Juan-Manuel Anaya, MD, PhD.Center for Autoimmune Diseases Research

Universidad del RosarioBogota, Colombia

Polyautoimmunity and Familial Autoimmunity

in Sjögren's Syndrome

Polyautoimmunity and Familial Autoimmunity

Polyautoimmunity in SS, and other autoimmune diseases.

Factors influencing polyautoimmunity Does polyautoimmunity influence the severity

of autoimmune diseases? Familial autoimmunity Why polyautoimmunity and familial

autoimmunity are important?

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”

Semin Arthritis Rheum 2012;41:589-98.

After a mean of 7.9 years of disease, 57.9% of 161 patients still satisfied MCTD classification; 17.3% evolved into SSc, 9.1% into SLE, 2.5% into RA, 11.5% was

reclassified as affected by undifferentiated connective tissue disease, and 1.7% as suffering from overlap syndrome.

Autoimmune diseases are a spectrum ranging from the incomplete forms or "forme frustre" and lenient and slow evolution syndromes

to the rapidly progressive and fatal forms

Autoimmune DiseasesPrevalence 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.

Polyautoimmunity in Sjögren's SyndromeN=410

Amador-Patarroyo MJ, et al. J Autoimmun. 2012;39:199-205.

AITD RA SLE APS SSc VAS IBD MS VIT AIH PSO PeA0

5

10

15

20

2521.5

8.3 7.6

2.61.4 1.1 0.7 0.3 0.4 0.4 0.4 0.4

Autoimmune Disease

Prev

alen

ce %

Polyautoimmunity in Sjögren's Syndrome

Amador-Patarroyo MJ, et al. J Autoimmun. 2012;39:199-205.

SS-AITD-SLE SS-AITD-RA SS-SLE-APS SS-SLE-RA

0

2

4

6

8

10

87

6 6

Polyautoimmunity in Sjögren's SyndromeMAS cases

MAS phenotypes

Prev

alen

ce

Amador-Patarroyo MJ, et al. J Autoimmun. 2012;39:199-205.

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.

Ameridian Ancestry Influences Polyautoimmunity

Amerindian ancestry European ancestry

p: 0.001 p: 0.003

Molano-González N et al. Submitted

Polyautoimmunity in 1.083 patients with Autoimmune Diseases

Rojas-Villarraga et al. Autoimmune Dis. 2012

SLE RA MS SSc

N % N % N % N %

N 335 30.9 304 28.1 154 14.2 290 26,8

Polyautoimmunity 136 40.6 98 32.2 21 13.6 118 40.7

AITD 60 17.9 64 21.1 14 9.1 67 23.1

SS 47 14.0 36 11.8 4 2.6 43 14.8

VIT 2 1.3

PAS 48 14.3 8 2.6

PBC 15 5.2

MAS 39 11.6 16 5.3 3 2 28 9.7

Sjogren´s syndrome 33% - 52%Amador-Patarroyo MJ, et al. J Autoimmun. 2012;39:199-205.Lockshin MD, et al. Lupus Sci Med. 2015;2:e000084.

Celiac Disease 33%Demirezer Bolat A, et al. Digestion. 2015;92:185-91.

Primary Biliar Cirrhosis 32%Gershwin ME, et al. Hepatology 2005;42:1194-202.

Vitiligo 27%Amerio P, et al. Eur J Dermatol. 2010;20:354-8.

Autoimmune Thyroid Disease. 14%Boelaert K, et al. Am J Med 2010;123:183.e1-9.

Miastenia Gravis. 13%Mao ZF, et al. Int J Neurosci 2011;121:121-9.

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

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.

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;82:438-43Avouac et al. J Rheumatol 2010;37:608-14

Rojas-Villarraga et al. Lupus 2010 19: 150Franco et al. EULAR 2014

How does Autoimmune Diseases Cluster in families?

Autoimmune Familial DiseaseAggregation

Familial AutoimmunityCo-Aggregation

Familial Autoimmunity in Sjögren’s SyndromeRisk of Autoimmune Disease (AD) in First Degree Relatives (FDR)

0.014 (1.36-11.78)5 (4)13 (12.9) > 2 FDR

0.11.7 (0.9-3.37)22 (17.8)25 (24.7) 1 FDR

0.0142.2 (1.2-3.9)27 (21.8)38 (37.6) Yes

97 (78.2)63 (62.4) No

Families with a FDRpresenting an AD

pOR (95% CI)Controls N= 124 (%)

SS N= 101 (%)

Anaya et al. J Rheum 2006;33:2227-34

Familial Autoimmunity in Sjögren’s SyndromeAutoimmune Diseases in First Degree Relatives

* OR: 2.6, 95%CI = 1.66-3.98, p<0.0001

33/14332.3%*

56/9805.7%

FDR with at least one AID

1725Hashimoto

11Graves

13T1D

01Multiple sclerosis

34Vitiligo

01PBC

02SSs1015RA18SLE04SS

ControlsN= 124

SSN= 101

Autoimmune Disease

Anaya et al. J Rheum 2006;33:2227-34

1.571.591.47All ADNANANAMS

1.083.17NAVITNANANAPBCNANANASSc

1.211.590.91RA6.473.17NASLE1.171.031.47AITD2.43NA0.91T1DNANANASS

λRELλSIBλP/O

Autoimmune Disease

λ = KSS/KCI

Co-Aggregation of Autoimmune Diseases in Sjögren's Syndrome

Anaya et al. J Rheum 2006;33:2227-34

Cárdenas-Roldan et al. BMC Medicine 2013

How do Autoimmune Diseases Cluster in families?

Polyautoimmunity and Familial AutoimmunityConclusions

Polyautoimmunity and familial autoimmunity are frequent conditions (10-40%).

Factors associated with polyautoimmunity include gender (female), 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.

The assessment of autoimmune diseases' clustering (i.e., polyautoimmunity and familial autoimmunity) 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.

Polyautoimmunity and Familial AutoimmunityConclusions

• Female predominance • Shared subphenotypes

• Polyautoimmunity • Familial aggregation • Age at onset • Similar pathophysiology• Autoimmune ecology • Ancestry and genetic factors • Treatment

The Autoimmune TautologyCommon mechanisms of autoimmune diseases

Identification of commonalities among ADs may provide insights about salient mechanisms that are necessary and perhaps sufficient for autoimmunity to occur.

Polyautoimmunity and familial autoimmunity, as extreme phenotypes, would be critical for dissecting the common mechanisms of autoimmunity, including genes of major effects.

Polyautoimmunity and Familial AutoimmunityConclusions

HLA-DRB1, HLA-DQB1, CD226, PTPN22, STAT4, GPR103, TNFAIP3, LRP1/STAT6

Polyautoimmunity Genes