chronology score; R4, drug responsibility seems to be definite; R3, probable drug responsibility; R2, possible drug responsibility; R1, doubtful drug responsibility; R0, responsibility of drug seems to be ruled-out.

  2. * Translated in English from Begaud et al.19

Ch0R0R0R0
Ch1R1R1R2
Ch2R1R2R3
Ch3R3R3R4

Besides the use of Begaud's score adapted to MC for assessing individual case reports, we took into account the number and clinical details of published case reports, as recommended in all drug causality assessment methods.18, 19 We rated the literature score on a scale of 0–3. This scores takes first into account the number of published cases (either in specific reports of putative drug-induced MC or cited in large series of MC) as possibly drug-related: 0, no case; 1, 1–7 cases and 2, ≥8 cases. Secondly, for a given drug, an additional point is added if a detailed chronology (specific time from initial exposure to development of diarrhoea; specific time to resolution after drug withdrawal) is available in at least one patient, either as a published case or unpublished personal cases of the authors.

Finally, we combined the literature score with the R score (determined using the methods discussed above) to determine the final probability that the particular drug might cause MC (Table 5).

Table 5.  Resulting scoring of the likelihood that a given drug may cause microscopic colitis (MC)
Highest resulting score of individual cases of MC suspected to be because of the drugLiterature score*
0123
  1. L, low probability that the drug can cause MC; I, intermediate probability that the drug can cause MC; H, high probability that the drug can cause MC.

  2. * This score takes into account the number of published cases (either in specific reports of putative drug-induced MC or cited in large series of MC) as possibly drug-related: 0, no case; 1, 1–7 cases; 2, ≥8 cases. An additional point is added if a detailed chronology (specific time from initial exposure to development of diarrhoea; specific time to resolution after drug withdrawal) is available in at least one patient.

R0LLLL
R1LLLI
R2LLII
R3LIIH
R4IIHH

As an illustrating example, let us consider the case of a 32-year-old woman with no previous history of diarrhoea and no permanent treatment; 4 weeks after the introduction of a new drug ‘x’, the patient developed diarrhoea with 6–10 watery stools/day. Colonoscopy to the terminal ileum was normal. Random right and left colon biopsy specimens revealed typical features of LC. Stool culture was negative. After 5 weeks of diarrhoea, the drug ‘x’ was stopped. Within 7 days of discontinuing the drug, the patient had resolution of symptoms with normalization of stool frequency to two bowel movements per day. There was no rechallenge. There was only one previously published observation of ‘x’-associated LC with no chronological details, and the gastroenterologist managing the patient decided to submit his personal observation for publication as a possible ‘x’-induced LC. The time between the onset of treatment and the onset of diarrhoea and the time between treatment withdrawal and diarrhoea resolution are both suggestive of the role of the drug (Table 2). This leads to a chronology score of Ch3 (Table 1) and a causality score of Ca2 (Table 3). The resulting Begaud's score adapted to MC in this particular patient is R3 (Table 4). After publication of the case, the final score matching the score derived from Begaud and the literature score 2 leads to an intermediate level of evidence that the drug ‘x’ might cause LC (Table 5).

Review of the literature

  1. Top of page
  2. Summary
  3. Introduction
  4. Development of a scoring system for critical review of published and submitted case reports of drug-induced MC
  5. Review of the literature
  6. Suggestions for clinical management of individual patients suspected of having drug-induced MC according to the level of evidence in the literature that the drug may cause colitis
  7. References

Methods

Selection of published reports was made using PubMed and updated on 1 January 2005. We selected articles that included the mesh terms ‘colitis/chemically induced’ or ‘diarrhoea/chemically induced’ and whose title included the terms ‘microscopic colitis’, ‘lymphocytic colitis’ or ‘collagenous colitis’. Thus, the search was formulated as follows: [(colitis/chemically induced) OR (diarrhoea/chemically induced)] AND [(‘microscopic colitis’ [ti]) OR (‘lymphocytic colitis’ [ti]) OR (‘collagenous colitis’ [ti])]. Forty-three articles fulfilled these criteria.13, 14, 16, 17, 22–60 We added two articles reporting apoptosis as a histological marker of drug-induced MC,61, 62 several reports of possible drug-induced CC63, 64 and two large series of patients with MC in which medications possibly related to the onset of colitis were cited.64, 65

Results

As indicated in Table 6, 21 drugs or drug classes had sufficient information upon which to perform an analysis. Eight were associated with a high likelihood of inducing MC (acarbose, aspirin, cyclo3 fort and cirkan, lansoprazole, NSAIDs, ranitidine, sertraline and ticlopidine). Nine were associated with an intermediate likelihood [carbamazepine, flutamide, lisinopril, modopar (levodopa and benserazide), oxetorone, paroxetine, simvastatin, tardyferon (iron sulphate and ascorbic acid), and vinburnine]. Four drugs were associated with a low level [cimetidine, daflon (flavonoids), gold salts, piascledine].

Table 6.  Assessment of the level of likelihood that a specific drug can trigger microscopic colitis (MC): review of the literature
DrugsIndividual clinical cases with the best resulting score (detailed score, related reference)Literature score (references)Likehood that the drug can cause MC
  1. * Vegetable extract from Ruscus aculeatus, hesperidine methylchalcone and ascorbic acid.

  2. † Flavonoids.

  3. ‡ Levodopa and benserazide.

  4. § Unsaponifiable fraction of avocado and soya oil.

  5. ¶ Iron sulphate and ascorbic acid.

AcarboseR4 (Ch3Ca3, 45)3 (45)High
AspirinR3 (Ch3Ca1, 67)3 (51, 55, 67, 68)High
CarbamazepineR3 (Ch3Ca1, 65)2 (30, 65)Intermediate
CimetidineR1 (Ch2Ca1, 28)2 (28)Low
Cyclo3 Fort*, Cirkan*R4 (Ch3Ca3, 17)3 (16, 17, 26)High
Daflon†R1 (Ch3Ca1, 38)2 (38)Low
FlutamideR3 (Ch3Ca1, 66)2 (66)Intermediate
Gold saltsR1 (Ch2Ca1, 64)1 (63, 64)Low
LansoprazoleR3 (Ch3Ca1, 56)3 (56, 57)High
LisinoprilR3 (Ch3Ca1, 64)1 (64)Intermediate
Modopar‡R3 (Ch3Ca1, 46)2 (46)Intermediate
NSAIDsR3 (Ch3Ca2, 52)3 (13, 14, 39, 51–53, 55, 65, 67–69)High
OxetoroneR3 (Ch3Ca1, 54)2 (54)Intermediate
ParoxetineR3 (Ch3Ca1, 65)1 (65)Intermediate
Piascledine§R3 (Ch3Ca1, 60)1 (60)Low
RanitidineR4 (Ch3Ca3, 23)2 (23)High
SertralineR3 (Ch3Ca3, personal cases (L.B.))3 (65 and three personal unpublished cases (L.B.))High
SimvastatinR3 (Ch3Ca1, 70)2 (65, 70)Intermediate
Tardyferon¶R3 (Ch3Ca1, 27)2 (27)Intermediate
TiclopidineR3 (Ch3Ca1, 61)3 (15, 55, 61, 68)High
VinburnineR3 (Ch3Ca1, 33)2 (33)Intermediate

Comments

The pathophysiology of MC is not well understood. Several cases appear to have an identifiable environmental trigger, including infections and exposure to certain medications. The weight of evidence for possible medication triggers to date ranges from convincing to speculative at best. In this report, we propose an objective scoring system, adapted from other established systems, by which to judge the likelihood that a given compound causes MC. This judgement is based on the number of reported cases, details of chronology between exposure and development of diarrhoea, evolution of diarrhoea after withdrawal of the drug, recurrence of diarrhoea with rechallenge, exclusion of other possible causes of diarrhoea and demonstration of suggestive histological or immunopathological features.

Suggestions for clinical management of individual patients suspected of having drug-induced MC according to the level of evidence in the literature that the drug may cause colitis

  1. Top of page
  2. Summary
  3. Introduction
  4. Development of a scoring system for critical review of published and submitted case reports of drug-induced MC
  5. Review of the literature
  6. Suggestions for clinical management of individual patients suspected of having drug-induced MC according to the level of evidence in the literature that the drug may cause colitis
  7. References

We found evidence to suggest a high or intermediate probability of causality for 17 drugs (Table 6). There were not enough cases to make the distinction between drugs that cause LC and those that cause CC. However, the drugs associated with the greatest number of published cases of drug-induced MC have been shown to induce either CC or LC.56 In patients diagnosed with MC who are taking one of these drugs and who have a suggestive interval between exposure to the drug and development of diarrhoea, the drug should be stopped if possible with close observation of the clinical course. If the drug in question is thought to be necessary for the patient's management, a careful rechallenge with close clinical follow-up may be considered. For drugs with low-level probability and for those drugs not yet associated with MC, but with a significant time interval, we also encourage a drug holiday as described above. For drugs for which a complete drug holiday might be considered hazardous (e.g. aspirin in a patient with significant cardiovascular disease, carbamazepine with a history of seizures, or antidepressants), a drug with similar efficacy but from an unrelated class of compounds should be considered. In some individual cases, stopping the suspected treatment is followed by a frank improvement in diarrhoea but not by a complete histological healing.23 This observation suggests that in some cases drugs may act only as the triggering factor of self-evolving MC in predisposed hosts. In such patients, drug withdrawal remains necessary but does not always lead to complete and definite resolution of colitis. In patients with persistent diarrhoea despite drug withdrawal and treatment with cholestyramine and/or antidiarrheals, treatment with budesonide should be considered.66

To help further our understanding of drug-induced MC, we encourage investigators to perform specific tests of causality, such as CD25 expression in lamina propria mononuclear cells, HLA-DR expression on epithelial cells, or assessment of the presence of apoptosis in cases of suspected drug-induced MC. These specific tests of causality should be performed if possible whilst on the suspect drug, 3–6 months after drug withdrawal and resolution of symptoms, and again if a rechallenge is performed.17, 23, 45 We also strongly encourage the publication of these cases.

This report represents a starting point for the objective consideration of drug-induced MC. Indeed, the literature includes references to many other drugs that were not analysed using this scoring system because of lack of specific information. This issue will continue to evolve, and case reports or case series of patients with possible drug-induced MC are encouraged with as much detail as possible regarding the factors considered in this report. For patients taking several drugs at the time of diarrhoea onset, the role of each drug must be successively and independently assessed.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Development of a scoring system for critical review of published and submitted case reports of drug-induced MC
  5. Review of the literature
  6. Suggestions for clinical management of individual patients suspected of having drug-induced MC according to the level of evidence in the literature that the drug may cause colitis
  7. References
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