FormalPara Key Points

High index of suspicion is essential for early diagnosis of CAPS, TRAPS, MKD and DIRA.

To provide a diagnosis for patients with suspected phenotypes, genetic testing using next-generation sequencing (NGS) is necessary. Sanger sequencing of a single gene may be utilized in the presence of family history and/or classic clinical features.

Early treatment with IL-1 inhibitors is required to reduce morbidity and mortality.

The lifelong necessity for IL-1 inhibition in monogenic autoinflammatory diseases CAPS, TRAPS, MKD and DIRA mandates ensuring safety monitoring.

1 Introduction

Systemic autoinflammatory diseases (SAIDs) are a large and heterogeneous group of disorders characterized by dysregulation of the innate immune system. Most SAIDs are associated with mutations in genes involved in the innate immune response. A specific group of genetically defined SAIDs are associated with increased inflammasome-mediated production of active interleukin (IL)-1 that are usually referred as “Hereditary Periodic Fever Syndromes” [1].

The IL-1 mediated autoinflammatory disorders are ultra-rare systemic autoinflammatory diseases with an estimated prevalence of less than one in a million. Accepted strategies to study these disorders, such as placebo-controlled trials are often not feasible due to the rarity, small sample size and severity of these diseases [2, 3]. Therefore, it is challenging to conduct research in various areas such as the development of biomarkers, outcome instruments or new treatment approaches. Extensive knowledge has been gained from functional and/or genetic studies over the past 20 years since the term “autoinflammation” was first described [4], however, many obstacles still remain when applying this knowledge in clinical setting for the benefit of individual patients. Until confirming the diagnosis, these complex patients are often seen by multiple health practitioners and disease flares may result in frequent emergency room visits, and/or hospitalizations. In addition, there are limited number of physicians who specialize in these disorders. All these challenges cause diagnostic delays, high costs to the health care system, and frustration from patients and their families. Early identification of these diseases, initiation of targeted therapy, and development of a unified delivery of multidisciplinary care are vital to prevent diagnostic delays, organ damage, morbidity, and mortality as well as to improve quality of life (QOL) measures [5, 6].

In July 2022, the European Alliance of Associations for Rheumatology (EULAR) and American College of Rheumatology (ACR) published provisional points to consider for the diagnosis, management and monitoring of four IL-1 mediated autoinflammatory diseases, including cryopyrin-associated periodic syndromes (CAPS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), and deficiency of the IL-1 receptor antagonist (DIRA) [5]. In this review, we focus on those four IL-1-mediated SAIDs: CAPS, TRAPS, MKD, and DIRA, and provide insights into the general pathophysiological concepts, clinical features, suggested diagnostic workup, and current and future perspectives for therapy on the basis of the EULAR and ACR points to consider. Our goal is to increase awareness and provide health care professionals with a practical approach on the diagnosis and management of these four diseases.

2 Immunopathological Mechanisms of IL-1-Mediated SAIDs

In CAPS, TRAPS, MKD, and DIRA, different pathophysiologic mechanisms cause increased IL-1β (Fig. 1). To date, it is still unclear how increased IL-1 signaling causes different clinical phenotypes. Nevertheless, it is now well established that IL-1-mediated cytokines, and in the context of monogenic autoinflammatory diseases, mainly IL-1β, IL-1α, and IL-1 receptor antagonist (IL-1RA), are tightly regulated inflammatory mediators involved in response to tissue damage, the presence of pathogen- and danger-associated molecular patterns (DAMPs and PAMPs), and cell death pathways [7]. Inflammasomes, intracellular ensembles of multiple proteins, usually remain inactive under normal circumstances, but can be activated in the presence of specific triggers, such as pathogen toxins, intracellular metabolites, or stress, triggering innate inflammatory responses [7, 8].

Fig. 1
figure 1

Pathophysiology of the IL-1-mediated diseases. Pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) stimulate innate immune sensors NLRP3 and pyrin in the cytoplasm. Stimulated NLRP3 and pyrin form ASC and activate the inflammasome complex, which subsequently drives pro-caspase 1 and caspase 1 formation. Caspase 1 mediates cleavage of pro-IL-1β and pro-IL-18 into bioactive forms of proinflammatory cytokines, IL-1β and IL-18, which then activate intranuclear NF-κB for the transcription of proinflammatory cytokines. Gain-of-function mutations in the NLRP3 gene result in CAPS. In healthy cells, IL-1β binding to its cytoplasmic IL-1 receptor is naturally inhibited by IL-1RA. DIRA causes uncontrolled IL-1β binding, resulting in a hyperinflammatory response. RhoA GTP molecules regulate the pyrin inflammasome through serine–threonine kinases. Loss-of-function mutations in the mevalonate kinase gene result in reduced mevalonate kinase activity, inactivation of the RhoA GTPase, and increased pyrin inflammasome formation, which then leads to excessive cytokine production in MKD. In TRAPS, disease-causing variants affect receptor structure and binding to the TNF ligand. Although disease mechanisms remain unclear, intracellular accumulation of the misfolded TNF receptor 1 is thought to cause ER stress, overproduction of ROS, and ultimately activation of different pathological immune responses. ASC apoptosis-associated speck-like protein containing a caspase-recruitment domain, CAPS cryopyrin-associated periodic syndrome, DIRA deficiency of interleukin-1 receptor antagonist, ER endoplasmic reticulum, GSDMD gasdermin D, IL interleukin, IL-1R interleukin-1 receptor, IL-1RA interleukin-1 receptor antagonist, MKD mevalonate kinase deficiency, MVK mevalonate kinase, NF-κB nuclear factor kappa B, NLRP3 nucleotide-binding domain-like receptor 3, ROS reactive oxygen species, TNFR1 tumor necrosis factor receptor 1, TRAPS TNF receptor-associated periodic syndrome

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Inflammasomes consist of oligomers of a sensor protein, caspase 1, and an adaptor. The sensor is responsible for recognizing danger signals and gives the inflammasome its specificity. The most common sensors are one of ten different nod-like receptor (NLR)-family proteins and the sensor protein pyrin. After recognition of microbial or endogenous ligands, the sensors oligomerize with an adaptor protein, and subsequently, inactive caspase 1 is converted to its active version forming the inflammasome complex. Activated caspase 1 then cleaves pro-IL-1 and pro-IL-18 to produce biologically active IL-1β and IL-18, which in turn trigger acute inflammation, innate immune cell activation, and classical clinical features seen in these patients, such as fever [9, 10].

2.1 Cryopyrin-Associated Periodic Syndromes (CAPS)

Autosomal dominant (AD) or de novo heterozygous gain-of-function mutations in the NOD-like receptor protein 3 (NLRP3) gene result in persistent intrinsic activation of the NLRP3 inflammasome, or a decreased threshold for its activation, constituting the prototype of inflammasomopathies [11]. NLRP3 protein was shown to contain a pyrin domain in the amino terminus, and it is a critical sensor triggered by diverse molecular and cellular mechanisms, including microbial toxins, ionic influx, and mitochondrial reactive oxygen species (mROS), leading to innate immune system activation [12, 13]. Overactivated NLRP3 in CAPS patients drives consequent NLRP3 inflammasome assembly, caspase 1 activation, and overproduction of active IL-1β and IL-18 [12].

2.2 Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS)

TRAPS is caused by autosomal dominant (AD) heterozygous gain-of-function (GOF) mutations on chromosome 12, in the TNFRSF1A gene, which encodes for tumor necrosis factor (TNF) receptor 1 (TNFR1). Although precise TRAPS immunopathological mechanisms have not been completely defined, a few affected immune pathways have been discovered in recent studies. The discoveries are as follows: (1) intracellular accumulation of the misfolded mutant TNF receptor proteins were found to be associated with increased endoplasmic reticulum (ER) stress and unfolded protein response, causing excessive production of mROS, leading to increased cell death and abnormal autophagy [7, 14]; (2) ER stress and mROS have been shown to activate nuclear factor ĸB (NF-κB) and, consequently, transcription of proinflammatory target genes, promoting proinflammatory cytokine production; and (3) heterozygous variants affect the structure of the extracellular domain of the TNFR1 and impair its binding to the TNF ligand and shedding from the cell surface, affecting TNFR1 counter regulatory mechanisms [14,15,16].

2.3 Mevalonate Kinase Deficiency (MKD)

MKD is caused by autosomal recessive loss-of-function (LOF) mutations in the gene of the mevalonate kinase (MVK) enzyme [17], causing decreased or absent MVK enzymatic activity, and affecting a crucial step in the isoprenoid biosynthesis pathway that yields many lipid products that diminish inflammatory responses [7, 18]. Recent human and murine models have shown the role of Rho GTPase in regulating pyrin activity in normal conditions which has helped clarify the mechanism by which loss of MVK leads to autoinflammation [19]. Shortage of nonsterol isoprenoids causes defective protein prenylation and impaired attachment of isoprenoids to GTPases, such as the Rho family of GTPase, thereby resulting in an uncontrolled release of IL-1β from innate immune cells, presumably in a pyrin–inflammasome-dependent pathway [7, 19, 20].

2.4 Deficiency of the IL-1 Receptor Antagonist (DIRA)

IL-1RA competitively binds to the IL-1 receptor (IL-1R), thus preventing IL-1α and IL-1β binding to the IL-1R and acting as a natural inhibitor of IL-1-mediated inflammatory responses [7]. In DIRA, autosomal recessive homozygous LOF mutations in IL1RN, the gene encoding the IL-1RA, lead to unopposed IL-1 signaling and uncontrolled IL-1-mediated hyperinflammation, which is responsible for the disease phenotype [21, 22].

3 Clinical Evaluation and Diagnostic Approach

Early diagnosis is vital in patients with autoinflammatory disorders to control the disease activity and prevent long-term immune-mediated damage by starting targeted treatment in a timely manner. However, diagnostic delays still occur and remain an important issue, often due to limited awareness and limited experience in autoinflammatory disorders [6]. Detailed patient and family history, as well as physical examination should be the first steps in diagnosis because recognition of the signs and symptoms of autoinflammatory disorders warrants further evaluation and genetic testing [23].

Patients with CAPS, TRAPS, MKD, and DIRA present with systemic inflammation; however, clinical signs, symptoms, and disease severity vary based on diagnosis. Each disease has a specific pattern of clinical features that may determine the workup for evaluation and diagnosis. Common and disease-specific signs and symptoms of CAPS, TRAPS, MKD, and DIRA are summarized in Table 1.

Table 1 Typical clinical manifestations of CAPS, TRAPS, MKD, and DIRA prompting diagnostic workup (please see Table 2)
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3.1 CAPS

CAPS is a spectrum with mild, moderate, and severe forms. Across the spectrum of severity, patients with CAPS share symptoms of urticaria-like rash with neutrophilic infiltrate, ocular manifestations, fevers, and joint pain. The mildest form of CAPS is familial cold autoinflammatory syndrome (FCAS), which is characterized by cold-triggered episodes of neutrophilic urticaria, typically lasting less than 24 h [24,25,26]. Muckle–Wells syndrome (MWS) is the moderate form of CAPS, and patients typically present with progressive sensorineural hearing loss, neutrophilic urticaria, and arthritis [27,28,29]. Neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic cutaneous and articular syndrome (CINCA) is the most severe form of CAPS [30]. It is associated with nearly persistent systemic inflammation with neonatal-onset neurologic manifestations (chronic aseptic meningitis, increased intracranial pressure, papilledema, cognitive impairment), severe progressive sensorineural hearing loss, and skeletal manifestations (frontal bossing, distal femur overgrowth) [31]. Age at disease onset varies for each CAPS, which can aid the diagnosis. MWS presents in childhood, while CINCA/NOMID manifests early in life, even in the neonatal period [32]. FCAS may present at any age. Family history is often positive in patients with FCAS and MWS, but often negative in patients with CINCA/NOMID [33].

Markers of systemic inflammation should be monitored during clinical disease flares, even if the the patient is clinically quiescent. These markers include complete blood count (CBC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and, if available, serum amyloid A (SAA) and S100 [34, 35]. Additionally, organ involvement and damage should be assessed during the diagnostic process (Table 2). Most FCAS and some MWS patients develop typical skin lesions triggered by cold air, but not by contact with an ice cube or cold water. The ice cube test is helpful in differentiating FCAS from cold urticaria [36]. Skin biopsy of urticaria-like rashes reveals a neutrophilic dermatosis that is common in CAPS patients [36]. Comprehensive ophthalmologic and audiologic evaluation is necessary for all patients with suspected CAPS. Although acute conjunctivitis is the most common eye manifestation during disease flares, it can also become chronic. Other eye manifestations include keratitis, episcleritis, and uveitis. Most CINCA/NOMID patients develop papilledema due to chronic elevated intracranial pressure. Papilledema and uveitis can cause progressive vision loss [37,38,39]. Due to ongoing cochlear inflammation, progressive sensorineural hearing loss is a main concern for MWS and CINCA/NOMID phenotypes. Hearing loss can be irreversible if left untreated or if treatment is delayed; however, reversing or stabilizing the progression of hearing loss may be possible by treating patients early in the disease course [40,41,42].

Table 2 Suggested initial diagnostic workup in patients with suspected CAPS, TRAPS, MKD, and/or DIRA
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3.2 TRAPS

Typical clinical symptoms of TRAPS include recurrent fever episodes lasting longer than 7 days, sometimes lasting for weeks, along with maculopapular migratory rash, periorbital edema, abdominal pain, chest pain, and/or musculoskeletal complaints. Some patients present with episodes of inflammations, and others present with a continuous disease course [1, 43,44,45]. Periorbital edema is a pathognomonic feature of the disease in the context of the other typical clinical findings, and it may be a sign of a disease flare when combined with myalgia. Other ocular manifestations include recurrent conjunctivitis or anterior uveitis. Skin lesions are typically migratory, painful/tender macular, edematous, or urticarial lesions. Abdominal pain in TRAPS can also mimic an acute abdomen similar to what is observed in patients with familial Mediterranean fever (FMF). Arthralgia during attacks is more common than frank synovitis, but patients can present with nonerosive, asymmetric, and monoarticular arthritis. Neurological manifestations such as headache, aseptic meningitis, optic neuritis, and pleuritis are also seen in TRAPS [44,45,46]. Although presence of family history and febrile episodes lasting longer than 7 days are highly predictive clinical features of TRAPS, patients with low-penetrance TNFRSF1A mutations may have a negative family history and a later clinical onset [47, 48].

Systemic inflammation is present during febrile episodes, demonstrated by elevated acute phase reactants. Depending on the disease severity, inflammatory markers may remain elevated between fever episodes. Systemic amyloid A (AA) amyloidosis may occur especially in the context of mutations in cysteine residues, delayed diagnosis and/or prolonged disease activity; in these cases, monitoring of S100 and serum amyloid A (SAA) can have clinical utility [44, 45, 49]. Lesioned skin biopsies display a mild perivascular lymphocytic infiltrate in the edematous areas of the papillary dermis [49].

3.3 MKD

This disorder is commonly divided into two forms based on MVK activity: hyper immunoglobulinemia D and periodic fever syndrome (HIDS) describes the milder form with reduced MVK enzyme activity, whereas mevalonic aciduria is the severe form with nearly absent MVK enzymatic activity [1, 50].

Patients usually present with MKD features in the first year of life with disease episodes, whereas some patients present with a continuous course through exacerbations. Inflammatory episodes of MKD are generally triggered by immunizations, surgery, stress, or trauma and characterized by fever lasting for 4–6 days. Severe abdominal pain is a common feature and is mostly associated with diarrhea or vomiting. Lymphadenopathy is also frequently observed, with most presentations being bilateral, tender, cervical nodes, though generalized lymphadenopathy may also be present. Most patients present with a variety of mucocutaneus symptoms such as a rash (maculopapular or urticarial-like), aphthous stomatitis and/or pharyngitis. Patients can have arthralgia and nonerosive arthritis. Persistent arthritis has also been reported and recorded in these patients [50,51,52,53]. Patients with mevalonic aciduria, the most severe form of MKD, can also present with severe cognitive impairment, macrophage activation syndrome, dysmorphic features, and failure to thrive [5, 44, 50].

Systemic inflammation is present and reflected by elevated acute phase reactants, leukocytosis, and neutrophilia in laboratory workups. Persistent elevation of serum immunoglobulin D (IgD) level is observed in the majority of HIDS patients. Serum IgD levels can be normal in patients with HIDS, especially in children younger than 3 years. IgD can also be elevated in other autoinflammatory conditions. Therefore, IgD levels have low diagnostic sensitivity and specificity [5, 50, 54]. On the other hand, during disease flares, mevalonate levels increase in urine secondary to reduced MVK enzyme activity leading to the accumulation of mevalonic acid. Urine mevalonate level is a more specific test for MKD and can be used to aid diagnosis. Nevertheless, a definitive diagnosis can only be confirmed through genetic testing [5, 55].

3.4 DIRA

Patients with DIRA present with early onset neutrophilic pustular rashes, multifocal sterile osteomyelitis [e.g., chronic recurrent multifocal osteomyelitis (CRMO)-like disease, rib flaring and cloaking of the femoral head, odontoid lesions/osteomyelitis], periostitis, and nail changes (onychomadesis). Hypoxemia and dyspnea are frequently seen in infants secondary to interstitial pneumonia, areas of atelectasis or gastroesophageal reflux. Pustular skin lesions resemble pustular psoriasis and can be triggered by mechanical stress (pathergy). Lesions can be sparse, occur in clusters, or present as severe generalized pustular dermatosis. In contrast to CAPS, TRAPS and MKD, fever is rarely present in DIRA disease flares, although marked elevation in inflammatory markers with neutrophilia is typical [7, 22, 44, 56].

In patients with presumed DIRA, a diagnostic workup should be initiated to assess peripheral neutrophilia and elevated inflammatory markers. To determine bone involvement, X-ray or bone magnetic resonance imaging (MRI) should be performed. Typical radiographic manifestations show widened ribs and clavicles, as well as multifocal osteolytic lesions mainly observed in long bones. Computerized tomography (CT) or MRI can be used to screen for vertebral involvement presenting with odontoid osteomyelitis, vertebral block formation, and gibbus-like spinal changes. However, even with all of these presentations, genetic testing is crucial for a definite diagnosis [5, 22].

4 Genetic Testing

As mentioned above, while clinical features and laboratory tests typically suggest specific SAIDs, genetic testing needs to be performed to confirm the exact diagnosis and provide accurate genetic counseling [57,58,59]. Although this step is crucial for diagnosis, accessing appropriate genetic testing can be challenging [5]. There are important points that need to be considered when ordering genetic testing, and these are outlined in Table 3. If available, next-generation sequencing (NGS) is recommended over Sanger sequencing. The initial genetic test should be an NGS–autoinflammatory diseases (AIDs) panel [57]. Sanger sequencing should be limited to patients with a clear family history and classic clinical phenotypes, or in areas where NGS is not available or is prohibitively expensive [60]. Care providers can find worldwide available panels in the Genetic Testing Registry database (https://www.ncbi.nlm.nih.gov/gtr/). In any NGS report, detected variants are classified as follows: pathogenic mutation; variant, likely pathogenic (VLP); variant, unknown significance (VUS), variant, likely benign (VLB); and benign. Some databases, such as MOLGENIS and INFEVERS offer clinicians clear, accurate, clinically relevant details about those variants [61, 62]. However, it can still be challenging to interpret genetic testing results for some variants as they may cause a less severe clinic phenotype than a low-penetrance mutation. Therefore, collaboration among rheumatologists, immunologists, and medical geneticists is necessary to achieve an accurate diagnosis.

Table 3 Different types of genetic testing methods utilized to diagnose CAPS, TRAPS, MKD, and DIRA
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Although NGS should be the first step of genetic evaluation where available, it comes with some limitations such as inability to detect somatic mosaicism. Therefore, deep sequencing with a much greater NGS depth (e.g., > 1000×) [60] may be necessary for CINCA/NOMID patients since somatic NLRP3 mosaicism can be present in mutation-negative NOMID/CINCA, which was identified in 69.2% of patients with mutation-negative NOMID/CINCA in one study [63]. Another genetic diagnostic challenge with NGS is seen in DIRA patients. A large deletion in IL1RN gene is one of the genetic reasons for DIRA, and large deletions sometimes cannot be determined by NGS; therefore, resequencing may be necessary [64, 65]. If the targeted NGS panel returns negative results, consideration should be given to whole-exome sequencing (WES) and whole-genome sequencing (WGS) to enhance the likelihood of making a genetic diagnosis by discovering novel variants [66]. If the genetic diagnosis cannot be made with NGS, patients should be referred to a SAIDs center of excellence.

5 Treatment

Early diagnosis is the first step of treatment as it will guide us to implement etiological anti-inflammatory treatment with biologics (see below). A multidisciplinary team-based approach is crucial for accurate and prompt diagnosis, initiating treatment early in the disease course, minimizing disease complications, and improving prognosis. The implementation of outcome instruments, quality-of-life (QOL) measures, and patient-reported outcomes (PRO) will help identify patients’ needs and prospectively evaluate the quality of service provided.

5.1 Pharmacological Treatment

Specific inhibitors of IL-1 signaling is the standard therapy for patients with CAPS, TRAPS, MKD, and DIRA. Early and sustainable normalization of all clinical signs and symptoms of inflammation and inflammatory markers is the primary treatment goal to reduce inflammation burden, organ damage, and the need for other therapies. Strong clinical suspicion may authorize starting anti-IL-1 therapy before a definitive genetic diagnosis to prevent organ damage secondary to treatment delays [5].

Anakinra (Kineret), rilonacept (Arcalyst), and canakinumab (Ilaris) are three IL-1 inhibitors that have been shown to be effective and safe in controlling disease activity. These drugs are approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) [67]. Anakinra, the recombinant human IL-1 receptor antagonist (IL-1Ra), efficiently blocks IL-1α and IL-1β signaling by competitively binding to the IL-1 receptor. A daily subcutaneous injection is required due to its short half-life, which is a disadvantage in many cases. However, its good central nervous system (CNS) penetration may make it the therapy of choice in cases with CNS involvement [68,69,70]. Rilonacept, a dimeric fusion protein, also blocks IL-1α/β with longer half-life than Anakinra [71]. Canakinumab is a fully human IgG monoclonal antibody selective to IL-1β so it does not block the IL-1α signaling pathway [72]. The significant advantage of canakinumab over anakinra and rilonacept is monthly/bimonthly administration due to its longer half-life [73]. All three anti IL-1 treatments can be used subcutaneously. Dosing regimens are summarized in Table 4.

Table 4 Recommended dosage regimens of canakinumab, rilonacept, and anakinra for treatment of CAPS, TRAPS, MKD, and DIRA in the pediatric patient population
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Anakinra has shown to be a safe and effective treatment for all CAPS phenotypes [74,75,76,77,78]. Although the recommended anakinra dosage for FCAS patients is 1–2 mg/kg/daily, higher dosages are recommended (1–8 mg/kg/daily) for patients with more severe phenotypes, such as MWS and CINCA/NOMID. Kullenberg T et al. showed that anakinra treatment was safe and well tolerated for up to 5 years in 43 patients with severe CAPS [75]. The most frequently reported adverse events (AEs) were typical CAPS symptoms such as headache and arthralgia, or injection site reactions, which resolved mainly after the first month of anakinra treatment. Infections including pneumonia and gastroenteritis were the most common types of severe adverse events (SAEs) observed. There were no permanent treatment discontinuations due to AEs.

The efficacy and safety of rilonacept in MWS and FCAS have been shown in three randomized controlled trials [71, 79, 80]. A loading dose of 4.4 mg/kg (max 320 mg) is administered subcutaneously once, followed by the weekly maintenance doses of 2.2 mg/kg (max 160 mg). Rilonacept is not yet approved by FDA for the severe phenotype of CAPS (i.e., CINCA/NOMID). The most common AEs were injection site reactions and upper respiratory tract infections during the rilonacept treatment course. No SAEs have been documented in CAPS patients [71, 80].

Several studies showed the long-term safety and efficacy of canakinumab in all CAPS phenotypes [81,82,83,84]. Yokota S. et al. [83] enrolled 19 patients (12 NOMID, 7 MWS) for a median of 109 weeks. All patients achieved a complete response by week 48. At the end of the study, 11 (57.9%) patients had no disease activity according to the physician global assessment (PGA). All patients experienced at least one AE, the most common being infections (100%) and a total of five SAEs were reported. Brogan PA et al. [84] showed that canakinumab was safe and effective in 17 children ages 5 years and younger (12 MWS, 4 CINCA, 1 FCAS). In addition, no negative impact was found regarding postvaccination antibody production following the administration of non-live vaccines in nine pediatric patients treated with canakinumab.

Limited data suggest that canakinumab may be insufficient for neutralization of IL-1β in the central nervous system (CNS) [70]. Patients with severe CAPS phenotypes require higher and more frequent dosing (up to 8 mg/kg/q4w) to achieve remission [81, 83].

Canakinumab is the only anti-IL-1 treatment currently approved by the FDA [85] and EMA [86] for patients with TRAPS or MKD, on the basis of data from clinical trials and real-world effectiveness and safety [87,88,89]. Anakinra has also been used in both diseases, but effectiveness data remains scarce, mostly from small case series and a patient registry [67, 90,91,92]. Anti-IL-1 treatment can be sufficient when used at the beginning of a flare in patients with mild MKD [67]. In cases of anti-IL-1 treatment failure or lack of availability, anti-TNF or anti-IL-6 therapies may be considered, especially for those with TRAPS and MKD [93,94,95,96,97]. Finally, TRAPS and MKD flares may also respond to short-term glucocorticoid therapy [97, 98].

To conclude on pharmacological treatment, anakinra and rilonacept are FDA-approved treatments for DIRA [99, 100]. Both drugs are useful in controlling disease flares and preventing complications [22, 64, 65, 101]. Anakinra is the drug of choice for initial DIRA treatment, followed by maintenance therapy with rilonacept. Canakinumab exhibits a failure to control bone disease in patients with DIRA, likely because it only blocks IL-1β and IL-1α blockade may be additionally required to control osteitis. The recommended anakinra dosage for DIRA is 1–8 mg/kg/day, and rilonacept dosage is 4.4 mg/kg once weekly or 320 mg once weekly [99, 100].

In addition to targeting downstream cytokines in the IL-1 pathway (IL-1β, IL-1R, and IL-1α), studies have been aiming to directly inhibit a protein that is altered in a monogenic disease by developing small-molecule inhibitors. The most prevalent small-molecule target for treating autoinflammatory diseases has been NLRP3. Multiple companies are currently studying their own NLRP3 antagonists for CAPS [e.g., DFV90 (NCT04868968), ZYIL1 (NCT05186051)]. Small-molecule inhibitors with targets upstream and downstream of the inflammasome pathway are similarly under investigation such as selective PTX (7) receptor antagonist. Finally, other drugs that block downstream IL-1R signaling, including IRAK4 and MK2, are in development.

5.2 Treatment Monitoring

Anti-IL-1 therapies have overall excellent safety profiles but patients on anti-IL-1 therapy still require safety monitoring (Table 5). Furthermore, physicians should be aware of increased risks of infection, especially respiratory tract infections with streptococcus pneumonia and staphylococcal skin infections [81, 87]. Patients should be immunized according to local immunization guidelines. Although Brogan et al. showed that anti-IL-1 therapies do not affect the ability to produce antibodies against standard childhood inactivated vaccines [84], it is recommended that scheduled immunizations should be completed (particularly attenuated vaccines) before starting anti-IL-1 therapy, if possible. This recommendation includes MKD patients with increased disease flare risk by vaccination and CAPS patients with the potential risk of local and systemic reactions [84, 102, 103]. Live vaccines should not be administered concurrently with anti-IL-1 therapy. Coronavirus disease 2019 (COVID-19) mRNA vaccines are non-live vaccines so they can be administered to patients on anti-IL-1 therapy, but they may cause disease flares, and the immunogenicity of the COVID-19 vaccine may be decreased [104].

Table 5 Safety monitoring for anti-IL-1 therapy (patients on anti- IL-1 therapy should be monitored for medication specific side effects detailed below)
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6 Disease Monitoring

Disease activity and end-organ damage should be regularly monitored by a multidisciplinary team consisting of primary health care providers as well as experts in SAIDs, ideally based in a center of excellence. Rheumatologists, immunologists, hepatologists, ophthalmologists, otolaryngologists, nephrologists, neurologists, genetic counselors, physiatrists, occupational therapists, speech therapists, nutrition team, social support experts, and psychological health experts may be involved in the patients’ care according to individual patient needs. The frequency of monitoring depends on the disease activity, disease severity, treatment status, and timing of the treatment. Another crucial aspect of monitoring is the necessity for treatment adjustments based on patients’ changing needs. The multidisciplinary patient care team should be attentive to the varying needs of children, adolescents, adults, reproductive-age women, and seniors while monitoring these patients [105, 106].

Clinical symptoms, patient-reported outcomes (PROs), acute phase reactants, growth, and development should be evaluated at every visit to monitor disease activity and prevent long-term morbidity and mortality by using a treat-to-target approach. The most commonly used laboratory workup to evaluate systemic inflammation includes neutrophil count, CRP, ESR, and, if available, SAA and S100 protein. Overall disease activity and patient weight are important parameters for adjusting anti-IL-1 drug doses. Systemic inflammation may cause amyloidosis, so patients should be regularly monitored for kidney amyloidosis through urinalysis. Growth and development should also be assessed regularly at every visit, as chronic inflammation can significantly impact these parameters in children.

7 Conclusions

The diagnosis of IL-1-mediated SAIDs requires a high index of suspicion due to their rarity. Early recognition can lead timely treatment with appropriate biologic medications and referral to specialized health care teams, with the goal of improving patient outcomes and reducing morbidity and mortality. A coordinated care approach can decrease the burden secondary to multiple subspecialty visits and may assist decreasing hospitalizations for these medically complex patients. Moreover, streamlining access to specific genetic testing and treatment not only makes the diagnostic process easier but also proves to be more cost-effective. This comprehensive approach is instrumental in diagnosing these patients early, thereby preventing morbidity and mortality and improving overall healthcare outcomes.