Primary Immunodeficiencies and Rheumatic Diseases

Introduction

Immunological derangements are recognized to play a significant role in the pathogenesis of rheumatic diseases in children, and primary immunodeficiency disorders (PIDDs) or inborn errors of immunity (IEIs) can occasionally be identified in children who have otherwise typical juvenile arthritis (JIA), systemic lupus erythematosus (SLE), or vasculitis. Moreover, many children referred to rheumatology services with a suspicion of inflammatory rheumatologic disorders present with a range of nonspecific features such as fevers, a variety of rashes, limb pains and/or swellings, and variable multiple organ dysfunctions. Progress over the last two decades has helped in understanding the important role of monogenic IEI of both the innate and adaptive immune systems. Monogenic IEI plays a role not only in increased susceptibility to various infectious agents (conventional PIDDs) but also in inflammation, autoimmunity, allergy, malignancy, and senescence, rapidly changing the diagnosis, classification, and treatment of rheumatologic disorders. This chapter will present an approach to diagnosis, a brief description of key clinical features in the most commonly encountered IEIs relevant to inflammatory rheumatologic disorders, and a discussion of the main management approaches.

Overview of the Inborn Errors of Immunity

Many immunologists now use the term inborn errors of immunity rather than primary immunodeficiency, recognizing that these conditions can have prominent manifestations of allergy/atopy, malignancy, autoimmunity, or inflammation ( Fig. 43.1 ). The phenotype in any one patient is often not predictable; as within a single family, individuals may have either a strong infection predisposition or a strong phenotype of autoimmunity and in some cases, both clinical aspects may occur. ^, It has long been appreciated that conventional PIDD can be associated with pleomorphic autoimmune manifestations. Autoimmune cytopenias, endocrinopathies, inflammatory bowel disease, and inflammatory and autoimmune rheumatologic and skin disorders have all been reported with much higher frequency in patients with defects of T-cell (e.g., Omenn syndrome, a variant of “leaky” severe combined immunodeficiency [SCID]) and B-cell immunity (e.g., selective IgA deficiency, common variable immunodeficiency [CVID]), combined immunodeficiency disorders, CID, (e.g., Wiskott–Aldrich syndrome [WAS]), hyper-IgM syndrome resulting from CD40L or CD40 deficiency, DiGeorge anomaly (DGA), deficiencies of early components of the classical complement system (C1q/r/s, C2, C4), and neutrophil function (chronic granulomatous disease [CGD]). ^, However, over the last two decades many patients presenting with various rheumatologic, inflammatory, and/or autoimmune features were diagnosed with monogenic autoimmune and/or inflammatory disorders. These novel disease entities classified within IEIs as immune dysregulation disorders, defects in intrinsic and innate immunity, and autoinflammatory disorders are associated with marked immune dysregulation and are characterized by varied and complex clinical phenotypes, further broadening the differential diagnosis of rheumatologic disorders ( Box 43.1 ).

Fig. 43.1, Inborn errors of immunity (immune system “failures”).

BOX 43.1

Real-Life Examples of Interplay between Rheumatologic Disorders and PIDD/IEI

IEI , Inborn errors of immunity; PIDD , primary immunodeficiency disorders.

These examples are provided to offer a sense of the spectrum of clinical issues.

A take home point is that all of these children were not typical.

A teenager with sarcoid-like presentation (intermittent inflammatory arthropathy, mild splenomegaly) followed for 3 years developed an episode of acute idiopathic thrombocytopenia (ITP); further investigation revealed a diagnosis of autoimmune lymphoproliferative syndrome (ALPS-sFAS).

A 3-year-old child with history of short stature since birth but normal bone radiography presented with a year-long history of erythematous skin rash on extremities resembling vasculopathy, which progressed to unusual granulomatous lesions associated with fevers, raised inflammatory markers, and persistent lymphopenia. This prompted further immunological investigations revealing severe T-cell dysregulation and eventually confirming the diagnosis of cartilage hair hypoplasia (CHH) resulting from compound heterozygosity in the RMRP gene. The child developed florid intestinal Epstein–Barr virus (EBV) lymphoma while awaiting a search for a suitable unrelated donor for eventually curative allogeneic hematopoietic stem cell transplantation (HSCT).

There are fewer studies defining the prevalence of these disorders in cohorts of patients with rheumatologic disorders, but there is a growing sense that they are not uncommon in pediatric rheumatology cohorts. As one example, adult patients with SLE have approximately 1% prevalence of complement deficiency. In cohorts of children with pediatric-onset SLE, the prevalence of antibody and complement deficiencies was 30% to 60%. Because these disorders represent the easiest to diagnose, it may be that this is an underassessment of the true prevalence of IEI in rheumatology settings.

In considering which patients presenting with a rheumatic disease should have an immunological evaluation, several features may indicate that an IEI may be present, including family history, infection predisposition, age of onset, severity of rheumatic disease and/or the evolving pattern of affected organs, or an unusual constellation of multiple autoimmune disorders ( Box 43.2 ).

BOX 43.2

Features Pointing to IEIs in the Differential Diagnosis of Rheumatic Disease

IEI , Inborn errors of immunity.

Settings of a strong family history of immunologically mediated diseases
Parental consanguinity
Unusually early onset with a severe course
A pattern of evolving organs affected by autoimmune disease or an unusual constellation of multiple autoimmune disorders
A predisposition to infection (frequent and severe)

Infection-Driven Approach

Although infections can be less prominent than might be expected in children with IEI, they are nevertheless helpful guideposts when they do occur. Each of the five main effector arms of the immune system, antibodies, T cells, natural killer (NK) cells, complement system, and myeloid cells, act as key mediators of host defense against specific infections. The latter three are components of the innate immune system and act together with a range of nonhematopoietic cells (e.g., fibroblasts, keratinocytes, epithelial cells), microbial sensors, and pattern-recognition receptors (PRRs) (e.g., Toll-like receptors [TLRs], DNA sensors) involved in the initial recognition of pathogen-associated molecular patterns (PAMPs) (e.g., lipopolysaccharide [LPS], lipoproteins, peptidoglycan, microbial nucleic acids), resulting in activation of downstream signaling cascades. The end result is a rapid initial inflammatory innate immune response. This short-lived response is followed by a specific adaptive immune response mediated by B and T lymphocytes, characterized by long-term immunological memory.

Importantly, both the infection and immune dysregulation features can be allelic, caused by mutations in the same gene. This is exemplified by loss of function (LOF) mutations of the signal transducer and activation of transcription 1 ( STAT1 ), causing susceptibility to mycobacterial and viral infections, whereas gain of function (GOF) mutations underlie a variety of phenotypes ranging from isolated susceptibility to mucocutaneous candidiasis and combined immunodeficiency to immune dysregulation disorders (e.g., vasculopathy, hypothyroidism). Similarly, mutations affecting the TLR/interleukin (IL)-1 signaling cascade of the canonical nuclear factor kappa light-chain enhancer of activated B cells (NFκB) pathway, a key player in the innate immune response to pyogenic bacteria and fungi, can cause either immunodeficiency or immune dysregulation (or both) depending on their diminished (LOF) or enhancing (GOF) effect. ^,

The immune system works collaboratively to protect humans from infections, but there are pivotal tasks that are more dependent on one specific effector arm ( Fig. 43.2 ). Therefore defects in a particular effector arm are often associated with specific types of infections.

Fig. 43.2, The most common types of infections and autoimmune conditions are shown schematically.

Table 43.1 summarizes the infectious susceptibilities associated with a defect in a specific effector arm of the immune system. This is a useful approach when infections are a prominent feature. Table 43.2 replicates that structure with a focus on screening tests.

TABLE 43.1

Summary of the Infectious Susceptibilities Based on the Effector Arm of the Immune System

Type of Infections	B Cell/Antibody	T Cell	Complement	Myeloid	NK Cells	Somatic Cells
Common bacteria	++++	+	+++	++++	-	-
Mycobacteria	-	+++	-	++++	+	-
Fungi	-	+	-	++++	-	-
Viruses (containment)	+	++++	-	-	+	++

NK, Natural killer.

TABLE 43.2

Routine Tests for Assessing the Effector Arm of the Immune System

Testing	B Cell/Antibody	T Cell	Complement	Myeloid	NK Cells	Somatic Cells
Screening tests	B-cell enumeration; IgG, IgA, IgM; Vaccine responses	T-cell enumeration	CH50	Neutrophil count; Oxidative burst (NBT, DHR)	NK-cell enumeration
Second tier tests	B-cell subsets	T-cell subsets and mitogen stimulation	AH50		CD107a
Sequencing useful?	++++	++++	+	++++	++++	++++

Ig, Immunoglobulin; NK, natural killer.

Antibody Deficiencies

Antibody deficiencies are associated most typically with recurrent bacterial infections such as recurrent sinopulmonary infections. However, autoimmunity can dominate the clinical picture when most common features include arthritis, SLE, autoimmune cytopenias, granulomatous inflammation, and lymphoproliferative disorders. Age of disease onset is highly variable. In complete absence of B-cell development and lack of antibodies (agammaglobulinemia), the age of onset of infections follows the disappearance of transplacentally acquired maternal antibodies (at around age 6 to 9 months). At the other end of the spectrum, selective immunoglobulin A deficiency (sIgAD) and specific antibody deficiency, where patients have normal IgG levels but low titer antibody responses, ^, are associated both with infections and rheumatic disease (JIA, SLE). Antibody deficiencies are identified by measurement of serum IgG, IgA, and IgM levels along with a test of function such as antibody titers to vaccines (e.g., tetanus, Haemophilus influenzae , and pneumococcus). Interpretation of these tests must consider that rituximab (anti-B cell monoclonal antibody) is associated with low IgM levels and diminished B-cell numbers, typically for 6 to 12 months after administration. Treatment with other biologics, anti-tumor necrosis factor (TNF) agents in particular, has been reported to alter the ability to produce or maintain good specific antibody levels. It should be noted that vaccine titers reflect the state of the immune system at the time of vaccination rather than the time of testing. Whereas patients with agammaglobulinemia have no B cells and no antibody production from birth, most other antibody defects such as CVID result from a gradual attrition of antibody production. When the initial tests are not diagnostic, response to a booster vaccine such as tetanus or the polysaccharide pneumococcal vaccine can be measured 4 to 8 weeks later. When this first-line testing demonstrates compromise of antibody production or function, genetic testing focused on antibody deficiencies, or whole exome sequencing (WES), if available, can be performed. Genetic testing is important because several antibody deficiency conditions with high rates of autoimmunity (such as certain CVIDs) and activated phosphoinositide 3-kinase (PI3K)-delta syndrome (APDS) have quite specific treatments, and allogeneic hematopoietic stem cell transplantation (HSCT) can be considered in some cases ^, ( Fig. 43.3 ).

T-Cell Deficiencies

The infection pattern in T-cell deficiencies is typically a combination of opportunistic and prolonged viral infections (such as pneumocystis, enteroviruses, cytomegalovirus [CMV], and Epstein–Barr virus [EBV]) occasionally associated with somatic features that can be helpful in focusing the diagnostic approach (e.g., short stature and sparse hair can suggest cartilage hair hypoplasia [CHH] ; see Box 43.1 ). Patients with overt SCID will not likely appear in a rheumatology clinic because with a complete lack of T cells, there is almost no autoimmunity, and neonatal screening for this condition is becoming available. ^, It is the children with slightly milder features, usually affected by hypomorphic mutations in genes such as RAG which, when affected by fully null mutations, are responsible for the SCID phenotype, where immune dysregulation and autoimmunity is extremely common. ^, ^, ^, The majority of patients with DGA because of 22q11.2 deletion are on the very mild end of the spectrum of T-cell defects, typically with a mild decrease in T-cell counts resulting from thymic hypoplasia. About 10% of children and adults with DGA have autoimmune manifestations including JIA-like inflammatory arthropathy. ^, Various CID disorders could have a high rate of autoimmunity and/or immune dysregulation such as autoimmune cytopenias, granulomatous inflammation of different organs (e.g., skin, intestine, liver, spleen, and lymph nodes), lymphoproliferation (splenomegaly, lymphadenopathy), and so on. In fact, autoimmunity can dominate the clinical picture and infections may not be a prominent part of the clinical picture.

Initial testing for T-cell deficiencies involves a peripheral blood differential white cell count with absolute lymphocyte count (as persistent lymphopenia in early infancy is strongly suggestive of a T-cell defect) and CD3, CD4, and CD8 T-cell counts. Some test panels include CD4/CD45RA and CD4/CD45RO testing, a B-cell marker such as CD19, and a marker for NK cells such as CD3-/CD16+/CD56+. Results of these tests can focus the diagnostic considerations because some conditions affect multiple lineages. Interpretation is straightforward but does require consideration of age. Infants have much higher lymphocyte counts than adults, therefore age-specific normal ranges must be used for correct interpretation. The CD4/CD45RA count measures the number of naïve T cells. Infants should have a naïve to memory ratio of 10:1 and the ratio should be 1:1 at about 18 to 35 years of age. Thereafter, the phenotype of CD4/CD45RO memory T cell predominates. If the total T-cell count is normal but the ratio of naïve to memory T cells is skewed, with a low naïve-to-memory ratio indicating proliferative stress on the T-cell compartment, this is consistent with a primary T-cell deficiency and/or T-cell dysregulation. Naïve T cells convert to memory cells upon antigen engagement. Therefore autoimmune disease leads to change of the naïve-to-memory ratio; however, when this effect is very large, it implies a congenital T-cell defect. In vitro T-cell proliferation can be useful to confirm that the low T-cell counts are associated with dysfunction. There are few conditions in which the T-cell counts are normal and proliferation is defective (e.g., Omenn syndrome). Finally, gene sequencing approaches can be valuable once a T-cell defect is suspected based on the screening tests. Prognosis can depend on both the genetic etiology and in some cases the specific mutation. For moderate to severe T-cell deficiencies, allogeneic HSCT is often used as definitive treatment.

A subset of T-cell deficiencies affects cytolysis of target cells, a particular function of CD8 T cells. The absence of this function in both CD8 T and NK cells, resulting from mutations in several genes encoding proteins necessary for perforin-related lymphocyte cytotoxicity, causes a group of severe immunodysregulatory disorders traditionally referred to as primary hemophagocytic lymphohistiocytosis (HLH). In patients with different rheumatologic disease, a secondary HLH known as macrophage activation syndrome (MAS) can be a severe, life-threatening complication (both MAS and HLH are discussed in depth in Chapter 42 ).

Complement Deficiencies

The complement system, a cascade of soluble and membrane-bound proteins, has a crucial role in maintaining immune homeostasis by clearing apoptotic cells and immune complexes, as well as in host defense by opsonization and direct killing of microbial pathogens. Monogenic deficiencies of complement components are associated with susceptibility to infection by encapsulated bacteria and/or immune dysregulation disorders such as SLE-like disease, glomerulopathies, and vasculitides (see later in chapter).

Classical pathway deficiencies (C1, C4, C2) associated with SLE are all associated with a markedly diminished function (i.e., absent of nearly absent CH50 results), as the functional CH50 test requires an intact complement cascade from C1 through C9. Genetic testing is rarely performed except for the deficiencies associated with hemolytic uremic syndrome (HUS), factor H (CFH), factor I (CFI), membrane cofactor protein (MCP), GOF mutations in C3, and factor B, where the functional tests are not adequate for diagnosis.

As complement deficiency, both hereditary and secondary (e.g., drug-induced as in the case of treatment of HUS with eculizumab) are strongly associated with susceptibility to severe pyogenic bacterial infections (e.g., streptococci, Neisseria ), these patients should be advised regarding appropriate immunization and prophylactic antibiotics.

Myeloid Immunodeficiencies

Neutrophil deficiencies in quantity (neutropenias), function (e.g., CGD), or mobility (leukocyte adhesion deficiency [LAD]) are associated with susceptibility to bacterial and fungal infections. Besides recurrent infections with certain catalase-positive bacteria (staphylococci, Burkholderia, Serratia, Nocardia ) and fungi most commonly affecting the lungs, skin, and lymph nodes, the noninfection related hyperinflammatory features of CGD such as inflammatory bowel disease (IBD) and chronic lung disease occur with cumulative prevalence reaching almost 30% in adults. Discoid lupus or SLE are also associated with CGD ^, (see later in chapter).

One key distinguishing feature is that severe congenital neutropenia and LAD both prevent the accumulation of pus, which is largely made up of dying and dead neutrophils at the site of infection, whereas in CGD, pus generation is intact, but intracellular killing by superoxide anion generation (respiratory burst) is deficient. The dihydrorhodamine (DHR) test reveals a diminished neutrophil oxidative burst and is highly sensitive and specific for the diagnosis of CGD, although mild decrements may be seen in sepsis and with myeloperoxidase deficiency. HSCT is a cure for severe congenital neutropenia, LAD, and CGD, and it has led to resolution of IBD in most cases. ^, Both neutrophils and monocytes are the main immune system cells affected in a subcategory of autoinflammatory disorders (see Chapter 39 ).

Natural Killer Cell Deficiencies

Insufficient NK cell (and CD8 T cell) cytotoxicity is one of the main characteristics of primary HLH, where in the absence of a cytolytic response, antigen stimulation persists and drives the “cytokine storm” (see Chapter 42 ). Diagnosis of NK cell deficiency is usually carried out by either quantitation of the NK cells or by measuring their degranulation through flow cytometry for CD107a.

Somatic Tissue Immune Deficiencies

Besides cells of the immune system, certain somatic cells (e.g., fibroblasts, epithelial cells) harbor pathways that allow an adequate response to infections. In affected individuals this category of IEI of the innate immune system can present as autoinflammatory disorders both associated with overproduction of type I interferons (the interferonopathies) and associated with susceptibility to viral infections if production of type I interferons is deficient. ^,

Autoimmunity and Inflammation-Driven Approach

The difference between autoimmunity and autoinflammation is not always clear. The former implies a loss of tolerance and the defect is in the adaptive immune system (i.e., T cells, B cells, or both), ^, whereas autoinflammation implies that the myeloid cells are autonomously producing inflammatory mediators (see Chapter 39 ). The usual criteria for defining a process as autoimmune in nature are the presence of autoantibodies, self-reacting T cells, and/or a strong major histocompatibility complex (MHC) association. Clinically, autoimmunity can manifest either as systemic disease such as SLE or as organ-specific such as endocrinopathies, cytopenias, and so forth. Autoantibodies can be present in inflammatory states, but these are often many and varied, unlike in a typical autoimmune condition where the autoantibodies are fairly disease specific. Notably, the inborn errors of innate immunity may lead to impaired production or complete absence of important mediators (e.g., cytokines) necessary for the function of T and B cells, resulting in adaptive immunity dysregulation and autoimmunity.

Two critical points in the history of a patient with a rheumatic disease may suggest the presence of an IEI (see Box 43.2 ). First, early disease onset is strongly suggestive of IEI. Thus prepubertal onset of SLE is unusual and is associated with complement deficiencies. The stronger association is with onset less than 5 years of age, when complement deficiencies are the rule. ^, Similarly, IEI can be found in adults with IBD but occurs in approximately 20% of patients with onset less than 6 years of age. Second, the evolution of autoimmunity with accrual of different organ system involvement (e.g., new organ system involvement in SLE and/or Sjögren syndrome) suggests the possibility of an IEI. Clinical features of IEIs characterized by immune dysregulation are usually extremely variable and overlapping ( Box 43.3 ).

BOX 43.3

Autoimmune and InflammatoryPhenotypes Associated with Inborn Errors of Immunity

ALPS , Autoimmune lymphoproliferative syndrome; IPEX , immunodysregulation polyendocrinopathy

enteropathy X-linked syndrome; MAS , macrophage activation syndrome; SLE , systemic lupus erythematosus.

Arthritis
Systemic lupus erythematosus
Inflammatory skin disorders, vasculitis, and vasculopathy
Hemophagocytic lymphohistiocytosis
Inflammatory bowel disease (autoimmune enteropathy, colitis)
Autoimmune cytopenias
Autoimmune endocrinopathies
Autoimmune lung disease
Lymphoproliferation (hepatosplenomegaly, lymphadenopathy)
Complex autoimmune/inflammatory phenotype (SLE-like; IPEX-like; ALPS-like; MAS)

In the next section, the association of specific IEIs with specific rheumatic manifestations is discussed.

Arthritis

Chronic inflammatory arthropathy (polyarticular JIA, or JIA-like) is seen in 5% to 30% of patients with antibody deficiency. It is also seen in a significant number of patients with several T-cell and combined immunodeficiencies (e.g., DGA, WAS, CHH, STAT5b deficiency), ^, ^, in disorders of immune dysregulation, ^, ^, and occasionally in those with complement deficiencies (C2, C4, C7, and C8). For patients with CGD, septic arthritis caused by pyogenic bacteria, mycobacteria, and fungi, typically affecting multiple small joints, is more common.

The following sections discuss some recently described disorders in which arthritis is one of the major clinical features of a complex phenotype characterized by variable gastrointestinal, endocrine, inflammatory, and lymphoproliferative features that can be associated with immunodeficiency.

LACC1 Deficiency

Laccase domain-containing 1 ( LACC1) encodes FAMIN (fatty acid metabolism and immunity nexus) protein, predominantly expressed in macrophages and involved in lipid balance control and reactive oxygen species production. Similar to NOD2 (where an autosomal dominant [AD] mutation causes Blau syndrome, an autoinflammatory disorder characterized by granulomatous inflammation, Crohn disease, uveitis, and arthropathy), LACC1 function is central for pathogen clearance and granulomatous inflammation. Autosomal recessive LACC1 deficiency (LOF mutations) causes increased IL-1 activity and a clinical phenotype of early-onset Crohn disease and familial, early-onset severe systemic JIA, so far mainly reported from the Middle East. Blocking cytokines IL-1, TNF, and IL-6 is only partially helpful in controlling disease activity, and allogeneic HSCT may be indicated.

PSTPIP1-Associated Inflammatory Disease

Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1), a cytoskeleton protein highly expressed in hematopoietic tissues, has a role in modulation of T-cell activation and release of IL-1. Disruption of its interaction with regulatory tyrosine phosphatase leads to uncontrolled secretion of IL-1 via deranged (prolonged) binding to pyrin (affected in familial Mediterranean fever). PSTPIP1 heterozygous AD mutations are associated with pyogenic sterile arthritis and pyoderma gangrenosum and acne (PAPA) syndrome. However, specific E250K and E257K mutations underlie a separate syndrome, hyperzincemia/hypercalprotectinemia (Hz/Hc). The clinical phenotype is of early-onset (∼1 year old) severe, life-threatening inflammatory disease characterized by cutaneous inflammation and arthritis, hepato- and splenomegaly, lymphadenopathy, and failure to thrive. Most patients have marked neutropenia, anemia, and thrombocytopenia because of dysregulated hematopoiesis. Extremely high serum levels of calprotectin, and of accumulated zinc because of the zinc-binding capacities of MRP8/14, are characteristic laboratory markers (see Chapter 4 ). Blocking (single and/or combination of different multiples) proinflammatory cytokines (e.g., TNF, IL-1, IL-6) has only partial effect on disease activity and often there is need for combined corticosteroid and/or cyclosporine treatment. Allogeneic HSCT may be indicated the in most severe disease.

COPA Deficiency

Coatomer protein A (COPA) has an important role in intracellular protein trafficking. COPA deficiency is an AD condition characterized by endoplasmic reticulum (ER) stress resulting from a defect in intracellular trafficking leading to aberrant autophagy; increased levels of IL-1, IL-6, and T helper (Th)-17 cells; and formation of autoantibodies. Typical presentation is prior to 5 years of age with interstitial lung disease, occasionally with pulmonary hemorrhage, and polyarticular arthritis in over 90% of patients, arising in the teenage years. Computed tomography (CT) scans usually demonstrate ground glass opacities, and lung biopsies show lymphocytic interstitial pneumonia and follicular bronchiolitis. Pulmonary neuroendocrine cell hyperplasia has been seen in two adults. Glomerular disease occurs in a subset of patients. Diagnosis may be suspected based on elevated Th17 cells, but sequencing is usually required for diagnosis. Acute exacerbations of lung disease have been treated with cyclophosphamide, corticosteroids, or rituximab with some effect. The optimal long-term management is not known, and the pulmonary disease may be intrinsic to the tissue, at least in part.

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