Elsevier

Autoimmunity Reviews

Volume 15, Issue 1, January 2016, Pages 9-15
Autoimmunity Reviews

Review
Clinical and genetic characterization of the autoinflammatory diseases diagnosed in an adult reference center

https://doi.org/10.1016/j.autrev.2015.08.008Get rights and content

Abstract

Introduction

Autoinflammatory diseases (AID) are usually diagnosed during the pediatric age. However, adult-onset disease or diagnosis during adulthood has been occasionally described.

Objectives

To assess the clinical and genetic characteristics of adult patients diagnosed with an AID in an adult referral center for AID.

Methods

We retrospectively evaluated clinical and genetic features of adult patients (≥ 16 years) diagnosed with an AID or referred after AID diagnosis to the Clinical Unit of AID, at the Department of Autoimmune Diseases, Hospital Clínic of Barcelona, from 2008 to 2014.

Results

During the study period, a genetic study for suspected AID was requested to 90 patients at the Department of Autoimmune Diseases. A final diagnosis of monogenic AID was achieved in 17 patients (19% of patients tested). Five additional cases were diagnosed with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome and 10 patients with AID were referred from other adult departments. Finally, a total of 32 patients with AID were finally diagnosed or monitored in our Clinical Unit. These included 12 (37.5%) familial Mediterranean fever, 6 (18.8%) tumour necrosis factor-receptor associated periodic syndrome, 8 (25%) cryopirin-associated periodic syndromes (Muckle–Wells syndrome [MWS] or overlap familial cold-associated periodic syndrome/MWS), 1 (3.1%) mevalonate kinase deficiency, and 5 (15.6%) PFAPA. Clinical evidence of disease-onset during childhood and adulthood was observed in 15 (47%) and 17 (53%) patients, respectively. Overall, the final diagnosis was obtained after a delay of a mean of 12 years (range 0–47 years). Compared to children, adult patients with AID in our series presented more frequently with non-severe manifestations and none of them developed amyloidosis during follow-up. Adult patients also carried higher proportion of low-penetrance mutations or polymorphisms and all genetic variants were presented in heterozygosis or as heterozygous compounds.

Conclusions

Adult disease-onset or delayed diagnosis of AID during adulthood is associated with milder disease phenotypes, and seem to be driven by mild genotypes, with predominant presence of low-penetrance mutations or polymorphisms.

Introduction

The term autoinflammatory diseases (AID) was first delineated in 1999 to encompass a group of disorders of the innate immune system characterized by recurrent episodes of inflammation without a known trigger [1]. The most frequent AID share a genetic background and are caused by mutations in genes encoding proteins directly involved in the biology of inflammasome, in which interleukin-1 (IL-1), a proinflammatory cytokine and important mediator of the systemic inflammatory response, plays a crucial role. In contrast to autoimmune diseases, no high titer autoantibodies or specific-T or B-cell autoreactivity are detected in AID [2], [3], [4]. Although AID are considered dominant or recessive inherited diseases with a Mendelian inheritance pattern, in some conditions genetic variants have been described as “de novo” mutations in almost 50% of patients [5].

The most common AID in the Mediterranean area include familial Mediterranean fever (FMF), tumour necrosis factor (TNF)-receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD)/hyper-immunoglobulin D (IgD) syndrome and periodic fever (HIDS), the family of cryopyrin associated periodic syndromes (CAPS) [familial cold induced autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS) and chronic infantile neurologic, cutaneous and articular syndrome (CINCA)] and periodic fever, aphtous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome. All of them have a monogenic origin [4], with the exception of PFAPA syndrome, in which the underlying etiology is still unknown [6], [7].

The diagnostic process of AID is often difficult since awareness for these rare and relatively new diseases is still low for general practitioners. In an appropriate clinical setting, a positive genetic study usually provides a definite diagnosis. On the other hand, although monogenic AID and PFAPA syndrome are usually diagnosed during childhood, all of them may have an adult onset [8], [9], [10], [11], [12]. In addition, many of these syndromes present with overlapping manifestations, frequently shared with other autoinflammatory conditions, which can usually make the diagnostic process even more difficult.

AID diagnosis may be reached during adulthood in patients with a clinical onset in adult life and in those in whom symptoms started during the infancy but were probably misinterpreted by physicians over the years. In this regard, investigations of AID in adults are still scarce. However, several studies have reported clinical and genetic differences between patients with a disease-onset during adulthood and those with pediatric onset [9], [10], [11], [12].

In the present study, we retrospectively reviewed clinical and genetic features of patients diagnosed with an AID in an adult reference center for AID or referred for treatment and control. We also compared our results with those reported in the literature from other studies about AID in pediatric age.

Section snippets

Patients' selection and data collection

From January 2008 to March 2014, all adult patients in whom AID were suspected and a genetic test for a known AID was requested at the Department of Autoimmune Diseases of the Hospital Clínic of Barcelona were included in the study. Patients transferred from other adult departments to our unit after a confirmative diagnosis of AID were also analyzed.

All monogenic AID patients were diagnosed by the presence of suggestive clinical features, genetic confirmation and response to

Results

From 2008 to 2014, 90 genetic tests were requested at the Department of Autoimmune Diseases of the Hospital Clínic of Barcelona for a suspected AID. A final diagnosis of a monogenic AID (FMF, TRAPS, CAPS and MKD/HIDS) was achieved in 17 (19%) patients. With the addition of 5 patients diagnosed with PFAPA, 22 patients were diagnosed with an AID, which accounts for 24.4% of the patients screened for AID. Ten patients diagnosed with AID were also referred to our Clinical Unit of AID from other

Discussion

AID are inherited conditions typically occurring in pediatric age. Their diagnosis usually presents a challenge, often more complex when they occur in adult patients. To date, the detection rate of mutations in patients with high suspicion for AID is low, accounting for less than 20% in most pediatric series [9], [24]. Of note, we found a similar rate of positive genetic tests in adult patients with an initially suspected AID. With the aim of improving genetic diagnosis in adults with suspected

Conclusions

AID, although infrequently, may have an adult-onset. Our results support that adult patients diagnosed with AID may develop disease-related symptoms during the adult age or have a delayed diagnosis of symptoms starting during infancy. These patients usually present with mild forms of the disease leading to a remarkable diagnostic delay until adulthood. Some of them may also present with atypical manifestations that are frequently shared by other AID, which might be classified as overlap

References (46)

  • L. Cantarini et al.

    Tumour necrosis factor receptor-associated periodic syndrome (TRAPS): state of the art and future perspectives

    Autoimmun Rev

    (2012)
  • L. Cantarini et al.

    The expanding spectrum of low-penetrance TNFRSF1A gene variants in adults presenting with recurrent inflammatory attacks: clinical manifestations and long-term follow-up

    Semin Arthritis Rheum

    (2014)
  • L. Obici et al.

    Amyloidosis in autoinflammatory syndromes

    Autoimmun Rev

    (2012)
  • R. Goldbach-Mansky

    Immunology in clinic review series; focus on autoinflammatory diseases: update on monogenic autoinflammatory diseases: the role of interleukin (IL)-1 and an emerging role for cytokines beyond IL-1

    Clin Exp Immunol

    (2012)
  • S. Savic et al.

    Familial Mediterranean fever and related periodic fever syndromes/autoinflammatory diseases

    Curr Opin Rheumatol

    (2012)
  • I. Aksentijevich et al.

    De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases

    Arthritis Rheum

    (2002)
  • L. Cantarini et al.

    Diagnosis of PFAPA syndrome applied to a cohort of 17 adults with unexplained recurrent fevers

    Clin Exp Rheumatol

    (2012)
  • S. Chandrakasan et al.

    Clinical and genetic profile of children with periodic fever syndromes from a single medical center in South East Michigan

    J Clin Immunol

    (2014)
  • L. Cantarini et al.

    Childhood versus adulthood-onset autoinflammatory disorders: myths and truths intertwined

    Reumatismo

    (2013)
  • L. Cantarini et al.

    Caution should be used in the recognition of adult-onset autoinflammatory disorders: facts or fiction?

    Front Immunol

    (2013)
  • L. Cantarini et al.

    Adult-onset autoinflammatory disorders: a still debated entity?

    Clin Exp Rheumatol

    (2015)
  • H.J. Lachmann et al.

    The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry

    Ann Rheum Dis

    (2014)
  • Y. Shinar et al.

    Guidelines for the genetic diagnosis of hereditary recurrent fevers

    Ann Rheum Dis

    (2012)
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    Supported by the Excellence Integrated Project co-funded by Instituto de Salud Carlos III and FEDER (PIE 13/00033) and Ministerio de Economía y Competitividad (SAF 14/57708-R).

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