Review Article: Monitoring of Immunomodulators in Inflammatory Bowel Disease

F. N. Aberra; G. R. Lichtenstein

Aliment Pharmacol Ther. 2005;21(4):307-319.

Summary and Introduction

The armamentarium of medications for the treatment of inflammatory bowel disease is growing and becoming more complicated to use. Immunomodulators are a class of medications that have found a niche for the treatment of Crohn's disease and ulcerative colitis. Because of the mounting supporting evidence for efficacy, the most commonly-used immunomodulators are azathioprine, mercaptopurine, methotrexate and ciclosporin. These medications are being used more often due to their steroid-sparing and potentially surgery-sparing effects. Immunomodulators are also known for a significant side-effect profile and require careful monitoring. This review provides the latest information for clinicians on efficacy, side-effects, dosing and monitoring of these medications for treatment of inflammatory bowel disease.

Treatment of inflammatory bowel diseases (IBD) commonly requires utilization of immunodulatory medications. This class of medications includes azathioprine (AZA), mercaptopurine (MP), ciclosporin, methotrexate, and on occasion mycophenolate mofetil and tacrolimus. The most commonly used immunomodulators for treatment of IBD are AZA, MP, ciclosporin and methotrexate. These medications have shown to be effective and great care must be taken in monitoring patients receiving these medications to maximize clinical benefit and reduce the risk of side-effects and toxicity. This review will provide information on clinical pharmacology, clinical indications for use, methods of dose adjusting, monitoring of metabolites for efficacy and for potential side-effects, and the adverse event profile for each medication. This review will hopefully provide guidance on utilizing immunomodulators for Crohn's disease (CD) and ulcerative colitis (UC) based on the published literature.

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Metabolite Levels and Possible Clinical Correlations*
6-TGN level	6-MMP level	Clinical response
Low	Low	Subtherapeutic dosing or non-compliance
Low	High	MP resistant
Normal	High	MP resistant or high risk for abnormal liver chemistries
Normal	Low	Responders or refractory
High	Low	True refractory, responder or risk of leucopoenia
High	High	Over-dosed

* Low 6-TGN is defined as <235 pmol/8 ×10⁸and high >450 pmol/8 ×10⁸. High 6-MMP is defined as >5700 pmol/8 ×10⁸.
MMP, 6-methylmercaptopurine; MP, mercaptopurine.

Utility of 6-TGN Level for Determining Remission of Inflammatory Bowel Disease
Study and 6-TGN level	Total number of subject^†( n )	IBD population	Sensitivity (%)	Specificity (%)	Positive predictive value (%)	Negative predictive value (%)
Belaiche et al .^[36]
>250*	28	Adult CD	26	88	83	36
>230	28	Adult CD	32	78	75	35
Cuffari et al .^[38]
>250	82	Adult CD, UC	69	86	86	70
Dubinsky et al .^[39]
>235	93	Paediatric CD, UC	65	73	70	60
Goldenberg et al .^[116]
>235	74	Adult CD, UC	47	82	24	82
Gupta et al .^[117]
>235	101	Paediatric CD, UC	54	70	64	67
Mardini and Arnold^[118]
>230	44	Adult CD, UC	100	61	65	100
Su et al .^[119]	29	Adult CD, UC	55	73	41	83
>230		Subgroups
		Luminal CD	86	80	60	84
		Fistulizing CD	33	66	17	83
		UC	40	71	36	79
Cuffari earlier study^[120]	10	Paediatric CD	80	83	80	83

* pmol/8 ×10^8†Studies may have multiple measurements of 6-TGN.

Table 3. Adverse Events in Trials of Intravenous Ciclosporin for Ulcerative Colitis*
	Lichtiger and Present^[121†]	Lichtiger et al .^[64]	Hermida-Rodriguez et al .^[122†*]	D'Haens et al .^[65]	Van Assche et al .^[66]
Duration of study (days)	10	≤14	7–10	8	8
Ciclosporin dose (mg/kg)	4	4	4	4	2 vs. 4
Ciclosporin mean blood levels (ng/mL)	NR	482^‡	250^§	376^¶	237/332^¶
Response ciclosporin/control (%)	73	82/0	70	64/53	86/84
Paresthesias ciclosporin/control (%)	40^¶	36/0	0	0/7	6/8
Hypertension ciclosporin/control (%)	13	36/11	0	7/0	9/24
Nausea/vomiting ciclosporin/control (%)	0	9/11	4	7/0	NR
Nephrotoxicity ciclosporin/control (%)	7	0/0	9	0/0	17/18
Hepatoxicity ciclosporin/control (%)	0	0/0	0	NR	NR

^†No control group.
^‡Ten of 11 subjects with mean blood levels provided, based on radioimmunoassay technique.
^§Enzyme multiplied immunotest.
^¶ Monoclonal antibody-based fluorescence polarization immunoassay technique.
NR, not reported.
* Also included Crohn's disease patients.

Table 4. Laboratory Monitoring of Immunomodulators
Immunomodulator	Pre-treatment assessment	Treatment assessment
Azathioprine/ Mercaptopurine	TPMT	CBC
	CBC	LFT
	LFT	Metabolites (6-TGN, 6-MMP)
Ciclosporin	CBC	CBC
	LFT	LFT
	Serum electrolytes (potassium, magnesium)	Serum electrolytes (potassium, magnesium)
	Serum creatinine	Serum creatinine
	Serum cholesterol	Serum cholesterol
		Ciclosporin level
Methotrexate	CBC	CBC
Methotrexate	LFT	LFT

* TPMT, thiopurine methyltransferase; 6-MMP, 6-methylmercaptopurine; CBC, complete blood count; LFT, liver function test.

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Review Article: Monitoring of Immunomodulators in Inflammatory Bowel Disease

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