Interface between inborn errors of immunity and rheumatological disorders in children: A pediatrician’s conundrum

Abstract

Rheumatological disorders encompass a broad and complex spectrum of conditions, often driven by dysregulated immune responses and autoantibody formation. Increasing evidence highlights the significant overlap between rheumatological diseases and inborn errors of immunity (IEIs). The 2024 update of the International Union of Immunological Societies phenotypic classification describes 559 IEI, including 67 novel monogenic defects and 2 new phenocopies. This review examines the clinical spectrum of rheumatological manifestations associated with IEIs, encompassing arthritis, cytopenias, vasculitis, macrophage activation syndrome, systemic lupus erythematosus, inflammatory bowel disease phenotypes, polyautoimmunity, and autoimmune lung disease. Several soft clinical “red flags” can alert physicians to an IEI in a child with rheumatological disease, including very early age of onset, atypical or severe disease course, recurrent or unusual infections, lymphoproliferation, multi-organ autoimmunity, and poor or refractory response to standard therapies. Understanding the mechanisms of immune dysregulation in IEIs provides critical insight into their clinical expression. Defects in central and peripheral tolerance checkpoints, impaired T- and B-cell regulation, abnormal cytokine signaling, and skewed interferon responses contribute to the loss of self-tolerance and autoimmunity. Pediatric rheumatologists and pediatricians should remain highly vigilant for IEI when evaluating children who present with atypical, severe, or treatment-resistant rheumatologic conditions. While these disorders may mimic polygenic autoimmunity, their aggressive nature, multi-system involvement, and association with infections often distinguish them. Early genetic diagnosis not only clarifies prognosis but also enables precision-based therapies, significantly improving outcomes.

Key Words: Inborn errors of immunity; Rheumatology; Monogenic disease; Immune dysregulation; Children

Core Tip: Rheumatological disorders in children may represent the initial manifestation of inborn errors of immunity (IEIs), a rapidly expanding group of monogenic immune dysregulation syndromes. Increasing overlap exists between IEIs and pediatric rheumatologic diseases, including arthritis, vasculitis, cytopenias, lupus, macrophage activation syndrome, and polyautoimmunity. Early age of onset, atypical or severe disease, recurrent infections, multi-organ involvement, and poor response to standard therapy are key red flags. Early recognition and genetic diagnosis enable precision-based targeted therapies, significantly improving outcomes.

INTRODUCTION

Rheumatological disorders are complex, heterogeneous conditions that manifest in various ways, including arthritis, systemic lupus erythematosus (SLE), vasculitis, dermatomyositis, and connective tissue disorders. The pathophysiology of autoimmune disorders is multifactorial. Paediatric autoimmune diseases may differ from their adult-onset counterparts in clinical phenotype, disease severity and treatment response. All of these factors have contributed to the consideration of genetic involvement in rheumatological disorders.

Inborn errors of immunity (IEIs) represent a diverse group of disorders characterized by impaired immune regulation, leading to recurrent or severe infections, autoimmune and autoinflammatory manifestations, and an elevated risk of malignancy. Recently, the term “primary immunodeficiency” has been replaced with “IEI” to reflect the broader spectrum of immune dysfunction that extends beyond mere deficiency. In its latest update (2024), the International Union of Immunological Societies has described 504 genes causing IEI, including 67 novel monogenic defects and 2 new phenocopies[1]. Rheumatological manifestations are more common among autoinflammatory disorders, complement deficiencies, antibody deficiencies, and disorders associated with defects in regulatory T cells (Tregs)[2,3].

An analysis of 5058 patients enrolled in the United States Immunodeficiency Network registry revealed rheumatological manifestations in 5.49% of patients, most frequently among patients with interferonopathies, followed by autoimmune lymphoproliferative syndrome (ALPS) and immunoglobulin G subclass deficiency[4,5]. The study also reported a higher frequency of SLE among patients with chronic mucocutaneous candidiasis (CMCC) and higher frequencies of arthritis and inflammatory myositis among those with antibody deficiencies[5].

Autoimmunity in IEIs arises primarily from defects in T- and B-cell development. Under normal conditions, developing T and B lymphocytes are subjected to mechanisms of central and peripheral tolerance that prevent self-reactivity. Central tolerance is established in the thymus and bone marrow, whereas peripheral tolerance is maintained within secondary lymphoid organs[6-8]. A crucial step in T cell development is the formation of Tregs, which occurs in both central and peripheral tolerance. Because Tregs play a critical role in maintaining immune tolerance by preventing T and B cells from interacting with self-antigens, their absence or functional abnormalities can lead to various autoimmune manifestations. Similarly, B-cell tolerance occurs by receptor editing. Apart from this, the second checkpoint occurs in peripheral lymphoid organs; impairment of these regulatory pathways compromises immune tolerance and facilitates the emergence of autoreactive B-cell populations[8,9].

The interface between IEIs and pediatric rheumatological disorders represents an increasingly recognized and clinically challenging overlap. The complex interplay between immune dysregulation and inflammatory manifestations often blurs traditional diagnostic boundaries, making differentiation between primary rheumatological disease and underlying IEIs particularly difficult. With the advent of high-throughput sequencing technologies and growing awareness among pediatric rheumatologists, there has been a notable surge in the identification of IEIs in children initially presenting with rheumatological symptoms (Figure 1). Early recognition of these disorders is crucial, as timely diagnosis can significantly influence management strategies and long-term outcomes. This review provides a comprehensive overview of the rheumatologic manifestations associated with IEI, highlights key clinical features that aid in their recognition, and discusses the implications for pediatric practice.

Figure 1 Rheumatological manifestations in patients with underlying inborn errors of immunity. IBD: Inflammatory bowel disease; MAS: Macrophage activation syndrome; HLH: Hemophagocytic lymphohistiocytosis.

WHEN TO SUSPECT IEI IN CHILDREN WITH RHEUMATOLOGICAL DISORDERS

Recognizing when a child’s rheumatological presentation may reflect an underlying IEI is essential, as timely diagnosis can significantly influence treatment strategies and long-term outcomes. Several clinical features, often subtle, should raise suspicion for IEIs (Figure 2). These soft pointers include early age of onset, particularly when symptoms begin in infancy or early childhood; unusual or atypical disease presentations that do not fit classic rheumatological patterns; and the coexistence of recurrent, severe, or opportunistic infections, suggesting impaired immune function. Additional red flags include lymphoproliferation (such as hepatosplenomegaly, chronic lymphadenopathy, or persistent cytopenias), aggressive or rapidly progressive disease, and refractoriness to treatment, especially when children fail multiple standard therapies or develop unexpected infectious complications on immunosuppression. Understanding these early clues is the first step in appreciating the broader interface between pediatric rheumatology and IEIs. When such features are present, clinicians should consider an underlying immune defect and proceed with targeted immunological evaluation and genetic testing.

Figure 2  Red flags that point towards inborn errors of immunity presenting with rheumatological manifestations.

In this review, we explore specific rheumatological manifestations associated with IEIs, organized under key thematic subheadings: Arthritis, cytopenias, SLE–like presentations, vasculitis, myositis, macrophage activation syndrome (MAS)/hemophagocytic lymphohistiocytosis (HLH), polyautoimmunity, autoimmune lung disease, and inflammatory bowel disease (IBD) (Figure 1). These categories represent the most frequently encountered autoimmune and inflammatory complications in children with IEIs and underscore the diverse ways in which immune dysregulation can mimic or overlap with primary rheumatological disease.

IEI IN THE SETTING OF ARTHRITIS

Bone and joint manifestations are seen in many IEIs, and they are predominantly observed in IEIs with humoral defects like agammaglobulinemia or common variable immunodeficiency (CVID)[10-14], hyper-IgM syndromes[15,16], and IgA deficiencies[17] (Figure 3). Apart from predominant antibody deficiency, it is also seen in combined immunodeficiencies, such as Wiskott-Aldrich syndrome (WAS)[18,19], RAG defects, DiGeorge syndrome[20], and phagocytic disorders, including chronic granulomatous disease (CGD)[21]. Primary immune dysregulatory disorders, such as haploinsufficiency of CTLA4, LRBA, and BACH2, and CD25 deficiency, are characterized by autoimmunity, with arthritis as a primary manifestation. Arthritis can be both a primary manifestation and complication of IEI. Mycoplasma, Ureaplasma, and Echovirus[22] have been reported to cause reactive arthritis, as have many other viral infections. Arthritis in these patients is attributed to a decrease in or defective Treg cells, clonal proliferation of autoreactive T cells, altered AIRE expression, or low IgA levels[23-26].

Figure 3  Various inborn errors of immunity that can present with arthritis as one of the predominant manifestations.

Arthritis in infancy should raise the suspicion of an autoinflammatory disorder. The periodic fever, characteristic rash, and specific symptoms help confirm the diagnosis. These include inflammasomopathies [NLRP3-associated diseases, familial Mediterranean fever (FMF), mevalonate kinase deficiency (MKD), TNFRSF1A-associated periodic syndrome], interferonopathies such as STING-associated vasculopathy of infancy (TMEM173 gene) (SAVI) and coatomer protein complex subunit alpha (COPA) syndrome, Blau syndrome, adenosine deaminase 2 (ADA2) deficiency, and autoinflammatory disorders affecting bones[27-30]. Inflammasomopathies are characterized by recurrent fever, rash, systemic inflammation, and arthritis. In NLRP3 spectrum disorder, patients present with destructive bony lesions and bizarre swelling[28]. Blau syndrome results from pathogenic mutations in NOD2 and is classically characterized by a triad of arthritis, granulomatous uveitis, and dermatitis. The arthritis typically presents as a symmetrical polyarthritis involving both small and large joints, with prominent boggy synovitis and tenosynovitis; joint deformities may develop as a consequence of longstanding disease[31]. Autoinflammatory bone disorders include chronic recurrent multifocal osteomyelitis (CRMO), which presents with bony swelling and pain. They generally affect adolescent females, predominantly affecting the lower limb and the clavicle[32]. Complement deficiency is often associated with early-onset systemic lupus and/or recurrent infections, with arthritis being a common manifestation.

IEI IN CYTOPENIA

Although cytopenia frequently occurs in autoimmune disorders, it may represent an important laboratory clue to an underlying IEI. Immune thrombocytopenia (ITP), autoimmune hemolytic anemia, Evans syndrome, pernicious anemia, autoimmune neutropenia, aplastic anemia, and refractory cytopenia can be presentations of IEI. Cytopenia is commonly associated with combined immunodeficiency (CID), humoral defects, and disorders of immune dysregulation[33] (Table 1).

Table 1 Inborn errors of immunity associated with immune-mediated cytopenias.

Disorders causing cytopenia		Clinical manifestations	Immunological abnormality responsible to cytopenias	Management
Humoral defects	CVID (CD19, CD81, NFkB2, BAFFR, and TACI)	ITP, AIHA, Evans syndrome, pernicious anemia, infection induced bone marrow suppression	Autoreactive T and B cells, increased CD21 low B cells, decreased somatic hypermutations, increased BAFF-R, decreased CD8 T cells, and increased B10 or IL10	Corticosteroids, IVIG, rituximab
Combined immunodeficiency	Leaky SCID, hypomorphic mutations in RAG1, RAG2, Omenn syndrome and WAS	ITP, AIHA, Evans syndrome, infection induced suppression	Autoreactive B and T cells, autoantibody formations	Corticosteroids
Immune dysregulatory disorders	LRBA, CTLA4, APDS, IKAROS, ALPS, STAT3 GOF, IPEX, APECED	ITP, AIHA, Evans syndrome, pernicious anemia, infection induced suppression. Inflammation and lymphoproliferation induced cytopenia	Reduced T regs, reduced B regs, autoreactive T and B cells, increased CD21 low B cells, and autoantibody formation	Abatacept- LRBA, CTLA4, APDS- mTOR inhibitor, leniolisib, ALPS- Sirolimus, STAT3 GOF- JAK inhibitors
	IEIs associated with increased susceptibility to EBV	Due to lymphoproliferation	Due to lymphoproliferation and bone marrow suppression	EBV in B cells- rituximab. EBV in T and NK cells- chemotherapy. Magnesium for MAGT1 deficiency
	HLH- familial HLH 2-5, Griscelli syndrome, Chédiak-Higashi syndrome, and Hermansky-Pudlak syndrome	Pancytopenia	Inflammation due to increased IL-6, IL-18, IL-1 and interferon gamma	HLH protocol. Emapalumab
Bone marrow failure syndromes	GATA2 deficiency/MonoMAC syndrome, dyskeratosis congenita, Schimke syndrome, Shwachman-Diamond syndrome	Aplastic anemia	Bone marrow suppression	HSCT
Autoinflammatory disorders	Interferonopathies, monogenic lupus and complement deficiency	Thrombocytopenia, anemia	Cytokine mediated, chronic inflammation and auto anitbody formation	Steroids, JAK inhibitors, and-FFP transfusion

CVID: Common variable immunodeficiency; CD: Cluster of differentiation; ITP: Immune thrombocytopenia; AIHA: Autoimmune hemolytic anemia; IVIG: Intravenous immunoglobulin; TACI: Transmembrane activator and calcium- modulator and cyclophilin ligand interactor; SCID: Severe combined immunodeficiency; RAG: Recombination-activating gene; WAS: Wiskott Aldrich syndrome; LRBA: Lipopolysaccharide responsive beige like anchor protein; CTLA4: Cytotoxic T lymphocyte associated protein 4; APDs: Activated phosphoinositide 3 kinase delta syndrome; ALPS: Autoimmune lymphoproliferative syndrome; APECED: Autoimmune polyendocrinopathy candidiasis - ectodermal dystrophy; GOF: Gain of function; EBV: Epstein-Barr virus; MAGT1 deficiency: Magnesium transporter 1; HLH: Hemophagocytic lymphohistiocytosis; Monomac: Monocytopenia and mycobacterial infection; HSCT: Hematopoietic stem cell transplantation; FFP: Fresh frozen plasma.

The pathophysiology of cytopenia varies across different types of immune defects. These include: (1) Formation of autoantibodies; (2) Cellular and humoral defects causing autoreactive T and B cells; (3) Immune dysregulatory disorders characterized by a decrease in the number and function of Tregs; (4) Lymphoproliferation and defective apoptosis of autoreactive T cells; (5) Myelofibrosis, dyserythropoiesis, or bone marrow failure syndromes; (6) Infections due to underlying IEI; (7) Drugs used for the treatment of IEI; (8) Autoinflammatory disorders with increased interferon signature; (9) Hemophagocytosis; and (10) Complement disorders.

Of the various immune defects, CVID is the most common IEI with cytopenia. Nearly 30% of patients with CVID have polyautoimmunity[34]. CVID patients are at higher risk for lymphoproliferation, granulomatous inflammation and autoimmunity. ITP is the most common form of cytopenia in CVID, occurring in 7.4%-19% of patients[34]. Cytopenia can be the only and first manifestation in patients with CVID. The pathogenesis of autoimmunity in CVID is characterized by increased numbers and survival of autoreactive B and T cells, increased CD21⁺ cells, decreased somatic hypermutation, quantitative and functional defects of Tregs, and the presence of a TACI mutation that affects central B cell tolerance[35-37]. They often respond to corticosteroids but may occasionally require higher immunosuppressants, such as rituximab. Apart from CVID, cytopenia is a common manifestation of immune dysregulatory disorders. This can be attributed to a reduction in regulatory T and B cells, accompanied by an increase in autoreactive B and T cells. Lymphoproliferation also contributes to cytopenia by destroying cells in the spleen, and it predisposes to infection, leading to bone marrow suppression. CID due to hypomorphic mutations in the RAG1 and RAG2 genes causes defective VDJ recombination. Collectively, these defects lead to the emergence of autoreactive B and T cells, culminating in autoimmune manifestations. Other CIDs, such as those caused by WAS, WHIM, or ZAP70 mutations, and PNP can also cause autoimmune cytopenias.

IEI IN VASCULITIS

Vasculitis and vasculopathy are recognized manifestations across several IEIs. They are prominent in autoinflammatory disorders such as ADA2 deficiency, SAVI, and A20 haploinsufficiency, while FMF and TRAPS may occasionally mimic IgA vasculopathy. Vasculitis-like features have also been reported in IEIs with immune dysregulation, including WAS, mendelian susceptibility to mycobacterial disease (MSMD), CTLA4 haploinsufficiency, LRBA deficiency, CGD, and NEMO defects. Additionally, STAT3 GOF mutations have been increasingly associated with vasculitis. Together, these conditions highlight the diverse immune pathways through which IEIs can present with vascular inflammation.

ADA2 deficiency was first described in 2014 as a monogenic form of vasculitis resulting from homozygous or compound heterozygous mutations in ADA2, previously known as CECR1[38]. It can present with diverse manifestations, ranging from vasculopathy and immune dysregulation to cytopenias, lymphoproliferation, and malignancy[39]. Clinical presentation may occur at any time from childhood to adulthood[3]. The most plausible mechanism is that ADA2 deficiency leads to extracellular adenosine accumulation, which promotes skewing towards proinflammatory M1 macrophages and reduces anti-inflammatory M2 macrophages, resulting in a proinflammatory state characterized by increased tumor necrosis factor-α[3,7]. This, in turn, causes small- and medium-sized vessel vasculopathy that mimics polyarteritis nodosa[3,6]. Cutaneous involvement is the most common presentation and may occasionally be the sole manifestation. In a recent study of 60 patients with DADA2, cutaneous manifestations were observed in 90% of cases, with livedo racemosa being the most frequent (74%)[39]. Systemic vasculopathy frequently involves the central nervous system, most commonly presenting as recurrent ischemic lacunar strokes, followed by gastrointestinal involvement, predominantly due to mesenteric vasculitis. Recurrent lacunar infarctions are a hallmark of central nervous system involvement in patients with DADA2[6].

SAVI is an interferonopathy associated with elevated levels of type 1 interferons due to a GOF mutation in TMEM173 (STING1)[40]. GOF mutations in STING1, encoding STING, a key adapter protein of DNA signaling to interferon production, causes vasculopathy of skin and lungs, which presents as erythematous purpuric lesions, chilblains, ulcers or gangrene of the nasal tips, ear lobes and interstitial lung disease (ILD)[41]. These patients usually have multiple antibody positivity, which delays disease diagnosis. Patients can also present with polyarthritis, myositis, thyroiditis or other major organ involvement (renal and brain)[42]. Heterozygous mutations in COPA cause inflammatory arthritis, ILD, and renal involvement. Disease-associated mutations in COPA, which encodes a component of the coatomer complex involved in intracellular cargo trafficking, have been linked to enhanced type I interferon signaling[43].

Behchet’s disease, a variable-vessel vasculitis, usually presents with recurrent aphthous ulcers, erythema nodosum, arthralgia and panuveitis. Conventionally, Behçet’s disease is considered a polygenic disorder that more frequently affects males, with a concentrated epidemiological distribution along the ancient Silk Road and a strong association with HLA-B51 positivity[44]. However, several monogenic IEIs can mimic Behçet-like disease. Haploinsufficiency A20 is a notable example, presenting in early childhood with recurrent oral and genital ulcers, arthralgia, erythema nodosum, and severe gastrointestinal involvement. Diffuse ulcers from the pharynx to the anus and life-threatening gastrointestinal hemorrhage have been reported, mimicking Behçet’s syndrome[45]. Other disorders, including NEMO[46] and CGD[47,48], can have Behcet-like manifestations. Otulin-related autoinflammatory syndrome (ORAS), associated with Otulin (FAM105B) loss-of-function (LOF), is a recently identified autoinflammatory disease that can mimic juvenile-onset Behcet's disease. OTULIN deficiency causes dysregulated linear ubiquitination with excessive NF-κB–mediated inflammation, along with increased interleukin-1 (IL-1) signaling, which explains the spectrum from immunodeficiency to inflammation[49]. Children affected by Otulin deficiency can experience early onset inflammation, prolonged fever, painful skin nodules, and joint involvement[50].

WAS is associated with varied autoimmune manifestations. These include hemolytic anemia, vasculitis, arthritis, neutropenia, nephritis in the form of IgA nephropathy, uveitis, dermatomyositis, and IBD[51,52]. Vasculitis in WAS presents either as skin manifestations or as large vessel vasculitis in the form of aortitis, Takayasu arteritis, or cerebral arteritis[52]. Vasculitis may be the sole or initial manifestation in WAS, or it can develop during the disease. Autoimmunity pathophysiology in WAS is due to multiple reasons involving both innate and adaptive immunity. In patients with WAS, a qualitative defect in Tregs is observed, despite normal numbers. Among the autoimmune manifestations, vasculitis is the second most common presentation of WAS, occurring in approximately 1.5%-29% of patients[53]. It is classified as large, small, or medium vessel vasculitis and can involve multiple organs, such as the hepatic, renal, coronary, or cerebral arteries[54-56]. It can present as leukocytoclastic vasculitis[53,55,57]. Kawasaki disease (KD) has also been reported in a patient with WAS[55,56]. Additionally, Pellier et al[58] described five patients with WAS who developed aortic aneurysms. Authors described the association of virus-like varicella zoster, Epstein-Barr virus, and human herpes virus 6, which have been demonstrated in the histopathology of aortic aneurysms.

Similar to WAS, ARPC1B-related platelet abnormalities, immunodeficiency, and immune dysregulation represent an autosomal recessive CID characterized by early-onset severe infections, eczema, food allergies or anaphylaxis, asthma, lymphoproliferation, and autoimmune manifestations, such as IBD and leukocytoclastic vasculitis. Hematopoietic stem cell transplantation is considered the primary curative treatment. Characteristic laboratory findings include defective T-cell migration and proliferation, eosinophilia, elevated serum IgE and IgA levels, abnormal platelet morphology and function, and variable degrees of thrombocytopenia[59].

MSMD is an IEI caused by genetic defects in the IL-12/23-IFN-γ pathway. One such defect is the IL12RB1 deficiency, which presents with disseminated mycobacterial and Salmonella infection. Typically, several patients with IL12RB1 mutations are associated with leukocytoclastic vasculitis[60-63]. The vasculitides in these patients are attributed to an infectious etiology[62]. Monogenic lupus disorders can also present with features of vasculitis[42].

IEI IN MAS

MAS is a rheumatological emergency[64]. It is more common in rheumatological disorders like systemic juvenile idiopathic arthritis[65,66], SLE[67], and KD[68,69]. MAS may complicate systemic autoinflammatory disorders and may occasionally be their presenting manifestation[70,71], often as an initial manifestation of these rheumatological disorders or during flares of primary diseases[72,73]. NLRC4 GOF mutations, which are part of inflammasomopathies, present with recurrent episodes of MAS[74]. MAS resembles several histiocytic disorders, especially primary HLH[75,76]. Primary HLH is caused by defects in genes involved in cytolytic pathways. MAS has substantial clinical and biological overlap with primary HLH. Despite its usual presentation later in life, rheumatologic HLH is often linked to heterozygous or compound heterozygous variants in genes regulating cytolytic function[77]. Single-nucleotide polymorphisms and genetic mutations are found in adult-onset MAS, including perforin defects, and mutations in UNC13D, STXBP2, XIAP and LIPA[78]. Apart from genes in the cytolytic pathway, defective genes in viral control that lead to X-linked lymphoproliferative disorders or other immune defects, such as IKBKG and IRF8, have also been associated with MAS[78,79].

SLE AND IEI

The term “monogenic lupus” refers to lupus caused by pathogenic variants in a single gene. It represents a form of SLE that presents early in life, typically before the age of 5, and is characterized by unusually severe and organ-specific manifestations. Along with autoimmunity, classical lupus is also characterized by dysregulated and deficient immune responses. Genetic causes of lupus/Lupus-like disease can be grouped based on their pathophysiology (Table 2).

Table 2 Inborn errors of immunity in pediatric systemic lupus erythematosus.

Category	Gene(s)	Lupus phenotype	Other clinical features
Complement deficiencies	C1QA, C1QB, C1QC, C1R, C1S, C2, C4A, C4B	Severe cutaneous lupus without major organ involvement (particularly C2 deficiency); CNS disease, glomerulonephritis and severe skin involvement in C1q deficiency; arthritis; ANA positivity; extractable nuclear antigen antibodies, including anti-Ro/SSA (especially in C2 and C4 deficiency)	Recurrent infections, predominantly pneumococcal sinopulmonary infections
Type I interferon pathway disorders	ADAR1, SAMHD1, TREX1, IFIH1, RNASEH2A/B/C	ANA positivity; cutaneous lesions; oral ulcers; anti-dsDNA and ENA antibodies; Jaccoud’s arthropathy	Aicardi–Goutières syndrome; early-onset encephalopathy; basal ganglia calcification; chilblains
	ACP5	ANA positivity; anti-dsDNA and ENA antibodies; lupus nephritis; autoimmune cytopenia	Spondyloenchondrodysplasia (SPENCD); skeletal dysplasia; developmental delay; intracranial calcifications
	DNASE1, DNASE1 L3	ANA positivity; anti-dsDNA antibodies; hypocomplementemia; ANCA positivity	Hypocomplementemic urticarial vasculitis
	ISG15 (loss of function)	Recurrent fever; oral ulcers; facial rash; myositis; ANA and anti-dsDNA positivity	Mendelian susceptibility to mycobacterial disease; intracranial calcifications
	PSMA3, PSMB4, PSMB8	ANA positivity; fever; diffuse rash	Proteasome-associated autoinflammatory syndrome; lipodystrophy; panniculitis; neutrophilic dermatosis; heliotrope peri-orbital rash; myositis; basal ganglia calcifications
Apoptosis pathway defects	FAS (formerly TNFRSF6), FASL	ANA positivity; early autoimmune cytopenias; glomerulonephritis	Lymphoproliferation; hepatosplenomegaly; hypergammaglobulinemia; elevated DNTs
	KRAS, PTPN11, SHOC2	ANA positivity; anti-dsDNA antibodies	Noonan syndrome phenotype; splenomegaly; increased B cells; monocytosis; hypergammaglobulinemia
Loss of immune tolerance	PRKCD	Autoimmune lymphoproliferative syndrome-like presentation; Lupus nephritis; vasculitis; antiphospholipid syndrome; ANA/ENA positivity; hypocomplementemia; hypergammaglobulinemia	CD19 B-cell lymphopenia; low IgG; elevated IgM; recurrent infections
	RAG1, RAG2	Erosive polyarthritis; urticarial rash; class V lupus nephritis; ANA, anti-dsDNA, anti-Smith antibodies	Impaired antibody responses; recurrent sinopulmonary infections; destructive midline granulomatous disease
Other associated disorders	SLC7A7	Lupus nephritis; immune cytopenia; ANA positivity; positive extractable nuclear antigen antibodies; Anti-dsDNA may be indeterminate	Failure to thrive; Lysinuric protein intolerance; hepatosplenomegaly; pulmonary alveolar proteinosis; cognitive delay
	PEPD	ANA positivity; anti-Smith antibodies; arthritis; HLH/MAS	Chronic ulcerations (mostly of the lower limbs); dysmorphic features affecting the eye and nose; developmental delay; recurrent infections; hematological abnormalities; hepatosplenomegaly; chronic pulmonary disease
	CYBB	Affected males: Discoid lupus-like lesions; photosensitivity; carrier states: Raynaud phenomenon; photosensitivity; oral ulcers; arthritis	Recurrent, localized, deep-seated infections (skin, lung, lymph nodes); recurrent pneumonia. Carrier states are usually asymptomatic

ANA: Antinuclear antibody; SSA: Anti-Sjögren’s syndrome antigen A; ENA: Extractable nuclear antigen; SPENCD: Spondyloenchondrodysplasia; dsDNA: Double-stranded DNA.

Pathophysiology of monogenic lupus subtypes

Early complement deficiencies: Early classical complement components, including C1q, C1r, C1s, C2 and C4, are important for the clearance of apoptotic material and immune complexes. This results in a decrease in the autoantigen load through the clearance of nucleolar proteins and autoantigens. Moreover, C1q can inhibit in vitro interferon-alpha production by directly inhibiting the function of plasmacytoid dendritic cells[80]. In the absence of these early complement components, the balance between antigen load and effective clearance is disturbed, predisposing patients to autoimmunity[81-83]. Hypocomplementemic urticarial vasculitis (McDuffie syndrome)[84], antineutrophil cytoplasmic antibody positivity[85] and IBD have also been reported. Autosomal dominant DNASE1 mutations have been linked to SLE[86].

Interferonopathies: These disorders are characterized by increased type I interferon activation induced by recognition of self-nucleic acids via activation of toll-like receptors (TLR3, TLR7, TLR8, or TLR9) or cytosolic pattern recognition receptors (cGAS-STING, RIG-I, or MDA5). Mutations in genes that maintain cellular homeostasis can result in increased cytosolic DNA (TREX1/SAMHD1/RNASEH2A), defects in RNA editing (ADAR1), proteasomal dysfunction (PSMA3, PSMB8)[87,88], and defects in proteins required to limit the interferon signal (USP18, ISG15)[89]. The resulting increase in type I interferon signatures leads to dendritic cell maturation and activation, which accelerates the presentation of both exogenous and endogenous antigens, as well as the activation of T cells along both the Th1 pathway and the cytotoxic pathway[90]. Type I interferons also promote the differentiation of Th17 cells, increase the development of CD4 and CD8 memory cells and downregulate Treg functions[91].

ALPS and ALPS-like disorders: Apoptosis is indispensable for immune system homeostasis[92,93]. In the context of autoimmunity, apoptosis of self-reactive T and B cells is necessary. If dysregulated, it can provide a source of autoantigens and increased DNA fragments. These disorders classically present with generalized lymphadenopathy, hepatosplenomegaly, autoimmune cytopenias and hypergammaglobulinemia.

Loss of tolerance (RAG/PRKCD): Protein kinase C delta, which is an essential regulator of proliferation, survival, and apoptosis in different cells, including lymphocytes. It regulates B cell negative selection, i.e., deletion of autoreactive B cells, and its deficiency may lead to lupus-like autoimmunity or lymphoproliferative changes. The rapid resolution of autoimmune features with anti-CD20 agents suggests a key role for B cells in the pathogenesis of autoimmunity in this disease[94]. Autoimmunity results from the breakdown of central B-cell tolerance. Re-expression of RAG proteins in the bone marrow initiates secondary rearrangement of the light chain locus to decrease antibody self-reactivity. The breach of RAG-dependent tolerance checkpoints may contribute to SLE pathogenesis in some patients[95].

In patients with CGD, inadequate generation of reactive oxygen species (ROS) leads to poorly controlled infections due to defective killing by ROS, defective neutrophil extracellular trap formation, and defective autophagy, resulting in persistent antigen exposure[96]. This leads to higher levels of pro-inflammatory cytokines and an attempt to control infection via extensive granuloma formation[97-99]. The pathogenesis of immune dysregulation in lysinuric protein intolerance, leading to a lupus-like phenotype, remains to be defined[100].

IEI IN AN IBD PHENOTYPE

While conventional IBD results from the cumulative influence of multiple genetic susceptibility variants, several rare inherited disorders are characterized by intestinal inflammatory phenotypes that mimic IBD.

Many of these genetic disorders are also associated with inherent immunodeficiency[101], which alters intestinal homeostasis and disrupts epithelial responses, leading to reduced bacterial clearance. This, in turn, leads to hyperactivation of immune responses and dysregulated hyperinflammation, leading to an IBD phenotype[102].

Alternatively, immune response hyperactivation due to a defect in the immune inhibitory mechanism (IL-10 signaling defect, dysfunctional T-regulatory cell activity) or epithelial barrier defects (dystrophic epidermolysis bullosa, X-linked ectodermal dysplasia and immunodeficiency) can also result in a similar phenotype[103-110]. A comparison of the clinical characteristics of polygenic IBD and monogenic immunodeficiency-associated IBD is presented in Table 3.

Table 3 Disorders with clinical features suggestive of inflammatory bowel disease and inborn errors of immunity.

Category	Disease/gene	IBD phenotype	Immunodeficiency phenotype
Neutrophil disorders	Chronic granulomatous disease (CYBB, CYBA, NCF1/2/4)	Crohn’s disease–like intestinal inflammation with granulomas and strictures	Recurrent deep-seated infections, including liver abscess and pneumonia
	Congenital neutropenia (G6PC3)	Non-specific IBD phenotype	Gingivitis; aphthous ulcers; pneumonia; deep tissue abscess; colitis
	Leukocyte adhesion deficiency (ITGB2)	Non-specific IBD phenotype	Neutrophilic leukocytosis; chronic skin ulcers; delayed umbilical cord separation
	Glycogen storage disorder type 1b (SLC37A4)	Crohn's disease–like intestinal inflammation	Gingivitis; fever; hepatomegaly; growth retardation
T cell/B cell	Agammaglobulinemia; hyper-IgM syndrome; CVID	Crohn’s disease-like or ulcerative colitis-like inflammation	Recurrent sinopulmonary infections; chronic infectious diarrhea
	Wiskott-Aldrich syndrome	Ulcerative colitis-like inflammation	Eczema; thrombocytopenia; recurrent viral infections
	Atypical SCID (DCLRE1C, ZAP70, RAG2, LIG4, ADA, CD3G)	Non-specific IBD phenotype	Recurrent infections, including chronic diarrhea and pneumonia
	TTC7A deficiency	Early-onset severe enterocolitis	Multiple intestinal atresia; severe T-cell lymphopenia
Regulatory T-cell/IL-10 signalling defects	IL10, IL10RA, IL10RB	Early-onset IBD; perianal disease; Folliculitis	Extra-intestinal inflammation; arthritis; lymphoma predisposition
	IPEX syndrome	Autoimmune enteropathy with chronic diarrhea	Multiple autoimmune diseases, including type 1 diabetes and autoimmune cytopenias
	CD25 (IL2RA) deficiency	IPEX-like autoimmune enteropathy	Recurrent CMV infection and bacterial infections
	LRBA deficiency; CTLA4 haploinsufficiency	Chronic diarrhea; IBD-like phenotype	Hypogammaglobulinemia; otitis media and recurrent pneumonia; lymphoproliferation (EBV induced); autoimmunity; reduced T-cell proliferation response
Autoinflammatory disorders	MVK deficiency	Very early onset IBD; peritoneal adhesions; small bowel occlusion/perforation/necrosis	Hyper-IgD syndrome; recurrent fever; tender lymphadenopathy; aphthous ulcers
	RIPK1 deficiency	Very early onset IBD	Combined immunodeficiency; inflammatory arthropathy
HLH-associated disorders	XIAP, SH2D1A	Crohn’s disease-like enterocolitis	X-linked lymphoproliferative disease; EBV-associated HLH
	STXBP2	Chronic diarrhea; colitis	Familial hemophagocytic lymphohistiocytosis
	HPS1, HPS4, HPS6	Crohn’s disease-like granulomatous colitis	Hermansky-Pudlak syndrome with albinism and bleeding diathesis

IBD: Inflammatory bowel disease; G6PC3: Glucose-6-phosphatase catalytic subunit 3; SLC37A4: Solute carrier family 37 member 4; ITGB2: Integrin subunit beta 2; MVK: Mevalonate kinase; STXBP2: Syntaxin-binding protein 2; XIAP: X-linked inhibitor of apoptosis protein; SH2D1A: SH2 domain containing 1A; ZAP70: Zeta-chain associated protein kinase 70 kDa; LIG4: DNA ligase 4; DCLRE1C: DNA cross-link repair 1C; IL: Interleukin.

Clinical features that should prompt clinicians to consider an underlying monogenic disorder include very early age of onset, a family history suggestive of a genetic condition such as consanguinity or multiple affected members, recurrent or atypical infections, coexisting autoimmune manifestations, episodes of HLH, and abnormalities of the skin, nails, or hair. Among these, the age of onset is particularly important, as the likelihood of an underlying monogenic etiology substantially increases when symptoms begin early in childhood and even more so during infancy[102,111-113].

POLY-AUTOIMMUNITY

The coexistence of multiple autoimmune diseases in a single individual is referred to as polyautoimmunity and is frequently driven by genetic defects in pathways that regulate immune tolerance and immune control. These defects may impair central tolerance, as seen with mutations in AIRE, RAG1, and RAG2, or disrupt peripheral tolerance, as observed in Tregopathies, STAT1 GOF disorders, STAT3 GOF disorders, and STAT5b LOF disorders. An overview of the underlying mechanisms is depicted in Figure 4. Defects in the AIRE gene have been associated with APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy), characterized by the classical triad of CMCC, hypoparathyroidism, and adrenal insufficiency. Affected patients may also exhibit nail dystrophy and alopecia. The development of CMCC in these individuals has been linked to the presence of autoantibodies directed against IL-17 cytokines[114,115]. STAT1 GOF mutations have been associated with multi-organ autoimmunity, along with CMC, likely due to suppression of STAT3 resulting in inadequate Th17-mediated epithelial barrier response[116,117]. STAT3-GOF mutations are thought to predispose to polyautoimmunity via overactivation and imbalance between Th17 and Treg cells, resulting in Th17 skewing and an absolute reduction in Treg cells[118]. These patients present with autoimmune cytopenias, lymphoproliferation, ILD and endocrine disorders, most commonly type I diabetes[119]. STAT5b deficiency affects a key signaling molecule downstream of growth hormone, erythropoietin, thrombopoietin, and IL-2, resulting in reduced transcription of regulatory genes such as CD25 and FOXP3. Patients typically present with growth hormone–resistant growth failure, chronic lung disease, recurrent viral infections, atopy, and poly-autoimmunity[120]. Itchy E3 ubiquitin protein ligase (ITCH) deficiency causes a syndromic multisystem autoimmune disease characterized by early-onset pulmonary disease, failure to thrive, dysmorphic facial features, and multiple endocrinopathies[121]. ITCH was found to be essential for inducing T-cell anergy, thereby preventing prolonged, stable contact between antigen-presenting cells and the TCR. Additionally, it regulates TGF-β signaling and further induces FOXP3 expression in Treg cells[122]. Thus, polyautoimmunity must prompt clinicians to evaluate for underlying IEIs.

Figure 4  Genes affecting central and peripheral tolerance resulting in polyautoimmunity.

AUTOIMMUNE LUNG DISEASE

Early-onset inflammatory lung disease presenting as ILD is rare; however, it is severe and portends a poor prognosis for the patient. It has classically been associated with type I interferonopathies, particularly those mediated by STING (stimulator of IFN genes, also known as TMEM173). SAVI is caused by heterozygous GOF mutations in STING, leading to constitutive activation and increased interferon production. COPA plays a constitutive role in the downregulation of STING, and thus, dominant negative heterozygous mutations result in similar clinical phenotypes[123].

Although ILD is slightly more common in SAVI compared with COPA syndrome, it is still considered to be stereotypical of these two disorders. Recurrent diffuse alveolar hemorrhage is more characteristic of COPA syndrome. Computed tomography chest findings include ILD, DAH, fibrosis and intrathoracic lymphadenopathy (especially in SAVI syndrome). Other clinical findings include severe erosive joint arthritis (more common in COPA), acral osteolysis and severe skin vasculopathy (in SAVI) and immune-related kidney involvement in the form of glomerulonephritis. Laboratory evaluation revealing positivity for antinuclear antibodies and rheumatoid factor, along with this complex of symptoms, should alert the physician to these disorders[123]. Multisystem autoimmunity, resulting in inflammatory cell infiltration and early-onset chronic or ILD, has also been reported in diseases characterized by loss of peripheral tolerance, as described above (i.e., STAT3 GOF, STAT5b LOF, ITCH-AR LOF). Therefore, the presence of early-onset pulmonary disease, whether non-specific chronic fibrosing lung disease or ILD, should alert clinicians to investigate for an underlying monogenic cause, particularly in the context of polyautoimmunity.

SYSTEMIC AUTOINFLAMMATORY DISEASES AT THE IMMUNOLOGY–RHEUMATOLOGY INTERFACE

Systemic autoinflammatory diseases (SAIDs) are more commonly encountered within rheumatology practice and often demonstrate significant clinical overlap with pediatric rheumatologic disorders. These conditions can closely mimic inflammatory, infectious, or autoimmune diseases, posing diagnostic challenges[124]. Recognizing SAIDs as part of the spectrum of IEIs is crucial, as accurate identification not only clarifies disease pathogenesis but also has important implications for management, prognosis, and therapeutic decision-making, including the use of targeted biologic therapies. FMF is the most frequent autoinflammatory disorder characterized by short, repeated, and self-limiting crises of fever and serositis[124].

Hyper-IgD syndrome, also referred to as MKD, is an inflammasomopathy characterized by recurrent febrile episodes with rash and is frequently associated with hypogammaglobulinemia and recurrent pneumococcal infections[125]. Relopathies, including HOIL-1 and HOIP deficiencies, are characterized by recurrent fever, organomegaly, lymphangiectasia, recurrent bacterial and viral infections, and impaired vaccine responses[126]. GOF mutations in PLCG2 lead to phospholipase C-γ2–associated antibody deficiency and immune dysregulation (APLAID), characterized by autoinflammation due to impaired calcium signaling. Clinically, APLAID presents with vesiculopustular skin lesions, fever, uveitis, and gastrointestinal inflammation, along with hypogammaglobulinemia, reduced switched memory B cells, and recurrent sinopulmonary infections[127].

Actinopathies have also been linked to autoinflammatory phenotypes, with sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD) syndrome, caused by pathogenic variants in TRNT1, being the most well-characterized example. SIFD predominantly presents with recurrent fevers and anemia and is frequently complicated by recurrent pneumonia, B-cell lymphopenia, and hypogammaglobulinemia[128].

SAIDs may also manifest as sterile inflammation, presenting with abscesses or pyogenic arthritis that mimic infectious processes. Pathogenic variants in PSTPIP1 give rise to pyogenic arthritis, pyoderma gangrenosum, and acne syndrome, which is characterized by erosive inflammatory arthritis, recurrent oral ulceration, and persistently elevated inflammatory markers[129]. CRMO is associated with Majeed syndrome, caused by LOF mutations in LPIN2, in which dyserythropoietic anemia is a hallmark feature. Majeed syndrome may also present with transfusion-dependent anemia and cutaneous inflammatory manifestations, and treatment with IL-1 receptor antagonists such as anakinra has demonstrated therapeutic benefit. Deficiency of the IL-1 receptor antagonist, caused by biallelic IL1RN variants, presents with neonatal-onset sterile osteomyelitis, periostitis and pustulosis and responds to IL-1 blockade.

CONCLUSION

Diseases that mimic rheumatologic and polygenic autoimmune disorders may represent underlying IEIs. Clinical features such as early age of onset, recurrent fevers and infections, and involvement of multiple family members should prompt clinicians to investigate for an underlying genetic etiology. Although these conditions may initially resemble polygenic autoimmune diseases, monogenic disorders are often more aggressive and potentially life-threatening, with poor or unpredictable responses to conventional immunosuppressive therapies. A high index of suspicion is therefore essential, as timely identification of the underlying genetic defect has important implications for prognosis and enables the use of targeted therapies that can significantly alter the disease course and outcomes.