The innate immune system plays a key role in protecting the host against microbiological agents. Pattern recognition receptor (PRR) proteins, expressed mainly by cells of the innate immune system, can recognize pathogen-associated molecular patterns (PAMPs) associated with microbial pathogens and damage-associated molecular patterns (DAMPs) associated with host cell elements that are released during cell damage or death.

The recognition of a ligand by a PRR triggers a signaling cascade that, in turn, leads to the expression of immune genes. Most PRRs can discriminate between self and non-self in a highly conserved and tightly regulated mechanism that defends the host against microbiological pathogens while avoiding attacks on the self. TMEM173 encodes STING, a key signaling molecule in cytosolic DNA-sensing pathways. Upon activation in response to cytosolic DNA, STING dimerizes and induces the phosphorylation of transcription factors IRF3 and NF-κB, leading to their translocation to the nucleus and the production of IFNs and inflammatory cytokines. Secreted type I IFN acts in an autocrine and paracrine way by binding the interferon-α receptor (IFNAR), which in turn activates several downstream signaling pathways, most notably the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway.

Structural modeling in SAVI demonstrates the constitutive activation of the mutated STING protein due to stabilized dimerization. This was confirmed by Jeremiah et al., who found that STING was mostly localized, at a steady state, in the Golgi and perinuclear punctiform vesicles of the patient's fibroblasts, which was previously reported to correspond with STING activation (2). Upon 2′3′-cGAMP stimulation, the mutant STING remained localized in the same structures confirming its activation in patient cells independently from ligand addition.

Disease onset is usually in the first weeks of life, rarely after 1 year of age. Initial symptoms often include intermittent low-grade fever, recurrent cough, and failure to thrive. Moreover, patients usually present with progressive interstitial lung disease (ILD) and cutaneous chilblain lesions.

In a recent systematic review of the literature, respiratory symptoms (tachypnea, dyspnea, cough, and milk choking) or skin manifestations associated with growth failure were the presenting features in 35% and 57% of patients, respectively (3).

The most typical skin lesions are erythematous–purpuric patches and plaques on cold-sensitive areas mainly the cheeks, nasal tip, ears, and acral sites. Cutaneous manifestations typically worsen after exposure to cold and may progress to painful ulcerations with eschar formation and tissue loss. Histological characterization shows a dermal inflammatory infiltrate with features of leukocytoclastic vasculitis and microthrombotic angiopathy of small dermal vessels (1).

Lung involvement should be sought in case of respiratory symptoms, even if it may be found in asymptomatic patients. Nail clubbing may be an early sign of ILD and may appear before other pulmonary symptoms.

On CT scan, ILD may present as ground glass areas, cysts, reticulations, interlobular septal thickening, or pleuritis. Additional features such as consolidations, bronchiectasis, emphysema, lymphadenopathy, and pulmonary hypertension may be found. Liu et al. (1) described a scattered mixed lymphocytic inflammatory infiltrate, interstitial fibrosis, and emphysematous changes in the lung biopsies of two patients. Pulmonary function tests demonstrate a severe restrictive pattern with a decreased diffusing capacity for carbon monoxide (DLCO).

The clinical spectrum of disease manifestations has expanded since the first description, and patients may present with polyarthritis, myositis, kidney, brain, thyroid involvement, photosensitivity, and hair loss, demonstrating important phenotypic variability. Moreover, three patients with exclusive pulmonary disease (4, 5) and 16 patients with only cutaneous involvement (1, 6–8) have been reported.

This variability seems to be partially related to the different genotypes, and patients carrying variants outside the dimerization domain of the protein appear to have more atypical phenotypes (9).

Jeremiah et al. (6) speculated that intrafamilial phenotypic differences may be related to modifying genes acting downstream of STING or to viral infections that promote IFN signaling.

During disease flares, SAVI patients usually display increased acute phase reactants (C-reactive protein and erythrocyte sedimentation rate). Moreover, some patients may have transiently positive or low-titer autoantibodies [antinuclear antibodies (ANA), RF], and the majority of patients present with hyperimmunoglobulinemia, mainly IgG.

T-cell and natural killer (NK) lymphopenia are consistent features of the disease; however, patients usually do not present with recurrent infections.

The therapeutic approach of SAVI patients is often challenging, and the prognosis is poor, especially in the case of severe lung disease with a high mortality early in life. Glucocorticoids are only partially effective and are burdened with important side effects for prolonged therapies due to the development of steroid dependence. Moreover, there has been minimal success with the use of other disease-modifying therapies, such as methotrexate, mycophenolate mofetil, antimalarials, infliximab, and rituximab (1, 10, 11).

According to the evidence of a prominent pathogenetic role of constitutive type I IFN signaling, attempts with JAK inhibitor drugs to block the JAK-STAT pathway at the IFNAR receptor have been made.

The first report of a suppressive effect of JAK inhibition on type I IFN signaling came from Liu et al. (1) who demonstrated a sustained blockade of constitutive STAT1 phosphorylation following the treatment of blood mononuclear cells (PBMC) in a patient with SAVI with tofacitinib, ruxolitinib, or baricitinib.

Subsequently, other case reports showed a good response to JAK inhibitors in children with SAVI. Frémond et al. (12) described three children aged 5–12 years, two of whom had prominent pulmonary involvement and systemic inflammation, and one a prevalent skin involvement, treated with ruxolitinib, a JAK1/2 inhibitor. All patients experienced a pronounced improvement in general condition, a reduction of fever episodes, an almost complete resolution of skin manifestation, and an amelioration of pulmonary function. All of them were able to taper off the glucocorticoids.

The same encouraging results with ruxolitinib were described by Volpi et al. (13) in three children aged 3–13 years, with cutaneous and pulmonary involvement associated with recurrent fever and growth failure and renal involvement in one child. Ruxolitinib was associated with a general improvement in skin and pulmonary disease and was able to resolve the microhematuria. All patients were able to taper glucocorticoids. However, one patient displayed multiple severe viral infections after starting therapy, suggesting that these drugs may significantly increase this risk.

Tofacitinib significantly improved skin lesions in a 9-year-old child with SAVI, but did not ameliorate pulmonary involvement after two months of treatment. This was attributed to already-established lung damage (14). In another case report, Balci et al. (15) reported a 6-month-old child who failed previous treatment with ruxolitinib responding to baricitinib, another JAK1/2 inhibitor.

A larger cohort of 18 patients affected with SAVI (4 patients), CANDLE (10 patients), and a CANDLE-like disease (4 patients) were treated with baricitinib for a mean duration of 2.3 years under a compassionate use protocol (16). The patients experienced a significant amelioration of general conditions, demonstrated by a reduction in mean autoinflammatory diary scores as well as glucocorticoid doses by at least 50% from baseline. The most common adverse events in these patients were upper respiratory tract infections and BK viruria. The clinical significance of low positive BK titers was not clear, and serum and urine BK titers along with renal function were regularly monitored. Among the SAVI patients, three-fourths presented with respiratory tract infections, all presented with mucocutaneous infections, and two-fourths had osteomyelitis.

Altogether, these findings demonstrate that JAK inhibition may be an effective therapeutic strategy for SAVI, although the clinical response may be different and some features (i.e., pulmonary involvement) only partially respond to the treatment. This may be due to already-established organ damage prior to the initiation of the therapy or to the involvement of other pathways contributing to the damage. In this regard, Luksch et al. (17) demonstrated that a SAVI-associated STING mutation can determine a pulmonary disease independently of type I IFN in mice.

In conclusion, although promising, future clinical trials are necessary to fully understand the therapeutic effect and the safety profile of long-term JAK inhibition with particular regard to the risk of infections or malignancies.

Adenosine deaminase (ADA) is a ubiquitously expressed metabolic enzyme involved in purine metabolism. Humans express two enzymes, namely, ADA1 and ADA2, that catalyze the deamination of adenosine and 2'-deoxyadenosine to inosine and deoxyinosine, respectively. ADA2 has been previously considered as an isozyme of ADA1, but they are different in structure, substrate affinity, cellular localization, and expression.

Cellular damage stimulates adenosine formation. Its effect on cellular activity and local inflammation depends on several factors such as local concentration, receptor expression, receptor type, and affinity. Upon binding to four different cell surface receptors (A1, A2A, A2B, and A3), either a decrease or increase in intracellular cyclic AMP is triggered that, in turn, influences cellular activation through multiple biological pathways.

ADA1 is the major ADA expressed in almost all cells in humans. It reduces the amount of adenosine in the intracellular space. Mutant ADA1 causes a severe combined immunodeficiency (SCID) resulting from the effect of toxic metabolites accumulated in developing lymphocytes, with consequent increased B- and T-cell apoptosis.

Conversely, ADA2 is an extracellular homodimer. It is secreted by activated monocytes, macrophages, and dendritic cells. In a physiologic state, ADA2 is present at low concentrations with low affinity for adenosine. It is not known whether it has a role in controlling the extracellular homeostasis of adenosine under these conditions. However, in stress conditions, ADA2 seems to play an important role in the degradation of extracellular adenosine at the site of inflammation produced by excessive ATP breakdown.

Apart from the deaminase activity, ADA2 seems to have a growth factor activity on the development of endothelial and hematopoietic cells (19–21).

The formation of NETs by neutrophils (NETosis) is an important instrument of the innate immune system to fight infections, and it has been demonstrated to cause inflammation in different autoimmune conditions such as systemic lupus erythematosus (SLE) and antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis (22, 23).

Carmona-Rivera et al. recently demonstrated in vitro that an increased amount of adenosine in the extracellular space in the absence of ADA2 can stimulate NET formation.

DADA2 patients have higher levels of plasma adenosine and an increased number of circulating low-density granulocytes that are primed to undergo NETosis.

NETosis also stimulates activated macrophages to produce large amounts of TNF-α. This observation is important because it provides a novel mechanistic link between a defective ADA2 function and inflammatory cytokine production, in addition to a rationale for the use of TNF inhibitors in DADA2 patients with an inflammatory/vasculitis phenotype. It is still not clear whether NETosis and NET-induced TNF-α also occur in DADA2 patients presenting with a predominantly hematological or immunodeficient clinical phenotype.

However, it has been speculated that increased TNF-α levels may be responsible for the hematological manifestations of the disease, as TNF-α may have a role in bone marrow failure (BMF) in patients with aplastic anemia (24).

At the time of the description, inflammatory vasculitis was the hallmark of the disease. Nowadays, the spectrum of clinical manifestations has significantly broadened, and DADA2 patients presenting with immunodeficiency or hematologic manifestations are increasingly described. Sometimes these features may even predominate the clinical phenotype.

As in other autoinflammatory diseases, patients may complain of constitutional symptoms, such as recurrent fever, weight loss, failure to thrive, fatigue/malaise, myalgia, and arthralgia.

Both inter- and intrafamilial phenotypic variability can be observed, which mainly depends on the residual enzymatic activity. Nowadays this can be measured and may be of great help, especially in those patients with atypical clinical phenotypes or non-confirmatory genetic analyses.

In general, patients with the vasculitis phenotype usually carry variants that determine a residual ADA2 activity up to 40%–60% of the normal range (hypomorphic mutations) unlike patients with a prominent hematological phenotype in which the residual enzymatic activity is usually <3% (25).

However, some individuals carrying two pathogenic ADA2 mutations and with absent residual enzymatic activity may remain asymptomatic until late in life or never present clinical manifestations of the disease (26). On the other hand, it may happen that some carriers of pathogenic ADA2 mutations with enzymatic activity levels in the carrier range develop mild and/or late-onset features of the disease. Moreover, heterozygous individuals may present symptoms of the disease, among which are vascular strokes (19, 27) underscoring the need for additional studies to determine the clinical impact of ADA2 haploinsufficiency.

In addition to the amount of residual enzymatic activity, a possible genotype/phenotype correlation has been suspected following the identification of different disease patterns. Recently, Lee (25) analyzed a cohort of 167 DADA2 patients classified into three groups based on the main phenotype: 100 with a vasculitis/stroke phenotype, 38 with pure red cell aplasia (PRCA), and 29 with BMF. In total, 61 different mutations were identified, 45 of which were fairly uniquely associated with one group (21 to the vasculitis group, 12 to the PRCA group, and 12 to the BMF group). Only two mutations were described as associated with all three different phenotypes, thus suggesting that some variants are mostly associated with a specific phenotype.

In agreement with the first published papers, a typical vascular involvement with features of vasculitis or vasculopathy is described in more than 75% of patients involving the skin brain, gastrointestinal tract, and renal vessels.

The involvement of medium and small vessels is similar to that seen in panarteritis nodosa. Skin biopsies reveal medium-vessel vasculitis or leukocytoclastic vasculitis that may determine amputation when involving arteries supplying the extremities (18, 28). Not surprisingly, many DADA2 patients were previously diagnosed as having PAN. Caorsi et al. (28) performed the genetic analysis for ADA2 in 48 children diagnosed with PAN in Italy. Fifteen patients turned out to carry biallelic ADA2 mutations. When compared clinically, DADA2 patients displayed an earlier disease onset and more frequent skin and neurologic manifestations.

Pathogenic ADA2 mutations have been found in patients with Sneddon syndrome and one child diagnosed with HHV-8-negative Castleman disease (29).

Skin is involved in nearly 90% of cases. Livedo racemosa is the most typical manifestation found in up to 73% of patients. It is usually subtle and patchy and mainly localized to the lower limb, even if it may present in the upper limb or the torso (26). Subcutaneous nodules/edema, erythema-multiforme–like lesions, ulcers, and less commonly non-specific erythematous maculopapular rash and urticarial and psoriasiform rash have also been described (30–32).

Neurologic involvement of DADA2 is found in 50%–77% of patients (26, 33–36).

Ischemic strokes are usually localized in the brainstem, thalamus, basal ganglia, and internal capsule (37). They may represent the initial features of the disease and may be recurrent (38, 39). The majority are small lacunar infarcts but larger ones, causing permanent neurologic impairments and sometimes death, may develop (36). Over time, the recurrence of these small, sometimes undetectable strokes, can determine a severe neurologic impairment (40).

The occurrence of transient ischemic attacks without radiological findings (41) and ischemic lesions on MRI in patients with normal cerebral angiography suggest a prevalent small-vessel involvement of the CNS (39, 42, 43).

Vascular spasms in the absence of inflammation may also contribute to the development of strokes (42).

Consequently, ADA2 deficiency should be considered despite normal inflammatory markers and/or evidence of cerebral vasculitis and ADA2 mutation screening should be conducted in children with otherwise unexplained ischemic stroke.

Hemorrhagic strokes have also been reported (Figure 1). Zhou et al. (19) revealed in the cerebral biopsy of two patients with intracranial hemorrhage and the absence of signs of cerebral vasculitis, the presence of extravasal red blood cells from small vessels.

A wide range of neuropathies may be found in DADA2 patients (28). Cranial nerve (CN) palsies and neurosensory hearing loss have been reported. In some cohorts, peripheral neuropathy is described in up to 50% of cases, and spastic paraplegia has been reported as a presenting symptom of the disease (28, 44). Ophthalmologic involvement including vision loss, central retinal artery occlusion, optic nerve atrophy, uveitis, diplopia, nystagmus, and strabismus has also been reported (19, 36).

Bone marrow dysfunction, which can include pure red blood cell aplasia (PRCA) with transfusion dependence resembling Diamond–Blackfan anemia (34), isolated refractory thrombocytopenia, and leukopenia, is now recognized as a prominent and sometimes isolated manifestation of the disease (34, 45).

Leukopenia is found in approximately 60% of cases and involves both the myeloid and lymphoid lineage. Neutropenia, reported in 10%–50% of cases (46), may be quite severe leading to recurrent infections and abscess formation. Functional studies do not reveal any neutrophil impairment; conversely, a recent paper describes their increased propensity to netosis and activation in patients with the autoinflammatory phenotype (47). Lymphopenia involving both the B and T compartments is present in approximately 10% of patients with B cells usually being more affected. Finally, the NIH group described a case of severe monocytopenia associated with mild neutropenia in a patient who was thought to have GATA2 haploinsufficiency (48). These hematologic defects are often combined with multiple cases of pancytopenia.

A mild immunodeficiency with low IgM levels has been described since the initial description of the disease (19). In a paper from Schepp et al. (49), 11/181 screened patients with antibody deficiencies and unknown genetic defects with or without vascular manifestations turned out to carry two ADA2 mutations with decreased ADA2 plasma activity. In more than 50% of these patients, recurrent infections, rather than the classic features of inflammatory vasculitis, were the presenting manifestation of the disease.

A low immunoglobulin (Ig) level is caused by both B-cell intrinsic and extrinsic factors. In a recent paper, Schena et al. (50) confirmed that DADA2 patients have a reduced total number of CD27 positive memory B cells compared to healthy subjects and that, within the memory compartment, the number of class-switched memory B cells is also decreased. Defective class-switching may be partly due to the functional impairment of T follicular helper (TFH) cells, but it cannot be responsible by itself for deficient IgM production. A reduction in the number of antibody-producing cells is probably a contributing factor. Schepp et al. demonstrated an inverse correlation between C-reactive protein and Ig levels in a patient, suggesting that inflammation may directly act on the B-cell compartment (49).

Apart from TFH impairment, no other T-cell function defects are reported. Infection may then be caused by a quantitative reduction due to generalized lymphopenia.

Both viral and bacterial infections are frequent in DADA2 patients with antibody deficiencies (49), whereas fungal and mycobacterial infections are rare and limited to cases with severe reduction in the number of white blood cells (34, 48).

The concurrence of DADA2 and lymphoproliferative diseases has been also reported (40, 46, 51, 52).

As vasculitis is a main feature of the disease, other organs with dense vascularization may be affected, among which are the gastrointestinal and renal systems.

Among the gastrointestinal symptoms, abdominal pain and chronic gastritis are often reported. Vasculitis may lead to intestinal necrosis, bowel perforation, and arterial stenosis (33, 53). Liver biopsies may show evidence of nodular regenerative hyperplasia and/or hepatic sclerosis, potentially leading to end-stage liver disease (40).

Renal aneurysm and infarction have been reported in some patients (18, 26, 36). Hypertension can be seen independent of other renal involvement and may contribute to the development of stroke and intracranial hemorrhage (26, 28, 33).

Finally, some other inflammatory manifestations have been described, including pleuritis, pericarditis, myocarditis, meningitis, and amyloidosis (18, 19).

An increased type I IFN score (IS) has been demonstrated in some patients with DADA2. In 2018, Insalaco et al. analyzed the IS in 5 patients with DADA2 and 10 healthy donors (54). The authors found some degree of correlation between disease severity and the elevation of the IS and a reduction/normalization of the IS score after the introduction of TNF inhibitors therapy, concluding that the IS score may be used as a biomarker of disease activity, severity, and response to treatment in DADA2.

Recently, multidisciplinary consensus statements for the evaluation and management of DADA2 patients have been developed (55).

Early treatment is very important to prevent potentially devastating complications. During flares, high-dose systemic glucocorticoids are effective in most cases, but the majority of patients have refractory or relapsing disease upon tapering (28).

TNF inhibition has been demonstrated to be highly effective in patients with a predominant vasculitic/inflammatory phenotype, resulting in a control of inflammation, reduction/resolution of skin rash and hepatosplenomegaly, the occurrence of a catch-up growth, and an improvement of red blood cell and platelet counts due to relief of the inflammatory burden.

However, the most important effect of this therapy seems to be the dramatic protection against strokes. After a few case reports, this was confirmed in a study by the NIH group, in which a retrospective analysis of a cohort of 15 DADA2 patients showed a total of 37 strokes, all occurred prior to the initiation of TNF inhibitors vs. none post-treatment with a median follow-up of 47 months (range, 25–128). Among TNF inhibitors, etanercept, adalimumab, or infliximab are the most used (18, 19, 26, 33), but there is not enough data to support the use of one over the other. In those cases not achieving a complete clinical response, an increase of the dosage or a switch from a TNF inhibitors to another is possible.

TNF inhibitors may be associated with intravenous immunoglobulin replacement and antimicrobial/antiviral drugs in those patients with low serum immunoglobulins and recurrent infections (49).

Given the genetic nature of the disease TNF inhibitors should be continued for life because of the risk of relapse after therapy discontinuation, especially in those with vasculitis and CNS manifestations (56). Conversely, TNF inhibitors seem not to be as effective in rescuing severe bone marrow abnormalities.

Hematopoietic stem cell transplantation (HSCT) can be curative, returning plasma ADA2 activity to normal levels in individuals with BMF and/or immune dysregulation that is non-responsive to TNF inhibition.

After initial case reports (41, 48, 57), this was well demonstrated in one study in which 14 patients with bone marrow dysfunction or immunodeficiency (6 of whom also had vasculitis and 3 intracranial hemorrhages obtained a complete resolution of the hematologic and immunologic phenotype after HSCT. In about half of the cases, a DADA2 diagnosis was made after transplant, the indication of which was respectively PRCA, neutropenia, immune-mediated thrombocytopenia, and pancytopenia (45).

Finally, initial studies focusing on understanding the potential role of gene therapy in DADA2 patients are ongoing.

Regarding asymptomatic individuals with biallelic ADA2 pathogenic variants, there are no predictors that future strokes or other disease manifestations might occur. Because of the potentially devastating consequences of strokes, patients who have biallelic ADA2 pathogenic variants should probably be treated with TNF inhibitors.

HA20 is caused by loss-of-function mutations in TNFAIP3 coding A20 protein. These result in a reduced suppression of NF-κB activity, and as an enhancement of nucleotide-binding domain-like receptor protein (NLRP3) inflammasome activation. Both of these pathways determine an overproduction of proinflammatory cytokines, among which IL-1β, IL-6, IL-18, and TNF-α (67–69).

A total of 75 variants have been described in the TNFAIP3 gene, mostly classified as pathogenic or likely pathogenic (Infevers). Disease-causing variants are inherited in an autosomal dominant pattern or may be de novo. A20 protein, also known as tumor necrosis factor alpha-induced protein 3 (TNFAIP3), is encoded by the TNFAIP3 gene. It is composed of an N-terminal ovarian tumor domain (OTU) followed by 7 zinc finger domains (ZnFs) including 790 amino acid residues (70). The OTU domain has a deubiquitinating activity for k63-linked ubiquitin chains, whereas the zinc finger (ZnF) recognizes k63-linked ubiquitin chains. This region is also crucial for A20 E3 ligase activity and dimerization to add k48-linked ubiquitin chains, and it accelerates protein degradation in the proteasome (71, 72).

A20 both removes ubiquitin chains bound to K63 thanks to its OTU domain (deubiquitination) and attaches ubiquitin chains to K48 (ubiquitination). The former destabilizes protein substrates, and the latter accelerates their degradation in proteasome. Through these activities, A20 suppresses NF-κB activity by targeting substrates such as NF-κB essential modifier (NEMO), receptor-interacting serine/threonine kinase 1 (RIP1), and TNF receptor-associated factor 6 (TRAF6) for proteasomal degradation (73, 74). In mice, A20 deficiency leads to insufficient downregulation of NF-κB activity and dysregulation of the NLRP3 inflammasome, both NF-κB dependent and NF-κB independent (75–78). Recently, Rajamäki reported a novel caspase-8-dependent mechanism linking reduced A20 function to enhanced NLRP3 inflammasome activation in the HA20 patients’ immune cells (79).

The broad expression of A20 in different cells of the immune system (dendritic cells, B cells, T cells, and macrophages) means that this protein plays a key role in immune dysregulation (80). B-lineage deletion of A20 perturbs lymphoid homeostasis and leads to an autoimmune disease resembling SLE (81).

Patients affected by HA20 present with recurrent fevers, oral, and/or genital ulcers, gastrointestinal manifestations, skin rash, polyarthritis, and neurological symptoms. HA20 is frequently misdiagnosed as BD. However, it differs from classical BD in terms of early age at onset, a less common eye involvement, a higher incidence of recurrent fever, a poor association with HLAB51, and an overrepresentation of gastrointestinal symptoms (82–85). Additionally, unlike typical BD, some papers recently reported HA20 patients presenting with a predominantly autoimmune picture including thyroiditis, diabetes, rheumatoid arthritis, SLE, and autoimmune lymphoproliferative syndrome (ALPS) (68, 86–88).

The severity of the disease varies greatly regardless of the genotype (67). In a recent systematic review of the literature about published cases of HA20, the authors collected 61 cases (62% female) from 26 families carrying a heterozygous loss-of-function mutation in TNFAIP3. The clinical presentation was very different, even between members of the same family carrying the same mutation. Disease onset was at a mean age of 14 years with two-thirds of patients having their first symptoms before the age of 10. All patients initially received another diagnosis, including Behcet's disease, juvenile idiopathic arthritis or rheumatoid arthritis, PFAPA syndrome, autoimmune thyroiditis, Crohn's disease, SLE, and adult-onset Still disease (68). Oral and/or genital ulcers were reported in two-thirds of the patients. Almost half of them presented recurrent episodes of fever, resembling other inflammatory conditions, a skin rash (ranging from non-specific rash, erythema nodosum-like lesions, psoriasis, folliculitis, pustules, to malar rash), and/or gastrointestinal symptoms, including abdominal pain, vomiting, diarrhea, abdominal lymphedema, and intestinal edema. One-third of patients had musculoskeletal manifestations, such as arthralgia or arthritis while only a few patients displayed an ocular involvement.

As in inflammatory bowel diseases (IBD) or BD, the gastrointestinal involvement may be extensive with ulcers diffusing along the entire gastrointestinal tract and signs of inflammation on endoscopy. In some cases, patients may present digestive life-threatening hemorrhages possibly leading to death (82–84).

The finding of autoantibodies in some patients may be non-specific and unrelated to an autoimmune disease or, conversely, associated with defined autoimmune diseases such as SLE, Hashimoto thyroiditis, or type 1 diabetes.

HA20 patients may also present other clinical symptoms, among which are cardiovascular manifestations, nephrotic syndrome, vasculitis, and respiratory tract infections.

The use of glucocorticoids, colchicine, TNF inhibitors, and IL1 blockade has been reported. Response to colchicine, a first-line therapy in classical BD, is inconstant and unpredictable, and pharmacological control of inflammation may not be easy (69). Colchicine has been reported as not or inadequately effective in more than half of the patients who have required glucocorticoids or other immunosuppressive agents (methotrexate, ciclosporin, thalidomide) (82). A biological treatment as second-line therapy has frequently been used mostly TNF inhibitors, IL1 inhibitors, IL 6 inhibitors, and B-cell-depleting therapies (anti-CD20) (82). In non-responsive patients, JAK inhibitors or HSCT have been used (69, 82).

This form refers to a specific subset of SLE patients characterized by distinct genetic abnormalities, early-onset of the disease (usually at <5 years of age), and a broad range of clinical symptoms (93). Among them, mucocutaneous alterations, particularly chilblain lesions and central nervous system (CNS) diseases, are prominent and may overlap with other diseases such as monogenic interferonopathies (94). Juvenile-onset systemic lupus erythematosus (JSLE) and monogenic lupus can manifest with vasculitis. JSLE-related vasculitis symptoms may be non-specific and affect different organs, including the CNS (95).

Upregulated IFN-I signaling represents a hallmark of SLE, and the persistent exposure of nuclear material to nucleic acid sensors is one of the critical risk factors (96). Indeed, the detection of apoptotic debris and nucleic acids activates nucleic acid sensing pathways, such as those involving Toll-like receptors (TLR) or cytosolic sensors, leading to excessive production of interferon α and the development of autoimmunity (97).

Monogenic lupus is associated with the alteration of three main pathways: (1) defects in the clearance of apoptotic bodies and self-derived nucleic acids such as complement deficiencies and mutations in extracellular DNase genes; (2) IFN signaling pathway defects involving either nucleic acid-sensing or the production and response to IFNs; and (3) B-cell and T-cell tolerance defects (98) (Table 2).

NGS and WES elucidated the genetic causes of SLE and helped identify monogenic lupus as a specific category of disease. These advances in the understanding of SLE pathogenesis may promote, in the future, novel target therapeutic options and personalized treatments to cure the disease. At present, despite these advancements, the management of monogenic lupus is still a challenge.

Regarding nuclear debris clearance defects, non-specific conventional therapeutic agents, including glucocorticoids and immunosuppressive drugs, are commonly used (162). There are case reports of effective therapy with fresh frozen plasma (FFP) to replace complement components in the cases of C2 and C1q-deficient SLE patients (163–165). However, it is challenging to consider a regular FFP infusion as a standard therapeutic option. In other small case series, HSCT has been reported as a promising treatment in C1q-deficient SLE patients (166, 167), but risks related to this treatment should always be considered.

B-cell targeting therapies may represent attractive options in B-cell–related monogenic lupus.

Belimumab is a monoclonal humanized IgG antibody that inhibits BAFF, a B-lymphocyte stimulator causing a reduction in the number of B cells and regulating their function. Favorable results were observed in adults with active SLE, particularly those with cutaneous disease and arthritis. Recently, belimumab has been approved for patients with cSLE older than 5 years of age, but its use in monogenic SLE is uncommon. However, it was recently administered to six patients with refractory monogenic SLE (five C1q deficiency and one DNase II deficiency) combined with conventional treatment. The main indications for belimumab administration were refractory mucocutaneous manifestations, arthritis, renal manifestations, and failure to decrease glucocorticoids. The belimumab infusion was well-tolerated, with variable clinical responses (168).

Rituximab (146) and ofatumumab (169) were effective in siblings with PKC-δ deficiency.

Moreover, considering the fundamental role of elevated type I interferon expression in lupus pathogenesis, new therapies targeting the IFN pathway in SLE patients could also be beneficial for some monogenic forms.

Hydroxychloroquine is one of the most commonly administered drugs because of its ability to downregulate the type I IFN signature (170), and it has been demonstrated useful in a patient with PKC-δ deficiency (149). Recently, anti-IFNa and anti-IFNAR monoclonal antibodies have been proposed and are currently under study for the treatment of SLE patients (143, 171, 172).

Last, several JAK inhibitors are under clinical trials in SLE patients, and they also may be promising for monogenic SLE (173, 174).