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Gluten Intolerance and
   Rheumatic Diseases
Dr. Alexander Shikhman MD PhD FACR
   Institute for Specialized Medicine
            November 2011
Gut and Rheumatic Disease
The gastrointestinal system is the main entry for foreign materials (foods)
into the human body and the main transitory route for an enormous mass
of microorganisms and products of their activity in the form of feces.

•   In an average person, the absorptive surface area of the small intestine is
    roughly 2700 square feet - the size of a tennis court

•   The total alveolar area of the lungs is equal to 1700 square feet

•   In comparison, the average skin surface area is only 17 square feet
Gut and Rheumatic Disease
• Food and microbial products are the main stimulants
  of the immune system and the main external
  regulator of various metabolic pathways.

• Accordingly, composition of the consumed food can
  influence immune responses and inflammatory
  processes leading to the development of distinct
  forms of rheumatic diseases.
Focus on Gluten Intolerance
• Most common food-driven autoimmune disease affecting
  humans

• 10 to 35% of general population are genetically
  predisposed

• The mortality rate in patients with gluten intolerance
  exceeds that in the general population by a factor of 1·9–
  3·8, mainly due to malignant diseases

• After 1–5 years on a gluten-free diet, the reduction in
  excess mortality suggests that this diet is protective against
  malignant diseases in patients with gluten intolerance
Dietary Grains and Proteins that
     Trigger Gluten Intolerance

         GRAIN                PATHOGENIC PROTEINS
WHEAT                              GLIADINS
RYE                                SEKALINS
BARLEY                            HORDEINS
                   DURUM
                    SPELT
                 TRITICALE   GLIADIN-LIKE PROTEINS
                   KAMUT
                  EINCORN
Gluten Intolerance—a disease that
       goes against the grain

Gluten intolerance is a permanent, genetically
   based intolerance to ingested gluten that
 results in chronic inflammation and systemic
             autoimmune responses
Why Gluten?
• Human digestive enzymes cannot completely digest gluten in the
  gastrointestinal tract

• Consumption results in formation of large protein fragments
  stimulating inflammatory reaction within the intestinal wall

• Gluten peptides can penetrate in systemic circulation and trigger
  immune responses in internal organs distant from the intestine
  (thyroid gland, salivary glands, brain etc)

• Gluten peptides can be detected in breast milk and can trigger
  various undesirable reaction in breast-fed infants
Genetics of Gluten Intolerance
• Patients with gluten intolerance demonstrate
  a strong association with specific HLA class II
  genotypes

• If people genetically predisposed to gluten
  intolerance do not ingest gluten, the illness
  will not manifest
Genetics of Gluten Intolerance
Approximately 95% of
patients with gluten
intolerance have a
particular type of HLA
DQ alpha and beta
chain encoded by two
genes, HLA-DQ2 (85-
90%), and HLA-DQ8 (5-
10%)
Immunology of Gluten Intolerance
• T lymphocytes invariably
  recognize gluten peptides
  that are presented by
  HLA-DQ2 orDQ8
  molecules.

• This results in the
  lymphocyte activation
  and initiation of the
  inflammatory reaction
  and autoimmune
  responses.
Genetics of Gluten Intolerance
MYO9B (myosin IXB)
gene polymorphisms is
associated with celiac
disease, ulcerative
colitis, SLE and RA
susceptibility,
presumably through
alteration of the
intestinal permeability
Spectrum of Gluten Intolerance
                                      Celiac disease
                                           3-5%


                                        Gluten intolerance without
 60-70%                                       celiac disease
  will be                                         30-35%
 affected
    by
              35-40% will develop
rheumatic
               gluten intolerance
 diseases
              during their lifetime
                                                   Latent gluten intolerance
                                                       HLA DQ2 or DQ8 +
                                                   without clinical symptoms
                                                            60-70%
Metabolic Problems Associated with
          Gluten Intolerance
• Malabsorbtion of vitamins (vitamin D, A, E, K, B1, B6),
  macroelements (iron, calcium, magnesium) and
  microelements (zinc, copper selenium)

• Leaky gut syndrome

• Pernicious anemia (vitamin B12 deficiency due to
  autoimmune damage of gastric parietal cells)

• Osteoporosis

• Disbacteriosis
Rheumatic Diseases Commonly
Associated with Gluten Intolerance
                                 OSTEOPOROSIS


                   PSEUDOGOUT                   SACROILIITIS




    FIBROMYALGIA                                               DERMATOMYOSITIS




SJOGREN’S                          GLUTEN                           PSORIASIS/PSORIATIC
SYNDROME                                                                 ARTHRITIS
                                INTOLERANCE
Sjogren’s Syndrome
Sjogren’s syndrome is an autoimmune disease
affecting glands that produce tears and saliva
(the lacrimal and salivary glands). Damage to
these glands causes a reduction in both the
quantity and quality of their secretions.
Sjogren’s Syndrome
Main symptoms are:

• Dry eyes –burning or itching, sandy feeling,
  blurry vision, light sensitivity

• Dry mouth –chalky or cotton like, difficulty
  swallowing, speaking, or tasting, dental decay
  (cavities) and mouth infections.
Sjogren’s Syndrome
Effects on other parts of the body:
• multiple sites of joint and muscle pain
• prolonged dry skin
• skin rashes on the extremities
• chronic dry cough
• vaginal dryness
• numbness or tingling in the extremities
• prolonged fatigue that interferes with daily life
Fibromyalgia
Fibromyalgia meaning muscle and connective
tissue pain. Is a disorder classified by the
presence of chronic widespread pain and a
heightened and painful response to gentle
touch.
Fybromyalgia
Other core features of the
disorder include:
• debilitating fatigue
• sleep disturbance
• joint stiffness
• difficulty with swallowing
• functional bowel and bladder abnormalities
• difficulty breathing
•  diffuse sensations of numbness and tingling (non-
  dermatomal paresthesia)
• abnormal motor activity (i.e. nocturnal myoclonus,
  sleep bruxism)
• cognitive dysfunction
Osteoporosis
• Bone disease that leads to an increased risk of fracture
• Bone mineral density is reduced
• Bone microarchitecture is disrupted
• Amount and variety of non-collagenous proteins in bone is
  altered
• No specific symptoms
• Increased risk of bone fractures.
   – Osteoporotic fractures are known as fragility or stress fractures. Typically,
     these fractures occur in the vertebral column, rib, hip and wrist
• Gluten intolerance increases risk of osteoporosis due to
  malabsorbption of vitamins (vitamin D in particular), minerals
  and microelements
Pseudogout
   Calcium Pyrophosphate Deposition Disease
• Type of arthritis that can mimic gout, and represents an
  inflammatory body reaction to the crystal deposits of
  calcium pyrophosphate
• Can cause severe episodes of localized pain and swelling
  resulting in incapacitation
• Can cause more chronic arthritis that mimics osteoarthritis
  or rheumatoid arthritis
• Knees are most often involved but wrists, shoulders, ankles,
  elbows or hands can be affected
• The most common cause of pseudogout in patients with
  gluten intolerance is vitamin D deficiency causing
  secondary hyperparathyroidism
Rheumatic Diseases Less Commonly
 Associated with Gluten Intolerance

• Scleroderma

• Rheumatoid Arthritis

• Lupus (SLE)

• Juvenile Rheumatoid Arthritis
SLE Symptoms with Potential Gluten-
         Driven Mechanism
• Aphtous stomatitis

• Intestinal vasculitis

• Mucosal dryness / Sjogren’s syndrome

• Methotrexate intolerance

• Thyroiditis
SLE Symptoms with Potential Gluten-
         Driven Mechanism
• CNS lupus: seizures, “brain fog”, vasculitis,
  encephalopathy
• Peripheral neuropathy
• Anti-phospholipid antibody syndrome
• Osteoporosis
• Malar rash
• Persistent lymphadenopathy
Nonrheumatic Diseases Commonly
Associated with Gluten Intolerance
IRRITABLE
                           DERMATITIS                   CELIAC
 BOWEL                                                                              AUTISM
                         HERPETIFORMIS                  DISEASE
SYNDROME




 BIPOLAR                  SECONDARY                                            PERIPHERAL
                                                        ADDH
DISORDER             HYPERPARATHYROIDISM                                       NEUROPATHY




                                                                  CHRONIC FATIGUE
            SEIZURE DISORDER            SCHIZOPHRENIA
                                                                    SYNDROME
Indicators of Gluten Intolerance
              Medical History

•   Thyroid disorders
•   Irritable bowel syndrome
•   Iron deficiency
•   Osteoporosis
•   Sjogren’s syndrome
•   Asthma
Indicators of Gluten Intolerance
        Skin Conditions
KERATOSIS    PERIUNGUAL    DERMATITIS
 PILARIS      ERYTHEMA    HERPETIFORMIS
Laboratory Findings Suspicious for
    Gluten-Driven Autoimmune Process

•   Low levels of vitamin D1 or D3
•   Elevated PTH
•   Positive anti-neuronal antibodies
•   Positive anti-SSA/SSB antibodies
•   Positive anti-cardiolipin antibodies
•   Hyperprolactinemia
•   Persistently elevated 2-microglobulin
•   Positive anti-TPO antibodies
•   Low level of vitamin A or retinol
How to Diagnose Gluten Intolerance
• Genetic testing

• Immunologic testing
   – blood
   – Feces

• Intestinal / colon biopsy

• Elimination diet with subsequent gluten
  challenge
Treatment of Gluten Intolerance
                     ELIMINATION OF
                        GLUTEN




                                      CORRECTION
        TUMOR                            OF
      SURVEILLANCE                    METABOLIC
                                      DISORDERS




                      CORRECTION
                          OF
                        IMMUNE
                       RESPONSES
Elimination of Gluten



              Management of    Desorption of
Gluten-Free
                 Gluten         Gluten from
    Diet
              Contamination   Intestinal Lining
Elimination of Gluten
       Gluten-containing grains to avoid
Wheat          Bulgar           Filler
Wheat Bran     Couscous         Triticale
Wheat Starch   Durum            Kamut
Wheat Germ     Einkorn          Matzo
Flour/Meal     Emmer            Barley
Semolina       Faro             Barley Malt/Extract
Spelt          Rye              Graham Flour
Elimination of Gluten
     Obvious Sources        Potential Sources
•   Bread               •   Candy
•   Bagels              •   Communion wafers
•   Cakes               •   Cured pork products
•   Cookies             •   Drink mixes
                        •   Gravy
•   Pasta/noodles
                        •   Imitation meat/seafood
•   Cereal
                        •   Sauce
•   Pastries/pies       •   Self-basting turkeys
•   Rolls               •   Soy sauce
Elimination of Gluten
•   Lipstick/gloss/balms
•   Mouthwash/toothpaste
•   Play dough
•   Stamp and envelope glues
•   Prescription or OTC medications
•   Vitamin, herbal and mineral preparations
Elimination of Gluten
• Only 50% of Americans with a chronic illness
  adhere to their treatment including:
  – Diet
  – Exercise
  – Medication
Correction of Metabolic Disorders
• Management of malabsorption and leaky gut
  syndrome

• Therapy of hormonal imbalance

• Management of osteopenia and osteoporosis
Correction of Metabolic Disorders
•   Low Iron               • Low B6 (rare)
•   Low Folate             • Low Beta-carotene
•   Low Vitamin B12        • Low Zinc
•   Low Vitamins A,D,E,K   • Essential fatty acid
•   Low Thiamine             deficiency
                           • Low Niacine
Correction of Immune Responses

• Therapy of autoimmune disorders

• Normalization of gastrointestinal ecology
Tumor Surveillance

• Biochemical markers

• Physical surveillance
• Institute for Specialized Medicine (www.ifsmed.com) was founded in
  San Diego in 2008

• The mission of the institute is to provide comprehensive medical care
  for chronic inflammatory, autoimmune and metabolic diseases

• Our philosophy is based on an integrative approach of patient
  care, which includes the most advanced technologies in traditional
  medicine in combination with the best of complementary therapies
Alexander R. Shikhman MD PhD FACR
         www.ifsmed.com

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Gluten Intolerance and Rheumatic Diseases

  • 1. Gluten Intolerance and Rheumatic Diseases Dr. Alexander Shikhman MD PhD FACR Institute for Specialized Medicine November 2011
  • 2. Gut and Rheumatic Disease The gastrointestinal system is the main entry for foreign materials (foods) into the human body and the main transitory route for an enormous mass of microorganisms and products of their activity in the form of feces. • In an average person, the absorptive surface area of the small intestine is roughly 2700 square feet - the size of a tennis court • The total alveolar area of the lungs is equal to 1700 square feet • In comparison, the average skin surface area is only 17 square feet
  • 3. Gut and Rheumatic Disease • Food and microbial products are the main stimulants of the immune system and the main external regulator of various metabolic pathways. • Accordingly, composition of the consumed food can influence immune responses and inflammatory processes leading to the development of distinct forms of rheumatic diseases.
  • 4. Focus on Gluten Intolerance • Most common food-driven autoimmune disease affecting humans • 10 to 35% of general population are genetically predisposed • The mortality rate in patients with gluten intolerance exceeds that in the general population by a factor of 1·9– 3·8, mainly due to malignant diseases • After 1–5 years on a gluten-free diet, the reduction in excess mortality suggests that this diet is protective against malignant diseases in patients with gluten intolerance
  • 5. Dietary Grains and Proteins that Trigger Gluten Intolerance GRAIN PATHOGENIC PROTEINS WHEAT GLIADINS RYE SEKALINS BARLEY HORDEINS DURUM SPELT TRITICALE GLIADIN-LIKE PROTEINS KAMUT EINCORN
  • 6. Gluten Intolerance—a disease that goes against the grain Gluten intolerance is a permanent, genetically based intolerance to ingested gluten that results in chronic inflammation and systemic autoimmune responses
  • 7. Why Gluten? • Human digestive enzymes cannot completely digest gluten in the gastrointestinal tract • Consumption results in formation of large protein fragments stimulating inflammatory reaction within the intestinal wall • Gluten peptides can penetrate in systemic circulation and trigger immune responses in internal organs distant from the intestine (thyroid gland, salivary glands, brain etc) • Gluten peptides can be detected in breast milk and can trigger various undesirable reaction in breast-fed infants
  • 8. Genetics of Gluten Intolerance • Patients with gluten intolerance demonstrate a strong association with specific HLA class II genotypes • If people genetically predisposed to gluten intolerance do not ingest gluten, the illness will not manifest
  • 9. Genetics of Gluten Intolerance Approximately 95% of patients with gluten intolerance have a particular type of HLA DQ alpha and beta chain encoded by two genes, HLA-DQ2 (85- 90%), and HLA-DQ8 (5- 10%)
  • 10. Immunology of Gluten Intolerance • T lymphocytes invariably recognize gluten peptides that are presented by HLA-DQ2 orDQ8 molecules. • This results in the lymphocyte activation and initiation of the inflammatory reaction and autoimmune responses.
  • 11. Genetics of Gluten Intolerance MYO9B (myosin IXB) gene polymorphisms is associated with celiac disease, ulcerative colitis, SLE and RA susceptibility, presumably through alteration of the intestinal permeability
  • 12. Spectrum of Gluten Intolerance Celiac disease 3-5% Gluten intolerance without 60-70% celiac disease will be 30-35% affected by 35-40% will develop rheumatic gluten intolerance diseases during their lifetime Latent gluten intolerance HLA DQ2 or DQ8 + without clinical symptoms 60-70%
  • 13. Metabolic Problems Associated with Gluten Intolerance • Malabsorbtion of vitamins (vitamin D, A, E, K, B1, B6), macroelements (iron, calcium, magnesium) and microelements (zinc, copper selenium) • Leaky gut syndrome • Pernicious anemia (vitamin B12 deficiency due to autoimmune damage of gastric parietal cells) • Osteoporosis • Disbacteriosis
  • 14. Rheumatic Diseases Commonly Associated with Gluten Intolerance OSTEOPOROSIS PSEUDOGOUT SACROILIITIS FIBROMYALGIA DERMATOMYOSITIS SJOGREN’S GLUTEN PSORIASIS/PSORIATIC SYNDROME ARTHRITIS INTOLERANCE
  • 15. Sjogren’s Syndrome Sjogren’s syndrome is an autoimmune disease affecting glands that produce tears and saliva (the lacrimal and salivary glands). Damage to these glands causes a reduction in both the quantity and quality of their secretions.
  • 16. Sjogren’s Syndrome Main symptoms are: • Dry eyes –burning or itching, sandy feeling, blurry vision, light sensitivity • Dry mouth –chalky or cotton like, difficulty swallowing, speaking, or tasting, dental decay (cavities) and mouth infections.
  • 17. Sjogren’s Syndrome Effects on other parts of the body: • multiple sites of joint and muscle pain • prolonged dry skin • skin rashes on the extremities • chronic dry cough • vaginal dryness • numbness or tingling in the extremities • prolonged fatigue that interferes with daily life
  • 18. Fibromyalgia Fibromyalgia meaning muscle and connective tissue pain. Is a disorder classified by the presence of chronic widespread pain and a heightened and painful response to gentle touch.
  • 19. Fybromyalgia Other core features of the disorder include: • debilitating fatigue • sleep disturbance • joint stiffness • difficulty with swallowing • functional bowel and bladder abnormalities • difficulty breathing • diffuse sensations of numbness and tingling (non- dermatomal paresthesia) • abnormal motor activity (i.e. nocturnal myoclonus, sleep bruxism) • cognitive dysfunction
  • 20. Osteoporosis • Bone disease that leads to an increased risk of fracture • Bone mineral density is reduced • Bone microarchitecture is disrupted • Amount and variety of non-collagenous proteins in bone is altered • No specific symptoms • Increased risk of bone fractures. – Osteoporotic fractures are known as fragility or stress fractures. Typically, these fractures occur in the vertebral column, rib, hip and wrist • Gluten intolerance increases risk of osteoporosis due to malabsorbption of vitamins (vitamin D in particular), minerals and microelements
  • 21. Pseudogout Calcium Pyrophosphate Deposition Disease • Type of arthritis that can mimic gout, and represents an inflammatory body reaction to the crystal deposits of calcium pyrophosphate • Can cause severe episodes of localized pain and swelling resulting in incapacitation • Can cause more chronic arthritis that mimics osteoarthritis or rheumatoid arthritis • Knees are most often involved but wrists, shoulders, ankles, elbows or hands can be affected • The most common cause of pseudogout in patients with gluten intolerance is vitamin D deficiency causing secondary hyperparathyroidism
  • 22. Rheumatic Diseases Less Commonly Associated with Gluten Intolerance • Scleroderma • Rheumatoid Arthritis • Lupus (SLE) • Juvenile Rheumatoid Arthritis
  • 23. SLE Symptoms with Potential Gluten- Driven Mechanism • Aphtous stomatitis • Intestinal vasculitis • Mucosal dryness / Sjogren’s syndrome • Methotrexate intolerance • Thyroiditis
  • 24. SLE Symptoms with Potential Gluten- Driven Mechanism • CNS lupus: seizures, “brain fog”, vasculitis, encephalopathy • Peripheral neuropathy • Anti-phospholipid antibody syndrome • Osteoporosis • Malar rash • Persistent lymphadenopathy
  • 25. Nonrheumatic Diseases Commonly Associated with Gluten Intolerance IRRITABLE DERMATITIS CELIAC BOWEL AUTISM HERPETIFORMIS DISEASE SYNDROME BIPOLAR SECONDARY PERIPHERAL ADDH DISORDER HYPERPARATHYROIDISM NEUROPATHY CHRONIC FATIGUE SEIZURE DISORDER SCHIZOPHRENIA SYNDROME
  • 26. Indicators of Gluten Intolerance Medical History • Thyroid disorders • Irritable bowel syndrome • Iron deficiency • Osteoporosis • Sjogren’s syndrome • Asthma
  • 27. Indicators of Gluten Intolerance Skin Conditions KERATOSIS PERIUNGUAL DERMATITIS PILARIS ERYTHEMA HERPETIFORMIS
  • 28. Laboratory Findings Suspicious for Gluten-Driven Autoimmune Process • Low levels of vitamin D1 or D3 • Elevated PTH • Positive anti-neuronal antibodies • Positive anti-SSA/SSB antibodies • Positive anti-cardiolipin antibodies • Hyperprolactinemia • Persistently elevated 2-microglobulin • Positive anti-TPO antibodies • Low level of vitamin A or retinol
  • 29. How to Diagnose Gluten Intolerance • Genetic testing • Immunologic testing – blood – Feces • Intestinal / colon biopsy • Elimination diet with subsequent gluten challenge
  • 30. Treatment of Gluten Intolerance ELIMINATION OF GLUTEN CORRECTION TUMOR OF SURVEILLANCE METABOLIC DISORDERS CORRECTION OF IMMUNE RESPONSES
  • 31. Elimination of Gluten Management of Desorption of Gluten-Free Gluten Gluten from Diet Contamination Intestinal Lining
  • 32. Elimination of Gluten Gluten-containing grains to avoid Wheat Bulgar Filler Wheat Bran Couscous Triticale Wheat Starch Durum Kamut Wheat Germ Einkorn Matzo Flour/Meal Emmer Barley Semolina Faro Barley Malt/Extract Spelt Rye Graham Flour
  • 33. Elimination of Gluten Obvious Sources Potential Sources • Bread • Candy • Bagels • Communion wafers • Cakes • Cured pork products • Cookies • Drink mixes • Gravy • Pasta/noodles • Imitation meat/seafood • Cereal • Sauce • Pastries/pies • Self-basting turkeys • Rolls • Soy sauce
  • 34. Elimination of Gluten • Lipstick/gloss/balms • Mouthwash/toothpaste • Play dough • Stamp and envelope glues • Prescription or OTC medications • Vitamin, herbal and mineral preparations
  • 35. Elimination of Gluten • Only 50% of Americans with a chronic illness adhere to their treatment including: – Diet – Exercise – Medication
  • 36. Correction of Metabolic Disorders • Management of malabsorption and leaky gut syndrome • Therapy of hormonal imbalance • Management of osteopenia and osteoporosis
  • 37. Correction of Metabolic Disorders • Low Iron • Low B6 (rare) • Low Folate • Low Beta-carotene • Low Vitamin B12 • Low Zinc • Low Vitamins A,D,E,K • Essential fatty acid • Low Thiamine deficiency • Low Niacine
  • 38. Correction of Immune Responses • Therapy of autoimmune disorders • Normalization of gastrointestinal ecology
  • 39. Tumor Surveillance • Biochemical markers • Physical surveillance
  • 40. • Institute for Specialized Medicine (www.ifsmed.com) was founded in San Diego in 2008 • The mission of the institute is to provide comprehensive medical care for chronic inflammatory, autoimmune and metabolic diseases • Our philosophy is based on an integrative approach of patient care, which includes the most advanced technologies in traditional medicine in combination with the best of complementary therapies
  • 41. Alexander R. Shikhman MD PhD FACR www.ifsmed.com