Page 854 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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Systemic Autoinflammatory Syndromes

Catharina M. Mulders-Manders, Jeroen C.H. van der Hilst,
Jos W.M. van der Meer, Anna Simon

Autoinflammatory diseases, which are also known as periodic fever KEY CONCEPTS
syndromes, encompass a group of rare disorders characterized by
recurrent or persistent inflammation. Autoinflammation is a term Autoinflammation Versus Autoimmunity
that has been used since the late 1990s to illustrate the difference • Common features:
between autoimmune disorders and diseases characterized by • Inflammation due to excessive immune activation
exuberant inflammation. Typically, autoinflammatory diseases do • Phenotypes characterized by exacerbations and remissions
not show features of excess adaptive immune system activation, • Distinctive features:
and autoantigens or auto-antigen specific T-cells are not present • Autoinflammation: dysregulation of innate immunity, no high-titer
in these diseases. It is now recognized that autoinflammation and autoantibodies or autoantigen-specific T cells
autoimmunity form two ends of a spectrum of inappropriate • Autoimmunity: dysregulation of adaptive immunity, defect in
lymphocyte function, autoantibodies may be present.
immune system activation and share several common features. • Autoinflammation and autoimmunity form two ends of a continuous
Located at the autoinflammatory end of this spectrum are the spectrum of excessive immune system activation.
classic monogenic autoinflammatory diseases: familial Mediter- • Many diseases show overlapping features between autoinflammation
ranean fever (FMF), cryopyrin-associated periodic syndrome and autoimmunity.
(CAPS), mevalonate kinase deficiency (MKD; also known as
hyperimmunoglobulin D and periodic fever syndrome [HIDS]),
and tumor necrosis factor (TNF) receptor–associated periodic EPIDEMIOLOGY
syndrome (TRAPS). The number of autoinflammatory diseases
is increasing rapidly. New monogenic autoinflammatory diseases It is important to realize that the incidence of specific diseases
have been identified in the last decades. For many of the recently varies widely among ethnic groups. With more than 100 000
described autoinflammatory diseases, no genetic cause has been patients worldwide, FMF is the most prevalent monogenic
found yet. autoinflammatory disease. It is most common in individuals
It has also become clear that autoinflammation is at least originating from around the Mediterranean basin, such as Turks,
partially involved in the pathogenesis of other, more common Jews (primarily non-Ashkenazi), Arabs, and in Armenians. In
diseases, such as gout, Crohn disease, and ulcerative colitis. these selected populations, the carrier frequency of mutations
1
As it is impossible to discuss all autoinflammatory diseases in the MEFV gene can be as high as one in three individuals.
in detail here, the classic monogenic diseases FMF, CAPS, TRAPS, This may indicate a survival benefit for carriers of heterozygous
and MKD have been selected as the main focus of this chapter. mutations, possibly through protection against certain unknown
Their pathophysiological mechanisms are understood to a much infectious agents.
higher degree than in many newer autoinflammatory diseases, The first patients with MKD were described in 1984 in The
2
and their clinical presentations have been described precisely. Netherlands (then referred to as HIDS). Over 200 patients have
In addition, two other autoinflammatory diseases are discussed, now been identified, most of Western European and Caucasian
one with relatively high prevalence and the other because of its ancestry. This could be partly explained by increased awareness
interesting pathophysiological mechanism: (i) periodic fever, for this disease among physicians in that part of the world. An
aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome alternative explanation is a common founder effect with clustering
and (ii) Schnitzler syndrome. of carriers, illustrated by a carrier rate of 1 : 153 for the most
The cornerstone of diagnosing an autoinflammatory disease common mutation in the mevalonate kinase gene (MVK) (V377I)
is the clinical assessment of the patient. This includes a detailed in Dutch newborns. 3,4
medical and family history and direct observation of an inflam- TRAPS is seen in patients from around the world, although
matory episode. The first step in the diagnostic process is to most patients originate from northwestern Europe. A few dozen
exclude other more common causes of recurrent inflammation, families and over 200 sporadic cases have been reported.
including infections, malignancy and paraneoplastic phenom- The exact prevalence of the CAPS is unknown, but over 130
1
ena, and autoimmune disease. A first differential diagnosis cases have been recognized. Disease awareness and recognition
can be made on the basis of age of onset, associated signs and among clinicians have improved because of the availability of
symptoms, duration of inflammation, family history, and ethnic effective treatment for this disease.
5
background, (Table 60.1), and this can guide targeted diagnostic PFAPA syndrome was first reported at the end of the 1980s.
testing. It is difficult to estimate the incidence of PFAPA, as the level of
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