PYD is the N-terminal domain of pyrin which binds the homonymous PYD domain of ASC, also interacting with both the actin cytoskeleton and microtubules, although a nuclear translocation and interaction with nuclear transcription factors have been assumed (14). Interestingly, its original name was PAAD due to the protein families from which it was observed: P – pyrin, A – AIM, A – ASC, D – Death-domain like (27). Thus, ASC (via its PYD domain) binds PYD (pyrin) and oligomerizes into filaments, recruiting pro-caspase-1 via its CARD region (CAspase Recruitment Domain) (27, 31). PYD is fully encoded by MEFV exon 1 and only a small group of likely pathogenic/pathogenic variants have been reported in literature [Infevers - Tabular list (umai-montpellier.fr)], probably with a mechanism of abnormal binding to ASC. Nonetheless, this point has not yet been clarified.

Despite the fact that the pyrin region between amino acids 93-369 does not belong to any particular pyrin domain, its presence is essential for protein function. Indeed, two specific residues, Ser208 and Ser242, encoded by MEFV exon 2 serve as phosphorylation sites for PKN1/2. Once pyrin is phosphorylated, the chaperones 14-3-3 are able to bind and maintain its inactive state (14, 28, 29). Thus, the binding between phosphorylated pyrin and 14-3-3 is directly dependent on PKN1/2, which are stimulated and phosphorylated by RhoA GTPase. Interestingly, the binding between 14-3-3 and pyrin occurs on the corresponding murine amino acids, as demonstrated by recent murine studies (32). Furthermore, as discussed below, specific missense mutations S242R and E244K, involving this region of interest, cause the AID named “pyrin-associated autoinflammation with neutrophilic dermatosis” (PAAND) (33). In the meanwhile, the homozygous pathogenic variant S208T has been observed in children with a different clinical phenotype characterized by arthralgia, lymphadenopathy, purpuric rash, and infiltrates in bone marrow (14, 34, 35). It has been suggested that the S208 amino acid is not so central for pyrin inactivation than S242 (14). However, both patients with PAAND and homozygous S208T variants show increased IL-1β and IL-18 serum levels (14, 34–36). In summary, pathogenic variants in the region of interest between PYD and B-box prevent PKN1/2 from phosphorylating pyrin, preventing the binding of 14-3-3 and leading to pyrin hyperactivation.

The central region of pyrin (370-596) contains the B-box and CC domains (370-412 and 420-440, respectively). This portion of pyrin is essential for the protein’s correct oligomerization via ASC. In fact, the B-box domain is thought to play an autoinhibitory role by enveloping the PYD domain and thereby interfering with its binding to ASC. In addition, via B-box and CC, pyrin interacts with the regulatory protein CD2-binding protein 1 (CD-BP1), which is encoded by the PSTPIP1 gene and primarily involved in the PSTPIP1-associated inflammatory diseases (PAIDs) (14, 35, 37). CD-BP1 and pyrin co-localize with the tubulin cytoskeleton and CD-BP1 triggers pyrin by binding B-box and CC, and therefore unmasking other domains, leading to its oligomerization (14, 38). Although a direct binding of CD-BP1 to B30.2/SPRY has been ruled out, the exact molecular mechanism of functioning has not been totally elucidated (28, 37). PSTPIP1 is thought to co-organize the cytoskeletal structure in macrophages, and the cytoskeleton itself has been proposed as a critical factor in these pathogenic mechanisms (14, 39). As discussed below in detail, PSTPIP1 pathogenic variants result in a hyperphosphorylated CD-BP1 and, therefore, a massive binding to B-box (29, 40). Heterozygous pathogenic variants of this key region P373L, H478T, and various T577 variants) have been associated severe presentations due to hyperinflammation with sterile serositis, colchicine resistance, and renal amyloidosis (28, 41–43). Interestingly, pathogenic phenotypes due to missense variants in this region are inherited in a dominant manner.

The C-terminal domain B30.2/SPRY (597-776) is encoded by the exon 10 and represents the hotspot for classical recessive-inherited MEFV pathogenic variants (28). Its function is still unclear, but there are much evidence that it represents a very important domain in the pathogenesis of diverse pyrin-related AIDs. Pathogenic variants of B30.2/SPRY induce a pathogen-independent activation of the pyrin responsible for FMF, and a direct binding with caspase-1 has been demonstrated in vitro despite the fact that the underlying molecular mechanisms are not fully understood (14, 27, 44–47). Recent research has attempted to elucidate the precise function of B30.2/SPRY fusing a human wild-type domain to murine pyrin, which naturally lack a B30.2/SPRY orthologous domain. The binding of PKN1 to pyrin was strongly reduced than in wildtype mouse pyrin, and it has been suggested that B30.2/SPRY could regulate the phosphorylation of the entire protein, and specifically that of the PKN1/2-binding residues (26). In addition, this study evaluated the phosphorylation levels of hybrid wildtype mouse pyrin with human B30.2/SPRY containing common pathogenic variants observed in FMF. Also in this instance, a decreased binding of PKN1/2 and, consequently, a disrupted binding of 14-3-3 to pyrin were observed (26). However, the exact mechanism that allows this key domain to regulate pyrin activity is not completely clear, and only some mechanisms have been hypothesized (14):

Nevertheless, it is currently unknown if B30.2/SPRY acts with a proinflammatory or missed autoinflammatory mechanism (49). A further investigation has elucidated an atypical method of pyrin activation, suggesting that endogenous steroid catabolites have the potential to induce autoinflammation via the pyrin inflammasome. This finding provides an explanation for the phenomenon known as “steroid fever,” which was first reported in the late 1950s following the administration of steroids to human subjects (50). Interestingly, high levels of pregnanolone and etiocholanolone, two catabolites of progesterone and testosterone, have been documented to active pyrin through the B30.2/SPRY domain, without involving RhoA GTPases, in PAAND and FMF patients (50).

RhoA GTPase is the target of several pathogens that aim to impair multiple defense mechanisms of the infected cell. The effects of such pathogens result in an impaired activity of this molecule, thus reducing its continuous stimulation of PKN1/2 and activating the pyrin inflammasome. This is an ancient mechanism of human organism to respond to pathogens and their toxins, and it could explain why up to 10% of the population of some countries has heterozygous pathogenic MEFV variants, typically observed in FMF (51, 52). This mechanism allowed individuals to have a greater immune response to some pathogens, in the case of MEFV mutations it was Yersinia Pestis. The main toxins interacting with RhoA GTPase are discussed below:

In addition, RhoA GTPase is dependent on a variety of enzymatic regulatory mechanisms. Rho GTPase requires geranylgeranylation for precise translocation to the cell membrane and appropriate function. This enzymatic process is in turn dependent on the enzyme geranylgeranyl pyrophosphatase, which is involved in the formation of cholesterol and is significantly reduced in MKD patients due to impaired functioning of the MVK gene (54). Growing evidence suggests that RhoA GTPase does not interact directly with pyrin, which is dependent on HAMPs in a particular immunity context.

FMF is the most known monogenic AID, caused by gain of function mutations of the MEFV gene, mostly affecting exon 10 and thus the B30.2/SPRY domain (14, 44, 86). This disease is quite common among populations surrounding the Mediterranean Sea. Indeed, in Turkey there is a very high prevalence between 1:400 and 1:1000, with similar prevalence rates reported in Israel and Armenia (86, 87). As described above, the high carrier frequency for MEFV mutations among Ashkenazi Jews and Turks may be explained with a selective advantage against Yersinia pestis, able to neutralize the classical pyrin inflammasome assembly producing a set of virulence proteins that interact with RhoA GTPases. FMF clinical phenotype often appears in pediatric age and is characterized by recurrent inflammatory attacks manifesting with high-grade fever, polyserositis, arthritis, and erysipelas like erythema (ELE) (88). High-grade fever and abdominal pain, due to sterile peritonitis, are by far the most common manifestations, reported in more than 90% of patients (86). Notably, a history of abdominal surgery is common among FMF patients (44). Comorbidities may occur (89). FMF clinical onset usually occurs before 5 years of age, and up to 90% of patients become symptomatic before the age of 20 years (88). The most feared complications of this disorder are represented by renal amyloid A amyloidosis and end-stage chronic renal disease, fortunately not common due to a growing number of correct diagnoses (44, 90, 91). Although FMF has an intermittent-recurrent inflammatory pattern, persistent inflammation between attacks can be detected in up to 30% of children, influencing growth and bone health, and evidencing a constant elevation of the indices of inflammation S100A8/A9 and serum amyloid A (SAA), with increased risk of developing renal amyloidosis over time (91, 92). The heterogeneous clinical expression is attributed to the various interactions between genetic and environmental factors, but the phenotype seems to be mainly determined by the MEFV variants carried (44). Indeed, among the 14 most common pathogenic variants observed in MEFV, 80% of them occurs in exon 10 and up to 20% in exons 2, 3 and 5 (93, 94). Many MEFV mutations have no certain pathogenic role, and the interpretation of genetic sequencing must be done very carefully (93, 94). M694V is a quite common and penetrant pathogenetic MEFV mutation that is associated with severe manifestations and early presentation (94). In addition, also biallelic exon 10 variants have been associated to severe course and early onset (44). The E148Q variant occurs in exon 2 and is one of the most common variants observed in MEFV, but it also occurs frequently in general population and its pathogenic role is still controversial (94). In a recent study, E148Q was not found to be related to FMF development, and E148Q/M694V patients were reported to be comparable to those with the M694V variant alone (95). The conclusions drawn from this study have generated controversy as a result of the small study population of E148Q/M694V patients (96). Further reports have related E148Q to FMF with a mild course, but it remains debatable whether the compound E148Q/M694V heterozygosity is associated with colchicine resistance (97–99). It is highly probable that the genotype alone is not sufficient for determining the entire clinical phenotype; thus, a multifaceted interplay exists among genetic background, environmental factors, and other modifier genes. Notably, patients from Turkey and Armenia have been more frequently reported to share FMF phenotypes with E148Q variants compared to patients from other countries (96, 100).

FMF classification criteria have changed over time: historical criteria did not consider the patient’s genotype, nowadays essential for an accurate diagnosis (9). In 2019, Gattorno et al. developed and validated the new Euro-Fever/PRINTO (Paediatric Rheumatology International Trials Organization) evidence-based classification criteria for hereditary recurrent fever, combining an international expert consensus and statistical evaluation of real patients, including for the first time the clinical genotype assessment (9). Therefore, FMF can be currently diagnosed when a confirming MEFV genotype is present, with at least one of the following symptoms: episodes lasting 1-3 days, arthritis, chest pain, or abdominal pain. Nevertheless, two of these requirements must be present when no confirmed MEFV genotype is found (9). A second set of criteria based only on clinical criteria was provided as a possible aid for the indication for molecular analysis or when genetic testing is not easily accessible ( Table 2 ) (9). In addition, recent evidence admitted an autosomal dominant (AD) pattern of transmission in presence of gain-of-function mutations of MEFV with a dose-dependent effect (9, 47, 101).

EULAR endorsed recommendations for the management of FMF has been published (102). Helpful recommendations for a better comprehension of MEFV mutations have been published (Infevers - Tabular list (umai-montpellier.fr)) (94). Given that even heterozygous genotypes have an increased risk of AA amyloidosis, treatment should be administered also in paucisymptomatic patients to prevent complications (91, 94). Colchicine is the first line of treatment for FMF and should be started as soon as possible and continued indefinitely (44, 91). In fact, its efficacy and safety have long been established, with reduction in the risk of renal amyloidosis to less than 1%, but no agreement over time to discontinue colchicine, with most of patients subjected to lifelong prophylaxis (44, 47, 91, 103, 104). As discussed above, colchicine inhibits neutrophil chemotaxis and extravasation, decreasing their flexibility through tubulin breakdown and microtubule instability, inhibiting pyrin inflammasome hyperactivation. Diarrhoea (up to 10,8%) and increased transaminases (up to 6%) are the most frequent side effects, although also important toxicities have been rarely observed (104–106). Particular attention should be paid to interaction with other drugs or foods such as macrolides, cyclosporin, statins, omeprazole, and even grapefruit. Moreover, almost 20% of patients are unable to maintain therapy, usually due to persistent diarrhoea (44, 103). In clinical practice, the dose of colchicine can be divided between two and three times daily to reduce side effects. However, about 5%–10% of patients do not respond to colchicine and need different therapeutic approaches (103, 107). M694V homozygous patients, biallelic variants of exon 10, and severe disease courses are at higher risk to be colchicine nonresponsive, while patients with serositis and heterozygous variants are usually more sensitive to lower drug doses (103, 107). Colchicine-resistant (crFMF) and intolerant patients are treated with biologic drugs, mostly IL-1 inhibitors (103). Several studies have been published on safety and efficacy of anakinra, canakinumab and rilonacept in crFMF, with good results (6, 103, 108–111). IL-1 inhibitors improve renal involvement and quickly resolve acute attacks, with low reported rates of collateral infections (111–113). The efficacy of on-demand use of anakinra has been documented in a cohort of crFMF patients, with a significantly long-term improvement (114). Interestingly, a single-dose anakinra has been recently retrospectively evaluated, resulting in a reduction in the duration and severity of inflammatory attacks (115). A double blind randomized trial evaluated the use of anakinra in crFMF, reporting good improvement and safety (116). Efficacy was also confirmed by following observational studies (117, 118). The “Canakinumab Pivotal Umbrella Study in Three Hereditary Periodic Fevers (CLUSTER)” was a lead randomized placebo-controlled study that evaluated the efficacy and safety of canakinumab in 63 crFMF patients. After 16 weeks of treatment with canakinumab at 150 mg/monthly, 61% of them reported a full response; while at 300 mg/monthly, 71% of patients was in full health (6). Thus, canakinumab has received approval by the “U.S. food and drug administration” (FDA) for crFMF (6), while both anakinra and canakinumab are currently approved for FMF in Europe by the “European medicines agency” (EMA) (110). A systematic review and meta-analysis were conducted in 2018 to assess the safety and efficacy of treatments available for FMF patients. Colchicine resulted in a reduction in the number of symptomatic patients independently of its administration strategy (single-dose or divided into three doses) (119). Nevertheless, only two studies using anakinra and rilonacept were included, not resulting in a significant reduction in the severity and frequency of FMF attacks (119). However, since 2018, many studies have demonstrated the efficacy of IL-1 inhibitors on FMF, as discussed above.

Two distinct mutations in MEFV exon 2, S242R and E244K, have been linked to the development of PAAND (120). This is an AD inherited disease, characterized by early onset of periodic fever, severe acne, neutrophilic dermatosis, pyoderma gangrenosum (PG), non-infectious cutaneous abscesses, and arthromyalgia (120). Its pathogenetic mechanism consists in the loss of a 14-3-3 binding motifs at phosphorylated pyrin, with the consequent pyrin inflammasome activation and IL-1β hyperproduction (36). PAAND is usually treated with IL-1 inhibitors, even though oral retinoids and TNFα inhibitors may effectively control dermatosis (36, 120). Nonetheless, over 385 MEFV variants have been recorded, although the real role of the majority of them remains unclear (121).

MKD is a rare AR inherited AID, caused by loss of function mutations in the MVK gene, located on chromosome 12q24.11 and encoding the enzyme mevalonate kinase (MVK) (122). MVK is physiologically involved in the isoprenoid biosynthesis pathway, catalysing ATP-dependent phosphorylation of mevalonate to produce 5-phosphomevalonate, essential in cholesterol biosynthesis (123). Its deficiency reduces the prenylation of proteins such as geranylgeranyl pyrophosphatase, necessary for the activation of RhoA GTPase and thus the inhibition of the pyrin inflammasome (26, 123, 124). To date, more than 175 pathogenic or likely pathogenic MVK variants have been described: most are substitutions, and small intragenic rearrangements, including three deletions of exons 2, 3 or 5 (Infevers - Tabular list (umai-montpellier.fr) (122). The most frequent MVK variant V377I is derived from a founder effect (125). In addition, also I268T, H20P, H20N, and P167L have been reported in in up to 71% of MKD patients (122, 126–128). However, few studies of phenotype-genotype correlation are currently available and more accurate details are needed (122). Originally, two distinct syndromes have been identified, classic “mevalonic aciduria” (MA) and “hyperimmunoglobilinemia D with periodic fever syndrome” (HIDS), but after the discovery of a common cause, recognized in the deficiency of MVK, they have been respectively considered as the severe and mild form of the same disease (122). MKD is a spectrum of disorders, ranging from mild to severe phenotype, depending on residual enzyme activity (122). Autoinflammatory symptoms, such as recurrent high-grade fever lasting 3-7 days, arthritis, abdominal pain, hepatosplenomegaly, and lymphadenopathy, are prevalent in milder HIDS forms, with preserved enzyme function (usually greater than 1%) (122, 124, 126). When no residual enzymatic function is present (< 1%), the clinical phenotype is characterized by MA, with recurrent high-grade fever, arthritis, growth failure, dysmorphism and severe cognitive disability (122, 124, 126, 129). The onset of autoinflammatory attacks is usually within the first 6 months of life, and may relapse every 1-2 months (124, 126). Several triggers have been associated with the appearance of inflammatory attacks, such as viral infections, emotional stress, and surgery (122). For a correct diagnosis of MKD, both genetic and clinical criteria have been established by the new Euro-Fever classification for HRF ( Table 3 ) (9). Renal AA amyloidosis is rarer than in FMF, although patients carrying the V377I and I268T variants are considered at higher risk (91, 127, 130). Proinflammatory cytokines, such as IL-1β, IL-6 and IFN γ, are dramatically increased during attacks, and a strong molecular connection has been attributed to FMF and MKD, basing on their pathophysiological mechanisms (123). Nevertheless, colchicine is not helpful in MKD patients (26, 123).

Dominant pathogenic MVK variants have been recently related to the development of PK, a severe localized skin disorder totally different from the systemic form MKD (122, 131). This rare dermatologic disorder is considered dominantly inherited but recessively expressed following a second acquired somatic mutation (128). Environmental factors, such as ultraviolet A (UVA)-mediated DNA alterations of epidermis cells, appear to play a key role in precipitating cell death in patients with heterozygous pathogenic germline MVK variants (122). Mevalonic acid may have a protecting role in keratinocytes cell damage induced by UV radiations (129). Keratotic lesions appear in adolescents as small atrophic plaques with a keratotic rim, mainly localized on sun-exposed areas, but new lesions may also appear in adult age (122). To date, several clinical trials have examined the use of IL-1 inhibitors in the treatment of MKD (132). An analysis of the effectiveness of various therapeutic strategies was conducted on a cohort of 103 patients from the International MKD/HIDS Registry, and those receiving conventional therapies showed little to no response, except for high doses of glucocorticoids and biologics (126). In addition to FMF, the CLUSTER study has also evaluated the efficacy of canakinumab in 72 MKD patients (6). After 16 weeks, substantially more patients receiving canakinumab at 150 mg/monthly had better responses than those receiving placebo, and more than 80% of responders continued to be responsive to canakinumab for up to 8 weeks (6). No serious opportunistic infections or fatalities have been reported, and canakinumab received FDA and EMA approval for the treatment of MKD. In addition, IL-1 inhibitors represent a hope for future local therapy for PK patients (122). Treatment for MVK-related diseases may have exciting prospects. A study was conducted on two sisters carrying the same homozygous genotype (V377I/V377I), showing opposite phenotypes: one sister was asymptomatic, while the other presented with a classical phenotype (133). Thus, a STAT1 missense mutation R241Q was identified, influencing the phenotype of the symptomatic patient. Such mutation provided an hyperactivation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, which has a central role in inflammation (133). Thus, JAK/STAT pathway may strongly influence MKD phenotype, with good therapeutic perspectives (133, 134).

Gain of function mutations affecting the proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1) gene are responsible for the “pyogenic arthritis, pyoderma gangrenosum and acne” (PAPA) syndrome, a rare AD inherited autoinflammatory disease. As discussed previously, PSTPIP1/CD2-BP1 is involved in cytoskeletal organization and acts has a positive regulatory function for pyrin inflammasome activation. As observed in pyrin-deficient mice, the enhanced interaction of PSTPIP1 with pyrin may contribute to a PAPA clinical phenotype by sequestering pyrin and tipping the regulatory scales in favour of an increased IL-1β production by peripheral blood leukocytes (37). Joint and skin involvement are hallmarks of PAPA syndrome. The former usually appears in childhood as sterile oligo arthritis, before healing in adult age. Instead, skin manifestations may include oral lesions, pyoderma gangrenosum, aseptic abscesses, and severe cystic acne. Acne in PAPA syndrome occurs from puberty onwards, developing at about 13 years of age with often a nodulocystic phenotype, while skin ulcers typically develop during adolescence, frequently leaving unsightly scars and psychosocial involvement (135). Less than half of patients show moderate acne, while only a few cases of acne fulminans have been described in PAPA syndrome (136). The two main relevant pathogenic PSTPIP1 variants increasing the binding of CD-BP1 to pyrin are considered A230T and E250Q (37, 81). In the meanwhile, many other heterozygous variants have been reported and identified as pathogenic, such as Y119C, E277D, and R228C (81, 135). PSTPIP1-associated autoinflammatory diseases (PAIDs) represent a wide group of disorders, with a common genetic background ( Table 4 ). A recent report examined 43 cases of pyoderma gangrenosum, acne and hidradenitis suppurativa (PASH) syndrome (136). Males appear to be more frequently affected than females, all patients present with acne, with an average age of onset of 17 years. Despite being the earliest symptom to manifest and primarily affecting the face or the face and trunk, features of acne are infrequently reported in literature. However, the frequency of nodulocystic lesions produces an acne phenotype quite similar to PAPA syndrome, despite acne fulminans is most commonly documented (136). In addition to acne, patients may also have papulopustular lesions, abscesses, and fistulae developing in draining sinuses and scars (137). PASH patients show a heterogeneous genetic background, and PSTPIP1 abnormalities in the number of CCTG microsatellites in the PSTPIP1 promoter region have been reported in a minority of cases. Otherwise, also different mutations in other AIDs-related genes or no genetic abnormalities have been described in PASH patients (136). Given the wide variability of PASH syndrome’s genetic background, PG, and its syndromic form PASH may constitute a spectrum of polygenic autoinflammatory disorders, as supported by the overexpression of proinflammatory cytokines IL-1β, IL-17, and TNFα, in affected patients (137). PG, acne, seronegative spondyloarthritis, with or without hidradenitis suppurativa (PASS) syndrome is a recently described PAID. Notably, all the few cases reported in literature were males, often with a nodulocystic acne spread to the face and trunk (138). A variant of unknown significance (VUS) of the NLRP3 gene was discovered in a 20-year-old boy who had severe axillary and perineal SH, bilateral sacroiliitis, and PG (139). In a young PASS patient, the IL-17 inhibitor secukinumab was reported to be effective (140). Pyogenic arthritis, PG, acne, and hidradenitis suppurativa (PAPASH) syndrome is another different PAID. Two PSTPIP1 gene mutations and one MEFV variant have been documented in PAPASH patients to date (141–143). PsAPASH is a different clinical form of PASH that includes psoriatic arthritis (PsA), with an unidentified underlying genetic background. It was first described in a 50-year-old male patient with PASH features and PsA (144). A 33-year-old male patient with nodulocystic acne was diagnosed with PG, acne, and ulcerative colitis (PAC) syndrome. Two years following the onset of the inflammatory colitis, pustulosis broke out, and a VUS of the PSTPIP1 gene was detected. However, because it affected a gene’s highly conserved area, harmful consequences are likely (145). An uncommon and distinctive clinical PAID has been named as PSTPIP1-associated myeloid-related proteinaemia inflammatory (PAMI) syndrome. More than 35 cases of PAMI syndrome have been reported so far, mostly with childhood onset, and one of them dramatically improved after a combining therapy with prednisone and doxycycline for three months. Heterozygous variants of PTPSTP1 are the most common pathogenic variants reported in PAMI syndrome (146). Its diagnosis is based on the results of DNA sequencing, the clinical features of typical lesions, leukopenia, and the significantly elevated serum calprotectin levels. However, high levels of this blood protein can be utilized as a screening indicator in suspected instances and are a characteristic of both PAPA and PAMI syndromes (146). Treating acne is frequently a main objective in PAIDs, and systemic medications are widely used to control other different symptoms, such as pyogenic arthritis, and inflammatory colitis. Isotretinoin is frequently the first treatment option for acne, although some patients do not entirely respond and require additional medications (136, 147). Current reports mostly focus on IL-1 inhibitors, and TNFα antagonists, with reported good results (145, 148–150). Indeed, traditional approaches using other anti-inflammatory drugs are often ineffective, and dual therapies rarely reported (147, 150). According to a recent review of the literature, anakinra, glucocorticoids, infliximab, and adalimumab generally produce good response in PAIDs, whereas nonsteroidal anti-inflammatory drugs seem to be only partially beneficial on moderate phenotypes of PAPA syndrome (147). However, clinical improvement can vary significantly from patient to patient, and due to the low prevalence of PAPA syndrome and PAIDs, no therapeutic strategies based on guidelines are available (136, 151).

Infancy-onset periodic fever, recurring respiratory infections, and thrombocytopenia are common features of PFIT. Even though severe viral illnesses, such as varicella, have been recorded, recurrent bacterial infections are more commonly reported (65). In addition to the classical phenotype, PFIT patients may also present with skin and mucosal ulcerations, aphthous stomatitis, nodulocystic acne, bronchiectasis, and poor growth. Leukocytosis, increased neutrophils, and elevated ferritin, but also lymphopenia, mild neutropenia, and anemia have been described during autoinflammatory attacks (65–67). Although bone marrow transplantation may be effective, prognosis is usually not favourable (65–67).