Juan-Manuel Anaya, MD, PhD
Center for Autoimmune Diseases Research
Universidad del Rosario
Bogota, Colombia
Polyautoimmuni...
Polyautoimmunity
 Polyautoimmunity:
Autoimmune diseases (ADs)
co-occurring within patients.
 Multiple Autoimmune
Syndrom...
Multiple Autoimmune Syndromes
Humbert P, Dupond JL. Ann Med Interne Paris 1988;139:159-68.
Three or more well defined auto...
Polyautoimmunity
 Polyautoimmunity in RA, SS, SLE,
and other autoimmune diseases.
 Factors influencing
polyautoimmunity
...
Polyautoimmunity in Rheumatoid Arthritis
• 130/ 955 (13.6%) patients disclosed polyautoimmunity.
• 161 additional ADs were...
Familial Autoimmunity and Polyautoimmunity in RA
When familial autoimmunity was present, the risk of developing polyautoim...
Familial RA and Polyautoimmunity
Anaya JM, et al. EULAR 2015 THU0152
Toxics and Polyautoimmunity in RA
Anaya JM, et al. EULAR 2015 THU0152
Multiple Autoimmune Syndrome
and extra-articular manifestations in RA
Anaya JM, et al. EULAR 2015 THU0152
RA RA + 1
Autoim...
Rhupus (SLE&RA)
Amaya-Amaya J, et al. Lupus. 2015 Feb 9.
Characteristics of patients with Rhupus
(as compared with SLE pat...
Polyautoimmunity in Systemic Lupus Erythematosus
0%
5%
10%
15%
20%
25%
30%
35%
40%
APS SS AITD
Rojas-Villarraga A, et al. ...
Factors Influencing Polyautoimmunity
in Systemic Lupus Erythematosus
Variable AOR 95% CI p
Gender (female) 2.30 1.03 5.15 ...
Does ancestry influence
polyautoimmunity?
• Population: 508 individuals: 240 single autoimmune disease,
51 with polyautoimmunity, 36 with MAS, and 181 matched-
cont...
Reference populations and
Colombian population.
Ameridian Ancestry Influences Polyautoimmunity
Molano-González N et al. Su...
Ameridian Ancestry Influences Polyautoimmunity
Amerindian ancestry European ancestry
p: 0.001 p: 0.003
Molano-González N e...
Autoimmune Thyroid Disease in Systemic Lupus Erythematosus
Franco J, et al. Clin Endocrinol (Oxf). 2014 Nov 8.
Sjögren's syndrome and smoking
are predictive factors associated with the development of AITD in SLE
Franco J, et al. Clin...
Autoimmune Diseases
Prevalence
N = 410 (%)
SS alone 275 (67)
SS + AD (Polyautoimmunity) 135 (33)
SS + 1 AD 101 (24.6)
SS +...
Characteristic SS alone
N=276
SS – PA
N=134
p
Disease duration 4 (6) 7.86 (7) 0.003
Age at diagnosis 46.7 ± 14.8 47.9 ± 14...
21.5
8.3 7.6
2.6
1.4 1.1 0.7 0.3 0.4 0.4 0.4 0.4
0
5
10
15
20
25
AITD RA SLE APS SSc VAS IBD MS VIT AIH PSO PeA
Autoimmune...
8
7
6 6
0
2
4
6
8
10
SS-AITD-SLE SS-AITD-RA SS-SLE-APS SS-SLE-RA
Polyautoimmunity in Sjögren's Syndrome
MAS cases
MAS phen...
Characteristic
SS Alone
%
SS-PA
%
AOR 95% CI p
Positive smoking
status
27.6 51.5 2.86 1.18-6.94 0.02
Spontaneous
abortions...
Systemic Sclerosis. 38%
Hudson M, et al. J Autoimmun 2008;31:156-9.
Elhai M, et al. Autoimmun Rev. 2013;12:1052-7.
Primary...
Clustering of autoimmune diseases is not random
Anaya et al. Clin Rev Allergy Immunol. 2012;43:256-64.
Polyautoimmunity
 Polyautoimmunity in SS, SLE, and
other autoimmune diseases
 Multiple Autoimmune Syndrome
 Factors inf...
Polyautoimmunity and Severity
Some reports favor severity
• More erosive disease in Rhupus and anti-CCP antibodies
• Highe...
Polyautoimmunity and Severity
Some reports indicate less severity
• Milder disease in MG and AITD
• Milder disease in SSc ...
Polyautoimmunity
Conclusions
 Polyautoimmunity is a frequent condition (10-40%).
 Factors associated with polyautoimmuni...
Polyautoimmunity
Conclusions
 The assessment and clustering of polyautoimmunity will
help to define plausible approaches ...
ταυτολογία
Rhetoric
From Greek tauto, “the same”;
logos, “word/idea”.
Tautology is an obvious statement.
Logic
Tautology i...
• Female predominance
• Shared subphenotypes
• Polyautoimmunity
• Familial aggregation
• Age at onset
• Similar pathophysi...
Shared Subphenotypes Among Autoimmune Diseases
• Clinical
– Non-erosive arthritis
– Photosensitivity
– Raynaud´s phenomeno...
Luu VP et al. Autoimmunity 2014;47:1-12.
Vadasz Z et al FEBS Lett. 2013;587:2074-8.
Yang M, Cell Mol Immunol 2013;10:122-3...
Singh RP, et al Autoimmun Rev. 2014
Th17 Cells in Inflammation and Autoimmunity
• Presence of IFN signature in
autoimmune diseases.
• Regulation of MHC expression.
• Increased amounts of IFN α.
• Activa...
IgG anti-EBV
Epstein–Barr virus and Autoimmune Diseases
Anaya et al. Autoimmunity. From bench to bedside. 2013
Primary Biliary
Cirrhosis
Systemic Lupus
Erythematosus
Autoimmune
Thyroid Disease
Rheumatoid
Arthritis
Smoking is a risk f...
The genetic factors for
autoimmune diseases consist
of 2 forms: those common to
many diseases and those
specific for a giv...
• Female predominance
• Shared subphenotypes
• Polyautoimmunity
• Familial aggregation
• Age at onset
• Similar pathophysi...
Polyautoimmunity
Conclusions
 Identification of commonalities among ADs may
provide insights about salient mechanisms tha...
HLA-DRB1, HLA-DQB1, CD226, PTPN22, STAT4, GPR103, TNFAIP3, LRP1/STAT6
Polyautoimmunity Genes
Acknowledgments
Thank you!
of 44

Polyautoimmunity

Autoimmune diseases (ADs) are often diagnosed according to classification criteria, however they share similar subphenotypes including signs and symptoms, non-specific autoantibodies and other immune changes, which are prone to taxonomic problems. Polyautoimmunity, the topic of this presentation, is defined as the presence of more than one AD in a single patient. When three or more ADs coexist, this condition is called multiple autoimmune syndrome, which represents the best example of polyautoimmunity.
Published on: Mar 4, 2016
Published in: Health & Medicine      
Source: www.slideshare.net


Transcripts - Polyautoimmunity

  • 1. Juan-Manuel Anaya, MD, PhD Center for Autoimmune Diseases Research Universidad del Rosario Bogota, Colombia Polyautoimmunity Diagnosis and Significance
  • 2. Polyautoimmunity  Polyautoimmunity: Autoimmune diseases (ADs) co-occurring within patients.  Multiple Autoimmune Syndrome : 3 or more ADs in the same patient.  Other terms: “associated”, “overlap syndrome” “coexistent” “secondary”
  • 3. Multiple Autoimmune Syndromes Humbert P, Dupond JL. Ann Med Interne Paris 1988;139:159-68. Three or more well defined autoimmune diseases in a single patient
  • 4. Polyautoimmunity  Polyautoimmunity in RA, SS, SLE, and other autoimmune diseases.  Factors influencing polyautoimmunity  Does polyautoimmunity influence the severity of autoimmune diseases?
  • 5. Polyautoimmunity in Rheumatoid Arthritis • 130/ 955 (13.6%) patients disclosed polyautoimmunity. • 161 additional ADs were observed. • AITD 76 (8%) • SS 50 (5.2%) • SLE 24 (2.5%) • MAS 23 (2.4%) • Factors influencing polyautoimmunity in RA : • Familial autoimmunity, Familial RA, and toxics. • Multiple autoimmune syndrome was associated with extra-articular manifestations. Anaya JM, et al. EULAR 2015 THU0152
  • 6. Familial Autoimmunity and Polyautoimmunity in RA When familial autoimmunity was present, the risk of developing polyautoimmunity was similar in men and women, whereas the risk of polyautoimmunity without FAI was higher in women than in men. Anaya JM, et al. EULAR 2015 THU0152
  • 7. Familial RA and Polyautoimmunity Anaya JM, et al. EULAR 2015 THU0152
  • 8. Toxics and Polyautoimmunity in RA Anaya JM, et al. EULAR 2015 THU0152
  • 9. Multiple Autoimmune Syndrome and extra-articular manifestations in RA Anaya JM, et al. EULAR 2015 THU0152 RA RA + 1 Autoimmune Disease MAS
  • 10. Rhupus (SLE&RA) Amaya-Amaya J, et al. Lupus. 2015 Feb 9. Characteristics of patients with Rhupus (as compared with SLE patients) • Older (46.42 ± 13.47 vs. 36.37 ± 13.47 yrs, p <0.001) • Later age at onset of the disease (35.9 ± 15.25 vs. 28.84 ± 12.58 yrs, p=0.017). • Similar duration of the disease (9 ± 7.5 vs. 7.5 ± 7.3 years, p=0.3). • The mean age at onset of RA was 30 ± 11.63 yrs. • RA preceded SLE in 15 patients (62.5%). • The PPV and NPV of anti-CCP3 for rhupus were 0.62 and 0.91 respectively.
  • 11. Polyautoimmunity in Systemic Lupus Erythematosus 0% 5% 10% 15% 20% 25% 30% 35% 40% APS SS AITD Rojas-Villarraga A, et al. Autoimmun Rev. 2010;9:229-32. Franco J, et al. Clin Endocrinol (Oxf). 2014 Nov 8. Franco JS, et al. PLoS One. 2014;9:e110242.
  • 12. Factors Influencing Polyautoimmunity in Systemic Lupus Erythematosus Variable AOR 95% CI p Gender (female) 2.30 1.03 5.15 0.043 Articular involvement 2.02 1.26 3.23 0.003 Familial autoimmunity 1.61 1.14 2.28 0.007 Anti-Ro Ab 1.54 1.10 2.16 0.013 Origin (Colombia vs Spain) 1.78 1.40 2.27 < 0.0001 Rojas-Villarraga A, et al. Autoimmun Rev. 2010;9:229-32.
  • 13. Does ancestry influence polyautoimmunity?
  • 14. • Population: 508 individuals: 240 single autoimmune disease, 51 with polyautoimmunity, 36 with MAS, and 181 matched- controls. • Marshfield Screening Set 16. 353 STRs, 32 AIMs. • The individual Admixture map was built using STRUCTURE 2.3.4 • The number of cluster was set in 3, the number of burn-in simulations was set in 5000 and 100000 simulations for inference. • A MANOVA model on arl transformed ancestral profiles was adjusted to evaluate differences in ancestral profiles among different cases (AD, POLY and MAS) and controls. Influence of Ancestry on Polyautoimmunity Molano-González N et al. Submitted
  • 15. Reference populations and Colombian population. Ameridian Ancestry Influences Polyautoimmunity Molano-González N et al. Submitted Colombian population by autoimmune disease status.
  • 16. Ameridian Ancestry Influences Polyautoimmunity Amerindian ancestry European ancestry p: 0.001 p: 0.003 Molano-González N et al. Submitted
  • 17. Autoimmune Thyroid Disease in Systemic Lupus Erythematosus Franco J, et al. Clin Endocrinol (Oxf). 2014 Nov 8.
  • 18. Sjögren's syndrome and smoking are predictive factors associated with the development of AITD in SLE Franco J, et al. Clin Endocrinol (Oxf). 2014 Nov 8. Autoimmune Thyroid Disease in Systemic Lupus Erythematosus
  • 19. Autoimmune Diseases Prevalence N = 410 (%) SS alone 275 (67) SS + AD (Polyautoimmunity) 135 (33) SS + 1 AD 101 (24.6) SS + 2 or more ADs (MAS) 35 (8.5) Polyautoimmunity in Sjögren's Syndrome Amador-Patarroyo MJ, et al. J Autoimmun. 2012;39:199-205.
  • 20. Characteristic SS alone N=276 SS – PA N=134 p Disease duration 4 (6) 7.86 (7) 0.003 Age at diagnosis 46.7 ± 14.8 47.9 ± 14.2 0.95 Age at onset 45.4 ± 13.8 43.3 ± 13.3 0.2 Polyautoimmunity in Sjögren's Syndrome N=410 Amador-Patarroyo MJ, et al. J Autoimmun. 2012;39:199-205.
  • 21. 21.5 8.3 7.6 2.6 1.4 1.1 0.7 0.3 0.4 0.4 0.4 0.4 0 5 10 15 20 25 AITD RA SLE APS SSc VAS IBD MS VIT AIH PSO PeA Autoimmune Disease Prevalence% Polyautoimmunity in Sjögren's Syndrome Amador-Patarroyo MJ, et al. J Autoimmun. 2012;39:199-205.
  • 22. 8 7 6 6 0 2 4 6 8 10 SS-AITD-SLE SS-AITD-RA SS-SLE-APS SS-SLE-RA Polyautoimmunity in Sjögren's Syndrome MAS cases MAS phenotypes Prevalence Amador-Patarroyo MJ, et al. J Autoimmun. 2012;39:199-205.
  • 23. Characteristic SS Alone % SS-PA % AOR 95% CI p Positive smoking status 27.6 51.5 2.86 1.18-6.94 0.02 Spontaneous abortions 2.1 17.5 10.87 1.47-80.08 0.02 ANAs (+) 83 93.5 8.55 1-73.05 0.05 Polyautoimmunity in Sjögren's Syndrome Amador-Patarroyo MJ, et al. J Autoimmun. 2012;39:199-205.
  • 24. Systemic Sclerosis. 38% Hudson M, et al. J Autoimmun 2008;31:156-9. Elhai M, et al. Autoimmun Rev. 2013;12:1052-7. Primary Biliary Cirrhosis. 32% Gershwin ME, et al. Hepatology 2005;42:1194-202. Vitiligo. 27% Amerio P, et al. Eur J Dermatol. 2010;20:354-8. Myastenia Gravis. 13% Mao ZF, et al. Int J Neurosci 2011;121:121-9. Autoimmune Thyroid Diseases. 14% Boelaert K, et al. Am J Med 2010;123:183.e1-9. Multiple Sclerosis. 8% Deretzi G, et al. Acta Neurol Scand. 2015;131:225-30. Marrie RA, et al. Mult Scler. 2015;21:282-93. Polyautoimmunity in SSc, PBC, Vitiligo, AITD and MS
  • 25. Clustering of autoimmune diseases is not random Anaya et al. Clin Rev Allergy Immunol. 2012;43:256-64.
  • 26. Polyautoimmunity  Polyautoimmunity in SS, SLE, and other autoimmune diseases  Multiple Autoimmune Syndrome  Factors influencing polyautoimmunity  Does polyautoimmunity influence the severity of autoimmune diseases?
  • 27. Polyautoimmunity and Severity Some reports favor severity • More erosive disease in Rhupus and anti-CCP antibodies • Higher Incidence of malignancy in RA and SS • Low rates of remission in MG and AITD • More severe disease in T1D and celiac disease • Vasculitis is associated with high SLEDAI score in SLE • More severity of SLE+APS. Christensen et al. Acta Neurol Scand 1995;91:192-5. Valerio et al. Diabetologia 2002;45:1719-22. Ramos-Casals et al. Medicine (Baltimore). 2006;85:95-104. Chan et al. J Rheumatol. 2008 Jan;35:77-83. Kauppi et al. Cancer Causes Control 1997;8:201-4. Franco JS, et al. PLoS One. 2014;9:e110242.
  • 28. Polyautoimmunity and Severity Some reports indicate less severity • Milder disease in MG and AITD • Milder disease in SSc and AITD • SS or AITD do not influence outcome in SLE (nephritis) Marinó et al. J Clin Endocrinol Metab 1997;82:438-43 Avouac et al. J Rheumatol 2010;37:608-14 Rojas-Villarraga et al. Lupus 2010 19: 150 Franco et al. EULAR 2014
  • 29. Polyautoimmunity Conclusions  Polyautoimmunity is a frequent condition (10-40%).  Factors associated with polyautoimmunity include gender (female), familial autoimmunity, tobacco smoking, ancestry (amerindian).  Based on polyautoimmunity and depending on severity, autoimmune diseases may be categorized as major and minor conditions. In this sense, how polyautoimmunity affects major autoimmune diseases warrants further investigation.
  • 30. Polyautoimmunity Conclusions  The assessment and clustering of polyautoimmunity will help to define plausible approaches to studying the common mechanisms of these diseases (i.e., the autoimmune tautology).  Identification of commonalities among autoimmune diseases may provide insights about salient mechanisms that are necessary and perhaps sufficient for autoimmunity to occur.  Polyautoimmunity, as an extreme phenotype of autoimmunity, would be critical for dissecting genes of major effect conferring susceptibility to autoimmunity.
  • 31. ταυτολογία Rhetoric From Greek tauto, “the same”; logos, “word/idea”. Tautology is an obvious statement. Logic Tautology is a formula, which is true in every possible interpretation. Vpq = AD1 ~ AD2 ~ AD3 Anaya JM. Arthritis Res Ther. 2010;12:147. Anaya JM. Autoimmun Rev. 2012;11:781-4. Anaya et al. Clin Rev Allergy Immunol. 2012;43:256-64. Anaya et al. Autoimmune Dis. 2012;2012:297193.
  • 32. • Female predominance • Shared subphenotypes • Polyautoimmunity • Familial aggregation • Age at onset • Similar pathophysiology • Autoimmune ecology • Ancestry and genetic factors • Treatment The Autoimmune Tautology Common mechanisms of autoimmune diseases
  • 33. Shared Subphenotypes Among Autoimmune Diseases • Clinical – Non-erosive arthritis – Photosensitivity – Raynaud´s phenomenon – Alopecia – Depression – Cardiovascular disease • Laboratory – Antinuclear antibodies – Rheumatoid factor – Anti-Ro antibodies
  • 34. Luu VP et al. Autoimmunity 2014;47:1-12. Vadasz Z et al FEBS Lett. 2013;587:2074-8. Yang M, Cell Mol Immunol 2013;10:122-32. Berthelot JM, et al. Joint Bone Spine 2013;80:18-22. Imbalance of Regulatory Cells in Autoimmune Diseases
  • 35. Singh RP, et al Autoimmun Rev. 2014 Th17 Cells in Inflammation and Autoimmunity
  • 36. • Presence of IFN signature in autoimmune diseases. • Regulation of MHC expression. • Increased amounts of IFN α. • Activates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, leading to transcription of IFN-stimulated genes (ISGs). Type 1 interferon is a central factor in Autoimmunity Ivashkiv LB, Donlin LT. Nat Rev Immunol 2014;14:36-49. Wahren-Herlenius M, Dörner T. Lancet 2013;382:819-31.
  • 37. IgG anti-EBV Epstein–Barr virus and Autoimmune Diseases Anaya et al. Autoimmunity. From bench to bedside. 2013
  • 38. Primary Biliary Cirrhosis Systemic Lupus Erythematosus Autoimmune Thyroid Disease Rheumatoid Arthritis Smoking is a risk factor for autoimmune diseases and their severity Multiple Sclerosis Brix TH, et al. Arch Intern Med. 2000;160:661-6. Belbasis L, et al. Lancet Neurol. 2015;14:263-73. Juran BD, et al. Semin Liver Dis. 2014;34:265-72. Costenbader KH, Karlson EW. Lupus 2006;15:737-45. Di Giuseppe D, et al. Arthritis Res Ther. 2013;15:R56.
  • 39. The genetic factors for autoimmune diseases consist of 2 forms: those common to many diseases and those specific for a given disorder.
  • 40. • Female predominance • Shared subphenotypes • Polyautoimmunity • Familial aggregation • Age at onset • Similar pathophysiology • Autoimmune ecology • Ancestry and genetic factors • Similar treatment The Autoimmune Tautology Common mechanisms of autoimmune diseases
  • 41. Polyautoimmunity Conclusions  Identification of commonalities among ADs may provide insights about salient mechanisms that are necessary and perhaps sufficient for autoimmunity to occur.  Polyautoimmunity, as an extreme phenotype of autoimmunity, would be critical for dissecting genes of major effect conferring susceptibility to autoimmunity.
  • 42. HLA-DRB1, HLA-DQB1, CD226, PTPN22, STAT4, GPR103, TNFAIP3, LRP1/STAT6 Polyautoimmunity Genes
  • 43. Acknowledgments
  • 44. Thank you!

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