Autoimmune Disorders In Celiac Disease

What Are Autoimmune Disorders?

[dropcap]A[/dropcap]utoimmune disorders refer to those conditions that involve an abnormal immune attack on the body’s own tissues perpetuated by the production of autoantibodies directed against the body, or “self.” Auto means self.

Q: Why does the immune system attack the body?

A: The exact answer is not yet known why the immune system turns against body tissue or “self.” 

Normally, the immune system protects the body from harmful substances and pathogens and produces antibodies against the offending foreign substances, called antigens, to get rid of them. The immune system (humoral) thereafter remembers all antigens and is ready for the next encounter should it happen.

Production of autoimmune antibodies is catastrophic because there is no turning off the readiness to attack a remembered threat (antigen) which is unfortunately “self.” 

Yes, steroids and anti-inflammatory drugs can control symptoms, but nothing can undo the memory programmed into the immune system to produce autoantibodies. There is an enormous research effort ongoing for the answer. 

Autoimmune disorders cover a wide range of diseases that may target only a particular organ, such as autoimmune hepatitis (liver), while others are systemic because the autoantibodies target a particular tissue that is part of more than one organ, such as scleroderma (connective tissue).

Autoimmune diseases as a group affect approximately 8.5% of people worldwide.

What Are Autoimmune Disorders In Celiac Disease and/or Gluten Sensitivity?

• Relationship between autoimmune disorders and celiac disease. Autoimmune disorders are serious, chronic associated disorders in celiac disease.
• Relationship between autoimmune disorders and risk. Prevention is key to reducing risk. Development of autoimmune disorders in celiac disease is clearly related to the duration of exposure to gluten.¹  That is, the longer treatment for celiac disease is put off, the greater the risk of developing other autoimmune disease.
• Relationship between autoimmune disorders and gluten free diet responsive. Some gluten triggered autoimmune diseases, such as chronic bullous dermatosis in childhood, can be controlled so long as gluten is strictly eliminated from the diet.
• Relationship between autoimmune disorders and gluten free diet non-responsive. Unfortunately, others do not respond to gluten free diet such as autoimmune thyroiditis, or have caused irreversible damage such as destruction of bile ducts in autoimmune cholangitis or destruction of insulin producing cells in type 1 diabetes mellitus.
• Relationship between autoimmune disorders and incidence in celiac disease. These autoimmune diseases are more commonly associated with celiac disease:

• Addison’s Disease.
• Alopecea Areata.
• Autoimmune Cholangitis.
• Autoimmune Hepatitis.
• Chronic Bullous Dermatosis of Childhood.
• Dermatomyositis.
• IgA Nephropathy.
• Juvenile Autoimmune Thyroid Disease.
• Juvenile Idiopathic Arthritis.
• Polymyositis.
• Primary Sclerosing Cholangitis.
• Psoriasis.
• Sarcoidosis.
• Sjögren’s Syndrome.
• Systemic Lupus Erythematosus.
• Type 1 Diabetes Mellitus.
• Vitiligo.

• Relationship between autoimmune disorders and hyposplenism. Autoantibodies were detected in significantly more patients with hyposplenism than in healthy controls, and in significantly more celiacs with hyposplenism than celiacs with normal blood films. The increased incidence of autoantibodies in celiacs with hyposplenism compared with other celiacs was not associated with a difference in the incidence of HLA-B8.²

How Prevalent Are Autoimmune Disorders In Celiac Disease and/or Gluten Sensitivity?

• In a large study, 21% of patients with celiac disease had associated autoimmune disorders present.³
• Endocrine and connective tissue disorder associations that occurred in the same individual were found in 19.1% of patients with celiac disease over an average of 10 years.⁴
• The cumulative risk of autoimmune disease in a study of 924 patients was 8.1% +/- 1% at age 15, and 15.7% +/- 1.5% at age 30. After diagnosis of celiac disease, 55 of 788 patients developed an autoimmune disease. The cumulative risk of subsequent autoimmune disease was lower in patients compliant to a gluten-free diet versus noncompliant patients (at 10 years, 6% +/- 2% vs 15.6% +/- 5.9%), respectively. The incidence of autoimmune diseases was 5.4 per 1000 patient-years during adherence to a gluten-free diet versus 11.3 per 1000 patient-years during nonadherence to the diet. Results were similar in both the pediatric and the adult populations.⁵
• There is increased prevalence of autoimmune diseases in first degree relatives of patients with celiac disease. 4.8% of first degree relatives of children with celiac disease had autoimmune disorders disorders. First degree means mother, father, sister, brother, or child. The prevalence of autoimmune disorders in first degree relatives of patients with celiac disease is most likely connected with unrecognized subclinical or silent forms of celiac disease. Please note, 82% of first degree relatives with silent or subclinical forms of celiac disease in this study had flat mucosa on intestinal biopsy.⁶ Silent or subcinical means these people did not have digestive symptoms that would suggest celiac disease.

What Are Symptoms Of Autoimmune Disorders?

• Symptoms of various autoimmune disorders in celiac disease are marked by their individual features as well as those of celiac disease. For example, psoriasis would have mainly skin, joint and nail lesions while sarcoidosis would affect many different systems with devastating effects throughout the body.

How Do Autoimmune Disorders In Celiac Disease and/or Gluten Sensitivity Develop?

• Autoimmune disorders in celiac disease result from gluten exposure and an associated autoimmune mechanism not fully understood.
• It is understood that the risk of developing associated autoimmune disorders increases with increased diagnostic delay.
• Mercury toxicity due to amalgam dental work (metal fillings) is shown to be a trigger for the development of autoimmunity. In celiac disease, the use of metal fillings to correct dental cavities, which result from nutritional deficiencies and unnatural acidity (low pH), may be an additive factor provoking the development of autoimmune diseases. Amalgam is a composite of metals held together by 50% mercury. Dental amalgam is by far the main source of human total mercury body burden. This is proven by autopsy studies which found 2-12 times more mercury in body tissues of individuals with dental amalgam.⁷

Do Autoimmune Disorders Respond To Gluten-Free Diet?

Once an associated autoimmune disorder is triggered to activity, the response to a gluten free diet varies with the autoimmune disorder. The object is to prevent the formation of autoantibodies by keeping a strict diet.

6 Steps To Improve Risk of Autoimmune Disorders In Celiac Disease and/or Gluten Sensitivity:

• [dropcap]1[/dropcap]Remove the Trigger. Maintain a Strict, Nutritious Gluten Free Diet:

[box type=”shadow” ]Treatment. This condition responds to the complete elimination of gluten, which is the required treatment that improves both associated autoimmune disorders and gut health.

• Gut health is the foundation to restore ALL health. Restored health will enable you to maintain a strict gluten free diet, just as other life tasks will be easier.
• A strict gluten free diet means removing 100% of wheat, barley, rye and oats from the diet.
• Cutting out bread and other obvious sources of gluten is not good enough for recovery. Even 1/8th teaspoon of flour or bread crumb is enough to sustain the inflammation that is damaging your small intestine, causing increased permeability (leaky gut) and allowing undigested gluten to enter your body where it can damage structures and function, and instigate immune inflammatory responses.

Correct Your Individual Nutritional Needs.

• Eat foods that can replenish missing nutrients. Find them under NUTRIENT DEFICIENCIES.
• Take nutritional supplements as needed. Find them under NUTRIENT DEFICIENCIES.

Recovery. You should begin to feel better within a week and notice more energy as inflammation subsides and the  absorbing cells that make up the surface lining of your small intestine are better able to function.

• Intestinal lining cells are replaced every 5 days. The healing process is like sunburn where the damaged surface layer of skin sloughs off and is replaced with new normal cells.
• Leaky gut normally resolves in two month after starting a gluten free diet and brings about a big improvement in health. Improvement in intestinal permeability precedes morphometric recovery (cell appearance and structure) of the small intestine in celiac disease.⁸
• The intestinal lining may take up to a year to heal.[/box]

• [dropcap]2[/dropcap] Reduce Inflammation. Foods to Eat and Foods Not to Eat:

Because gluten is inflammatory, eliminate OTHER inflammatory foods from your diet to reduce an additive effect to gluten. At the same time, try to eat foods that reduce inflammation (anti-inflammatory).

[box type=”shadow” ]Here Are Major Inflammatory Food Types That Reduce Healing:

• Damaging Foods. In susceptible persons, includes corn, dairy (cow), and soy. Lactose, the sugar in any animal milk disrupts intestinal permeability causing leaky gut.⁹
• Allergenic Foods. Includes foods that trigger the immune sytem to produce IgE antibodies. Allergy testing is the usual way to discover these offending foods.
• Shelf Stable Processed Foods. Includes any that contain additives and preservatives. Look for them on the nutrition label of the box or package. Additives and preservatives also disrupt intestinal permeability causing leaky gut.⁹
• Fats. Limit deep fried foods, trans-fats, saturated fats (animal fat/butter), and EXCESSIVE omega-6 fatty acid oils like corn oil. Rancid fats, sodium caprate (a medium chain fat), and sucrose monester fatty acid (a food grade surfactant) induce significant disruption of the intestinal barrier that causes leaky gut.⁹.
• Excessive Refined White Flours (bran layer removed). Includes products made from them such as cookies, bread, cakes, pies. Bran contains the vitamins and minerals that metabolize grains and slows the otherwise rapid entry of sugar from their digestion into the bloodstream. Also disrupt intestinal permeability causing leaky gut.⁹
• Refined Sugars.  Includes white sugar, corn fructose and high fructose corn syrup.
• Certain Spices. Includes paprika and cayenne pepper which disrupt intestinal permeability causing leaky gut.⁹
• Alcohol and Caffeine. Disrupt intestinal permeability causing leaky gut.⁹[/box]

[box type=”shadow” ]Here Are Important Anti-Inflammatory Food Types to Promote Health:

• Fruits. Contain ample amounts of vitamins, minerals and phytochemicals which are naturally occuring components in plants that detoxify toxins, carcinogens (reducing the risk by 50%) and mutagens.
• Non-Starchy Vegetables. Support intestinal integrity and provide ample amounts of vitamins, minerals and phytochemicals. Includes green leafy vegetables such as lettuce and kale, also onion, broccoli, garlic, and others.
• High Quality Complex Carbohydrates. Provide vitamins, minerals, and fiber while boosting serotonin levels to help you relax and feel calm. Includes whole grains, legumes, and root vegetables such as carrots, parsnips, sweet potatoes, turnips, red beets, and others.
• Antioxidants. Protect the body from inflammatory oxidant molecules that continually occur and help us handle stress and reduce irritability. Includes vitamin C-containing foods such as lemon, grapefruit, apricot, Brussels sprouts and strawberries, and others. Also, includes vitamin E-containing foods such as nuts, seeds, avocado, olive oil, and others. Cocoa is good, too.
• Omega-3 Fatty Acids. Balance opposing omega-6 fatty acids and bad fats. Fish sources includes tuna, salmon, cod, and others. Plants sources include flax, chia seeds, canola oil, and others.
• Probiotics. Supply normal microbes needed for colon health and health of the body such as these fermented foods: yogurt, kefir, and unpasteurized apple cider vinegar.
• Prebiotics/ High Fiber Foods.  Food with fiber keeps our population of colonic microbes healthy.
• Protective Herbs and Spices.  See below #6 below for examples.[/box]

• [dropcap]3[/dropcap] Information Sheet You Can Take to Your Doctor or Other Health Professional:

Click here.

• [dropcap]4[/dropcap] Manage Your Medications Safely:

[box type=”shadow” ]

Certain medications that are used to treat inflammation in autoimmune disorder cause deficiencies that exacerbate malabsorption in celiac disease. Ask your doctor or pharmacist about this possible adverse effect if you are taking any of the drugs listed below or others specific to an associated autoimmune disease. Do not stop prescribed medications without supervision.

 This is not a complete listing.

ANTI-INFLAMMATORIES disrupt intestinal permeability which complicates celiac disease.

• Corticosteroids (Prednisone, Medrol®, Aristocort®, Decadron) deplete Calcium, Vitamin D, Magnesium, Zinc, Vitamin C, Vitamin B6, Vitamin B12, Folic Acid, Selenium, Chromium, Phosphorus.
• NSAIDS (Motrin®, Aleve®, Advil®, Anaprox®, Dolobid®, Feldene®, Naprosyn® and others) deplete Folic acid. [/box]

• [dropcap]5[/dropcap]Nutritional Supplements To Help Correct Deficiencies:

[box type=”shadow” ]

The type and quantity of nutritional supplements that may be needed depend on which nutrients are deficient.

• Multivitamin/mineral combination that provides 100% once a day is useful to improve overall nutrient levels. This is a safe dose, but always check with your doctor to avoid interactions with medications.
• B-Complex vitamins as prescribed. Vitamin B12, Folic acid , and Vitamin B6 blood levels should be tested for a baseline.
• Calcium citrate is the best absorbed of calcium supplements. Calcium carbonate is a poor choice.
• Vitamin D3 as prescribed following blood test for status.
• Chelated magnesium as prescribed but do not take at same time as calcium because they compete for absorption.
• Zinc, Selenium, or Chromium as prescribed following blood test for status.

Storage Note: Store container tightly sealed, away from heat, moisture and direct light to avoid loss of potency. That is, in a safe kitchen cabinet – not in the bathroom or on the kitchen table.[/box]

• [dropcap]6[/dropcap]Manage Natural Remedies: 

[box type=”shadow” ]Hydration:

• Eight glasses of water are recommended per day unless there is a contraindication such as kidney or heart disease. The Institute of Medicine recommends approximately 2.7 liters (91 ounces) of total water, from all beverages and foods, each day for women and 3.7 liters (125 ounces) daily of total water for men.
• If you are thirsty, drink water. Add fresh, squeezed lemon to water. Lemon is anti-inflammatory, alkalizing and provides vitamin C.
• Hydration Test: Urine should be pale yellow. Fingertips should be plump, without pruning but this may not be reliable when fingers are swollen with edema. Lips should be plump, without puckering. The feeling of thirst can be unreliable.
• What is wrong with soda, coffee, tea, and alcohol? These drinks are dehydrating, increase acid, and deplete nutrients.[/box]

[box type=”shadow” ]Carminatives. The following  anti-inflammatory plant sources called carminitives help heal the digestive tract. They also tone the digestive muscles which improves peristalsis, thus aiding in the expulsion of gas from the stomach and intestine to relieve digestive colic and gastric discomfort.

Carminative Food Remedies:

• Raspberry.
• Carrot is also a cleansing digestive tonic.
• Grape is also bile stimulating and a cleansing remedy for sluggish digestion and laxative.
• Redbeets also stimulate and improve digestion and are easily digested.
• Cabbage also stimulates and improves digestion and is also a liver decongestant.
• Lettuce also stimulates and improves digestion and is also an alterative, meaning it improves the function of organs involved with the digestion and excretion of waste products to bring about a gradual change.
• Potatoes are antispasmodic (due to atropine like properties) and a liver remedy.

Carminative Herb Remedies:

• Sage is also a digestive, astringent, bile stimulant and energy tonic that heals the mucosa.  Drink as tea or use in cooking.
• Chamomile, lemon balm, and fennel, (as a tea) also help relieve nervous tension.
• Parsley also relieves indigestion.
• Rosemary as a tea and in cooking also is a nervous system tonic for stress and fatigue, bile stimulant, and can relieve headaches and indigestion.
• Thyme is also soothing remedy useful for stimulating digestion of rich, fatty foods.

Carminative Spice Remedies:

• Cloves are also antispasmodic.
• Nutmeg is also useful for indigestion.
• Ginger.[/box]

[box type=”shadow” ]Exercise Helps:

Exercise improves circulation and rids the body of toxins.

• Walking is aerobic exercise that reconditions the whole body to improve stamina. Read more about Exercise and Fitness.
• Weight training builds muscle. Read more about Exercise and Fitness.
• Stretching improves flexibilty. Read more about Exercise and Fitness.

Note: Exercise is important, but the amount and type of exercise undertaken depends on your health. Your first priority is to heal. [/box]

What Do Medical Research Studies Tell About Autoimmune Disorders In Celiac Disease and/or Gluten Sensitivity?

RESEARCH STUDY SUMMARIES

“Incidence of autoimmune diseases in celiac disease: protective effect of the gluten-free diet.” This study investigating autoimmune diseases in celiac disease aimed to determine in celiac patients which factors modulate the risk of autoimmune disease and to evaluate the effect of the gluten-free diet. Researchers found that celiac patients most at risk for autoimmune disease are those diagnosed before age 36 years and having a family history of autoimmunity. The gluten-free diet has a protective effect.

The occurrence of autoimmune disease and compliance to gluten-free diet were specified retrospectively in 924 celiac patients recruited from 27 French pediatric and adult gastroenterology centers.

RESULTS: One or several autoimmune diseases had developed in 178 patients. The cumulative risk of autoimmune disease was 8.1% +/- 1% at age 15, and 15.7% +/- 1.5% at age 30. Factors associated with an increased risk were family history of autoimmunity and diagnosis of celiac disease before 36 years of age. After diagnosis of celiac disease, 55 of 788 patients developed an autoimmune disease. The cumulative risk of subsequentautoimmune disease was lower in patients compliant to a gluten-free diet versus noncompliant patients (at 10 years, 6% +/- 2% vs 15.6% +/- 5.9%), respectively. The incidence of autoimmune diseases was 5.4 per 1000 patient-years during adherence to a gluten-free diet versus 11.3 per 1000 patient-years during nonadherence to the diet. Results were similar in both the pediatric and the adult populations¹⁰

“Increased prevalence of autoimmune diseases in first degree relatives of patients with celiac disease.” This study investigating the prevalence of autoimmune disorders in first degree relatives of patients with celiac disease demonstrated that increased prevalence is most likely connected with unrecognized subclinical or silent forms of celiac disease. 82% of first degree relatives with silent or subclinical forms of celiac disease had flat mucosa on intestinal biopsy.¹¹

“Organ-specific autoantibodies in coeliac disease: do they represent an epiphenom or the expression of associated autoimmune disorders?” This study assessing the prevalence of organ-specific autoantibodies in celiac patients and evaluating whether their finding is an expression of associated autoimmune diseases demonstrated that the finding of organ specific autoantibodies in celiac patients discloses the coexistence of a wide spectrum of immunological diseases.¹²

Hyposplenism, adult celiac disease, and autoimmunity.” This study aiming to estimate the need for a small intestinal biopsy in the investigation of hyposplenism, and to assess the relationship of autoimmunity to hyposplenism and celiac disease found that small bowel biopsy should be carried out in the investigation of unexplained hyposplenism.

During one year, the features of hyposplenism were found in blood films of 27 patients who had not had a splenectomy (removal of spleen). Ten patients were already known to have celiac disease. Intestinal biopsy was performed in another 13 patients; celiac disease was diagnosed in six. Of the 23 patients biopsied, celiac disease was present in 16 (70%). Autoantibodies were detected in significantly more patients with hyposplenism than in healthy controls, and in significantly more celiacs with hyposplenism than celiacs with normal blood films. The increased incidence of autoantibodies in celiacs with hyposplenism compared with other celiacs was not associated with a difference in the incidence of HLA-B8.¹³

CASE REPORT SUMMARIES

“Multiple Disease Associations in Autoimmune Polyglandular Syndrome Type II. “ This case report describes the course of a patient with Autoimmune Polyglandular Syndrome Type II (APS II)  with a dramatic development of eight autoimmune diseases over the course of ten years. She developed Addison’s disease, hypothyroidism, type 1 diabetes, Hashimoto’s encephalopathy, vitiligo, celiac disease, sero-negative arthritis, and ulcerative colitis. This represents a particularly aggressive course of APS II and this combination of autoimmune diseases has not been previously reported. It highlights the potential complexity and severity of the clinical course of APS II.

A 25 year old female with a history of ulcerative colitis, celiac disease and type 1 diabetes presented with mental status changes. She was diagnosed with Hashimoto’s encephalopathy and treated with high dose steroids and intravenous immunoglobulin. She recovered well from her encephalopathy but her post-hospitalization course was complicated due to the development of Addison’s disease, vitiligo, sero-negative arthritis, and hypothyroidism.¹⁴

“Treatment-refractory hypothyroidism.” This case report describes diagnosing celiac disease and subsequent adrenal insufficiency showing autoimmune polyglandular syndrome type-2 in a 49-year-old man who was referred to an endocrine clinic because of rising thyroid-stimulating hormone (TSH) levels despite increasing doses of levothyroxine.

The patient had a history of Grave’s disease, which had been successfully treated with radioiodine ablation 15 years earlier. Over the past several years, his serum TSH levels had risen to 31.5 (normal 0.4–4.5) mU/L, and the dose of levothyroxine he was prescribed had been increased to 225 μg per day, or 2.7 (usual recommended dose 1.6) μg/kg daily. The patient’s adherence to the drugs he had been prescribed was confirmed, and to exclude impaired bioavailability of the medication,a medically supervised test for the absorption of levothyroxine was performed. The results of the test showed that only 30% of the medication administered was absorbed.

In the investigation of intestinal malabsorption, the screening serum test for gluten enteropathy was abnormal; the level of immunoglobulin A antibodies against transglutaminase was 75.4 (negative < 9.0, borderline 9–16, positive > 16.0) units/mL. A subsequent endoscopic biopsy of the patient’s bowel was consistent with a diagnosis of celiac disease. The patient was directed to follow a low-gluten diet. The patient’s histological abnormalities resolved, and his serum level of TSH normalized with his usual dose of thyroxine (225 μg daily).

Because of the patient’s previous Grave’s disease, an autoimmune polyglandular syndrome was investigated. Subsequent tests showed elevated antiadrenal and 21-hydroxylase antibodies, suggesting autoimmune adrenalitis. A short intravenous adrenocorticotropic hormone (ACTH) stimulation test was consistent with diminished adrenal cortisol reserve.¹⁵

Sources:

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2. Bullen A W, Hall R, Gowland G, Rajah S, and Losowsky M S. Hyposplenism, adult coeliac disease, and autoimmunity. Gut. 1981 January; 22(1): 28–33. [↩]
3. Volta U, De Franceschi L, Molinaro N, Tetta C, Bianchi FB. Organ-specific autoantibodies in coeliac disease: do they represent an epiphenom or the expression of associated autoimmune? Italian Journal of Gastroenterology and Hepatology. Feb 1997;29(1):18-21. [↩]
4. Reunala T, Collin P. Diseases associated with dermatitis herpetiformis. British Journal of Dermatology. Mar 1997;136(3):315-8. [↩]
5. Cosnes J, Cellier C, Viola S, Colombel JF, Michaud L, Sarles J, et al. Incidence of autoimmune diseases in celiac disease: protective effect of the gluten-free diet. Clin Gastroenterol Hepatol. 2008 Jul;6(7):753-8. doi: 10.1016/j.cgh.2007.12.022. Epub 2008 Feb 6. [↩]
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7. Mutter J. Is dental amalgam safe for humans? The opinion of the scientific committee of the European Commission. J Occup Med Toxicol. 2011 Jan 13;6(1):2. doi: 10.1186/1745-6673-6-2. [↩]
8. Cummins AG, Thompson FM, Butler RN, et al. Improvement in intestinal permeability precedes morphometric recovery of the small intestine in coeliac disease. Clinical Science. Apr 2001;100(4):379-86. [↩]
9. Farhadi A, Banan A, Fields J, Keshavarzian A. Intestinal barrier: an interface between health and disease. Journal of Gastroenterology and Hepatology. 2003;18:479-91. [↩] [↩] [↩] [↩] [↩] [↩]
10. Cosnes J, Cellier C, Viola S, Colombel JF, Michaud L, Sarles J, et al. Incidence of autoimmune diseases in celiac disease: protective effect of the gluten-free diet. Clin Gastroenterol Hepatol. 2008 Jul;6(7):753-8. doi: 10.1016/j.cgh.2007.12.022. [↩]
11. Cataldo F, Marino V. Increased prevalence of autoimmune diseases in first degree relatives of patients with celiac disease. Journal of Pediatric Gastroenterology and Nutrition. Apr 2003;36(4):470-3. [↩]
12. Volta U, De Franceschi L, Molinaro N, Tetta C, Bianchi FB. Organ-specific autoantibodies in coeliac disease: do they represent an epiphenom or the expression of associated autoimmune disorders? Italian Journal of Gastroenterology and Hepatology. Feb 1997;29(1):18-21. [↩]
13. Bullen A W, Hall R, Gowland G, Rajah S, and Losowsky M S. Hyposplenism, adult coeliac disease, and autoimmunity. Gut. 1981 January; 22(1): 28–33. [↩]
14. Maturu A, Michels A, Draznin B. Multiple Disease Associations in Autoimmune Polyglandular Syndrome Type II. Endocr Pract. 2014 Aug 22:1-13. [↩]
15. Ramadhan A, Tamilia M. Treatment-refractory hypothyroidism. CMAJ. 2012 Feb 7;184(2):205-9. doi: 10.1503/cmaj.110994. [↩]