Refractory sprue (RS) is a malabsorption syndrome defined by persisting villous atrophy with, usually, an increase of intraepithelial lymphocytes (IELs) in the small bowel despite a strict gluten-free diet (GFD) [1,2]. Persisting villous atrophy has been found in 5–8% of patients with celiac disease (CD) including patients with persisting gluten intake . Apart from these, however, there is clearly refractory CD, that is, patients with an established diagnosis of CD who do not respond to GFD, and such patients constitute the majority of patients with RS .
In addition, there is a group of RS patients without evidence for CD apart from small bowel histology who may have other underlying diseases . Such patients pose clinical problems very similar to refractory CD and are, therefore, often included in RS studies . Loss of T-cell antigens (CD8 and/or T-cell receptor-αβ) on IELs and mucosal T-cell clonality has been found in a subgroup of patients with RS [4,5]. The presence of an early enteropathy-type T-cell lymphoma (ETCL) is suggested by the progression into overt ETCL in some of these patients [4–6]. RS with signs of early ETCL has been termed RS type II in distinction to RS type I in which those signs are absent . Few studies are available for patients with RS, and standardized treatment has not been established so far [7–10]. Published data suggest that azathioprine may improve RS type I, but are inconclusive in RS type II [7,9]. Treatment modalities in RS II include chemotherapeutic options and high-dose regimens have been used as well [11,12]. Most published series of RS included highly selected patients with RS type II who often show an unfavorable outcome [5,6,13]. In a recent work by a group with special interest in CD and ETCL, long-term outcome of patients with RS and ETCL has been published . In unselected patients, however, the distribution between subtypes and clinical features, in particular those of RS type I, are not well defined.
Materials and methods
Our gastroenterological department is a tertiary center receiving referrals from primary and secondary care and treats approximately 7500 patients/year. Data from patients with RS who presented between 1993 and 2005 at our department and underwent a standardized investigation program were analyzed retrospectively. To be classified as RS, the following conditions were required: (i) partial villous atrophy or worse (Marsh IIIa–c) documented by duodenal histology , (ii) introduction of a GFD resulting in (a) neither clinical nor histological response after more than 6 months or (b) persistent villous atrophy and clinical deterioration requiring earlier therapeutic intervention. This definition excludes patients with slowly recovering histology but clinical improvement . As most patients were referrals, a meaningful statement of percentages of RS is not possible. For study inclusion, inadvertent persisting gluten intake had to be excluded by documented repeated dietary counseling including a visit to an experienced dietician. Patients with manifest lymphoma were excluded.
Patients were classified as RS type II in the case of T-cell antigen loss (CD8 and/ or T-cell receptor-β to less than 50% in IELs on immunohistochemistry), T-cell clonality, or both abnormalities in the duodenum as determined by T-cell receptor gene PCR . All patients underwent the following investigation program: in the search for underlying diseases, enterocyte antibodies and antinuclear antibody tests were carried out for diagnosis of autoimmune enteropathy, fasting gastrin levels for gastrinoma, quantitative immunoglobulins for exclusion of common variable immunodeficiency syndrome, H2-glucose breath test for detection of bacterial overgrowth, stool test and biopsy for giardiasis, and ileocolonoscopy and small bowel work up for exclusion of Crohn's disease.
Patients were investigated for osteoporosis by osteodensitometry, lactase deficiency by H2-lactose breath test, HIV-infection, and gastrointestinal infections by stool testing. Accompanying diseases were documented.
The following parameters were recorded from the patients' charts for analysis: age, sex, medication, history of CD, antibody status to endomysium, or tissue transglutaminase, HLA-DQ2 expression, response to GFD, duodenal histology according to the modified Marsh classification , duodenal immunohistology including number of IELs and detection of T-cell antigen loss and T-cell clonality in the duodenum as determined by T-cell receptor gene PCR . The body mass index was calculated using the formula, body weight (kg)/ height2 (square meters). Patients were classified as having CD according to the European Society of Paediatric Gastroenterology and Nutrition criteria modified by the United European Gastroenterology Week meeting in Amsterdam 2001 or, because even a transient response to GFD can be absent in RS patients [13,17], by detection of IgA-antibodies to endomysium or transglutaminase before the start of a GFD in concordance with HLA-DQ2 expression [18,19]. In case of a thrombembolic event deficiency for protein S, protein C, and antithrombin III, as well as factor V and prothrombin mutation were investigated.
Primary treatment strictly consisted of GFD for at least 6 months in all patients before study inclusion. If patients did not respond clinically or histologically or had evidence of CD (CD-antibodies, HLA-DQ2), GFD was stopped. If patients were clinically unstable, treatment with oral prednisolone was initiated in RS type I, followed by budesonide and consecutive azathioprine. In patients with RS type II without signs of an ETCL, treatment consisted of an oral prednisolone followed by budesonide in the case of persisting symptoms or clinical deterioration. Chemotherapeutic treatment (2x CHOP, 1x cladribine) was initiated in patients with RS type II not responding to prednisolone or budesonide or those who developed an ETCL. In patients with RS type I, therapeutic strategies were adjusted if an underlying disease was identified.
Continuous data are given as median and range. Groups were compared by the Mann–Whitney U test. Frequency data were compared by the χ2 test using a standard statistics program (Stat View 4.51+; Brain Power Inc., Calabasas, California, USA) on a Macintosh PC (Apple Computer Inc., Munich, Germany). Survival rates were calculated on overall survival with the method of Kaplan and Meier . Survival between groups was compared by the Mantel–Cox log rank test. Survival data are given as cumulative 5-year survival rates with 95% confidence intervals. P values below 0.05 were considered significant.
Thirty-two patients with RS were identified. The patients' median age at diagnosis of RS was 50.5 (17–75) years. RS patients were predominantly females, age was similar in both groups (Table 1). Sex distribution, age at diagnosis of RS, duration of symptoms, and initial body mass index were not different between RS type I and II (Table 1).
A diagnosis of CD was established in 12 out of 23 patients with RS type I and in seven out of nine patients with RS type II (NS). Accordingly, HLA-DQ2 and CD-associated antibodies were similar in patients with RS I or RS II (Table 1). The degree of villous atrophy was not different between RS types. The number of IELs was significantly higher in patients with RS type II in comparison with RS type I (P<0.01).
Two patients with an initial diagnosis of RS type I developed persisting clonal T-cell receptor rearrangements and loss of T-cell receptor-β during follow-up and were accordingly reclassified as RS type II. They, however, did not develop overt ETCL in the following observation time of 16 and 84 months, respectively.
Two patients with RS type I showed signs of collagenous sprue, diagnosed by duodenal biopsies. Final underlying diagnoses in the RS type I group were autoimmune enteropathy in two patients, common variable immunodeficiency disease, and immune reconstitution syndrome of the small bowel after infection of mycobacterium genavense in one patient each. All patients had villous atrophy Marsh III; however, one patient with autoimmune enteropathy had normal IEL counts. Antienterocyte and antinuclear antibodies were seen each in one patient, and both patients with autoimmune enteropathy showed loss of goblet cells and responded to an immunosuppressive therapy but were refractory to a GFD.
Nine (28%) (seven of 22 females, two of 10 males, NS) RS patients developed thrombembolic complications. The median age at occurrence of thrombembolic complications was 41 (17–55) years. Thrombembolic complications were similarly frequent in RS type I and type II (Table 1, P=0.47). Four patients had deep vein thromboses, one thrombosis of the superior mesenteric vein, one of the superior vena cava, two pulmonary vein thromboses and one cerebral arterial embolus after deep vein thrombosis because of patent foramen ovale. Two patients had central vein catheters at the time of the thrombembolic events as a possible predisposing reason. Only one patient had heterozygote factor V deficiency and functionally decreased protein S.
Seventeen (53%) (13 out of 22 females, four out of 10 males, NS) RS patients suffered from autoimmune diseases other than CD. These included autoimmune hepatitis (n=4), diabetes mellitus type I (n=2), ulcerative colitis (n=2), autoimmune hemolytic anemia (n=1), collagenous colitis (n=1), Hashimoto thyreoiditis (n=1), HLA-B27-positive polyarthritis (n=1), organizing pneumonia (n=1), primary biliary cirrhosis (n=1), sarcoidosis stage III (n=1), scleroderma (n=1), systemic lupus erythematodes (n=1), thyreoiditis De Quervain (n=1), and type A gastritis (n=1). Two patients presented with two autoimmune diseases. Autoimmune diseases occurred in 13 patients with RS type I and four patients with RS type II (Table 1, NS), and were not associated with CD (with CD: 11; without CD: 6).
Three patients suffered from nephrolithiasis, which turned out to be caused by oxalat stones. Osteopenia was detected in 12 patients (six each in RS type I and RS type II). Malignant diseases apart from ETCL occurred in two patients (localized plasmocytoma in patient 18 and small bowel adenocarcinoma in patient 25).
Mortality and development of overt intestinal non-Hodgkin lymphoma
Follow-up was longer in RS type I than in type II (Table 1). Overall, eight patients died during the observation period (four with RS type I). Five-year cumulative survival was 90% (76–100) in patients with RS type I and higher than in patients with RS type II [53% (12–94); P<0.05] (Fig. 1). Four patients with RS type I died of overwhelming pneumonia. Four patients with RS type II developed overt ETCL 42, 60, 5, and 4 months after diagnosis of RS. Three of them died from ETCL, whereas one died from ischemic stroke during the observation period.
RS is a rare small bowel disease with high morbidity that may complicate long-standing CD but may also develop independent of CD. Several studies have shown that patients with RS type II carry a high risk of developing ETCL [5,7]. Underlying and accompanying diseases as well as outcome in an unselected population of patients presenting with RS, however, need further attention. A single-center study has recently shown that patients with RS type II seem to have a dismal prognosis .
In contrast to most publications, the majority (72%) of our patients had RS type I, whereas only a minor number had RS type II [5,6,9,14]. CD was present in only 52 and 78% of patients with RS type I and type II in our study, respectively. This confirms that at least RS type I can occur independent of CD and explains the missing response to GFD in this proportion of RS patients. As expected, the proportion of RS patients with CD is lower compared with earlier studies that examined exclusively patients with refractory CD [7,21] or which focused on premalignant histopathological abnormalities [5,13]. Two patients with RS type II, however, showed a peculiar type of RS: one had RS with increased IELs of natural killer cell phenotype and persistent monoclonality, the other had a CD4-positive phenotype of IELs. These unusual cases were also HLA-DQ2 negative. Such patients and other patients suffering from the clinicopathological syndrome of RS without underlying CD are not covered by the nomenclature proposed by the working group report of 2001 .
ETCL occurred only in association with underlying CD in RS type II, but does not necessarily develop in all patients with RS type II during the observation time. Our data also demonstrate the transition of RS type I into type II without rapid progression into ETCL in two clinically stable patients. Although patients with RS type I did not develop ETCL or other malignant diseases reported to be increased in CD, 17% of patients with RS type I died during the observation period. Survival is higher in patients with RS type I in comparison with RS type II, but lower than in the general population . In RS type II, four patients developed ETCL and three died because of lymphoma. Diseases leading to death in our four patients with RS type I were pneumonia and consecutive septic heart failure. No predisposing immunodeficiencies were found in these four patients. Decreased immune status may be because of ongoing intestinal inflammation, malabsorption, and consecutive immunodeficiency as well as splenic hypofunction, which have been shown by reduced circulating IgM+ B lymphocytes in peripheral blood in RS . Currently, the only intervention for improvement of immune status in patients with RS is restitution of normal bowel function and reversion of malabsorption. Measures to be taken include additional enteral or parenteral nutrition, immunosuppression in case of autoimmunity, and probably locally acting steroids like budesonide .
The autoimmune nature of RS is further supported by other autoimmune diseases including severe life-threatening diseases like organizing pneumonia, autoimmune hemolytic anemia, or fulminant ulcerative colitis. An increased rate of autoimmune diseases in diet-responsive CD is well known [24–26]. This rate of autoimmune diseases is, however, significantly increased reaching about 53% in RS patients.
Surprisingly, 28% of patients with RS had thrombembolic diseases, which occurred only in two cases in association with a central venous catheter. This high incidence of thrombembolic diseases has not been described in CD or RS before [7,9,25]. Maurino et al.  describe that one of their seven patients with RS died of mesenteric artery infarction. Only one RS patient with thrombembolic disease had an underlying coagulation disorder indicating that other pathomechanisms such as fluid depletion or inflammatory states because of small bowel inflammation may be causative. In chronic inflammatory bowel disease, the frequency of thrombembolic complications is threefold higher in comparison with controls and the median age of 53 years in affected IBD patients is lower in comparison with control patients [27,28]. The median age of 41 years in our RS patients with thrombembolic disease was even lower in comparison with the median age in the study by Bernstein et al. . In studies of inflammatory bowel disease, risk factors for thrombembolic complications were not only disease activity and thrombocytosis but also immobilization and preceding surgery [29,30]. Thrombembolic events were detected during a period of immobilization in two cases in our patient population. In addition, chronic inflammation in RS may lead to increased clotting factor activity and decreased protein C and S activity, or vitamin B12 deficiency may lead to hyperhomocysteinemia. Hyperhomocysteinemia has, however, not been investigated in our patients. Independent of the underlying mechanism, as a clinical consequence, immobilized patients with RS should receive stringently prophylactic anticoagulation.
Other concomitant diseases with increased frequency were osteopenia and oxalate stones, which should direct involved clinicians to specifically investigate these problems and initiate treatment such as increase fluid intake as well as supplement calcium and vitamin D orally .
In conclusion, a high proportion of patients with RS type I and even type II may show no disease progression over a long period of time and suffer from a wide range of concomitant autoimmune and thrombembolic diseases. Thus, specific treatment should be directed to the possible underlying cause, as infectious complications may be life limiting and may be best prevented by reversion of malabsorption.
Conflict of interest: none declared.
1. Ryan BM, Kelleher D. Refractory celiac disease
. Gastroenterology 2000; 119:243–251.
2. Daum S, Cellier C, Mulder CJ. Refractory coeliac disease. Best Pract Res Clin Gastroenterol 2005; 19:413–424.
3. Howdle P, Losowsky M. Coeliac disease in adults. In: Marsh M, editor. Coeliac disease. Oxford: Blackwell Scientific Publications; 1992. pp. 49–80.
4. Daum S, Weiss D, Hummel M, Ullrich R, Heise W, Stein H, et al. Frequency of clonal intraepithelial T lymphocyte proliferations in enteropathy
-type intestinal T cell lymphoma, coeliac disease, and refractory sprue
. Gut 2001; 49:804–412.
5. Cellier C, Delabesse E, Helmer C, Patey N, Matuchansky C, Jabri B, et al. Refractory sprue
, coeliac disease, and enteropathy
-associated T-cell lymphoma. Lancet 2000; 356:203–208.
6. Bagdi E, Diss T, Munson P, Isaacson P. Mucosal intraepithelial lymphocytes in enteropathy
-associated T-cell lymphoma, ulcerative jejunitis, and refractory celiac disease
constitute a neoplastic population. Blood 1999; 94:260–264.
7. Goerres MS, Meijer JW, Wahab PJ, Kerckhaert JA, Groenen PJ, Van Krieken JH, et al. Azathioprine and prednisone combination therapy in refractory coeliac disease. Aliment Pharmacol Ther 2003; 18:487–494.
8. Wahab P, Crusius J, Meijer J, Uil J, Mulder C. Cyclosporin in the treatment of adults with refractory coeliac disease-an open pilot study. Aliment Pharmacol Ther 2000; 14:767–774.
9. Maurino E, Niveloni S, Chernavsky A, Pedreira S, Mazure R, Reyes HV, et al. Azathioprine in refractory sprue
: results from a prospective open-label study. Am J Gastroenterol 2002; 97:2595–2602.
10. Daum S, Ipczynski R, Heine B, Schulzke JD, Zeitz M, Ullrich R. Therapy with budesonide in patients with refractory sprue
. Digestion 2006; 73:60–68.
11. Al-toma A, Visser OJ, Van Roessel HM, Von Blomberg BM, Verbeek WH, Scholten PE, et al. Autologous hematopoietic stem cell transplantation in refractory celiac disease
with aberrant T cells. Blood 2007; 109:2243–2249.
12. Al-Toma A, Goerres MS, Meijer JW, von Blomberg BM, Wahab PJ, Kerckhaert JA, et al. Cladribine therapy in refractory celiac disease
with aberrant T cells. Clin Gastroenterol Hepatol 2006; 4:1322–1327.
13. Cellier C, Patey N, Mauvieux L, Jabri B, Delabesse E, Cervoni J, et al. Abnormal intestinal intraepithelial lymphocytes in refractory sprue
. Gastroenterology 1998; 114:471–481.
14. Al-Toma A, Verbeek WH, Hadithi M, von Blomberg BM, Mulder CJ. Survival in refractory coeliac disease and enteropathy
associated T cell lymphoma: retrospective evaluation of single centre experience. Gut 2007; 56:1373–1378.
15. Oberhuber G, Granditsch G, Vogelsang H. The histopathology of coeliac disease: time for a standardized report scheme for pathologists. Eur J Gastroenterol Hepatol 1999; 11:1185–1194.
16. Lee SK, Lo W, Memeo L, Rotterdam H, Green PH. Duodenal histology in patients with celiac disease
after treatment with a gluten-free diet. Gastrointest Endosc 2003; 57:187–191.
17. Al-Toma A, Verbeek WH, Mulder CJ. Update on the management of refractory coeliac disease. J Gastrointestin Liver Dis 2007; 16:57–63.
18. Walker-Smith J, Guandalini S, Schmitz J, Shmerling D, Visakorpi J. Revised criteria for diagnosis of coeliac disease. Arch Dis Child 1990; 65:909–911.
19. When is a coeliac a coeliac? Report of a working group of the United European Gastroenterology Week in Amsterdam, 2001. Eur J Gastroenterol Hepatol
20. Kaplan E, Meier P. Non parametric estimation from incomplete observations. J Am Stat Assoc 1958; 53:457–481.
21. Olaussen R, Lovik A, Andersen P, Vatn M, Bratlie J, Brandtzaeg P, et al. Elemental diet reduces the frequency of interferon-gamma-secreting mucosal T-cells in refractory coeliac disease. In: ISCD; 2004; Belfast; 2004.
22. Dinkel RH. The long-run development of mortality [in Germany]. Z Gerontol Geriatr 2002; 35:400–405.
23. Di Sabatino A, Rosado MM, Cazzola P, Riboni R, Biagi F, Carsetti R, et al. Splenic hypofunction and the spectrum of autoimmune and malignant complications in celiac disease
. Clin Gastroenterol Hepatol 2006; 4:179–186.
24. Sategna Guidetti C, Solerio E, Scaglione N, Aimo G, Mengozzi G. Duration of gluten exposure in adult coeliac disease does not correlate with the risk for autoimmune disorders. Gut 2001; 49:502–505.
25. Peters U, Askling J, Gridley G, Ekbom A, Linet M. Causes of death in patients with celiac disease
in a population-based Swedish cohort. Arch Intern Med 2003; 163:1566–1572.
26. Viljamaa M, Kaukinen K, Huhtala H, Kyronpalo S, Rasmussen M, Collin P. Coeliac disease, autoimmune diseases and gluten exposure. Scand J Gastroenterol 2005; 40:437–443.
27. Bernstein CN, Blanchard JF, Houston DS, Wajda A. The incidence of deep venous thrombosis and pulmonary embolism among patients with inflammatory bowel disease: a population-based cohort study. Thromb Haemost 2001; 85:430–434.
28. Irving PM, Pasi KJ, Rampton DS. Thrombosis and inflammatory bowel disease. Clin Gastroenterol Hepatol 2005; 3:617–628.
29. Talbot RW, Heppell J, Dozois RR, Beart RW Jr. Vascular complications of inflammatory bowel disease. Mayo Clin Proc 1986; 61:140–145.
30. Solem CA, Loftus EV, Tremaine WJ, Sandborn WJ. Venous thromboembolism in inflammatory bowel disease. Am J Gastroenterol 2004; 99:97–101.
31. Corazza GR, Di Stefano M, Maurino E, Bai JC. Bones in coeliac disease: diagnosis and treatment. Best Pract Res Clin Gastroenterol 2005; 19:453–465.