Autoimmunity And Immunodeficiency - PowerPoint Presentation

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Autoimmunity And Immunodeficiency

Anna Postolova, MD MPH

Allergy/Immunology/Rheumatology

Menlo Medical Clinic

Stanford Health Care

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Disclosures

Nothing to disclose

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Objectives

Recognize aspects of history and presentation that are suggestive of a primary immunodeficiency or immune dysregulatory syndrome in rheumatology patients

Be able to initiate a laboratory work up for primary immunodeficiency

Identify which rheumatologic disorders are most associated with primary immunodeficiency

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25% of patients with PID will develop an autoimmune disease

www.info4pi.org

; Fischer et al. J Allergy Clin Immunol. 2017

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More than just recurrent infections

Walter et al.

Curr

Opin

Pediatr

. 2019

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Autoimmune manifestations of primary immunodeficiencies

Currently there are 320 single-gene inborn errors of immunity underlying 330 disorders with diverse phenotypes including infection, malignancy, allergy,

autoimmunity, and auto-inflammation

Chinn et al. Ped In Review. 2019;

Bousfiha

et al. J Clin Immunol. 2018

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Fischer et al. J Allergy Clin Immunol. 2017

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When comparing the study population with the general population in Western Europe there was 40-fold increased risk of arthritis among patients with PIDs compared with control cohorts

Fischer et al. J Allergy Clin Immunol. 2017

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The Immunodeficiency/Autoimmunity Mosaic

Walter et al.

Curr

Opin

Pediatr

. 2019

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Putting Together the Pieces

In recent pediatric reviews of rheumatology clinic populations, the

incidence of PID disorders in established patients

was found to be anywhere between 14-22%

It is important for the rheumatologist to be able to identify patients who may present with

typical rheumatologic

findings

but who also have an underlying PID

When evaluating patients, a red flag for PID related disease could include a

personal or family history of recurrent infections, a family history of PID, and

other forms of

concomitant autoimmune

diseases

Dimitriades et al. Clin

Rheumatol

. 2016

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SLE

Arthritis

Vasculitis

Sjogren’s

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www.info4pi.org

Genetic Testing

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Case 1

54

yo

female with SLE (ANA+, dsDNA, SM/RNP+, Ro+, oral ulcers, pleurisy, CNS SLE)

Late 20s - diagnosed with SLE, but had longer history of discoid lesions

Late 30s - 3 TIAs (transient ischemic attacks) – SLE cerebritis

40s – demyelinating lesions found in CNS; microscopic colitis diagnosed after diarrhea ongoing for a month

50s - severe shortness of breath/chest pain – ground glass opacities, peribronchiolar consolidation, bronchiectasis ->ILD

CH50 <3

C3 130

C4 34

C2 <10

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Systemic Lupus Erythematosus

Complement deficiencies

90% of patients with C1q deficiency – early onset, severe, SLE with significant rash, oral ulcers and photosensitivity; 40% have recurrent infections

C1r/C1s, C2, C3, C4

Chronic Granulomatous Disease

Disorder of phagocyte function

Recurrent pyodermas, granulomatous abscesses of the lungs and liver, IBD

Female carriers of X-linked mutations have higher risk of discoid lupus and can show photosensitivity, oral ulcers and rashes without antibody positivity

Antibody deficiencies

Selective IgA deficiency, common

variable immunodeficiency (CVID)

Dimitriades et al. Clin

Rheumatol

. 2016

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Case 2

40

yo

female with CVID presents for hand pain

Early 30s - diagnosed with CVID, started on SCIG with good control

Late 30s - developed pain in wrists, fingers, occasional swelling

Exam with synovitis in PIPs and wrists, cannot make a fist

Negative serologies, XR negative

MSK Ultrasound

flexor tenosynovitis of the 2nd digit just proximal to the MCP joint

MCP dorsal aspect with mild synovial hypertrophy

brief review of the remaining digits revealed similarly located flexor tenosynovitis

brief review of the extensor digitorum bundle of the right wrist showed prominent extensor tenosynovitis, GS2, PD2, correlating with point tenderness on physical exam

Inflammatory Arthritis

Started on low dose prednisone with improvement, failed HCQ, doing well on leflunomide and SCIG

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Arthritis

Antibody deficiencies

Recurrent otitis media and sinopulmonary

infections due to encapsulated bacteria

Histology shows synovial hyperplasia and capillary proliferation with no major lymphocytic or polymorphonuclear infiltrate as seen in RA

XLA

- Loss of B cell maturation and differentiation due to lack of Bruton’s Tyrosine Kinase (BTK) causing poor antibody production

Failure of deletion of a small number of autoreactive B cells leads to a survival advantage to B cells with affinity to self-antigens resulting in autoimmunity

Higher incidence of arthritis in the large joints of the lower extremities, affecting approximately 20% of patients

CVID –

low IgG and IgM/IgA levels, poor AB responses to P23 vaccine, recurrent infections-> autoreactive clones

5-10% of patients present with RA and JIA

Dimitriades et al. Clin

Rheumatol

. 2016

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Sarcoidosis and CVID

Incidence of granulomas in CVID between 5-10%

Confusion with sarcoid but considered distinct entity

Park et al. 2005 - HRCT of 16 patients with granulomatous CVID

CT findings in sarcoid: small, well-defined nodules,

peribronchovascular

distribution, fibrosis, and

mid-and upper zone distribution

CT findings in granulomatous CVID: ILD – 80%

diffuse reticular

pattern,

lower zone predominance

. Large ill-defined

bronchocentric

nodules or small randomly distributed nodules in 50% of patients.

Busse

et al. Annals of Allergy Asthma Immunology. 2007; Park et al. European Journal of Radiology. 2005

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Sarcoidosis vs CVID

Verbsky

and Routes.

Semin

Respir

Crit

Care Med. 2014

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Vasculitis

Deficiency of Adenosine Deaminase 2 (DADA2)

Mutation in CERC1 gene

Characterized by livedoid rash, fever, arthralgia, elevated inflammatory markers and vasculopathy/vasculitis (associated with stroke or organ injury), vasculopathy overlapping with PAN

177 patients from Freiburg Medical Center with antibody deficiency with vascular manifestations had genetic sequencing

11 DADA2 patients were identified

Schepp et al. A&R. 2017

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Case 3

52 Y female with history of possible IgG4RD (recurrent pancreatitis, mild IgG4 elevation) s/p Rituxan, SS on prednisone, who presents to establish care

Early 40s - admitted for pancreatitis, elevated IgG4 -> IgG4RD

Mid 40s – Sjogren’s, Vasculitis, IgG4RD- treated with Rituxan, methotrexate,

cellcept

and prednisone for fatigue, dry eye, dry mouth, intermittent abdominal pain, and synovitis which were felt to be related to these diagnoses

50s – episodes of full body swelling

History of recurrent sinus infections, asthma, persistent rashes

Mom – died from rheum disorder NOS - lung issues, smoker, skin issues ?psoriasis +/- psoriatic arthritis, swelling in legs, PVD, passed away from sepsis 2/2 infection from trauma/procedure

Mutation in NOD2 - heterozygous - increased risk allele for Yao syndrome

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Yao and Shen. Am J Med. 2016

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Immune Dysregulatory Disorder

CTLA4 Haploinsufficiency

Heterozygous germ-line mutations in CTLA4 (haploinsufficiency) cause immune dysregulation and susceptibility to infections

Clinical manifestations include autoimmune cytopenias, lymphoproliferation, respiratory and GI inflammation, and arthritis

In a recent cohort of 133 patients, median age of evaluation was 23 years with 14% presenting with arthritis

Treatment includes abatacept and sirolimus

STAT 3 Gain of Function

GOF mutations present with cytopenias, enteropathy, inflammatory lung disease, arthritis, growth failure, psoriasis, lymphadenopathy and infection susceptibility

Treatment includes tocilizumab and JAK inhibitors

Leiding

et al. J Allergy Clin Immunol

Pract

. 2019; Schwab et al. J Allergy Clin Immunol. 2018

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Cumulative incidence of autoimmunity/inflammatory manifestations

in patients with PIDs

Probability of survival of patients with PIDs as a function of the occurrence of autoimmune/inflammatory manifestations.

Fischer et al. J Allergy Clin Immunol. 2017

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Treatment

Hoyt et al. Clin Immunol. 2020

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Thank You