4/30/15 1 Autoimmune Polyglandular Failure Mark S. Anderson, MD, PhD Professor UCSF Diabetes Center Goals • Review clinical Autoimmune Polyglandular Failure syndromes • Disease spectrum • Broad treatment, diagnostic recommendations • Highlight newly discovered mechanism of disease for APS type I • May have applications to more common autoimmune diseases
30
Embed
Autoimmune Polyglandular Failure - UCSF CME Anderson Autoimmune Diseases... · library, using serum samples from patients with APS-1 and hypoparathyroidism, to identify patients with
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
• 2 of the 3 required for diagnosis • Multiple minor clinical features
4/30/15
4
APS I: Clinical Presentation #
Cas
es (n
=41)
Betterle, JCEM 1998; 83(4):1050
Mucocutaneous Candidiasis • Most frequent major clinical feature (93%) • Presents: 1 month to 21 years of age • Affects nails, dermis, oral, vaginal, and
• Second major clinical manifestation • Occurs in 73-90% of APS 1 patients • Presents: 3 months to 44 years of age • Diagnosis: Ionized Ca/PTH • Nalp5 autoantibodies as a marker
4/30/15
6
original article
T h e n e w e ng l a nd j o u r na l o f m e dic i n e
n engl j med 358;10 www.nejm.org march 6, 20081018
Autoimmune Polyendocrine Syndrome Type 1 and NALP5, a Parathyroid Autoantigen
Marcel P. Keller, Ph.D., Olov Ekwall, M.D., Ph.D., Sarah A. Kinkel, B.Sc., Eystein S. Husebye, M.D., Ph.D., Jan Gustafsson, M.D., Ph.D., Fredrik Rorsman, M.D., Ph.D., Leena Peltonen, M.D., Ph.D.,
Corrado Betterle, M.D., Ph.D., Jaakko Perheentupa, M.D., Ph.D., Göran Åkerström, M.D., Ph.D., Gunnar Westin, Ph.D., Hamish S. Scott, Ph.D.,
Georg A. Holländer, M.D., and Olle Kämpe, M.D., Ph.D.
From University Hospital, Uppsala Uni-versity, Uppsala, Sweden (M.A., P.B., Å.H., O.E., J.G., F.R., G.Å., G.W., O.K.); Univer-sity of Helsinki and the National Public Health Institute, Biomedicum Helsinki (N.P., L.P.), and the Hospital for Children and Adolescents, Helsinki University Hos-pital ( J.P.) — both in Helsinki; Laboratory of Pediatric Immunology, University of Basel, and the University Children’s Hos-pital — both in Basel, Switzerland (G.S., N.S., M.P.K., G.A.H.); the Walter and Eliza Hall Institute of Medical Research and the University of Melbourne — both in Park-ville, Victoria, Australia (S.A.K., H.S.S.); the Institute of Medicine, University of Bergen, and Haukeland University Hos-pital — both in Bergen, Norway (E.S.H.); and the University of Padua, Padua, Italy (C.B.). Address reprint requests to Dr. Kämpe at the Department of Medical Sci-ences, Uppsala University Hospital, SE 75185, Uppsala, Sweden, or at [email protected].
BACKGROUNDAutoimmune polyendocrine syndrome type 1 (APS-1) is a multiorgan autoimmune disorder caused by mutations in AIRE, the autoimmune regulator gene. Though re-cent studies concerning AIRE deficiency have begun to elucidate the molecular pathogenesis of organ-specific autoimmunity in patients with APS-1, the autoanti-gen responsible for hypoparathyroidism, a hallmark of APS-1 and its most common autoimmune endocrinopathy, has not yet been identified.
MethodsWe performed immunoscreening of a human parathyroid complementary DNA library, using serum samples from patients with APS-1 and hypoparathyroidism, to identify patients with reactivity to the NACHT leucine-rich-repeat protein 5 (NALP5). Subsequently, serum samples from 87 patients with APS-1 and 293 controls, includ-ing patients with other autoimmune disorders, were used to determine the frequency and specificity of autoantibodies against NALP5. In addition, the expression of NALP5 was investigated in various tissues.
ResultsNALP5-specific autoantibodies were detected in 49% of the patients with APS-1 and hypoparathyroidism but were absent in all patients with APS-1 but without hypo-parathyroidism, in all patients with other autoimmune endocrine disorders, and in all healthy controls. NALP5 was predominantly expressed in the cytoplasm of para-thyroid chief cells.
ConclusionsNALP5 appears to be a tissue-specific autoantigen involved in hypoparathyroidism in patients with APS-1. Autoantibodies against NALP5 appear to be highly specific and may be diagnostic for this prominent component of APS-1.
• Affected patients have lifetime susceptibility to multiple organ-specific autoimmune diseases. Vigilant follow-up by an endocrinologist at least quarterly with replacement Rx carefully monitored.
• Particular attention to hypocalcemia and a low threshold for working up at risk syndromes is essential
• Immunosuppression only used in non-endocrine autoimmune diseases (i.e. autoimmune hepatitis)
• ?Role of genetic testing and counseling now that the causative gene has been identified
On Web: http://www.geneclinics.org/servlet/access?
• Onset late childhood to adulthood, peak is in third decade
• Females more commonly affected; at least 3:1 ratio
• Genetics complex; HLA DR/DQ
4/30/15
14
APS I (%) APS II (%) Comparative Frequency Less Common More Common Onset Infancy/early childhood Late childhood/adulthood Heredity Autosomal Recessive Polygenic Gender Male = Females Female Predominance Genetics AIRE gene; no HLA association HLA association; DR/DQ Hypoparathyroidism 77-89 None Mucocutaneous candiditis 73-100 None Ectodermal dysplasia 77 None Addison’s Disease 60-86 70-100 Type 1 Diabetes 4-18 41-52 Autoimmune thyroid disease 8-10 70 Pernicious anemia 12-15 2-25 Gonandal failure Females 30-60 3.5-10 Males 7-17 5 Vitiligo 4-13 4-5 Alopecia 27 2 Autoimmune hepatitis 10-15 Rare Malabsorption 10-18 Rare
Addison’s Disease • 50% of APS II cases present with Addison’s • Adrenal cortex Ab (anti-21 Hydroxylase) near 100% at Dx • Anti-adrenal Ab’s positive predicitive value • Diagnosis based on Cortrosyn Stimulation Test, elevated
ACTH, and clinical picture (hyponatremia, hyperkalemia). • Traditional management with corticosteroid replacement
(including mineralocorticoid rx) • ** Should be ruled out in suspected APS patients starting
thyroid replacement
4/30/15
15
Diabetes Mellitus Type 1
• Screening with fasting glucose and anti-GAD, I-A2, insulin Antibodies
• **Patients with co-existing Addison’s are excellent candidates for treatment with Glargine Insulin for prevention of hypoglycemia.
Celiac Disease • Relatively common in APS II patients • Disease risk very strong correlation with HLA-DQA1*0501
DQB1*0201 • Seen in >90% of cases • Also a risk allele for other APS II syndromes
• Antibody screening with anti-transglutaminase and anti-endomysial antibodies as a screen. If positive small bowel biopsy if diagnosis still uncertain.
• Antibody tests are excellent screen with anti-endomysial sensitivity and specificity 90 and 98%
4/30/15
16
Gonadal Autoimmunity • Occurs before age 40 in 10-20% of female
patients • Anti-Cyp450side chain or 17-OH
autoantibodies have predictive value for disease
• Fertility counseling
Autoantibody Screening Disease Autoantibody Sens/Spec Type 1 DM GAD, I-A2,Insulin Addison’s 21-OH Thyroid TPO, Tg, TSI All generally>90% Sens
• Affected patients have lifetime susceptibility to multiple organ-specific autoimmune diseases. Vigilant follow-up by an endocrinologist at least bi-annually with replacement Rx carefully monitored.
• Celiac disease should be screened for with autoantibody testing
• Females are at risk for premature ovarian failure and this should be carefully assessed
• Screening for Vit B12 deficiency at least annually • ** in newly diagnosed patients care must be taken with
starting thyroid replacement to rule out Addison’s disease.
Given the severity of autoimmunity in these
syndromes, can they provide a clue as to how autoimmune
disease occurs?
4/30/15
18
APS I: Genetics
• Autosomal recessive • Populations specific incidence
• 1 in 25,000 Finland • 1 in 9,000 Iranian Jewish descent • Sardinia
• Founder effect and genetic isolation • No HLA association • Variable phenotype among siblings
APECED: Genetics
p11-
13
q11
q21.
1
q21.
2
q21.
3
q22.
11
q22.
12
q22.
13
q22.
2
q22.
3
Chromosome 21
D21
S156
D
21S4
16
D21
S224
D
21S2
35
D21
S212
D
21S1
225
D21
S49
PFK
L D
21S1
71
Aaltonen, Nature Genetics 1994; 8(1):83 APECED
4/30/15
19
APECED Gene
• 1997: Two groups simultaneously reported isolation of the APECED gene by positional cloning