Autoimmune polyendocrine syndromes

Autoimmune polyendocrine syndromes

1. Autoimmune polyglandular syndromes. Types, pathogenesis, diagnosis, management Dr. Tarun P Betha 2nd year internal medicine resident Poona hospital and research centre

2. Outline Introduction Types APS1 APS2 IPEX

3. Introduction Autoimmune polyendocrine syndromes are insidious and are characterised by circulating autoantibodies and lymphocytic infiltration of the endocrine tissues and organs, eventually leading to organ failure. Source: Cecil textbook of medicine

4. Types Autoimmune polyglandular syndrome type 1 Autoimmune polyglandular syndrome type 2 IPEX * *immunedysregulation, polyendocrinopathy, enteropathy, x linked

5. Autoimmune polyglandular syndrome type 1 Also called polyendocrinopathy-candidiasis-Ectodermal dystrophy. (APECED) Autosomal recessive. Mutation in AIRE gene. Highest prevalence in Finnish countries.

6. APS1 cont’d Cardinal components Hypoparathyroidism Addisson’s disease Chronic mucocutaneous candidasis

7. Enamel hypoplasia Premature ovarian failure (60% in females) Testicular failure (rare) Bilateral keratitis Autoimmune hepatitis Nephritis, pancreatitis, asplenia. APS1 cont’d Other features

8. Chronic mucocutaneous candidiasis- squamous cell Ca (common cause of death) Other causes of death include- Hypocalcemic crisis, adrenal crisis. APS1 cont’d

9. APS1 cont’d Genetics and mechanisms ‘AIRE’ gene mTEC medullary thymic epithelial cells Source: NEJM

10. Mutations in AIRE gene. Absence of regulatory T cells. Auto reactive T cells escape removal These cells then act on the auto antigens which leads to disease in various organs. APS1 cont’d

11. APS1 cont’d Mutations Finnish major mutation (p.R257X). 13 base pair deletion in histone proteins. Autoantibodies NALP5 GAD65 21 hydroxylase Type 1 Interferon Source: NEJM

12. Autoimmune polyglandular syndrome type 2 More common Women predominate. Onset - young adult hood. Diagnosis - clinical features and autoantibodies identification.

13. Celiac disease Alopecia Vitiligo Primary ovarian insufficiency Pernicious anemia. APS2 cont’d Cardinal components Type 1 diabetes Mellitus Hypothyroidism Addison’s disease Other features

14. Polygenic- MHC etc DR3-DQ2, DR4-DQ8 Antibodies against TPO, GAD65, 21 hydroxylase are seen. APS2 cont’d Genetics and mechanisms

15. Diagnostic evaluation Source: NEJM

16. IPEX X linked Polyendocrinopathy Enteropathy Early onset type 1 diabetes Mellitus. Classically presents in infancy.

17. IPEX cont’d

18. Cardinal components Life threatening chronic diarrhoea Autoimmune endocrinopathy (type 1 DM or thyroiditis) Dermatitis IPEX cont’d Other features Immune related cytopenia. Nephritis Hyper reactivation of immune system to infections Allergic airway disease. Source: NEJM

19. Mutations FOXP3 gene mutations IPEX cont’d Other manifestations Gastrointestinal Endocrinopathies (diabetes m/c, thyroiditis, hypoadrenalism, growth hormone deficiency) Haematological disorders (haemolytic anemia’s, thrombocytopenia, neutropenia) Sepsis (enterococcal, staphylococcal, cytomegalovirus, Candida)

20. IPEX cont’d Lab evaluation

21. Source: NEJM

22. Management Outline General management Hormone replacement Patient education

23. Mucocutaneous candidiasis General management Antifungals Topical antifungals (clotrimazole oral paste) Oral antifungals (fluconazole, ketoconazole) Fluconazole : Oral: Loading dose of 200 mg on day 1 , then 100 to 200 mg once daily for 7 to 14 days; recommended for patients unresponsive to topical therapy or those with moderate to severe infection Source: medscape

24. Management cont’d Hypoparathyroidism Source: UpToDate

25. Type 1 Diabetes Mellitus HbA1c targets in most adults is 7% and 7.5% in children and adolescents (ADA). Target glucose range is 70- 180mg/dL Insulin replacement goal- intensive regimen. Meal time bonuses of rapid acting insulin. Management cont’d

26. Source: uptodate

27. Modified intensive regimen : offers benefit of fewer injections during school hours and flexibility around meals while at home. This includes NPH + rapid acting insulin at breakfast. Insulin glargine or detemir with dose of rapid acting insulin at dinner. This regimen avoids need of lunch time dose of insulin. Management cont’d

28. Intensive insulin regimen: closely approaches physiologic insulin secretion. Basal insulin + with premeal and presnack boluses of rapid acting insulin. Intensive insulin regimen showed better results in adults. * *In adults DCCT (diabetes control and complication trial) demonstrated intensive insulin therapy achieved better glycemic control and reduced long term sequelae. Management cont’d Source: UpToDate

29. Investigational therapies for type 1 diabetes Mellitus in children. Diabetes prevention- trials of vaccine against GAD, Rituximab, teplizumab. Artificial pancreas. Adjunctive therapies- pramlintide- most promising. Transplantation- limited to adults. Management cont’d

30. Thyroiditis Hyperthyroid phase- symptomatic treatment. propranolol 40-120 mg daily atenolol 25 to 50 daily Thyroid function should be monitored every 4 to 8 weeks. Glucocorticoids can be used in severe cases. Management cont’d

31. Hypothyroid phase- Treat when TSH exceeds 10mU/L, even in absence of symptoms. Usual dose of T4 is 50 to 100 mcg daily. Thyroid levels are monitored every 4 to 6 weeks. Management cont’d

32. Autoimmune enteropathy (IPEX) Management cont’d Acute management Correcting electrolyte derangement and hydration Treating infections Isolation to prevent nosocomial infections Immunesuppression Source: UpToDate

33. Management cont’d Long term management Intensive immune suppression (high dose prednisolone)
Steroid sparing agents- tacrolimus, cyclosporine, sirolimus. Nutrition- extensively formalised feeds to reduce exposure to allergens.
Replacing vitamins and minerals. Avoidance of vaccination- these can trigger fatal flares (IPEX) Hematopoetic stem cell transplantation Source: UpToDate

34. Pernicious anemia Replacement with cyanocobalamin is the goal of therapy. 1 mg IM once a day for 7 days, and then weekly for 1-2 months or until the hemoglobin is normalized. Long-term therapy is 1 mg/mo. Correction of hypokalemia. Management cont’d Source: medscape

35. Thyroid hormone replacement. premature ovarian failure OCP till the age of 50 to 51 years to all women with POI to manage estrogen deficiency symptoms, prevent long term risks. Management cont’d Hormone replacement

36. Estrogen-progesterone hormone therapy- transdermal estradiol (100mcg daily) or estradiol vaginal ring (100 mcg daily). Young women - low doses. Management cont’d Source: UpToDate

37. Progestin- first line progestin is micronised progesterone 200 mg per day for first 12 days of month. MPA (10 mg daily for 12 days per calendar month). Exogenous gonadotropin is ineffective. IVF with donor oocytes. Management cont’d Source: UpToDate

38. Oral capsule: Testosterone undecanoate: Initial: 237 mg twice daily. Dosage range: 158 to 396 mg twice daily. Pellet (for subcutaneous implantation): 150 to 450 mg every 3 to 6 months. SubQ (testosterone enanthate): Initial: 75 mg once weekly. Dosage range: 50 to 100 mg once weekly. Testosterone replacement Source: UpToDate

39. Buccal: 30 mg twice daily (every 12 hours) applied to the gum region above the incisor tooth. IM (testosterone enanthate or testosterone cypionate): Initial: 75 to 100 mg/week or 150 to 200 mg every 2 weeks; dosage range: 50 to 100 mg/week or 100 to 200 mg every 2 weeks (AUA [Mulhall 2018]; Endocrine Society [Bhasin 2018]). IM (testosterone undecanoate): Initial: 750 mg, followed by 750 mg administered 4 weeks later, then 750 mg administered every 10 weeks thereafter. Management cont’d Source: UpToDate

40. Replace steroids: ~15–25mg hydrocortisone daily, 2 –3 doses, eg: 10mg on waking, 5mg lunchtime. Avoid giving late (may cause insomnia). Mineralocorticoids to correct postural hypotension, Na+, K+: fludrocortisone PO from 50–200mcg daily. Adrenal insufficiency Management cont’d

41. Management cont’d Adrenal crisis

42. Asplenia vaccination and antibiotic prophylaxis Recommended vaccines 13-valent pneumococcal conjugate vaccine (PCV13) 23-valent pneumococcal polysaccharide vaccine (PPSV23) H. influenzae type b vaccine (Hib) Quadrivalent meningococcal conjugate ACWY vaccine series (MenACWY) Monovalent meningococcal serogroup B vaccine series (MenB-4C or MenB-FHbp) Management cont’d

43. Vaccination schedule Management cont’d Source: UpToDate

44. Immunocompromising conditions (eg, hematologic malignancy, hypogammaglobulinemia, solid organ transplantation, advanced liver disease, or HIV infection) antibiotic prophylaxis Management cont’d Daily antibiotic prophylaxis until age 5 and for at least one year. Immunocompromised - at least 18 yrs or until immunocompromised status or lifelong. history of sepsis or other severe infections caused by encapsulated organisms (eg, S. pneumoniae ), - lifelong prophylaxis. adults- daily antibiotic prophylaxis for at least one year. Source: UpToDate

45. antibiotic prophylaxis - cont’d Management cont’d Source: UpToDate

46. Outpatient management should include patient education on the various components of polyglandular autoimmune (PGA) syndrome, and the need to screen close relatives as appropriate. An important aspect of patient education is the provision of information about adrenal deficiency; subtle deficiency that goes unnoticed in normal, daily-life situations may become life-threatening in stressful situations. Patient education

47. Because  multiple  components  of  the syndrome can appear  asynchronously , periodic  evaluation for  the early  appearance  of  additional  disease  components  is  indicated. Source: Oxford handbook of clinical medicine.

48. Thank you