La tunisie Medicale - 2010 ; Vol 88 ( n°06 ) : 390 - 393
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Résumé

Prérequis : La ciclosporine par voie intraveineuse est un traitement efficace chez les patients présentant une colite aiguë grave résistante aux corticoïdes. Cependant, son utilisation est actuellement controversée du fait de la fréquence des effets indésirables d’une part et du doute sur les résultats à long terme d’autre part.
But : Le but de cette revue est de réunir les données concernant les indications, les modalités d’administration, les effets indésirables et la surveillance de la ciclosporine au cours des colites graves corticorésistantes. Méthodes: Revue de la littérature
Résultats : Sa toxicité est dominée par le risque d’infections opportunistes. Une neurotoxicité et une néphrotoxicité sont également possibles. Cette toxicité peut être réduite par l’utilisation de plus faibles doses, de la forme orale à type de micro-émulsion ou de monothérapie. La durée du traitement ne doit pas dépasser 3 à 6 mois. Actuellement, le rôle principal de la ciclosporine est un « bridge » au traitement d’entretien par azathioprine/6-mercaptopurine.
Conclusion : La ciclosporine est une alternative thérapeutique à la colectomie en urgence dans le colites ulcéreuses sévéres à court terme. Bien que ce bénéfice n’est pas obtenue chez tous les patients, plus de la moitié vont évité la colectotomie à long terme. Selection de patient, bien suivis avec une thérapie par voie orale à faible dose doit pouvoir diminuer les effets indésirables.

Mots Clés
Article

About 15% of patients with ulcerative colitis (UC) experience fulminant episodes requiring admission to hospital during the curse of their illness. Treatment with intravenous corticosteroids remains the mainstay of treatment for severe UC, but the colectomy rate for treatment failure is about 30 to 40%. The use of ciclosporin A (CSA) as a rescue therapy is the only significant advance in medical therapy since the introduction of intra-venous corticosteroids. In fact, CSA has provided an effective medical alternative to patients previously faced with the only surgical options. Nevertheless, the role of this drug remains controversial, with doubts about side effects and long-term efficacy and controversy has arisen whether the benefits use of CSA outweighs the risks.
This review will provide information on clinical pharmacology, clinical indications for use, methods of dose adjustment, monitoring of metabolites for efficacy and for potential side effects and the adverse event profile of ciclosporin in severe refractory colitis.

METHODS

To identify articles for this review, a PubMed search was conducted using the following key words individually and in various combinations: ciclosporin, severe refractory colitis, monitoring, adverse effects and toxicity. Search of reference lists from pertinent articles identified additional publications.

RESULTS

Mode of action:
CSA is a lipophilic cyclic peptide that binds with high affinity to its cytoplasmic receptor protein cyclophilin. This complex specifically and competitively binds to and inhibits calcineurin, a calcium and calmodulin dependant phosphatase. This prevents translocation of a family of transcription factors, nuclear factor activated T cells (NF-AT), which reduces activation of genes for interleukin (IL)-2, IL-3, IL-4, granulocyte macrophage colony-stimulating factor, tumor necrosis factor alpha and interferon gamma. T-cell transcription factors AP-1 and NF-kB are also inhibited. CSA acts predominantly on CD4 cells [1]. Consequently, CSA diminishes cytokine production and exerts an antiproliferative effect on lymphocytes [1,2,3].
Clinical evidence of benefit:
Promising results from uncontrolled trials [4,5] were substantiated by a randomized, double-blind, placebocontrolled trial conducted by Lichtiger, whereby intravenous
CSA showed an impressive 82% response rate in steroid refractory UC patients [6]. At 6 months, after conversion to oral CSA, 69% of patients were able to discontinue steroids and remain in remission. Intravenous CSA, with concurrent intravenous steroids has become an established therapy in severe steroid-resistant UC sparing 60-90% of patients from urgent colectomy [7]. Some responders to CSA will ultimately relapse, but 30-50% will not require surgery during long-term follow-up (table 1). The addition of azathioprine (AZA)/mercaptopurine (MP) improved long-term response rates. As a bridge to other maintenance therapy, CSA can be an effective treatment option, achieving rapid remission and even if the patients necessitate surgery, CSA offers the opportunity to avoid emergency colectomy and provides time for elective colectomy.

Table 1 : Results of intravenous ciclosporin in refractory ulcerative colitis.



Toxicity:
The use of CSA is associated with considerable morbidity. The risk of minor side effects ranges from 31 to 51%, including tremor, paraesthesia, malaise, headache, nausea/vomiting, abnormal liver function, gingival hyperplasia and hirsutism [1,3]. Major complications are reported with a frequency from 0 to 17%, including renal, infectious and neurotoxic effects [1].
Nephrotoxicity:
Mild, reversible renal impairment is common. There are only isolated reports of serious renal failure probably because of the short duration of therapy. Acute nephrotoxicity is due to a dose dependant vasoconstriction of afferent and efferent glomerular arterioles resulting in reduced renal blood flow and a fall in glomerular filtration rate. The effect can be reduced with calcium channel blockers, but may be increased by the concomitant prescription of other nephrotoxic drugs. A rare effect of CSA is a vascular lesion akin to that in haemolyticuraemic syndrome. This is idiosyncratic and leads to irreversible renal failure. Chronic nephrotoxicity results from obliterative arteriolopathy, ischaemic collapse or scarring of glomeruli, vacuolization of tubules, focal tubular atrophy and interstitial fibrosis. A fourth renal problem is tubular dysfunction, resulting in hyperuricaemia, metabolic acidosis, hypophosphataemia and hypomagnesaemia [1].
Infections:
The profound immunosuppressive effects of CSA result in a significant risk of infection. The risk is dose dependant and compounded by co-treatment with corticosteroids, or other immunomodulators and the general condition of the patient [1,2]. Infections include opportunistic pathogens, particularly Pneumocystis Carinii but also Nocardia, Aspergillus fumigatus, Listeria monocytogenes, cytomegalovirus, herpes simplex and candida infections. Septicemia from conventional infections also occurs such as Staphylococcus aureus and Haemophilus influenzae [1]. Pneumocystis prophylaxis should be considered.
Neurotoxicity:
Minor neurotoxic effects of CSA include tremor, burning paraesthesiae, headaches, blurred vision and malaise. Serious effects include seizures, coma, spasticity, and ataxia. These effects are dose related, and reversible, but they can occur at low doses. The risk of neurotoxicity may be increased by many factors, including high-dose corticosteroids, hypertension, low serum cholesterol and hypomagnesaemia. Consequently, it is recommended that patients do not receive CSA if the cholesterol is below 3 mM and hypomagnesaemia should be corrected prior to treatment.
Dose and route of administration:
Successful trials with CSA for UC used doses of 2-4 mg/kg/day intravenous (IV) [1,2]. The dose that was widely used, in the past decade, is 4 mg/kg/day by continuous IV infusion [1], but the majority of side effects are dose dependent. One approach to decreasing the toxicity is to reduce the dose of CSA. Actis et al. showed that outcomes using low-dose intravenous CSA (2 mg/kg/day) are comparable with those with high-dose therapy with less toxicity [5]. So a dose of 2 mg/kg/day is used nowadays to improve risk/benefit ratios [7].
Oral treatment:
Bioavailability ranges from 10 to 89% and can be reduced by fat-rich meal. The microemulsion-based formulation of CSA was developed to overcome problems of poor and unpredictable absorption of the standard oral preparation. Oral microemulsion CSA is now widely used and may eventually replace IV administration [8,9]. An oral dose of 5 mg/kg/day would be equivalent to 2 mg/kg/day intravenously.
Monotherapy:
Other strategies to lessen the adverse effects of CSA include its use as monotherapy without corticosteroids avoiding its concurrent morbidity [10]. This strategy may be safer; however, combination therapy still seems likely to be more effective. Monotherapy with intravenous ciclosporin, to achieve a minimum therapeutic concentration, [11] is an option for patients intolerant of intravenous steroids (recommendation grade C) .
Ciclosporin enemas:
In spite of early promise, CSA enemas have been shown to be ineffective in a placebo controlled study in 40 patients with leftsided colitis [12].
Monitoring:
Baseline medical history including patient’s medication list, physical examination and laboratory studies are needed prior to initiation of therapy (table 2 and 3).
Table 2 : Pre-treatment



Table 3 : Contra-indications



Bedside monitoring should be performed every 15 min for the first hour of the infusion for signs of allergy or anaphylaxis such as wheezing, urticaria, hypotension [1,3]. Blood pressure should be monitored every 4h while awake. Daily clinical monitoring of disease activity and for side effects is imperative. After initiating therapy as a continuous IV infusion, CSA levels should be obtained every day or 2 days [1,3]. Serum creatinine, potassium, magnesium and liver function test should be checked every 2 days, unless abnormal, in which case they should be checked daily. Serum cholesterol should be measured daily if ² 3.1 -3.6 mM. CSA dose should be reduced if drug levels are > 500 ng/mL for 2 consecutive days or if serum creatinine rises > 30% over baseline, serum liver enzymes double, diastolic blood pressure exceeds 90 mmHg, or systolic
blood pressure exceeds 150 mmHg despite antihypertensive treatment. If any of these occurs, the dose should be decreased of 25% at least [1,3]. Pneumocystis prophylaxis should be undergone with either trimethoprim/sulfamethoxazole 160/800 1 tab per os three times weekly or pentamidine aerosol (table 4). A clinical response should be noticed within 4 – 5 days. If clearly responding, CSA infusion should be continued for a minimum of 7 days before conversion to oral CSA. If there is not a significant improvement in clinical status after 10 days of IV therapy, patients should be referred for surgery [1,3].

Table 4 : Treatment schedule



Patients can be safely discharged home after 1 – 2 days of observation on oral CSA. The total daily oral dose is twice the daily IV dose, divided and given every 12 h. While on oral CSA, patients should be seen weekly for the first month, biweekly for the second month, and then every 3 – 4 weeks. CSA levels, serum chemistries, magnesium and full blood count should be performed at he same intervals as the clinic visits or weekly for any dose changes. Prednisone should be slowly tapered with a goal to be entirely weaned off by 6 months. AZA/MP should be started about 2 – 3 months after hospital discharge with plans to maintain remission on this medication after stopping CSA. CSA should be discontinued at 6 months, by reducing the dose by 50% for 2 weeks followed by complete CSA withdrawal. Others treat with CSA for a shorter period of time, stopping by 3 months, in which case maintenance therapy will need to be initiated sooner than 2 – 3 months after discharge [2].
Ciclosporin or surgery:
The timing of colectomy for severe colitis remains one of the most difficult decisions that a gastroenterologist has to make. CSA is indicated for patients with severe UC that are refractory to steroid therapy, as a second line therapy (recommendation grade B) [11]. This is generally defined as persistently active colitis despite 7 – 10 days of high dose intravenous steroids [3]. The primary use is to induce remission and serve as a bridge for AZA/MP therapy in UC patients with severe colitis [3, 13]. Patients with refractory colitis face a stark choice between prompt surgery and CSA therapy. CSA presents no easy option and should not delay appropriate surgery. Patients being
considered for CSA must be counseled about toxicity, the need for ongoing immunosuppression, and close follow-up, often over many months [1,2]. In spite of the risks, and inconvenience, most patients do opt for CSA, and the quality of life in responders has been reported to be better than in those who have undergone colectomy [14].
If CSA is considered, it must be considered at an early stage [11]. One approach is to use the 3-day predictive index of the stool frequency and C-reactive protein and abdominal radiography (recommendation grade B). If there is clinical deterioration colectomy is recommended. If there is no improvement within a further 4 – 7 days, colectomy should usually be recommended (recommendation grade D).

CONCLUSION


CSA is a viable alternative to emergency colectomy in severe UC in the short term. Although these benefits are not maintained in all patients [15, 16], more than a half will also avoid colectomy in the longer term. Careful selection and monitoring of patients, use of lower doses, and oral therapy will help to reduce side effects [1].

Références
  1. Barney Hawthorne A. Ciclosporin and refractory colitis. Eur J Gastroenterol Hepatol 2003; 15:239-44.
  2. Siegel CA, Sands BE. Practical management of inflammatory bowel disease patients taking immunomodulators. Aliment Pharmacol Ther 2005;22:1-16.
  3. Aberra FN, Lichtenstein GR. Monitoring of immunomodulators in inflammatory bowel disease. Aliment Pharmacol Ther 2005;21:307-19.
  4. Sandborn WJ. A critical review of cyclosporin therapy in inflammatory bowel disease. Inflam Bowel Dis 1995;1:48-63.
  5. Actis GC, Ottobrelli A, Pera A et al. Continuously infused cyclosporine at low dose is sufficient to avoid emergency colectomy in acute attacks of ulcerative colitis without the need for high-dose steroids. J Clin Gastroenterol 1993;17:10-3.
  6. Lichtiger S, Present DH, Kornbluth A. et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Eng J Med 1994;330:1841-5.
  7. Van Assche G, Vermeire S, Rutgeerts P. Treatment of severe steroid refractory ulcerative colitis. World J Gastroenterol. 2008;14:5508-11.
  8. De Saussure P, Soravia C, Morel P, Hadengue A. Low-dose oral microemulsion ciclosporin for severe, refractory ulcerative colitis. Aliment Pharmacol Ther 2005;22:203-8.
  9. Weber A, Fein F, Koch S, Dupont-Gossart AC, Mantion G, Heyd B, Carbonnel F. Treatment of ulcerative colitis refractory to steroid therapy by oral microemulsion cyclosporine. Inflam Bowel Dis 2006;12:1131-5.
  10. Rayner CK, McCormack G, Emmanuel V, Kamm MA. Long-term results of low-dose intravenous ciclosporin for acute severe ulcerative colitis. Aliment Pharmacol Ther 2003;182:303-8.
  11. Travis SPL, Stange EF, Lémann M, Oresland T, Bemelman WA, Chowers Y, Colombel JF, D'Haens G, Ghosh S, Marteau P, Kruis W, Mortensen NJ, Penninckx F, Gassull M for the European Crohn's and Colitis Organisation (ECCO). European evidencebased Consensus on the management of ulcerative colitis: Current management. J Crohn Colitis 2008;2: 24–62.
  12. Sandborn WJ, Tremaine WJ, Schroeder KW, Batts KP, Lawson GM, Steiner BL, et al. A placebo-controlled trial of cyclosporine enemas for mildly to moderately active left-sided ulcerative colitis. Gastroenterology 1994;106:1429-35.
  13. Cohen RD, Stein R, Hanauer SB. Intravenous cyclosporine in ulcerative colitis: a five-year experience. Am J Gastroenterol. 1999;94:1587-92.
  14. Message L, Bourreille A, Laharie D, Quinton A, Galmiche JP, Lamouliatte H, Alamdari A, Zerbib F. Efficacy of intravenous cyclosporin in moderately severe ulcerative colitis refractory to steroids. Gastroenterol Clin Biol 2005;29:231-5.
  15. Stack WA, Long RG, Hawkey CJ. Short and long-term outcome of patients treated with cyclosporine for severe acute ulcerative colitis. Aliment Pharmacol Ther 1998;12:973-8.
  16. Campbell S, Travis S, Jewell D. Ciclosporin use in acute ulcerative colitis: a long-term experience. Eur J Gastroenterol Hepatol 2005;17:79-84.
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