Ciclosporin (Sandimmun) bei juveniler chronischer Arthritis und M. Crohn?

Norbert J.:

Mein Sohn ist seit 11/1995 an JCA erkrankt; darüberhinaus leidet er seit 3/1996 an einer Darmerkrankung, die bisher trotz mehrerer Untersuchungen nicht exakt spezifiziert werden konnte; die Vermutungen reichten von Morbus Crohn über Colitis ulcerosa und Morbus Whipple bis hin zu einer medikamenteninduzierten Darmerkrankung.

Eine vor kurzem abgeschlossene neue Darmunter- suchung an einer Universitätskinderklinik führte zur Diagnose Morbus Crohn und zur Einleitung einer Sandimmun-Therapie.

Leider war dort die Informationsbereitschaft nicht im gleichem Maße vorhanden, wie ich sie von den die JCA behandelnden Ärzten kenne; meine Fragen nach medizinischer Literatur und eventuellen Studien zu Sandimmun bei Morbus Crohn blieben unbeantwortet.
Meine bisherige Suche nach Literatur über Sandimmun in Verbindung mit Morbus Crohn blieb ebenfalls erfolg- los; deshalb meine Frage, ob Sie mir möglicherweise weiterhelfen können.

Antwort: Eine schnelle Literaturrecherche ergibt aus meiner Sicht eher keine sehr überzeugenden Daten für die Therapie eines juvenilen M. Crohn mit Ciclosporin. Soweit ich das als Nicht-Gastroenterologe und Nicht-Kinderarzt beurteilen kann, scheint dabei vor allem die Gabe in Tablettenform nicht sehr gut abzuschneiden (was auch insofern gut nachvollziehbar ist, als ein M. Crohn durch die Entzündung im Darm ohnehin mit erheblichen Resorptionsproblemen einhergeht und Ciclosporin in der Resorption auch bei Darmgesunden nicht ganz unproblematisch ist).

Nach den wenigen Studien, die ich in einer der größten medizinischen Datenbanken unter dem Such-Algorithmus M. Crohn / juveniler M. Crohn und Ciclosporin gefunden habe, ist die Datenlage insgesamt relativ indifferent. Dies gilt in ähnlicher Weise für die Behandlung einer juvenilen chronischen Arthritis mit Ciclosporin (was ja u.U. ein Argument für den Einsatz dieses Medikamentes in der speziellen Kombination der beiden vorliegenden Erkrankungen sein könnte, wobei auch zu diskutieren ist, ob die Arthritis in Wirklichkeit nicht eine sogenannte enteropathische Arthritis ist und damit eine Manifestation des M. Crohn außerhalb des Darms.

Ich denke, man sollte die behandelnden Ärzte doch noch einmal genau befragen, was die genauen Argumente für die vorgeschlagene Therapie in dem sehr individuellen Einzelfall bei Ihrem Sohn sind und welche Alternativen in Frage kämen.

Einige ausgewählte Abstracts der Literaturrecherche (leider sind sie, wie fast die gesamte medizinische Fachliteratur, in Englisch):

Arch Dis Child 1994 Sep;71(3):243-7

Cyclosporin as initial treatment for Crohn's disease.

Nicholls S, Domizio P, Williams CB, Dawnay A, Braegger CP, MacDonald TT, Walker-Smith JA.

Department of Paediatric Gastroenterology, St Bartholomew's Hospital, West Smithfield, London.

Childhood Crohn's disease may cause significant morbidity. T cell activation is considered to be central to Crohn's disease pathology, and as cyclosporin is a powerful inhibitor of T cell activation, and has been used in adult Crohn's disease with encouraging results, it may offer the prospect of remission if given early in the course of disease. Children with newly diagnosed Crohn's disease or those relapsing off treatment were therefore given cyclosporin or conventional treatment (enteral nutrition or corticosteroids) by random allocation. Evaluation was performed initially and at two months. Twenty four children were studied (10 on cyclosporin and 14 on conventional treatment; one child on cyclosporin withdrew). Significant clinical improvement occurred in the group on conventional treatment, but not in the cyclosporin group. Colonoscopic improvement was noted in 5/9 on cyclosporin and 8/14 on conventional treatment, but neither group produced a significant fall in median colonoscopic index. Histological improvement was seen in 7/8 on cyclosporin and 8/13 on conventional treatment, but cyclosporin was not significantly better. Cyclosporin produced improved clinical and histological appearance without matched improvement in blood disease indices. It was not better than conventional treatment, and simple oral administration is probably not suitable for newly diagnosed patients with Crohn's disease.

J Clin Gastroenterol 1995 Apr;20(3):207-10

Intravenous cyclosporine for steroid-refractory attacks of Crohn's disease. Short- and long-term results.

Santos JV, Baudet JA, Casellas FJ, Guarner LA, Vilaseca JM, Malagelada JR.

Digestive System Research Unit, Hospital General Vall d'Hebron, Barcelona, Spain. A prospective, open trial was conducted to test whether i.v. cyclosporine was effective in the treatment of refractory Crohn's disease. Eight patients with acute steroid-refractory attacks were included. Intravenous cyclosporine, 5 mg/kg/day, was added to ongoing drug therapy. Patients who responded were then switched to oral cyclosporine for a mean 2.6-month period, and steroids were discontinued when possible. Six patients improved, with a mean latency time to onset of improvement of 9 days. Two did not improve, and both underwent urgent operation. On oral cyclosporine, five patients maintained remission and discontinued steroids, whereas one relapsed and underwent surgery. After discontinuation of oral cyclosporine, the five remaining patients relapsed, and two underwent surgery. One reversible episode of hepatobiliary toxicity and one of gastrointestinal intolerance were recorded. We conclude that i.v. cyclosporine effectively and rapidly induces improvement of acute steroid-refractory flare-ups of Crohn's disease, but after discontinuation relapse is to be expected.

Gastroenterology 1995 Sep;109(3):774-82

European trial of cyclosporine in chronic active Crohn's disease: a 12-month study. The European Study Group.

Stange EF, Modigliani R, Pena AS, Wood AJ, Feutren G, Smith PR.

Klinik fur Innere Medizin, Medizinische Universitat zu Lubeck, Germany.

BACKGROUND & AIMS: The role of cyclosporine in Crohn's disease is controversial. This study aimed to delineate the long-term effect of cyclosporine in chronic active Crohn's disease. METHODS: One hundred eighty-two patients from 33 European centers were included. The patient cohort was stratified at entry into a stratum with low Crohn's Disease Activity Index (CDAI) ( < 200) and high CDAI ( > 200). The low-activity group continued to receive the pretrial steroid dose for 2 months, and the high-activity group received 1 mg.kg-1.day-1 prednisone initially. During months 3 and 4, the dose of steroids was reduced stepwise to 5 mg/day in all patients. Placebo and cyclosporine (5 mg.kg-1.day-1) were administered throughout the 12-month study period. The main parameter of efficacy was the CDAI, and the main end point was the number of patients in remission at month 12. RESULTS: During cyclosporine therapy, 35% (95% confidence interval [95% Cl], 25%-46%) of the patients achieved a full remission (CDAI, < 150) after 4 months compared with 27% (95% Cl, 18%-38%) in the placebo group (P > 0.05). At month 12, only 20% (95% Cl, 12%-31%) vs. 20% (95% Cl, 12%-31%) of the patients had maintained a continuous remission. No major differences between treatment groups were found within each of the two strata. CONCLUSIONS: The long-term treatment of chronic active Crohn's disease with cyclosporine plus low-dose steroids does not offer an advantage compared with low-dose steroids alone.

Am J Gastroenterol 1998 Mar;93(3):442-8

Clinical outcome following treatment of refractory inflammatory and fistulizing Crohn's disease with intravenous cyclosporine.

Egan LJ, Sandborn WJ, Tremaine WJ.

Inflammatory Bowel Disease Clinic, Division of Gastroenterology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.

OBJECTIVE: To determine outcome following treatment of refractory Crohn's disease with intravenous (i.v.) cyclosporine (CYA). METHODS: The medical records of 18 patients with refractory Crohn's disease treated with i.v. CYA were reviewed. Nine patients had refractory inflammatory Crohn's disease and nine patients had complex fistulizing Crohn's disease. All patients were initially treated with i.v. CYA (4 mg/kg/day). Patients who responded were converted to standard oral CYA. Patient outcomes were classified as complete response, partial response, or nonresponse. RESULTS: Four of nine patients with severe inflammatory Crohn's disease and seven of nine patients with fistulizing Crohn's disease had a partial response to i.v. CYA. Four of four responding patients in the inflammatory group and four of six responding patients in the fistulizing group (plus one initial nonresponder) maintained or improved their response during oral CYA therapy. After discontinuing oral CYA, all four patients in the inflammatory group and five of seven patients in the fistulizing group relapsed despite 1-17 wk of concomitant treatment with azathioprine or 6-mercaptopurine (AZA/6MP). Two patients who received overlapping CYA and AZA/6MP for 17 and 23 wk maintained long-term responses. CYA toxicity was minimal: reversible nephrotoxicity (n = 2), headache (n = 2), oral candidiasis (n = 1), paresthesia (n = 2). CONCLUSIONS: I.v. CYA appears to benefit both refractory inflammatory and fistulizing Crohn's disease. Most patients who respond to i.v. CYA will maintain their response during oral CYA therapy. However, the majority of these patients relapse when oral CYA is discontinued, probably because of inadequate duration of overlap with the slow acting maintenance drugs, AZA/6MP.

Aust N Z J Med 1998 Apr;28(2):179-83

Oral cyclosporin in refractory inflammatory bowel disease.

Taylor AC, Connell WR, Elliott R, d'Apice AJ.

Department of Gastroenterology, St Vincent's Hospital, Melbourne, Vic.

BACKGROUND: The role of cyclosporin in patients with severe, refractory inflammatory bowel disease is unclear. METHODS: A seven year retrospective review of patients treated with oral cyclosporin for inflammatory bowel disease refractory to conventional medical therapy was undertaken. RESULTS: Twenty-eight patients (13 ulcerative colitis and 15 Crohn's disease) received oral cyclosporin for a mean of nine months (range 0.25-27 months). Within four weeks of starting cyclosporin, a complete clinical response occurred in 15 patients (nine with ulcerative colitis and six with Crohn's colitis), in whom conventional maintenance treatment was instituted concurrently. The clinical response was sustained during cyclosporin treatment in ten, but maintained after cyclosporin withdrawal in only five patients (18% of entire study group). Four of the five patients who relapsed after cyclosporin withdrawal had failed previously to respond to azathioprine. None of the five patients with continuing remission after cyclosporin withdrawal had received azathioprine in the past. There were three clinically significant infections and 14 cases of impaired renal function during treatment. CONCLUSIONS: Oral cyclosporin induces remission in some patients with severe ulcerative colitis or Crohn's colitis, but its benefits in cases refractory to azathioprine are over-shadowed by a high frequency of relapse after drug withdrawal.

J Clin Gastroenterol 1999 Sep;29(2):151-4

Cyclosporine therapy in inflammatory bowel disease: short-term and long-term results.

Gurudu SR, Griffel LH, Gialanella RJ, Das KM.

Department of Medicine, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Robert Wood Johnson University Hospital, New Brunswick 08901, USA.

Intravenous cyclosporine therapy followed by oral cyclosporine therapy reduce the need for urgent surgery in steroid-refractory inflammatory bowel disease (IBD). Our objective is to report short- and long-term results of cyclosporine therapy in IBD patients. Thirteen patients with steroid-refractory IBD, seven patients with ulcerative colitis (UC), and six patients with Crohn's disease (CD) were treated with intravenous cyclosporine (4 mg/kg/day) for a mean period of 11.4+/-2.8 days (range, 4-15 days). Subsequently the patients were started on oral cyclosporine (8 mg/kg/day) and followed for a mean of 10.3+/-10 months (range, 1-30 months). Twelve patients responded to intravenous cyclosporine therapy. One patient with UC developed sepsis on the fourth day of intravenous cyclosporine therapy and needed urgent colectomy. Nine of 12 initial responders (6 patients with UC and 3 patients with CD) relapsed during follow-up despite oral cyclosporine and underwent elective surgery. One patient with CD relapsed 3 months after discontinuation of oral cyclosporine. Only two patients with CD are in long-term remission. There were no long-term side effects in any of the 13 treated patients. In conclusion, intravenous cyclosporine was effective in inducing remission or significant improvement in 12 of 13 patients with steroid-refractory IBD. However, with subsequent oral cyclosporine the remission could be maintained only for a short while. Each of the six patients with UC needed colectomy and three of the five patients with CD had intestinal resection within 12 months despite oral cyclosporine therapy.

Sonstige Arbeiten (allerdings schon etwas älter):

Am J Gastroenterol 1993 Jan;88(1):44-8

Immunosuppressive therapy in pediatric inflammatory bowel disease: results of a survey of the North American Society for Pediatric Gastroenterology and Nutrition. Subcommittee on Immunosuppressive Use of the Pediatric IBD Collaborative Research Forum.

Markowitz J, Grancher K, Mandel F, Daum F.

Department of Pediatrics, North Shore University Hospital-Cornell University Medical College, Manhasset, New York.

We report the results of a survey of the membership of the North American Society for Pediatric Gastroenterology and Nutrition designed to determine pediatric gastroenterologists' attitudes toward the use of immunosuppressive therapy for inflammatory bowel disease (IBD), and to assess how these medications are actually being used in the treatment of children with IBD. One hundred five physicians (27% of surveys) responded. Eighty-eight (84%) had prescribed 6-mercaptopurine and/or azathioprine for IBD, and 66 believed that they were effective. Only 12 had used cyclosporine and four methotrexate. All physicians who had used immunosuppressives in IBD had prescribed them for patients with Crohn's disease, but only 50% had prescribed them for ulcerative colitis. The predominant indications for use included intractable symptoms despite traditional medical therapy (92%) and for corticosteroid-sparing effects (86%). Potential toxicities of greatest concern included marrow and immune suppression and malignancy. The vast majority of responders were not certain what to recommend with respect to the use of immunosuppressive agents prior to and during pregnancy. A clinical database was compiled from 165 retrospective case reports submitted by 45 physicians (33 medical facilities). At the start of immunosuppressive therapy, patients were 15.3 +/- 4.0 yr of age, and 52% were Tanner IV-V. Eighty-one percent had Crohn's disease, 8% ulcerative colitis, and 11% indeterminant colitis. One hundred twenty-two were treated with 6-mercaptopurine, and 43 with azathioprine. Five also received cyclosporine concomitantly. Overall, 68% of patients treated with an immunosuppressive improved. Complications requiring discontinuation of immunosuppressive therapy occurred in 6% of patients. It appears that immunosuppressives are commonly used to treat children with IBD despite a paucity of data regarding their safety and efficacy in this age group. Controlled, prospective trials are warranted to better define the role of immunosuppressive therapy in pediatric IBD.

Literatur zur Behandlung der juvenilen chronischen Arthritis mit Ciclosporin:

Rheumatology (Oxford) 2001 Aug;40(8):907-13

Efficacy and safety profile of cyclosporin A in the treatment of juvenile chronic (idiopathic) arthritis. Results of a 10-year prospective study.

Gerloni V, Cimaz R, Gattinara M, Arnoldi C, Pontikaki I, Fantini F.

Rheumatology Department, University of Milan, Centre for Rheumatic Children, Gaetano Pini Institute, Milan, Italy. OBJECTIVE: This open prospective trial was performed in order to assess the efficacy and safety of cyclosporin A in the treatment of patients with juvenile chronic arthritis (JCA). METHODS: Thirty-four of the patients enrolled were affected by systemic-onset disease and seven by chronic anterior uveitis associated with JCA. The cyclosporin dose was usually 3-5 mg/kg per day. The average duration of therapy was 1.4 yr, with a maximum of 7.2 yr. RESULTS: The efficacy of treatment was mainly evident in terms of control of fever and reduction of steroid therapy. The benefits with respect to arthritis, laboratory parameters and uveitis seemed to be less clear-cut. Side-effects were frequent but usually mild or reversible. Sixty-six per cent of the study population withdrew from therapy because of inefficacy or side-effects. Eight systemic patients withdrew from therapy owing to complete remission. CONCLUSION: Cyclosporin can be used in the treatment of JCA, its main benefits being the control of fever and a steroid-sparing effect.

Experte: Priv. Doz. Dr. med. H.E. Langer