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Found 38 results

  1. Celiac.com 09/05/2018 - About one out of every twenty celiac patients fails to respond to a gluten-free diet, and goes on to develop refractory celiac disease (RCD). RCD is a serious condition marked by appearance of intraepithelial T lymphocytes. Depending on the phenotype of the lymphocytes, people develop either RCD I or RCD II. Patients with RCD type II (RCDII) show clonal expansions of intraepithelial T lymphocytes, and face an especially poor prognosis. Just over half of these patients will die within five years of onset due to aggressive enteropathy-associated T-cell lymphoma. At this time, researchers don’t know whether genetic variations might play a role in the severe progression from celiac disease to RCDII. A team of researchers recently set out to try to get some answers. The team began by conducting the first genome-wide association study to identify the causal genes for RCDII, along with the molecular pathways at play in cases of RCDII. For their genome-wide association study, the team used 38 Dutch patients with RCDII, and replicated the 15 independent top-associated single nucleotide polymorphism (SNP) variants (P<5×10) in 56 independent French and Dutch patients with RCDII. The team found that, after replication, SNP rs2041570 on chromosome 7 was significantly associated with progression to RCDII (P=2.37×10, odds ratio=2.36), but not to celiac disease susceptibility. They also found that SNP rs2041570 risk allele A was associated with lower levels of FAM188B expression in blood and small intestinal biopsies. Stratifying RCDII biopsies by rs2041570 genotype revealed differential expression of innate immune and antibacterial genes that are expressed in Paneth cells. The team’s efforts resulted in the identification of a new SNP associated with the severe progression of celiac disease to RCDII. Their data suggest that genetic susceptibility to celiac disease might be unrelated to celiac progression to RCDII, and suggests that Paneth cells might play a role in RCDII progression. Source: Eur J Gastroenterol Hepatol. 2018 Aug;30(8):828-837. The research team included B Hrdlickova, CJ Mulder, G Malamut, B Meresse, M Platteel, Y Kamatani, I Ricaño-Ponce, RLJ van Wanrooij, MM Zorro, M Jan Bonder, J Gutierrez-Achury, C Cellier, A Zhernakova, P Nijeboer, P Galan, S Withoff, M Lathrop, G Bouma, RJ Xavier, B Jabri, NC Bensussan, C Wijmenga, and V Kumar. They are variously affiliated with the Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Department of Gastroenterology, VUMC, Amsterdam, The Netherlands, INSERM U1163, Imagine Institute and Paris Descartes University, the Department of Gastroeneterology, Georges Pompidou European Hospital, the Paris 13 University Sorbonne Paris Cité, UREN, Inserm (U557), Inra (U1125), Cnam, Bobigny, France, the scientific director of McGill University and Génome Québec Innovation Centre, Montréal, Québec, Canada, the Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, the Department of Medicine, University of Chicago, Chicago, Illinois, USA., and the K.G. Jebsen Coeliac Disease Research Centre, Department of Immunology, University of Oslo, Norway.
  2. Greetings fellow Celiacs! I was first diagnosed while living in Prague, and following an AIP diet and the advice of a Functional Medicine Naturopath there, I went into remission (ttg markers below 6) and lost 30+lbs, which allowed me to feel like my best self (and the weight was a sign of inflammation in my body in my case). There was less strain on my joints, more mental clarity, better memory function, more energy, etc. And I was happy. I had surgery and an IUD added to my life a year into that remission. It brought on a horrendous flare and I ended up in hospital with pneumonia. I lost more weight while sick, and ate a lot of (safe) carbs while I was trying to recover a healthy weight. I also moved back to Victoria, BC in the midst of that. I've added thyroid meds and LDN to my treatment since then, and swapped around a few supplements, and added in foods that weren't available in CZ. The first 1.5 years here I also lived adjacent to the kitchen ventilation of a busy gluten serving restaurant (I have reacted to airborne gluten in other situations too so that's not what's up for debate). I have been over my diet, supplements, and medications with a fine tooth comb and cannot find a source where gluten is getting in. And yet my ttg varies between 13 and 23 (it was 20 at preliminary diagnosis, 59 after eating a small portion of gluten daily for 4 days leading up to testing, which also made me violently ill for 6 weeks+++). I have also gained 35lbs+ and have experienced a relapse of almost every symptom I had prior to diagnosis/starting Autoimmune Paleo. I'm baffled. My care team is baffled. So I thought I would put this out there just in case somewhere in this forum there is another human dealing with similar things who has magically figured out the answers I need. Many thanks.
  3. Celiac.com 08/31/2017 - A possible mechanism behind the cause of refractory celiac disease and why fecal transplantation (fecal microbiota transfer) may provide a cure was presented in "Synthetic Stool May Advance Fecal Transplant Therapy for Celiac Disease" 02/13/2013.[1] In September 2016, the article "Serendipity in Refractory Celiac Disease: Full Recovery of Duodenal Villi and Clinical Symptoms after Fecal Microbiota Transfer" was published in the Journal of Gastrointestinal and Liver Disease[2] describing the first known case of refractory celiac disease cured by a fecal transplant. The patient in that case was being treated for a recurrent Clostridium difficile infection. This very important milestone article somehow missed the light of the news media at that time. The 68-year old woman patient was a 10-year diagnosed victim of refractory celiac disease on a gluten-free diet. On admission for treatment of severe diarrhea, the patient exhibited Marsh IIIA villous atrophy. The patient was already receiving on-going treatment for refractory celiac disease with drugs. Additional drugs and antibiotics were given to treat the diarrhea. Eventually, the patient tested positive for C. difficile. Antibiotics were ineffective to treat the recurrent C. difficile infection. A fecal microbiota transfer was then performed. The C. difficile infection and diarrhea resolved, and, 6 months after the fecal transplant, villous atrophy resolved and went to Marsh 0. All symptoms of refractory celiac disease were eliminated. The patient remains symptom free on a continuing gluten-free diet. The case clearly demonstrates the need to fully investigate the use of fecal microbiota transfers to treat celiac disease. As suggested in my earlier reference[1], a standardized synthetic stool should be developed to enable full scale clinical trials. Also a full scale research effort into completely healing and restoring the intestinal mucosa with the novel protein R-spondin1 needs to be funded and restarted. Sources: 1. Synthetic Stool May Advance Fecal Transplant Therapy for Celiac Disease. Roy S. Jamron. Celiac.com 2013 Feb 13. 2. Serendipity in Refractory Celiac Disease: Full Recovery of Duodenal Villi and Clinical Symptoms after Fecal Microbiota Transfer. van Beurden YH, van Gils T, van Gils NA, Kassam Z, Mulder CJ, Aparicio-Pages N J Gastrointestin Liver Dis. 2016 Sep;25(3):385-8.
  4. Jewels50

    Little C

    Suggestions please, I have been gluten free for 6 years and feel fairly confident about cross contamination, hidden gluten, my medications, toothpaste, lipstick, salad dressing, etc. I rarely eat out and when I do, it is at a restaurant that can be trusted to be thorough (well, as much as that is possible). And yet, I feel so tired, migraines, aching joints, brain fog, and words not coming out right when I talk. My GI ran many blood tests which came out normal except for low magnesium level and the presence of tTg in higher levels. When the assistant called, she began the conversation with a condescending lecture about cheating on the gluten free diet. I about lost it, but didn't. I let her know that I do not cheat and am diligent about what goes in and on my body. A follow up appointment has been made for 12 weeks out along with another intestinal biopsy. In the meantime, I am going through everything to find any hidden sources of gluten I may not be aware of. I am supposed to hear from a dietician but haven't yet. (I met with one early on in my diagnosis.) Salad dressings - any really good certified gluten-free ones? Are the vinegars used in them okay or no? I have changed my coffee and coffee maker out. I use Coffee Mate sweet Italian creamer. It states it is gluten free, but, has anyone else had problems? I have checked and rechecked my Rx pills as well as any OTC meds and supplements. I WAS eating Quaker Oats chocolate rice cakes (gluten free is stated on the packing but not certified) and suspect them; however, I stopped a couple of weeks ago and do not feel much better. (Migraine and brain fog yesterday along with joint pain). Has anyone else gone through this? What do you suggest I do? I would like to reeducate the nurse/assistant at my GI on her assumption that everyone must "cheat" and her lecture (I put in a call to my GI but was told by the nurse that she doesn't talk to patients outside of appointments ???) In all the blood work I have had done, my tTg levels are high. Am I non responsive to the diet? Ultra sensitive? Thanks for feedback.
  5. Celiac.com 07/03/2017 - Refractory celiac disease (RCD) is a serious complication of celiac disease. There are two types, RCD I, and RCD II. Unlike RCD type I, RCD type II often leads to enteropathy-associated T-cell lymphoma (EATL), which is associated with clonally expanding T-cells that are also found in the sequentially developing EATL. Using high-throughput sequencing (HTS), a team of researchers recently set out to establish the small-intestinal T-cell repertoire (TCR) in celiac disease and RCD to unravel the role of distinct T-cell clonotypes in RCD pathogenesis. The research team included J Ritter, K Zimmermann, K Jöhrens, S Mende, A Seegebarth, B Siegmund, S Hennig, K Todorova, A Rosenwald, S Daum, M Hummel, and M Schumann. They are variously affiliated with the Institute of Pathology, Charité-University Medicine, Berlin, Germany, the Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité-University Medicine, Berlin, Germany, HS Diagnomics GmbH, Berlin, Germany, the Center for Tumor Medicine, Charité-University Medicine, Berlin, Germany, the Institute of Pathology, University of Würzburg, and Comprehensive Cancer Center Mainfranken (CCCMF), Würzburg, Germany, the Berlin Institute of Health, Berlin, Germany, the Berlin-Brandenburg School for Regenerative Therapies, Berlin, Germany. Their team examined DNA extracted from duodenal mucosa specimens of 9 control subjects, 10 active celiacs, 9 celiacs on a gluten-free diet, 8 RCD type I patients, 8 RCD type II patients, and 3 unclassified Marsh I cases collected from 2002 to 2013. To make their examination, they used TCRβ-complementarity-determining regions 3 (CDR3) multiplex PCR, followed by HTS of the amplicons. They generated an average of 106 sequence reads per sample, consisting of up to 900 individual TCRβ rearrangements. In RCD type II, the most frequent clonotypes (sequence reads with identical CDR3) represent about 43% of all TCRβ rearrangements. This was substantially higher than in control subjects (6.8%; p Repeat endoscopies in individual patients showed that the clonotypes remain stable for up to a few years without clinical symptoms of EATL. Individual patients with RCD type II showed unique dominant clonotypes that were un-related among patients. Celiac-associated, gliadin-dependent CDR3 motifs were only detectable at low frequencies. TCRβ-HTS analysis unravels the TCR in celiac disease, and allows for detailed analysis of individual TCRβ changes. Patients with RCD type II have unique, dominant TCRβ sequences that are critically different from known gliadin-specific TCR sequences, which indicates that these clonal T-cells expand on their own, with no influence from gluten stimulation. Source: Gut. 2017 Feb 10. pii: gutjnl-2016-311816. doi: 10.1136/gutjnl-2016-311816.
  6. Celiac.com 02/09/2017 - Dermatitis herpetiformis is a skin disease that causes blistering, and is understood to be an external symptom of celiac disease. Refractory celiac disease, which does not respond to a gluten-free diet and which carries an increased risk of lymphoma, is well-known to clinicians and researchers. A team of researchers recently set out to determine if there were any cases of refractory dermatitis herpetiformis with active rash and persistent small bowel atrophy that do not respond to a gluten-free diet. The research team included K Hervonen, TT Salmi, T Ilus, K Paasikivi, M Vornanen, K Laurila, K Lindfors, K Viiri, P Saavalainen, P Collin, K Kaukinen, and T Reunala. They are affiliated with the Department of Dermatology, Tampere University Hospital and University of Tampere, in Tampere, Finland. For their study, the team analyzed their series of 403 patients with dermatitis herpetiformis. They found seven patients (1.7%), who had been on a gluten-free diet for a mean of 16 years, but who still required dapsone to treat the symptoms of dermatitis herpetiformis. Of these, one patient died from mucinous adenocarcinoma before re-examination. At re-examination, the team found skin immunoglobulin A (IgA) deposits in 5 of 6 refractory and 3 of 16 control dermatitis herpetiformis patients with good dietary response. At reexamination, they studied small bowel mucosa from 5 refractory and 8 control dermatitis herpetiformis patients; results were normal in all 5 refractory and 7 of 8 control dermatitis herpetiformis patients. One refractory dermatitis herpetiformis patient died from adenocarcinoma, but none of the patients developed lymphoma. This study marks the first time doctors have seen small bowel mucosa healing in patients with refractory dermatitis herpetiformis, where the rash is non-responsive to a gluten-free diet. This means that even though dermatitis herpetiformis sufferers may still have a rash, they can also have a healthy gut. This is sharply different from refractory celiac disease, where small bowel mucosa do not heal on a gluten-free diet. Source: Acta Derm Venereol. 2016 Jan;96(1):82-6. doi: 10.2340/00015555-2184.
  7. Celiac.com 01/30/2017 - A team of researchers recently set out to analyze potential changes in occurrence of complicated coeliac disease over the last 25 years. The research team included W. Eigner, K. Bashir, C. Primas, L. Kazemi-Shirazi, F. Wrba, M. Trauner, and H. Vogelsang. They are variously affiliated with the Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University Hospital of Vienna, Vienna, Austria, and with the Department of Pathology at the Medical University of Vienna in Vienna, Austria. The team included and evaluated a total of 1,138 patients based on time of first presentation at the Medical University of Vienna, Austria. They assessed occurrences of refractory celiac disease and associated malignancies in 5-year intervals from January 1990 until December 2014, and then compared results over time. Twenty-nine patients, or 2.6%, were diagnosed with refractory celiac disease. Of these, 65.6% were females averaging 62.8 years of age at diagnosis. The proportion of those patients was 2.6%, 3.1%, 3.3%, 2.7% and 0.5% for the 5 year intervals from 1990 through 2014. The number of refractory cases has been generally decreasing since 2000 (P = 0.024). During that time, a total of seven patients presented with lymphoma, totaling 0.6%, 0.4%, 1.1%, 0.8% and 0% of patients each year, respectively. Similarly the number of patients with adenocarcinoma, four patients total, decreased to 0% until 2014. Nearly 50% of patients suffering from refractory disease died during the study period. Meanwhile, 71.4% all patients diagnosed with lymphoma died, with a 5-year survival rate of 28.6%. Over the past 15 years, rates of complicated celiac disease have been decreasing. This may be due to increased celiac disease awareness, along with optimized diagnosis and treatment with avoidance of long-term immunological disease activity. Known risk factors for refractory celiac disease and related cancer include untreated symptomatic disease and delayed diagnosis. Source: Aliment Pharmacol Ther, 45: 364–372. doi:10.1111/apt.13867
  8. Celiac.com 12/07/2016 - Refractory celiac disease (RCD) is a form of celiac disease that does not respond to treatment with gluten-free diet, and often involves greater risk of complications. The guts of many RCD patients over-produce effector cytokines, which are supposed to amplify the tissue-destructive immune response. However, it remains unclear if the RCD-associated mucosal inflammation is sustained by defects in counter-regulatory mechanisms. A team of researchers recently set out to determine whether RCD-related inflammation is marked by high Smad7, an intracellular inhibitor of transforming growth factor (TGF)-β1 activity. The research team included S Sedda, V De Simone, I Marafini, G Bevivino, R Izzo, OA Paoluzi, A Colantoni, A Ortenzi, P Giuffrida, GR Corazza, A Vanoli, A Di Sabatino, F Pallone, and G Monteleone. They are variously affiliated with the Department of Systems Medicine at the University of Rome "Tor Vergata," the First Department of Internal Medicine at the Fondazione IRCCS Policlinico San Matteo of the University of Pavia, and with the Department of Molecular Medicine at San Matteo Hospital at the University of Pavia in Pavia, Italy. The team evaluated Smad7 in duodenal biopsy samples of patients with RCD, patients with active celiac, patients with inactive celiac disease and healthy controls by Western blotting, immunohistochemistry and real time-PCR. In the same samples, they used ELISA and immunohistochemistry to assess TGF-β1 and phosphorylated (p)-Smad2/3, respectively. They evaluated pro-inflammatory cytokine expression in RCD samples cultured with Smad7 sense or antisense oligonucleotide. Smad7 protein, but not RNA, expression was increased in RCD, as compared to active and inactive celiac patients and healthy controls. This increased expression was associated with defective TGF-β1 signaling, as marked by diminished p-Smad2/3 expression. TGF-β1 protein content did not differ among groups. Knockdown of Smad7 in RCD biopsy samples reduced IL-6 and TNFα expression. These results show that, in RCD, high Smad7 associates with defective TGF-β1 signaling, and sustains inflammatory cytokine production. These results suggest a novel mechanism by which amplifies mucosal cytokine response in RCD, and suggest that treatments targeting Smad7 might be helpful in RCD. Source: Immunology. 2016 Nov 14. doi: 10.1111/imm.12690.
  9. Celiac.com 11/03/2016 - Refractory celiac disease type II (RCDII) often transforms into an enteropathy-associated T-cell lymphoma (EATL), a serious condition that requires intensive treatment. Current treatment strategies for RCDII include cladribine(2-CdA) and autologous stem cell transplantation (auSCT). A team of researchers recently set out to assess long-term survival in refractory celiac disease type II, and to define clear prognostic criteria for EATL development comparing two treatment strategies. They also wanted to evaluate histological response as prognostic factor. The research team included P Nijeboer, RLJ van Wanrooij, T van Gils, NJ Wierdsma, GJ Tack, BI Witte, HJ Bontkes, O Visser, CJJ Mulder, and G Bouma. They are variously affiliated with the Department of Gastroenterology, the Department of Nutrition and Dietetics, the Department of Epidemiology and Biostatistics, the Department of Pathology, and the Department of Haematology at VU University Medical Centre in Amsterdam, The Netherlands. For their study, they retrospectively analyzed 45 patients. All patients received 2-CdA, after which they were either closely monitored (monotherapy, n=30) or received a step-up approach, including auSCT (step-up therapy, n=15). Ten patients (22%) developed EATL, nine of whom had received monotherapy. Absence of histological remission after monotherapy was associated with EATL development (p=0.010). A total of 20 patients (44%) died, with an average survival of 84 months. Overall survival (OS) in the monotherapy group was far better in those with complete histological remission compared to those with without histological remission. The monotherapy patients, who achieved complete histological remission, showed comparable EATL occurrence and OS as compared to the step-up therapy group (p=0.80 and p=0.14 respectively). Histological response is an accurate parameter to evaluate the effect of 2-CdA therapy and this parameter should be leading in the decisions whether or not to perform a step-up treatment approach in RCDII. Source: United European Gastroenterology Journal, April 2016; DOI: 10.1177/2050640616646529
  10. Celiac.com 10/17/2016 - Refractory celiac disease is a severe condition with few good treatment options, and which often eventually results in death. A group of researchers recently set out to create a prognostic model to estimate survival of patients with refractory celiac disease. The research team included A. Rubio-Tapia, G. Malamut, W. H. M. Verbeek, R. L. J. van Wanrooij, D. A. Leffler, S. I. Niveloni, C. Arguelles-Grande, B. D. Lahr, A. R. Zinsmeister, J. A. Murray, C. P. Kelly, J. C. Bai, P. H. Green, S. Daum, C. J. J. Mulder, and C. Cellier. They are variously affiliated with the Mayo Clinic, Rochester, MN, USA, the Hopital Europeen Georges-Pompidou, Paris, France, the Hospital Dr. Carlos Nonorino Udaondo, Buenos Aires, Argentina, the Columbia University Medical Center, New York, NY, USA, Beth Israel Deaconess Medical Center, Boston, MA, USA, the Charite-University Medicine Berlin, Berlin, Germany, and the VU University Medical Centre, Amsterdam, The Netherlands. Before setting up their prognostic model, the team first assessed predictors of 5-year mortality using Cox proportional hazards regression on subjects from a multinational registry. The team used bootstrap resampling to internally validate the individual factors and overall model performance. To calculate a risk score for 5-year mortality, the team averaged all estimated regression coefficients gathered from 400 bootstrap models that they formulated from their multinational cohort of 232 patients diagnosed with refractory celiac disease across seven centers. Average patient age was 53 years and the group included 150 women out of the 232 patient total. A total of 51 subjects died during a 5-year follow-up, which put the cumulative 5-year all-cause mortality at 30%. The results from a multiple variable Cox proportional hazards model showed that the following variables were significantly associated with 5-year mortality: age at refractory celiac disease diagnosis (per 20 year increase, hazard ratio = 2.21; 95% confidence interval, CI: 1.38–3.55), abnormal intraepithelial lymphocytes (hazard ratio = 2.85; 95% CI: 1.22–6.62), and albumin (per 0.5 unit increase, hazard ratio = 0.72; 95% CI: 0.61–0.85). A simple weighted three-factor risk score was created to estimate 5-year survival. The team's prognostic model for predicting 5-year mortality among patients with refractory celiac disease may help clinicians to guide treatment and follow-up. Source: Alimentary Pharmacology & Therapeutics. DOI: 10.1111/apt.13755View/save citation
  11. Celiac.com 05/24/2016 - People with type II refractory celiac disease (RCD), suffer from severe malabsorption syndrome and face a poor prognosis, as there is currently no effective treatment. Prompted by the regenerative and immune-influencing properties of mesenchymal stem cells (MSCs), a research team recently set out to assess the viability, safety, and efficacy of a series of infusions of autologous bone marrow-derived MSCs in a 51-year-old woman with type II RCD. The research team included R Ciccocioppo, A Gallia, MA Avanzini, E Betti, C Picone, A Vanoli, C Paganini, F Biagi, R Maccario, and GR Corazza. They are variously affiliated with the Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo and Università degli Studi di Pavia, the Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo and Università degli Studi di Pavia, the Cell Factory and Research Laboratory, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo and Università degli Studi di Pavia, the Clinic Cytometry Laboratory, Department of Hematology, Fondazione IRCCS Policlinico San Matteo and Università degli Studi di Pavia, Department of Molecular Medicine, Fondazione IRCCS Policlinico San Matteo and Università degli Studi di Pavia, all in Pavia, Italy. The team began by isolating, expanding, and characterizing mesenchymal stem cells using standard clinical protocols. For each patient, the team arranged to monitor malabsorption indexes, mucosal architecture, and percentage of aberrant intraepithelial lymphocytes at the time of enrollment, at each infusion, and after 6 months. The also arranged to assess mucosal expression of interleukin (IL)-15 and its receptor. Once the team determined that the expansion of MSCs was feasible, they provided the patient with four systemic infusions of 2 × 106 MSCs per kg body weight 4 months apart, with no adverse effects. Over the course of the treatment, the patient experienced gradual and durable improvement of her condition, including normalized stool frequency, body mass index, laboratory test results, and mucosal architecture. Most impressively, the expression of IL-15 and its receptor almost completely vanished. Based on this clinical case, treatment of RCD with serial MSC infusions seems to offer a path to recovery from this life-threatening condition, while blocking the IL-15 pathogenic pathway. This is the first successful treatment of refractory celiac disease. Stay tuned for further developments regarding the use of stem cell infusions to treat refractory celiac disease. Source: Mayo Clin Proc. 2016 Apr 14. pii: S0025-6196(16)30004-0. doi: 10.1016/j.mayocp.2016.03.001.
  12. Celiac.com 01/14/2011 - Researchers recently presented information at the American College of Gastroenterology that indicates that more people with celiac disease might stop responding to gluten-free diets. Their new study, in the form of a retrospective chart review, turned up 17 cases of refractory celiac disease, each of which was eventually treated successfully with thiopurines. Researchers Christopher Hammerle, MD, and Sheila Crowe, MD, of the University of Virginia in Charlottesville, reported the results at a meeting at the American College of Gastroenterology. Hammerle called thiopurines her "treatment-of-choice for refractory celiac disease to avoid long-term steroids." The researchers stated that refractory disease appear to be on the rise. Patients with refractory celiac disease have recurrent symptoms such as abdominal pain, severe malabsorption, and intestinal damage. While some people note that refractory sprue might be caused by non-compliance to the gluten-free diet, current guidelines for treating refractory sprue call for doctors to review the dietary compliance of their patients, and to press for stricter adherence, and to search for other triggers of non-responsiveness only once dietary adherence issues are ruled out. In order to best understand the natural history of the celiac disease and to establish best practices for treatment, the researchers examined non-responsive celiac patients who had been seen at the University of Virginia Medical Center over the previous 10-year period. They found 17 such patients; 16 of whom had intraepithelial lymphocytes, four with the polyclonal phenotype and 12 with the monoclonal phenotype. One patient was untyped, while five patients also suffered autoimmune disease. The average age for diagnosis of a polyclonal phenotype was 45 years, and for the monoclonal phenotype mean age at diagnosis was 59. Overall, patients received a diagnosis of refractive disease an average of 4.7 years after receiving their diagnosis of celiac disease. According to the data, diagnosis for refractive celiac disease seems to be happening more recently, with all but one diagnosis happening in the last five years, and 41% diagnosed within six months of the researchers report. Every patient diagnosed with refractive celiac disease showed evidence of malabsorption, while 71% suffered from iron deficiency Anemia, 59% suffered hypo-albuminuria, 47% had osteoporosis and 24% showed elevated liver enzymes. According to Dr. Hammerle, steroids are the most common treatment choice for truly refractive disease. Indeed, more than four out of five refractory celiac patients (82%) first received corticosteroid treatment, but two patients went on to become steroid-dependent. Instead, Hammerle prefers to treat refractory celiac disease patients with a thiopurine. Of 14 of patients who received a thiopurine, all but one showed a notable improvement in symptoms. Hammerle notes that, while diagnosis for refractory disease seems to be rising, celiac disease itself is still widely underdiagnosed. Brandt concurs, noting that people with undiagnosed celiac disease, or even persistent celiac disease, can develop serious complications, including lymphoma. In people with celiac disease, this can result from increased production of cytokines, including IL-15, Hammerle said, which promote the creation of T-cells that can turn malignant. Source: American College of Gastroenterology. Hammerle C, Crowe S "Natural history and treatment of refractory celiac disease: Experience with 17 patients at a single center" ACG 2010; Abstract 235.
  13. This article originally appeared in the Spring 2003 edition of Celiac.com's Scott-Free Newsletter. Refractory sprue. The specter of this condition is enough to cause fear in the hearts of many people living with celiac disease, yet this fear is based more on myth and misunderstanding than on medical science. For those who are concerned about their risk for developing refractory sprue, there is much that can be done. For those who have developed the condition, there are treatment options and new hope on the horizon. To begin, however, we must substitute fear with knowledge. What is refractory sprue? This question has been the subject of great scientific inquiry, and there are differing opinions on the relationship between celiac disease and refractory sprue. However, there are several general characteristics of refractory sprue that researchers seem to agree on: Presence of persistently damaged villi in the small intestine that are not repaired after the gluten free diet has been successfully initiated and/or maintained An increased presence of intraepithelial lymphocytes (IEL) in the small bowel Severe malabsorption Researchers think of celiac disease as the beginning of a spectrum of conditions that could, for a small percentage of patients, end up at the other end to be enteropathy associated T-Cell Lymphoma. Most people with celiac disease will respond to the gluten free diet and never move to the next stage in this spectrum. But for those that do, they will experience changes in their immune system and in the cells lining their intestine that could lead to cancer. The spectrum would start with celiac disease, and the next step would be the non-responsiveness of the immune system to the gluten-free diet, in other words, refractory sprue. Then in some cases, a condition called ulcerative jejunitis develops, and finally, the damaged lining of the intestine produces cancer cells that mimic the mutations of the abnormal immune system cells. How many people with celiac disease are affected by refractory sprue? First, there are no reported cases in the medical literature of celiac sprue in people under 20 years of age. Second, the number of celiacs affected by refractory sprue, while not known, appears to be very small. We know this because the current estimates for small bowel cancers in people affected by celiac disease, as reported at the 10th International Conference on Celiac Disease is less than 2.5%. Refractory sprue can result in small bowel cancers, but not in all cases. It is interesting to note that in a recent study of patients with "unresponsive" celiac disease, Dr. Joseph Murray and his colleagues found that of 49 patients evaluated, only nine actually had refractory sprue—25 were found to have gluten contamination in their diets. The most common symptoms presented by the patients who truly had refractory sprue were weight loss, steatorrhea and diarrhea, in that order. What makes refractory sprue different than celiac sprue? Again, there are several medical points of view on this, but all researchers would agree that one marker indicates the presence of refractory sprue, and it is not found in celiac disease. Abnormal Intraepithelial Lymphocytes (Immune Cells) The intraepithelial lymphocytes found in celiac disease have a normal-looking appearance under the microscope and they behave like normal celiac immune cells (they respond to gluten when they shouldnt). These lymphocytes have the ability to communicate with other cells using different types of messages on their cell surfaces. When diagnosing celiac disease, pathologists look for an increased number of IELs as an indication of celiac disease. In refractory sprue, however, there is a different kind of IEL that is found in great numbers. This immune cell does not look normal, and it ignores the presence or absence of gluten. This type of cell does not have the ability to communicate normally with other cells as it would be expected to do. However, it does have the ability to communicate with cancer cells, contributing to their development. It is not clear what causes this type of IEL to develop or mutate, contributing to refractory sprue. It is possible to have refractory sprue without having these abnormal lymphocytes; in this case, treatment with steroids often results in response to the gluten free diet and a reversal of the condition. French researchers have developed a test to determine whether a biopsy specimen reflects a normal course of celiac disease with a slow response to the diet, or the need for further testing because refractory sprue may be present. In paraffin wax, a specimen can be stained to determine whether or not the immune cells express CD8, a protein often found on intraepithelial lymphocytes in celiac disease. If CD8 is positive, the individual has celiac and is responding very slowly to the diet. If the sample is CD8 negative, refractory sprue could be the reason. How is refractory sprue diagnosed and treated? It must be established through a thorough diet history and antibody testing that the individual is adhering to a strict gluten-free diet. Then, all other gastrointestinal diseases have to be ruled out before a diagnosis of refractory sprue is made. Conditions to be ruled out include pancreatic insufficiency, lactose malabsorption, parasite infestation, intolerance to other food proteins, coexisting inflammatory bowel disease, and autoimmune enteropathy, among others. Diagnosis should include a test called an enteroscopy, which is a procedure that explores more of the small intestine, and often finds ulcerative jejunitis, a marker of damage in refractory sprue. In addition, because the abnormal IELs can proliferate throughout the gut, a colonoscopy is recommended to determine if lymphocytic colitis is present. Treatment options include the elemental diet (also used in Crohns Disease), total parenteral nutrition (tube feedings), steroids, immunosuppressive therapies such as Cyclosporine, Infliximab, and in some cases, chemotherapy. Treatment options depend on the extent of refractory sprue found on biopsy and the nature of the clinical symptoms involved. How can I reduce the chances of developing refractory sprue? Researchers agree that most cases of refractory sprue develop in people who were diagnosed very late in life or who didnt follow the diet completely. Note that it doesn't matter how much gluten was consumed in these patients, they still developed refractory sprue. So the best protection against developing refractory sprue is to follow the diet. Be honest with yourself, especially if you cheat a little. What are you eating? Are you sure there isnt a great gluten-free alternative out there? Hey, there's even beer nowadays, so don't dismiss the suggestion of great gluten-free brownies, cakes, pies, pasta, crackers, cookies, or whatever else you are craving. Deal with your feelings too. Its easy to get angry about how life is much harder for people with celiac disease—how everything related to food requires too much planning, preparation, and explanation. These feelings are perfectly justified, but they do not justify cheating on your diet. There are great "quick fix" cookbooks out there, even convenience meals that are gluten free. Do whatever it takes to stay healthy, and gluten-free for life. Don't forget regular visits to your gastroenterologist or internist. Follow-up care for people with celiac disease is incredibly important, even if the medical community hasn't recognized it yet. Regular antibody testing to monitor compliance with the diet is an extra level of protection that every celiac needs. A simple anti-gliadin antibody test (IGG and IGA), six months post diagnosis, a year post-diagnosis and then every year after that for the first three years is key. In fact, the most serious celiac disease complications tend to occur in the first three years after diagnosis. Veteran celiacs should have their antibody levels checked every couple of years. While refractory sprue remains a potential complication for any adult with celiac disease, a majority of adult celiacs in this country will not have to face this difficult condition. For those diagnosed, treatment options continue to improve and the disease is becoming easier to manage. Researchers continue to study refractory sprue in order to better understand how the condition behaves and to develop new treatments. For now, the best defense against refractory sprue is a good offense—living a completely gluten-free life.
  14. Celiac.com 06/17/2015 - Refractory celiac disease type II (RCDII) and EATL (Enteropathy Associated T-cell Lymphoma) are pre-malignant complications of celiac disease. However, there is scant medical literature and data what role malnutrition and intestinal absorption may play in these conditions. With this in mind, a team of researchers set out to conduct a comprehensive assessment of nutritional status and intestinal absorption capacity of patients with RCDII and EATL, and to compare that with data of newly diagnosed celiac disease patients. The research team included N.J. Wierdsma, P. Nijeboer, M.A. de van der Schueren, M. Berkenpas, A.A. van Bodegraven, and C.J. Mulder. They are affiliated with the Department of Nutrition and Dietetics, the Department of Gastroenterology, the Celiac Centre Amsterdam, the Department of Nutrition and Dietetics at VU University Medical Centre in Amsterdam, The Netherlands; and with the Department of Internal Medicine, Gastroenterology and Geriatrics at ATRIUM-ORBIS Medical Centre, Sittard, The Netherlands. They conducted an observational study in tertiary care setting in for 24 RCDII patients, averaging 63.8 ± 8.2 years of age, 25 EATL patients averaging 62.3 ± 5.7 years of age, and 43 celiac disease patients averaging 45.6 ± 14.8 years of age. At diagnosis, the team evaluated anthropometry (BMI, unintentional weight loss, fat-free mass index (FFMI), handgrip strength (HGS), nutritional intake, fecal losses and Resting Energy Expenditure (REE)). They found low BMI (<18.5) more often in RCDII patients than in celiac disease or EATL patients (in 33%, 12% and 12%, respectively, p = 0.029). Also, 58% of EATL patients had unintentional weight loss greater than 10% of total weight, compared to 19% of celiac disease patients, and 39% for RCDII patients (p = 0.005/0.082). The team found energy malabsorption (below 85%) in 44% of RCDII patients, and in 33% of EATL patients, compared with 21.6% in celiac disease (NS). Fecal energy losses were higher in RCDII than in celiac disease patients (589 ± 451 vs 277 ± 137 kcal/d, p = 0.017). REE was lower than predicted, with reulst greater than 10% in 60% of RCDII, 89% of EATL, and 38% of celiac disease patients (p = 0.006). Between one third and two thirds of all patients showed Low FFMI and HGS. Patients with RCDII and EATL show far worse nutritional profiles than untreated naïve celiac disease patients at presentation. This malnutrition is at least partly due to malabsorption as well as hypermetabolism. This study shows the importance of proper diagnosis, and of nutrition in the treatment of these conditions. Source: Clin Nutr. 2015 Apr 30. pii: S0261-5614(15)00124-7. doi: 10.1016/j.clnu.2015.04.014.
  15. Celiac.com 10/27/2014 - There have been a few reports tying cortical myoclonus with ataxia to celiac disease. Such reports also suggest that the former is unresponsive to a gluten-free diet. A team of researchers recently set out to determine if there is any significant connection between the two conditions. The research team included Ptolemaios G. Sarrigiannis, Nigel Hoggard, Daniel Aeschlimann, David S. Sanders, Richard A. Grünewald, Zoe C. Unwin, and Marios Hadjivassiliou. They are variously associated with the Departments of Gastroenterology, Neurology, Neurophysiology and Neuroradiology at Royal Hallamshire Hospital, in Sheffield, UK, and with the College of Biomedical and Life Sciences at Cardiff University in Cardiff, UK. The team presented detailed electro-clinical characteristics of a new syndrome of progressive cortical hyperexcitability with ataxia and refractory celiac disease. Regular follow ups of over 600 patients with neurological manifestations due to gluten sensitivity revealed 9 patients with this syndrome. They found that all nine patients, six men and three women, experienced asymmetrical irregular myoclonus involving one or more limbs and sometimes face. This was often stimulus sensitive and became more widespread over time. Three patients had a history of Jacksonian march, and five had at least one secondarily generalized seizure. Electrophysiology showed evidence of cortical myoclonus. Three showed a phenotype of epilepsia partialis continua at onset. All patients showed clinical, imaging and/or pathological evidence of cerebellar involvement. All patients followed a strict gluten-free diet, and most successfully eliminated gluten-related antibodies. However, all patients still showed evidence of enteropathy, suggests that refractory celiac disease is to blame. During the study, two patients died from enteropathy-associated lymphoma and one from status epilepticus. Five patients were treated with mycophenolate and one in addition with rituximab and IV immunoglobulins. These patients showed improvement of ataxia and enteropathy, but continued to suffer the effects of myoclonus. These results indicate that myoclonus ataxia might be the most common neurological manifestation of refractory celiac disease. The clinical involvement, apart from ataxia, covers the whole clinical spectrum of cortical myoclonus. Source: Cerebellum & Ataxias 2014, 1:11. doi:10.1186/2053-8871-1-11
  16. So I have been gluten free for a little over 8 months now and I am very strict to not cheat and minimize any chances of cross contamination. When I first started the gluten free diet I saw some improvements, but then these stopped and even regressed. I have continued to lose weight and my gut has not been a happy camper. My GI has said that I most likely have refractory celiac disease and expects to do a combination steroids and constant work with my dietician. The point of this being, has anyone had a similar experience and is there anything else I should know or expect?
  17. Celiac.com 03/12/2014 - Researchers and clinicians consider refractory celiac disease (RCD) to be rare, but they don't actually have solid, reliable information about how common the condition actually is. A team of researches recently set out to establish rates of refractory celiac disease, and to identify corresponding risk factors in a Finnish population with high rates of clinically diagnosed celiac disease. The research team included T. Ilus, K. Kaukinen, L. J. Virta, H. Huhtala, M. Mäki, K. Kurppa, M. Heikkinen, M. Heikura, E. Hirsi, K. Jantunen, V. Moilanen, C. Nielsen, M. Puhto, H. Pölkki, I. Vihriälä, and P. Collin. For their study, the team looked at data on 44 treated RCD patients, 12,243 clinically diagnosed celiac disease patients, and a compared results against a control group of 1.7 million adult inhabitants. Specifically, the team compared clinical characteristics upon celiac disease diagnosis between the RCD patients and patients with uncomplicated disease. RCD affected 0.31% of diagnosed celiac disease patients, but just 0.002% in the general population. Of the enrolled 44 RCD patients, 68% showed type I RCD, 23% type II RCD, and 9% remained undetermined. Compared with the 886 patients with uncomplicated celiac disease, the 44 patients who developed RCD later in life were, when first diagnosed for celiac disease, significantly older (median 56 vs 44 years, P < 0.001), more likely to be male (41% vs. 24%, P = 0.012) and largely seronegative (30% vs. 5%, P < 0.001). More patients with evolving RCD showed severe symptoms upon celiac disease diagnosis, including weight loss in 36% (vs. 16%, P = 0.001) and diarrhea in 54% (vs. 38%, P = 0.050). These results show that refractory celiac disease is very rare in the general population. However, patients who are male, older, who experience severe symptoms or seronegativity when first diagnosed with celiac disease have a higher risk of developing refractory celiac disease. These patients should be closely monitored over time.. Source: Alimentary Pharmacology & Therapeutics Volume 39, Issue 4, pages 418–425, February 2014. DOI: 10.1111/apt.12606
  18. Celiac.com 03/25/2011 - A group of researchers recently set out to evaluate cladribine [2-chlorodeoxyadenosine (2-CdA)] therapy in refractory celiac disease (RCD) â…¡. The team included Greetje J. Tack, Wieke H. M. Verbeek, Abdul Al-Toma, Dirk J. Kuik, Marco W. J. Schreurs, Otto Visser, Chris J. J. Mulder of the Department of Gastroenterology and Hepatology, at VU University Medical Center, Amsterdam, The Netherlands. Between 2000 and 2010, the research team conducted an open-label cohort-study of RCD â…¡ patients treated with 2-CdA. They assessed survival rate, enteropathy associated T-cell lymphoma (EATL) occurrence, clinical course, and histological and immunological response rates. The study followed a total of 32 patients over an average 31-month period. Eighteen patients responded well to 2-CdA. Patients responsive to 2-CdA showed markedly higher survival rates, compared to unresponsive patients. The responder group showed an 83% survival rate at the 3- and 5-year mark, compared to rates of 63% and 22% in the non-responder group. The responder group showed an 81% clinical, histological and immunological response rates at the 2-year mark, compared to rates of 47% and 41% in the non-responder group. 16% of non-responsive patients progressed into EATL, and all of these patients died. Because 2-CdA shows excellent clinical and histological response rates, and probably less frequent transition into EATL, it looks like a promising treatment for RCD II. Source: World J Gastroenterol. 2011 January 28; 17(4): 506–513. doi: 10.3748/wjg.v17.i4.506.
  19. Celiac.com 04/24/2013 - Doctors classify refractory celiac disease (RCD) depending on the presence or absence of monoclonal expansions of intraepithelial lymphocytes (IELs) with an aberrant immunophenotype. A team of researchers recently set out to determine whether IEL parameters have any connection with mortality and morbidity in cases of refractory celiac disease. The research team included C. Arguelles-Grande, P. Brar, P. H. Green, and G. Bhagat. They are variously affiliated with the Celiac Disease Center, and the Departments of Medicine, Pathology and Cell Biology, at Columbia University Medical Center in New York, NY. The team used immunohistochemistry to assess IEL phenotype and polymerase chain reaction to determine T-cell receptor (TCR) gene rearrangement in 67 patients with RCD type I, and six patients with RCD type II. They considered a monoclonal TCR gene rearrangement and presence of greater than 50% CD3 CD8 IELs to be abnormal. They used Kaplan-Meier and Cox proportional hazard analyses to determine the time to worsening of clinical symptoms and the predictors of worsening. The team found 30 patients with less than 50% CD3 CD8 IELs, and eight with monoclonal TCR rearrangements. Three patients died and 40 suffered clinical worsening despite treatment. Estimated 5-year survival rates were 100% in patients with greater than 50% CD3 CD8 IELs and polyclonal TCR, but just 88% in patients with less than 50% CD3 CD8 IELs and 50% in patients with monoclonal TCR. All patients with monoclonal TCR gene rearrangement with less than 50% CD3 CD8 IELs showed shorter average time to clinical worsening of symptoms (11 mo), when compared to patients with less than 50% CD3 CD8 IELs alone (21 mo), polyclonal TCR (38 mo), or greater than 50% CD3 CD8 IELs alone (66 mo). After the team adjusted for age and gender, they found that the presence of less than 50% CD3 CD8 IELs was the only factor associated with increased risk for clinical worsening, despite negative celiac blood screens (hazard ratio=4.879; 95% confidence interval, 1.785-13.336; P=0.002). This means that RCD patients with <50% CD3 CD8 IELs are at risk for clinical worsening, and that RCD patients who also show monoclonal TCR gene rearrangement have higher mortality rates. Overall, the assessment of IEL phenotype and TCR gene rearrangement can provide important information regarding morbidity and risk of death in cases of RCD. Source: J Clin Gastroenterol. 2013 Mar 6.
  20. For 10+ years I had terrible symptoms that I had no idea what they were caused by, leaving doctors stumped. I had everything from diarrhea, vomiting, severe abdominal pain, joint pain and inflammation, numbness and tingling in my toes, bone pain, sore tongue, burning gums, inability to gain weight, and acid reflux. I had a normal HIDA scan, normal liver, a small cyst in my gallbladder, H. Pylori in stomach, gastroparesis, and gastroenteritis. Finally at the age of 21 I was referred to a GI doctor and the first test he did on me was an endoscopy. It came back showing flattened villi in my small intestine and all he said to me was "it looks like Celiac Disease" then left it at that. I went back to him two weeks after having gone on a gluten-free diet and told him I was feeling better. I basically got no response from him and it didn't seem to matter to him either way if I felt better or not. But I continued to eat gluten-free and after a few months, I felt "normal" again. After nearly 5 years of being gluten-free, I've noticed my symptoms are coming back. They're not as severe and not all are back, but I'm still feeling sick. I have abdominal pain, diarrhea/constipation, and I've noticed if I don't take my B-complex vitamin I get irritability and mouth soreness. I don't ever go out to eat, I make most everything from scratch, and the only processed foods I eat are ones that are certified gluten free. I've thought about going on an elimination diet, but I'm breastfeeding and don't want to disturb the quality or quantity of my milk. Why are my symptoms coming back after all this time? Has anyone else had the same experience? What was the outcome? Thanks in advance.
  21. Celiac.com 01/02/2013 - Doctors use capsule endoscopy to assess the small bowel in a number of intestinal diseases, including celiac disease. The main advantage of capsule endoscopy is that it allows for complete visualization of the intestinal mucosal surface. A team of researchers recently set out to investigate whether capsule endoscopy can predict the severity of celiac disease, and detect celiac disease complications. The research team included M. Barret, G. Malamut, G. Rahmi, E. Samaha, J. Edery, V. Verkarre, E. Macintyre, E. Lenain, G. Chatellier, N. Cerf-Bensussan, and C. Cellier. They are affiliated with the Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Service d'Hépato-gastro-entérologie, and the Université Paris Descartes, Sorbonne Paris Cité, Faculté de médecine, both in Paris, France. For their study, the team reviewed medical files for nine patients with symptomatic celiac disease, eleven patients with refractory celiac disease type I (RCDI), 18 patients with refractory celiac disease type II (RCDII), and 45 patients without celiac disease who received both capsule endoscopy and upper endoscopy or enteroscopy. To properly diagnose the type of celiac disease in the patients, the researchers used a centralized histological review, flow cytometry analysis of intraepithelial lymphocytes, and the analysis of T-cell receptor rearrangement by multiplex polymerase chain reaction. A total of 47 capsule endoscopies were administered for the 38 celiac patients: ten for the patients with symptomatic celiac disease; eleven for patients with RCDI; and 26 for RCDII patients. Another 47 capsule endoscopies were administered for the 45 non-celiac patients were retrospectively reviewed. They found that patients with celiac disease had more villous atrophy, and more numerous, or distally located ulcers than the control subjects. They also found that, in celiac disease patients, capsule endoscopy was of acceptable quality in 96% of cases and was complete in 62% of cases. Moreover, the concordance of capsule endoscopy with histology for villous atrophy was better than that of optic endoscopy (κ coefficient =0.45 vs. 0.24, P<0.001). Extensive mucosal damage on capsule endocscopy was associated with low serum albumin (P=0.003) and the RCDII form (P=0.02). The also detected three cases of overt lymphoma by capsule endoscopy during the follow-up. Overall, the results show that capsule endoscopy provides a sufficient match with histology and nutritional status in patients with symptomatic or refractory celiac disease. Lastly, capsule endoscopy may predict the type of RCD and enable the early detection of overt lymphoma. Source: Am J Gastroenterol. 2012 Oct;107(10):1546-53. doi: 10.1038/ajg.2012.199. Epub 2012 Sep 11.
  22. Celiac.com 10/25/2012 - Abnormal intraepithelial lymphocytes (IELs) are the main feature of refractory celiac disease type II (RCDII). However, researchers still don't know exactly how these abnormal IELs originate. A pair of researchers recently commented on efforts to learn how these abnormal IELs might come about. The pair were Victor F. Zevallos, and Detlef Schuppan, of the center for Molecular and Translational Medicine, Department of Medicine I at the University Medical Center of Johannes Gutenberg University Mainz, in Mainz, Germany. Their commentary focuses on efforts by a separate research team, Schmitz, et al., which had already used a broad spectrum of cell specific markers, RNA array and immunological techniques, to explore abnormal IEL cell lines from four RCDII patients, and compare them with IELs from the fetal intestine, the intestine of children and adults and the thymus. IELs are highly varied lymphocytes cells with innate and adaptive features that live in the small and large intestine. IELs play an important role in maintaining gut tolerance to common food antigens versus defense against pathogens. A number of nutritional factors influence the development and spread of IELs, especially vitamins and their active metabolites, such as retinoic acid, and phytochemicals such as ligands of the aryl hydrocarbon receptor from cruciferous vegetables. However, when IELs activate and expand uncontrollably in response to chronic inflammatory conditions in the gut, they trigger mucosal damage, which can lead to celiac disease, and in some cases, to malignant cancers. Up to 5% of people with celiac disease, especially those who are over fifty years old when diagnosed, continue to suffer from clinical symptoms and villous atrophy even when following a gluten-free diet. After excluding ongoing gluten consumption and other potential underlying diseases, all four patients studied by Schmitz could be diagnosed with RCD, which is classically classified as type I or type II, based on the histological co-expression of CD3 and CD8 in RCDI, or absence of such co-expression in RCDII. Read the entire report in Gut. Source: Gut doi:10.1136/gutjnl-2012-303030
  23. Celiac.com 09/21/2012 - Refractory celiac disease type II (RCDII) is a severe complication of celiac disease that occurs when symptoms and intestinal damage continue even when the patient adopt a gluten-free diet. Refractory celiac disease marked by abnormal intraepithelial lymphocytes (IELs) of unknown origin that display an atypical CD3(-)CD7(+)icCD3(+) phenotype. About 40% of patients with RCDII lymphocytes develop a dangerous and invasive lymphoma. A team of researchers recently sought to identify possible origins of abnormal intraepithelial lymphocytes in refractory celiac disease type II. The research team included F. Schmitz; T.M. Tjon, Y. Lai; A. Thompson; Y. Kooy-Winkelaar; R.J. Lemmers; H.W. Verspaget; M.L. Mearin; F.J. Staal; M.W. Schreurs; T. Cupedo; A.W. Langerak; C.J. Mulder; J. van Bergen; and F. Koning. In their study, the researches sought to find the physiological counterpart of these abnormal intraepithelial lymphocytes cells. To do so, they used microarray analysis, real-time quantitative PCR and flow cytometry to compare RCDII cell lines with T-cell receptor positive (TCR(+)) IEL (T-IEL) lines. They then used their data to identify cells with an RCDII-associated phenotype in duodenal biopsies from non-refractory individuals by multicolor flow cytometry. They found that RCDII cell lines were distinct from T-IEL lines and showed higher levels of multiple natural killer (NK) cell receptors. In addition to the CD3(-)CD7(+)icCD3(+) phenotype, the RCDII lines showed an absence of CD56, CD127 and CD34, compared with other lymphocyte subsets. Moreover, they found cells matching this surface lineage-negative (Lin(-)) CD7(+)CD127(-)CD34(-) phenotype that showed a functional interleukin-15 (IL-15) receptor and comprised a substantial portion of IELs in duodenal specimens of patients without celiac disease, particularly children. They also found cells of this kind in the thymus. For patients without celiac disease, the Lin(-)CD7(+)CD127(-)CD34(-) subset was one of four subsets within the CD3(-)CD7(+)icCD3(+) population that showed a differential expression of CD56 and/or CD127. The results indicate that the CD3(-)CD7(+)icCD3(+) population is heterogeneous and show the existence of a Lin(-) subset that is different from T, B, NK and lymphoid tissue inducer cells. The team hypothesizes that the IL-15 cells are the counterpart of abnormal cells that are expanded in RCDII and transformed in RCDII-associated lymphoma. Source: Gut. 2012 Jul 6.
  24. Celiac.com 09/12/2012 - A team of researchers recently evaluated tioguanine as a treatment for refractory celiac disease type I. The very small study indicates that tioguanine, a thiopurine derivative, offers easy, efficient treatment for refractory celiac disease, compared with current treatment regimens. The research team included G. J. Tack; D. P. van Asseldonk; R. L. J. van Wanrooij; A. A. van Bodegraven; and C. J. Mulder. Refractory celiac disease type I is a form of celiac disease in which patients show resistance to a gluten-free diet, and suffer persistent or recurring intestinal villous atrophy, along with symptoms of malabsorption. Currently, the most common treatment for refractory celiac disease type I relies on corticosteroids, though azathioprine is also sometimes used. However, this small recent study shows that tioguanine might be better tolerated and more effective, in part because of its simpler metabolism towards bio-activation. For their study, the research team set out to assess how well patients with refractory celiac disease type I tolerate tioguanine, and how effective it is in relieving symptoms. The team studied a group of twelve patients with refractory celiac disease type I, who were treated with tioguanine between June 2001 and November 2010, including a follow-up period of at least 1 year. The team assessed and recorded adverse events, laboratory values, 6-thioguanine nucleotide concentrations and rates of both clinical and histological response at baseline and during follow-up. They noted that the average tioguanine treatment lasted 14 months. Ten patients tolerated long-term tioguanine treatment, while two patients discontinued treatment due to adverse reactions. The team found no nodular regenerative hyperplasia of the liver. Follow-up showed clinical and histological response in 83% and 78% of patients, respectively. Overall, patients decreased corticosteroid reliance by 50%. Because of its higher histological and similar clinical response rates compared with current treatments, tioguanine seems to be a good drug for treating refractory celiac disease type I. Source: Alimentary Pharmacology & Therapeutics. 2012;36(3):274-281.
  25. Celiac.com 04/23/2012 - Aberrant intra-epithelial lymphocytes (IELs) are one of the major features of refractory celiac disease type II RCDII. They are categorized as pre-malignant cells, which can give rise to aggressive enteropathy-associated T cell lymphoma (EATL). A medical research team recently studied the origin and immuno-phenotype of aberrant IEL in RCDII patients. The research team included G.J. Tack, R.L. van Wanrooij, A.W. Langerak, J.M. Tjon, B.M. von Blomberg, D.A. Heideman, J. van Bergen, F. Koning, G. Bouma, C.J. Mulder, and M.W Schreurs. They are affiliated with the Gastroenterology and Hepatology, VU University Medical Center, The Netherlands. The team set out to better understand the origin and characteristics of aberrant IELs by scrutinizing T-cell receptor (TCR) rearrangements, and through immunophenotypic analysis of aberrant IELs. For their study, the team looked for TCR delta, gamma, and beta rearrangements in duodenal biopsies from 18 RCDII patients. they also analyzed three RCDII cell lines. They also conducted phenotypical analysis on IELs isolated from biopsies taken from RCDII patients. They found that aberrant IELs showed an increased expression of granzyme B, along with a reduced expression of PCNA. Biopsies of RCDII patients showed heterogenic TCR rearrangements in the aberrant IEL cells. The researchers suggest that this is likely due to a variation in maturity. Similarly, RCDII cell lines showed a heterogenic TCR rearrangement pattern. From their data, the team concludes that aberrant IELs originate from deranged immature T lymphocytes and show clear differentiation to a cytotoxic phenotype. Among RCDII patients, aberrant IELs showed different stages of maturity, and only the patients who had the most mature aberrant IEL cells developed an EATL. Source: Molecular Immunology. 2012 Feb 22.
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