7.1.1. Diagnostic Criteria

CAPS is diagnosed clinically and genetically. Diagnostic criteria are used to guide the care of individual patients, and therefore must have a very high sensitivity and specificity in order that patients receive the correct diagnosis and treatment [90]. The diagnostic criteria of CAPS recognize that all but a few patients with CAPS have detectable systemic inflammation and use unique CAPS-specific clinical features along the whole disease spectrum to achieve reasonable specificity and sensitivity to aid clinicians in making the CAPS diagnosis [91]. These diagnostic criteria do not include genetic confirmation, and therefore can be applied in places where genetic testing is not available. If genetic testing is not available or it is negative, making a CAPS diagnosis is possible if raised inflammatory markers (CRP/SAA) can be detected plus at least two of the following symptoms: urticarial-like rash (neutrophilic dermatitis), cold-triggered episodes, sensorineural hearing loss, musculoskeletal symptoms, chronic aseptic meningitis, and skeletal abnormalities (Table 2) [91].

**Table 2.** Diagnostic criteria for CAPS (data from [91]).


#### 7.1.2. Classification Criteria

Classification criteria are primarily used to define cohorts of patients that can be included in clinical research. Using classification criteria may result in some patients with the disease not being captured (false negative); however, the chance of patients not having the indicated diagnosis (false positive) is very low [90]. In 2019, Gattorno et al. developed validated evidence-based classification criteria for hereditary AID with high sensitivity and specificity [92]. The classification criteria for CAPS are summarized in Table 3.


#### **Table 3.** Classification criteria for CAPS (data from [92]).

#### *7.2. Diagnostic Challenges*

As mentioned above, patients with low-penetrance variants or somatic mosaicism might present with atypical clinical CAPS phenotypes. AID panels and targeted NGS may be negative or inconclusive and the correlation of clinical phenotype and genetic result is critical [93]. Furthermore, patients might present with a heterogeneous multisystemic clinical presentation. Advanced genetic testing can enable a diagnosis in some AID patients [94,95].

#### **8. Treatment**

CAPS treatment is a multidisciplinary effort including medication, psychosocial support, physiotherapy and supportive care. Treatment aims are to suppress systemic inflammation, to improve functionality, to prevent organ damage, and to increase patients' quality of life. To achieve these aims, cytokine targeting drugs are important and evidencebased treatment plans including treat-to-target (T2T) strategies play a pivotal role in CAPS management [51,96]. The key component of T2T is the definition of a clinical target, such as disease remission or the lowest possible disease activity. Standardized and repeated examinations are required to determine if a previously defined target is achieved [97]. Different levels of disease activity may require different treatment selections and dosing approaches [51,96]. Since IL-1 plays a central role in CAPS pathogenesis, the anti-IL-1 treatment is recommended for the whole CAPS spectrum [51]. Currently, three anti-IL-1 treatments (anakinra, canakinumab, and rilonacept) are available, and several studies have addressed their safety and efficacy. However, symptomatic patients with low-penetrance

variants are at risk to achieve only a partial response to anti-IL-1 treatment, as inflammation seems to be mediated due to NLRP3 specific IL-1β release and NLRP3-independent IL-6 or TNF-α production [23,27].

#### *8.1. Anti-IL-1 Treatment*

Anakinra is a short-acting recombinant IL-1 receptor antagonist, which has been proven to have long-term efficacy and safety in several studies [54,98–101]. Anakinra is administered daily subcutaneously and blocks the binding of IL-1α and IL-1β to the IL-1 receptor. In a study of 43 CAPS patients treated with anakinra, for up to 5 years, the most reported serious adverse events were pneumonia and gastroenteritis [101]. Anakinra has been approved by the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) for CAPS. For anakinra, the typical dosing regimen varies from 1 to 2 mg/kg/day for patients with FCAS, up to 10 mg/kg/day for critically ill patients with NOMID/CINCA [14]. The CNS penetrance of anakinra seems to be superior, and therefore this might be the treatment of choice in cases with aseptic meningitis [102]. The recombinant soluble IL-1 receptor rilonacept binds to IL-1α and IL-1β. Weekly subcutaneous administration has shown a good safety and efficacy profile against CAPS [103,104]. So far, rilonacept has only been approved by the FDA. The dose of rilonacept for adults is 160 mg/week and varies from 2.2 to 4.4 mg/kg/week in children [14]. Canakinumab is a fully humanized anti-IL-1β monoclonal antibody that selectively binds to soluble IL-1β and has to be administered subcutaneously every four to eight weeks. Several studies have confirmed long-term efficacy and safety against CAPS [52,105–109]. In patients with mild to moderate CAPS, 150 mg of canakinumab can be administered if the body weight is >40 kg or it can be dosed with 2 mg/kg for patients from ≥15 to ≤ 40 kg, every four to eight weeks [14]. For children (15–40 kg) with an inadequate response, a dose increase, up to 3–4 mg/kg, might be necessary and dosing up to 8 mg/kg every four weeks has been described for NOMID/CINCA patients [110]. Canakinumab has been approved by the EMA and FDA.

#### *8.2. Supportive Therapy*

In patients with CAPS, supportive care plays an important role and can consist, for example, of hearing aids, physiotherapy, and orthopedic devices. Furthermore, adjunctive therapies, such as non-steroidal anti-inflammatory drugs for pain and fever or corticosteroid eye drops and tear substitutes, might help to overcome the disease symptoms. Particularly for patients with the mild CAPS phenotype, warming therapies and local protection for cold (gloves, wristlets) can be beneficial for flair prophylaxis.

#### *8.3. Psychosocial Needs*

In addition to anti-IL-1 treatment, CAPS patients can profit from psychosocial support. AID have been shown to be associated with depression, lower health-related quality of life, anxiety, and risk of isolation due to frequent canceling of social events [111–113]. Since AID can affect all areas of life and well-being is linked to psychological factors such as illness beliefs, coping strategies, and the distribution of dependency, these aspects have to be taken into account in the long-term management of CAPS [111,114]. Furthermore, patient support networks can provide emotional support.

#### *8.4. Outlook Drug Development*

Currently, there are new treatment approaches under development, which might be used to treat CAPS in the future. For example, small molecule inhibitors targeting NLRP3 directly are one promising drug development [115]. The diarylsulfonylurea compound MCC950 seems to be a potent selective small inhibitor of NLRP3, blocking canonical and non-canonical NLRP3 activation by closing the "open" confirmation of active NLRP3 [116,117]. MCC950-based therapies may effectively treat inflammation driven by wild-type NLRP3, and an evaluation of its ability to inhibit CAPS mutant variants

has provided a mechanistic framework for advancing therapeutic development and for understanding its therapeutic potential in patients [118]. Furthermore, Youm et al. showed that β-hydroxybutyrate (BHB) suppressed the activation of the NLRP3 inflammasome by preventing K+ efflux and reducing ASC oligomerization and speck formation [119]. In addition, several other ways to inhibit the NLRP3 inflammasome, such as autophagy or microRNAs, are under research [115].

#### **9. Monitoring**

Regular monitoring of disease activity is crucial to determine disease activity and organ damage [51]. Monitoring includes serial physical examinations, measurements of weight and height, audiology and ophthalmologic exams, radiographs and MRIs, as well as musculoskeletal, neurological, and laboratory examinations, such as blood count, liver and muscle enzymes, renal function, urine analysis, CSF measurements, and determination of SAA and CRP levels to detect ongoing inflammation. For monitoring of disease activity in CAPS, longitudinal patient diaries, such as the MWS disease activity score (MWS-DAS) or the AIDAI, can be used for systematic assessment of daily diseases symptoms. Both were initially developed for clinical trials but can be used by clinicians as well. The MWS-DAS captures disease symptoms in 10 domains; nine domains reflect the organ involvement in MWS (fever, headache, eye involvement, hearing impairment, oral ulcers, abdominal pain, renal disease, musculoskeletal disease, and rash), and the tenth is the patient's global assessment score [100,120]. The validated AIDAI is a simple tool for outpatients to assess CAPS disease activity at home [83], allowing treating physicians to better differentiate between inactive or active disease and the need for treatment adjustments. The autoinflammatory disease damage index (ADDI) is a reliable instrument for assessing disease-related organ damage [121]. The ADDI consists of 18 items grouped into the following eight categories: reproductive, renal/amyloidosis, developmental, serosal, neurological, auditory, ocular, and musculoskeletal damage [121,122]. The ADDI can be used to monitor structural damage in individual patients and allows outcome analysis and comparison of results in clinical trials [121].

#### **10. Prognosis**

The prognosis in CAPS patients depends, on the one hand, on the CAPS phenotype and, on the other hand, on an early diagnosis allowing the start of effective treatment. The prevalence for AA-amyloidosis in CAPS patients without treatment varies between 10% for mild phenotypes and 25% for moderate phenotype [123]. With the availability of anti-IL-1 treatment, the prognosis of patients with CAPS has improved considerably. However, early and aggressive treatment is crucial to improve quality of life and to avoid organ damage. Only an early start of treatment will prevent organ damage and avoid progress. Furthermore, starting treatment early can result in reversibility, for example, of hearing loss.

**Author Contributions:** Conceptualization, T.W. and J.B.K.-D.; writing—original draft preparation, T.W.; writing—review and editing, J.B.K.-D.; visualization, T.W.; supervision, J.B.K.-D. Both authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Conflicts of Interest:** T.W. declares no conflict of interest. J.B.K.-D. received grant support and speaker's fees from Novartis and SOBI. No funder had a role in the design of this article; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish this article.
