Remember rare systemic autoinflammatory diseases

The mixed bag of systemic autoinflammatory diseases (SAIDs) includes a subgroup of four exceedingly rare interleukin (IL)-1 mediated syndromes, which can now be definitively diagnosed with genetic testing [1]. These SAIDs: cryopyrin-associated periodic syndromes (CAPS); tumour necrosis factor (TNF)-associated periodic syndrome (TRAPS); mevalonate kinase deficiency (MKD); and deficiency of the IL-1 receptor antagonist (DIRA), are diagnosed in fewer than one in a million people [1]. Under-diagnosis, however, is likely, as both knowledge of these SAIDs and the availability of genetic screening are limited [2]. Despite the term “periodic syndrome”, the systemic and organ-specific inflammation in all four IL-1-mediated SAIDs is usually constant [3].

Recent advances in genetic testing and pharmacological therapies, particularly biologicals, provide life-changing opportunities for people with IL-1-mediated SAIDs [3]. This article summarises current recommended management of these four syndromes, as reviewed by Cetin Gedik et al. [1], with additional data sourced from the 2021 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) consensus [3] and a literature review by Li et al. [2]. Familial Mediterranean fever, another common IL-1-mediated autoinflammatory disease, is discussed elsewhere [3] and is outside the scope of this article.

Hyperinflammatory effects from various variations

The otherwise inexplicable symptoms characteristic of IL-1-mediated SAIDs stem from unwarranted increases in IL-1β, and IL-1⍺ in DIRA [2]. Despite overlapping symptoms, different gain- or loss-of-function genetic mutations cause the four IL-1-mediated SAIDs (Table 1) [1,2,3]. Elevated IL-1β results from either its overproduction (CAPS and TRAPS) or reduced immune response inhibition (MVD) [1, 2]. In DIRA, a loss-of-function mutation affects the IL-1 receptor antagonist, leaving unopposed proinflammatory IL-1⍺ and -1β activity [2]. While pathophysiology is not always clear, abnormal inflammasomes play a key role in some IL-1-mediated SAIDs [1].

Table 1 Key characteristics of interleukin-1-mediated systemic autoinflammatory diseases, as reviewed by Cetin Gedik et al. [1] and Romano et al. [3]
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In suspected IL-1-mediated SAIDs, the diagnostic process, similar for all four syndromes, begins with the basics, but may progress to genetic testing [1, 3]. The starting point is a standard laboratory workup to confirm systemic inflammation and (especially for CAPS [2] and TRAPS) any suspected systemic amyloid A (AA) amyloidosis [1, 3]. Investigations need to assess likely ocular, neurological, skeletal or other organ damage, then perform genetic testing where warranted (Table 1) [1, 3]. Initial next-generation sequencing is preferred, but Sanger sequencing is an alternative, especially in patients with a family history and/or a presentation very suggestive of these SAIDs [1].

Treat fast and forever to limit lifelong damage

In the absence of a cure, the goals of IL-1-mediated SAIDs therapy (Table 2) are to control disease activity as quickly as possible, limit irreversible organ damage and achieve the best possible quality of life [3]. Treatment should suppress systemic and organ inflammation, be titrated to age-appropriate effect and aim ultimately at remission [3]. Therapy prior to a genetically proven diagnosis may be warranted if there is a strong clinical likelihood of an IL-1-mediated SAID [1].

Table 2 First-line pharmacological options for interleukin-1-mediated systemic autoinflammatory diseases, as reviewed by Cetin Gedik et al. [1] and Romano et al. [3]
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The current standard of care is a subcutaneous biologic targeting IL-1 (Table 2) [1,2,3]. Disease severity (or mildness) may determine dosage levels and intervals [3]. Given the rarity and severity of the four conditions, data from randomized controlled trials is limited (Table 2) [1, 2].

In some cases, anakinra (which requires daily injections), then rilonacept (which has a somewhat longer half-life) are preferred, as they block both IL-1⍺ and IL-1β. [1]. Canakinumab, while often still effective [2], blocks only the latter and may not control bone or central nervous system (CNS) disease [11] or be effective in DIRA [1]. Anakinra is potentially advantageous in neurological disease, due to its good CNS penetration [1, 3]. However, in the absence of these specific concerns, canakinumab’s monthly or bi-monthly administration is an advantage [3].

Other than these biologics, treatment options for IL-1-mediated SAIDs are limited, although other agents targeting the CAPS gene (Table 1), inflammasome activity or the IL-1 receptor are in development [1]. In these SAIDs, disease-modifying antirheumatic drugs are less effective than IL-1 blockers [3]. Non-steroidal anti-inflammatory drugs or short-term glucocorticoid therapy may effectively treat mild disease or brief MKD or TRAPS flares [1, 2].

Case series support the use of the TNF-inhibitor etanercept in patients with MKD who cannot access or do not respond to IL-1 blockers, and an open-label study suggests it may also be effective in TRAPS [2]. TNF-inhibitors should be considered whenever IL-1 blockers are unavailable [3]. Anti-IL-6 agents such as tocilizumab are another option, particularly for MKD or TRAPS [1, 2].

Monitor and manage throughout lifetime

IL-1-mediated SAIDs require chronic therapy throughout childhood, adolescence and adult life, ideally through a multidisciplinary team, with transitions carefully managed, especially in adolescence [3]. Aside from monitoring inflammatory markers and hearing and vision loss, clinicians should be alert to signs of other serious organ damage, such as kidney failure from AA amyloidosis, CNS disease or bone deformities. This is especially relevant for adults with longstanding disease who have not benefited from early IL-1 targeted therapy [3].

The benefits of vaccinations outweigh the risks of MKD or other flares, and they should be administered as normal [3]. Therapy should be continued in the event of a viral illness, to avoid rebound inflammation [3].

Take home messages

  • Effective genetic diagnosis of and therapy for very rare IL-1-mediated SAIDs are now available

  • Consider these syndromes (CAPS, TRAPs, MVD and DIRA) in the differential diagnosis of children with regular or chronic unexplained fevers and symptoms of aseptic inflammation

  • First-line therapy includes three biologics targeting IL-1: anakinra, canakinumab and rilonacept

  • Therapy is lifelong, and monitor patients for uncontrolled inflammation and consequent renal, CNS, ocular, auditory and other organ damage