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To the Editor:

We report the unusual course of celiac disease associated with multiple sclerosis (MS). A patient who received natalizumab because of an interferon β1-resistant MS completely recovered from chronic digestive symptoms that proved to be due to celiac disease.

A 28-year-old woman was diagnosed with relapsing/remitting MS 5 years earlier, gradually exacerbated chronic diarrhea, post-meal abdominal cramps, and insidious weight loss during the last year. At that time she was treated for 4 years with interferon β1b 250 μg subcutaneously every other day and experienced her fifth MS relapse with a Lhermitte sign and hypoesthesia of the four limbs below a C4 level. A new gadolinium-enhancing cervical cord lesion was demonstrated and she received intravenous steroid pulses with a partial recovery. Two months later a brain magnetic resonance imaging (MRI) scan showed an increase of the total T2 lesion load (Fig. 1A–C) with one inflammatory lesion in the right frontal juxtaventricular region (Fig. 1A,B).

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Figure 1. (A–C) Typical RRMS demyelinating lesions on brain MRI, with a high T2/flair lesion load (A), one juxtaventricular active lesion (arrow in A,B) with gadolinium enhancement on a T1-weighted image (B), and callous and pericallous T2 lesions (C). Enteroclysis (D) showed a significant loss of duodenal folds (arrowhead) and a jejunization of the ileum (data not shown). Histological confirmation of the villous atrophy of the duodenum (hematoxylin and eosin, original magnification ×400) (E), with an intraepithelial infiltration by CD3-immunoreactive T lymphocytes (original magnification ×400) (F). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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She had lost 8 kg in the last 4 months without changing her diet. Gastroenterological investigations were then begun. A double contrast barium enema was performed and provided evidence of a near complete loss of duodenal folds (Fig. 1D). Besides this indirect sign of duodenal atrophy, the number and thickness of the folds in the ileum were increased (data not shown). Blood tests revealed an iron deficiency without anemia, high titers of anti-gliadin (IgG and IgA), and positive anti-endomysium antibodies. The duodenal biopsy finally demonstrated a moderate to severe villous atrophy (Fig. 1E), associated with a massive intraepithelial infiltration by CD3-expressing T lymphocytes (Fig. 1F). We diagnosed adult celiac disease.

Based on the clinical and radiological activity of her MS condition, it was decided to stop interferon β1b immunomodulatory treatment and switch to natalizumab as monotherapy (300 mg intravenously every 4 weeks, TYSABRI) in order to halt relapses and reduce neurological disability progression. The week immediately after the first dose of natalizumab her diarrhea and post-meal pain completely vanished. Three months later, after 3 doses of natalizumab she remained diarrhea- and pain-free and had regained 7 kg with no specific diet. However, mild abdominal cramps resumed after 5 months of natalizumab. A control biopsy then showed recurrent histological signs of celiac disease and a gluten-free diet had to be undertaken.

Natalizumab is a humanized monoclonal immunoglobulin G4 directed against α4 integrins. In the present case, the induction of α4 integrin blockade by natalizumab matched a rapid-onset and drastic, but transient, clinical remission of concurrent celiac disease. This remission occurred with no specific change in the diet while the patient continued to be exposed to daily intake of gluten-containing products.

The α4 integrin protein dimerizes either with the β1 or β7 subunits. The therapeutic effect of natalizumab is mediated by the ability to block the binding of α4β1 and α4β7 complexes expressed by lymphocytes to their respective endothelial receptors, vascular-cell adhesion molecule 1 (VCAM-1), and mucosal addressin-cell adhesion molecule 1 (MAdCAM-1). These molecular interactions are required for lymphocytes to enter the central nervous system (mediated by α4β1 and VCAM-1) and the intestine (mediated by α4β7 and MAdCAM-1). Previous studies have shown that natalizumab is effective as induction therapy for patients with moderate to severely active Crohn's disease,1–3 but nothing is known about the potential effect of this antibody in celiac disease. It is established that gliadin epitope specific T cells induced in peripheral blood after a gluten challenge in celiac disease patients express the intestinal homing integrin α4β7.4, 5 Hence, the present observation emphasizes that the α4 chain of α4β7 complex may play a crucial role in the pathogenesis of T-cell intraepithelial infiltration of the duodenum in celiac disease. Such a case paves the way for new therapeutic avenues6 in severe or gluten-free diet refractory celiac disease and sheds new light on the understanding of this enteropathy.

REFERENCES

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    Gordon FH, Lai CW, Hamilton MI, et al. A randomized placebo-controlled trial of a humanized monoclonal antibody to alpha4 integrin in active Crohn's disease. Gastroenterology. 2001; 121: 268274.
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    Ghosh S, Goldin E, Gordon FH, et al. Natalizumab for active Crohn's disease. N Engl J Med. 2003; 348: 2432.
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    Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab induction and maintenance therapy for Crohn's disease. N Engl J Med. 2005; 353: 19121925.
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    Ben-Horin S, Green PH, Bank I, et al. Characterizing the circulating, gliadin-specific CD4+ memory T cells in patients with celiac disease: linkage between memory function, gut homing and Th1 polarization. J Leukoc Biol. 2006; 79: 676685.
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    Anderson RP, van Heel DA, Tye-Din JA, et al. T cells in peripheral blood after gluten challenge in coeliac disease. Gut. 2005; 54: 12171223.
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    Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet. 2007; 369: 16411657.

Rémy Phan-Ba MD* † **, Nadine Lambinet MD* ‡ **, Edouard Louis MD, PhD* ‡ **, Philippe Delvenne MD, PhD* § **, Luaba Tshibanda MD* ¶ **, Jacques Boverie MD* ¶ **, Gustave Moonen MD, PhD* † **, Shibeshih Belachew MD, PhD* † **, * MYelin Disorders REsearch teAM (MYDREAM), C.H.U. de Liège University of Liège Liège, Belgium, † Department of Neurology C.H.U. de Liège University of Liège Liège, Belgium, ‡ Department of Gastroenterology C.H.U. de Liège University of Liège Liège, Belgium, § Department of Medical Imaging C.H.U. de Liège University of Liège Liège, Belgium, ¶ Department of Pathology C.H.U. de Liège University of Liège Liège, Belgium, ** Department of Neurology C.H.U. de Liège University of Liège Liège, Belgium.