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Last updated: 4/14/2025
Years published: 2006, 2010, 2013, 2016, 2025
NORD gratefully acknowledges Samantha O’Leary, Carolien Keefe, Abigail Benson and Ella Gaul, Editorial Interns from the University of Notre Dame, and Ciarán P. Kelly, MD, Professor of Medicine at Harvard Medical School and Director of the Celiac Center at Beth Israel Deaconess Medical Center in Boston, for assistance in the preparation of this report.
Refractory celiac disease (RCD) is a rare and complicated form of celiac disease that does not improve even after following a strict gluten-free diet (GFD) for 6 to 12 months.¹ People with RCD may continue to have symptoms such as unintentional weight loss, chronic diarrhea, stomach pain, malnutrition (poor absorption of nutrients) and low red blood cell levels (anemia) which can cause fatigue.¹
Celiac disease (CD) occurs when the immune system mistakenly attacks the small intestine after eating gluten, a protein found in wheat, barley, and rye.² Normally, following a gluten-free diet helps control symptoms of CD, but in RCD, the immune system continues to attack the intestine even if the affected person is avoiding gluten.
There are two types of RCD:3
Doctors diagnose RCD by ruling out other conditions that damage the small intestine such as lymphoma (a type of cancer), Crohn’s disease (a chronic digestive disorder), small intestinal bacterial overgrowth (SIBO) and hypogammaglobulinemia (a condition that weakens the immune system).⁴
The small intestine contains tiny finger-like structures called villi, which help absorb nutrients from food. In both celiac disease and RCD, these villi shrink, making it difficult for the body to get the nutrients it needs.⁵
RCD is rare, affecting only 1%-2% of people with celiac disease, mostly adults over the age of 50.⁶
Type I RCD is often treated with steroid therapy (such as budesonide) which helps suppress the immune system. With this treatment, about 80-90% of affected people survive for at least five years. Type II RCD is more severe and fewer than 50% of affected people survive for five years.⁷
Symptoms of refractory CD are similar to the symptoms of untreated celiac disease but are usually more severe and disabling. The onset of symptoms occurs at any point after diagnosis with celiac disease but is more commonly observed in people over 50 years of age.6 Initial symptoms typically present as CD; however, these symptoms do not improve with a gluten-free diet (GFD). Eventually, some people develop complications such as intestinal bleeding or an intestinal blockage or malnutrition.6
Major Symptoms
Minor Symptoms
There are two subtypes of RCD. Type I is milder than type II. Type II RCD is more difficult to treat and is associated with a higher risk of malnutrition and severe complications. Up to 50% of people with type II RCD develop a type of cancer known as enteropathy-associated T-cell lymphoma (EATL), usually within the first 18 months after diagnosis of RCD.3,7 People affected with type I RCD very rarely develop EATL.
Occasionally, examination of the intestine of a person with type II RCD by means of a swallowed, camera-like device (intestinal endoscope) or by a CT or MRI scan, reveals evidence of inflammation and ulceration of the middle portion of the small intestine.7 This may be a warning sign that RCD may have progressed to EATL.7
Celiac disease, the precursor to RCD, is triggered by an immune response in the body after the affected person eats gluten – a protein found in wheat, barley and rye. Normally, the immune system protects the body against threats like bacteria or viruses (antigens) and ignores harmless substances like gluten. However, in CD, gluten is mistakenly identified as a threat, triggering several immune events.1 In addition to attacking gluten, the immune system also attacks the lining of the small intestine, where the body absorbs nutrients from food. This leads to tissue inflammation and damage, which causes symptoms related to poor absorption of nutrients such as stomach pain, bloating and diarrhea.
Lymphocytes are a type of white blood cell in the immune system that help protect the body from infections. One of the two main types of lymphocytes involved in CD are T-cells. T-cells typically help identify and destroy threats in the body but in CD, they mistake gluten for a harmful substance and trigger the attack on both gluten and the small intestine.8
Intraepithelial lymphocytes (IELs) are T-cells that exist in the lining (intraepithelial) of the intestine. In CD, T-cells that recognize gluten proteins are activated and divide to make more cells. When gluten is removed from the diet, these T-cells become inactive and the intestinal damage heals.8 In RCD, however, these immune cells remain active even without gluten, continuing to damage the intestine.1
RCD is classified as an enteropathy, a disease that causes the shrinking (atrophy) of the intestinal villi. Some people with RCD may develop enteropathy-associated T-cell lymphoma (EATL), a rare and aggressive cancer that affects the small intestine. 9 Unusual or abnormal IELs appear to be the precursor cells in EATL as well.7
Type I RCD is characterized by villous damage, similar to that seen in conventional CD.6 Type I RCD has a better prognosis and a lower risk for EATL. In type II RCD, abnormal, immature IELs are found in the intestinal tissue when the tissue is examined under the microscope and there is an increased risk for severe complications of malnutrition, intestinal ulceration and EATL.10
Refractory celiac disease is rare in adults and is almost never seen in children. Data regarding the true incidence and prevalence of RCD is unreliable, but some have estimated that there might be 20,000 affected people in the U.S. However, those estimations are based on incomplete data. In one recent study, 1.5% of people diagnosed with celiac disease at a single U.S. center developed RCD. Of those with RCD, 85% had the less severe type I RCD.4
Most doctors studying RCD agree that diagnosis is best made by ruling-out other gastrointestinal and immune disorders that may cause persistent symptoms despite a strict GFD for at least 12 months.17
The best tool for the diagnosis is the examination of the interior wall of the intestine (upper and lower) by means of a camera (enteroscope or colonoscope). Evaluating small samples of small intestinal tissue (intestinal biopsies) under a microscope is also useful to rule out other disorders, as it focuses on examining the architecture of the intestine and the immune cells within the gut lining, intraepithelial lymphocytes (IELs). In type I RCD, IELs are increased but otherwise appear as normal, meaning they display typical immune cell markers and function. In type II RCD, IELs are abnormal, meaning they have some changes that could lead to a higher risk of progression to lymphoma.4,10,17 Other imaging studies (CT scan, capsule enteroscopy and magnetic resonance enterography (MRE) may be performed, especially if there is concern for the presence of a lymphoma.2
There is no known cure for RCD, but treatment can help manage symptoms. Usually, an affected person is first treated with budesonide, a steroid that reduces inflammation in the intestine.¹⁸ There are several treatments that have been used in some people but none have been effective in all cases. These treatment options include:14,18,19
The following are being studied as potential future treatment options, but more research is needed:18
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
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