Elsevier

Clinical Immunology

Volume 211, February 2020, 108326
Clinical Immunology

The immunologic features of patients with early-onset and polyautoimmunity

https://doi.org/10.1016/j.clim.2019.108326Get rights and content

Highlights

  • Patients with early-onset/polyautoimmunity share defining features.

  • Autoimmune cytopenias, lymphoproliferation, and GI involvement are common.

  • Recurrent infections, low T/B/NK cells, and low immunoglobulins are frequent.

  • A high percentage of patients have an underlying monogenic PID.

  • Co-management of these patients by immunologists and rheumatologists is vital.

Abstract

Inflammatory conditions are increasingly described in patients with primary immunodeficiencies; however, little is known about the prevalence of immune defects in patients who present first with autoimmunity. We describe the immunologic features of children with early-onset/polyautoimmunity followed in the Multiple Autoimmunity and Immunodeficiency (MAID) Clinic, where patients are co-managed by rheumatologists and immunologists. The most common autoimmune manifestations were cytopenias, lymphoproliferation, and colitis. Recurrent infections were noted in 65% of patients. Abnormalities in lymphocyte subsets and immunoglobulins were common. A pathogenic variant was identified in 19% of patients, and 2 novel inherited disorders were discovered. Additionally, 42% of patients had treatment changes implemented in the MAID clinic. By evaluating this unique cohort of patients, we report on the immunologic underpinning of early-onset/polyautoimmunity. The high rate of genetic diagnoses and treatment interventions in this population highlights the value of collaboration between rheumatologists and immunologists in the care of these complex patients.

Introduction

Patients with primary immunodeficiencies (PIDs) commonly present in childhood with recurrent and difficult to treat infections. Classically, it was thought that PID was on one end of the spectrum with an “overactive” immune system or autoimmunity (AI) on the other end. It is now increasingly appreciated that PIDs and AI co-exist in immune dysregulatory syndromes [[1], [2], [3], [4], [5]]. This may be due in part to the improved care of patients with PIDs and their longer lifespan, as time is typically needed for autoimmune phenomena to develop. In addition, better dissemination of information amongst immunologists and rheumatologists has allowed for the recognition of many monogenic immune dysregulatory syndromes over the past decade.

Autoimmune manifestations are frequently reported in patients diagnosed with monogenic PID [[1], [2], [3]]. Interrogation of different PID registries has provided estimates of the percentage of patients with PID who also have co-existing autoimmune disease. In 2014, Maggadottir and Sullivan queried the United States Immunodeficiency Network (USIDNET) records and estimated that between 1 and 11% of PID patients had a diagnosed autoimmune condition [4]. A recent large study of the French national PID registry found that 26.2% of PID patients developed autoimmune or inflammatory complications over their lifetime [5]. This increased risk of developing autoimmune/inflammatory complications was also present regardless of the type of PID, but patients with common variable immunodeficiency (CVID) and T cell deficient PIDs were most commonly affected [5]. CVID is the most commonly diagnosed PID after selective IgA deficiency, and autoimmune manifestations are estimated to occur in 27–48% of patients [[6], [7], [8]].

Fewer studies have examined the prevalence of PID in patients with autoimmune diagnoses. Barsalou et al. reviewed the records for patients referred to a single rheumatology clinic in Canada over 18 months. Patients diagnosed with autoimmune conditions aside from juvenile idiopathic arthritis (JIA) were included. Fifteen percent of their patients fulfilled criteria for a PID, and another 15% had abnormalities on their immune evaluation [9].

The Multiple Autoimmunity and Immunodeficiency (MAID) clinic at Boston Children's Hospital (BCH) was founded by Drs. Notarangelo and Hazen in 2009 with a focus on caring for patients with polyautoimmunity and/or co-existing AI and PID. The clinic was launched to facilitate better collaboration between immunologists and rheumatologists caring for affected patients and also to promote the use of cutting-edge molecular diagnostics. In addition to better characterizing each patient's disease, it was thought that a thorough immune evaluation would be helpful in choosing a targeted treatment plan. Since its inception, the MAID clinic has seen 144 unique patients and identified 28 patients with monogenic immune dysregulatory syndromes. The majority of these patients were referred from rheumatology, immunology, hematology, and gastroenterology clinics.

Section snippets

Study setting and ethical approval

This retrospective cohort study was conducted in the Immunology Division at BCH. Referrals to the MAID clinic are encouraged for patients with early-onset, atypical, or multiple autoimmunity. Patients are referred to the MAID clinic predominantly by physicians locally at BCH, but some are also referred at the national level. The physicians in the MAID clinic perform educational outreach to other pediatric specialties at BCH through emails, presentations at clinical conferences, and personal

Patient characteristics

From its inception in 2009 to 2018, 144 patients were seen in the MAID clinic (Table 1). Slightly more females (52%) were followed than males. Most individuals first presented to the MAID clinic before the second decade of life (average age 12 years, range 0.1–62 years) (Fig. 1). A majority of the patients were Caucasian, reflecting the demographics of the local population in the Boston area. BCH is a major referral center for several countries in the Middle East, and 4% of patients seen in the

Discussion

As our understanding of the genetic basis of immune dysregulatory syndromes advances, our ability to recognize and manage these potentially dangerous conditions has also improved. The experience in the MAID clinic over the last decade highlights the importance of a multidisciplinary immunologically-minded approach to children with immune dysregulation. By studying this cohort of patients, we were able to characterize the features of pediatric-onset immune dysregulatory syndromes as well as the

Conclusions

Patients with early-onset inflammation and polyautoimmunity are characterized by a unique constellation of clinical features. These patients manifest certain forms of autoimmunity that are also common in individuals with PIDs, including cytopenias, lymphoproliferation, and GI disease. Immunologic dysfunction in the form of recurrent infections and an abnormal immunologic profile underscores the high rates of monogenic disease in this population. To improve outcomes, further research is needed

Funding sources

This work was partially supported by the Rheumatology Research Foundation's Investigator Award (L.A.H), the National Institute of Arthritis and Musculoskeletal and Skin Diseases, P30 AR070253-01 and K08 AR073339-01 (LAH), and K08 AI114968 (EJ), the National Institute of Allergy and Infectious Diseases 5R01AI085090 (TAC), and the Division of Intramural research, National Institute of Allergy and Infectious Diseases, NIH (LDN).

Declaration of Competing Interest

None.

Acknowledgements

None.

References (31)

  • W. Rae et al.

    Autoimmunity/inflammation in a monogenic primary immunodeficiency cohort

    Clin. Transl. Immunol.

    (2017 Sep)
  • S.M. Maggadottir et al.

    The intersection of immune deficiency and autoimmunity

    Curr. Opin. Rheumatol.

    (2014 Sep)
  • A. Fischer et al.

    Autoimmune and inflammatory manifestations occur frequently in patients with primary immunodeficiencies

    J. Allergy Clin. Immunol.

    (2017 Nov)
  • C. Cunningham-Rundles

    Physiology of IgA and IgA deficiency

    J. Clin. Immunol.

    (2001 Sep)
  • J. Barsalou et al.

    High prevalence of primary immune deficiencies in children with autoimmune disorders

    Clin. Exp. Rheumatol.

    (2011 Jan-Feb)
  • Cited by (0)

    1

    Present Address: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 5W-3950, 10 Center Drive, MSC 1456, Bethesda, MD 20892, United States of America.

    2

    Co-senior authors.

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