Management of Autoimmune and Inflammatory Disorders in the Setting of Infection or Immunodeficiency
Host-microbiome symbiosis is contingent upon intact immune surveillance and competence. Compromised immunity with development of clinical infection may occur as a consequence of immunosuppressive therapy prescribed for treatment of inflammatory or autoimmune disease. Alternatively, autoimmune disorders not uncommonly develop in the context of underlying immune deficiency. In either setting, clinicians may need to develop strategies to suppress autoimmune-mediated inflammation in the setting of intercurrent infection. The optimal strategy is best informed by what host defenses are required to effect resolution of the infection, the current status of these defenses in a given patient, and recognition of how chosen therapies for managing autoimmunity and associated inflammation may (or may not) impact the ability of the needed defenses to eradicate specific pathogens.
KeywordsAutoimmune diseases Immunosuppressive therapy Infection Immunodeficiency
Adenosine deaminase deficiency
Activation-induced cytidine deaminase
Common variable immunodeficiency
Disease-modifying antirheumatic drug
Giant cell arteritis
Granulomatosis with polyangiitis
Interleukin 6 (17) receptor
Nonsteroidal anti-inflammatory drug
Selective IgA deficiency
Systemic lupus erythematosus
Transmembrane activator, calcium-modulator, and cyclophilin ligand interactor
Uracil nucleoside glycosylase
Managing Autoimmune Disorders in the Setting of Acquired Infection
Infection risk is increased in rheumatoid arthritis (RA) , primarily in the context of high disease activity and intercurrent use of corticosteroids [1, 2]. Risk of joint sepsis is increased due to hypervascular, proliferative synovium permitting easy access of circulating microbial pathogens into affected joints. RA patients with Felty’s syndrome may be at even greater risk due to the leucopenia and hypersplenism associated with this RA complication. Traditional disease-modifying antirheumatic drugs (DMARDs) as well as biologic DMARDs targeting inflammatory mediators in RA are highly effective in suppressing synovial inflammation and attendant structural damage due to RA. With the possible exception of anti-TNF antibodies, DMARDs have not been shown to significantly increase overall incident infection risk in RA [3, 4, 5]. However, traditional DMARDs such as methotrexate and biologic DMARDs may nonetheless impact host responses to acquired infection.
As a general rule, management of RA in the setting of suspected intercurrent infection entails withholding dosing of therapies known to impact phagocytic cell functions, minimizing corticosteroid dosing to the levels required for avoidance of adrenal crisis, assiduous attention to the possibility of joint seeding by bacteria, and prompt institution of antimicrobial therapy with joint drainage as needed. Nonsteroidal anti-inflammatory drugs (NSAIDs) or intra-articular corticosteroids can be used as needed to manage synovitis flares until infection has resolved. If NSAIDs are contraindicated, low-dose prednisone (5–10 mg/day) and/or non-acetylated aspirin (salsalate) which does not inhibit cyclooxygenase activity can be used for managing generalized joint flares. Considerations in this setting with respect to commonly used RA DMARDs and biologics are summarized below (see Chap. 34 for individual drugs and risk of infection).
The clinical efficacy of methotrexate (MTX) , one of the most commonly employed DMARDs in the management of RA, is attributed primarily to the inhibitory effects of intracellular MTX polyglutamates on AICAR transformylase, resulting in increased levels of adenosine which is inhibitory for trafficking of phagocytic cells into joints . As such, it is prudent to hold treatment with methotrexate until intercurrent bacterial infections affecting the lungs, skin, joints, or other tissues have clinically resolved. The presumed effect of MTX on immune cell trafficking has traditionally proscribed MTX use perioperatively with conflicting expert opinion on whether MTX should be held in the context of joint replacement procedures. However, recent studies have shifted expert opinion toward not withholding MTX around the time of elective joint replacement surgery, citing the increased morbidity associated with disease flare in this setting .
TNF promotes a variety of phagocytic cell activation responses including expression of adhesion molecules and activation of the respiratory burst in neutrophils. Although in vitro studies with etanercept showed no direct effect on neutrophil phagocytic cell or microbicidal activity , inhibition of TNF locally by etanercept or anti-TNF monoclonal constructs may nonetheless impair phagocytic cell-mediated host defenses to microbial pathogens. Indeed, treatment with TNF inhibitors has been shown to confer increased infection risk in multiple cohorts of patients with disorders in which treatment with these agents is included among the employed therapeutic options . TNF also appears to be an important cytokine in maintaining the integrity of granulomas, and the association of anti-TNF therapies with reactivation of tuberculosis and disseminated fungal infections is also well recognized [8, 9]. Thus, prescribing guidelines include testing for latent tuberculosis in all patients newly started on TNF inhibitors. The risk for non-viral opportunistic infection, including tuberculosis, appears to be higher in patients treated with anti-TNF monoclonal reagents such as infliximab relative to that noted in patients treated with sTNFR:Fc /etanercept .
Given the increased risk and morbidity of infection complications observed in patients on TNF inhibitor therapy, it is therefore appropriate to withhold and not initiate anti-TNF therapy in the setting of any active infection. Moreover, patients with RA who have comorbidities such as diabetes have a demonstrated increased risk for bacterial infections as well as increased infection-related morbidity during treatment with TNF inhibitors . An alternative to anti-TNF therapy with less direct impact on phagocytic cell responses might therefore best be considered for managing RA in patients with pre-existing comorbidities associated with increased infection risk.
Due to signaling that can occur through the interleukin (IL)-6 receptor (IL-6R) and trans-signaling through gp130 receptors that recognize IL-6:sIL-6R heterodimer, inhibitors of IL-6 such as tocilizumab have pleomorphic effects on immune as well as nonimmune cells. IL-6 mediates activation of macrophages, terminal proliferation and differentiation of B-cells, differentiation of Th17 cells, and also homeostatic processes including granulopoiesis, induction of some anti-inflammatory cytokines, and mucosal integrity [12, 13]. Given these considerations, it is generally prudent to withhold treatment with IL-6 inhibitors such as tocilizumab (anti-IL6R) or sirukumab (anti-IL6) in the setting of intercurrent infection. Since IL-6 signaling appears to govern homeostasis of the enteric mucosal epithelium, and anti-IL-6 therapy has been associated with increased risk of intestinal perforations , treatment with IL-6 inhibitors is not recommended in the setting of inflammatory bowel disease, diverticular disease, or recent colitis in which the integrity of the enteric mucosa may become compromised.
Janus Kinase Inhibitors
Janus kinase inhibitors such as tofacitinib block signal transduction mediating the effects of inflammatory cytokines such as TNF and IL-6, with potent inhibitory effects on the functions of phagocytic cells. Reported rates of infection in patients on treatment with tofacitinib are comparable to those reported in patients on anti-TNF or anti-IL6 therapies . The considerations alluded to above for these respective biologics are therefore equally applicable to tofacitinib, and it is advisable to withhold its use in the setting of intercurrent infection, resuming treatment once the infection is deemed resolved. The experience with other Janus kinase inhibitors is limited, but in the absence of data indicating otherwise, treatment with the newer agents is also advisably withheld in the setting of intercurrent bacterial infection.
Effective in blocking T cell co-stimulation and associated acquired responses to neo-antigens, abatacept does not have direct impacts on phagocytic cell responses. Serious bacterial infection occurs less commonly during treatment of RA with abatacept than with TNF inhibitors [16, 17], and risk of reactivation or acquired infection with tuberculosis is lower among RA patents treated with abatacept relative to those treated with TNF inhibitors . Whether it is necessary to withhold treatment with abatacept in the setting of acute bacterial infection has not been established. Since the occurrence of serious infections does not appear to be increased in RA patients treated with abatacept, this may be a preferred biologic option in patients with RA deemed to have increased risk for bacterial infection.
Depletion of CD20+ lymphocytes impacts primarily B cell-mediated acquired immunity and has little if any impact on the function of phagocytic cells. However, infection risk among RA patients treated with rituximab is nonetheless comparable to that observed among patients treated with TNF inhibitors [17, 19]. This may be due to the not insignificant numbers of patients who develop hypogammaglobulinemia with recurrent dosing of rituximab , with occurrence of serious infection events noted to be higher in such patients . Management of intercurrent infections in patients treated with rituximab or other B cell-depleting reagents (such as obinutuzumab, ofatumumab) is therefore best directed toward ensuring antecedent B cell depletion therapy has not rendered the recipient hypogammaglobulinemic. Should severe infection occur with IgG levels less than 500 mg/dL, consideration should be given to supportive immunoglobulin replacement therapy (usually 0.4 g/kg every 4 weeks as needed). Whether to initiate prophylactic immunoglobulin replacement therapy at lower levels of serum IgG in the absence of infection is subject to debate. Hypogammaglobulinemia in the setting of B cell depletion therapy may be transient, and provided the patient can produce adequate neutralizing antibodies, IgG replacement therapy in such patients may not be required. Assessment of responses to pneumococcal vaccination may be informative in this setting. With this caveat of needed vigilance for hypogammaglobulinemia, given the absence of its effects on phagocytic cell functions, rituximab may be another preferred option for managing patients with RA who either have comorbidities placing them at increased risk for infections or who have experienced recurring episodes of bacterial infections on anti-TNF biologics.
Patients with seronegative spondyloarthropathies (SNSA) are at some increased risk for infection due to chronic arthropathy as well as enteric complications due to underlying inflammatory bowel disease (IBD) or subclinical inflammation of the enteric mucosa that may occur in non-IBD-associated SNSA (see Chap. 16). A noted increased occurrence of mannose-binding lectin (MBL) deficiency in patients with SNSA may also confer increased risk for infection [21, 22].
Methotrexate, sulfasalazine, and TNFα inhibitors are commonly employed in the management of SNSA, and the same considerations with regard to the use of these therapies in patients with RA are applicable and relevant to patients with SNSA with intercurrent infection. As discussed below, use of alternative biologics targeting the IL-23/IL-17 pathway that are primarily used in the management of psoriasis and SNSA may also need to be curtailed in the setting of intercurrent infection. Apremilast, a phosphodiesterase-4 inhibitor that is used primarily for the management of psoriasis and psoriatic arthropathy, does not have any direct effects on phagocytic cell function and has not been shown in clinical trials to confer increased infection risk . As such, it is usually not necessary to curtail the use of apremilast during episodes of infection. The majority of joint manifestations in SNSA can otherwise be adequately managed with NSAID therapy during episodes of intercurrent infection when anti-TNF biologics or biologics targeting the IL23/IL17 axis need to be appropriately withheld.
Ustekinumab and IL-23 Inhibitors
Ustekinumab is a monoclonal reagent targeting the shared p40 subunit of the IL-12 and IL-23 receptors. Both IL-12 and IL-23 impact primarily T cell lineage development, with minimal if any direct effects on phagocytic cell functions. In clinical trials using ustekinumab in psoriasis as well as ankylosing spondylitis and inflammatory bowel disease, there have been no increased occurrences of serious infections in the ustekinumab treatment arms relative to the placebo treatment arms . While there is no evidence to support holding ustekinumab or IL-23-specific therapies during intercurrent bacterial infection, given the identified role of IL-12 and IL-23 in mediating host defense against mycobacterial, fungal, and Salmonella infections, it is prudent to withhold ustekinumab and agents targeting IL-23 (tildrakizumab and guselkumab) in the setting of infection with these pathogens.
Inhibitors of IL-17 and IL-17R
IL-17 is derived from both innate and lymphoid cells, promoting the induction and release of IL-6, TNF, CCL2, CCL3, and matrix metalloproteinase (MMPs) from macrophages as well as the proliferation, maturation, and chemotaxis of neutrophils. In trials with secukinumab and ixekizumab (inhibitors of IL-17A) as well as trials with brodalumab (an inhibitor of the IL-17R), infection rates were increased over those observed in patients randomized to placebo but comparable to what has been observed in similar populations of patients enrolled in trials with TNF inhibitors . Candida infections occurred more frequently in studies with the IL-17 inhibitor brodalumab . It is prudent to withhold therapies targeting IL-17/IL-17R in the setting of active infection with these classes of microbial pathogens. For patients with SNSA who have experienced recurrent serious infections, consideration should be given to use of alternative therapies associated with less infection risk such as apremilast or ustekinumab. Although the therapeutic benefits of ustekinumab in SNSA may be attributable in large part to decreases in the number and survival of Th17 lymphocytes which comprise a significant source of IL-17, there are other (innate) cellular sources of IL-17 and therapies that specifically target IL-17 or its receptor may therefore confer greater infection risk than therapies targeting the Th17 lineage.
Systemic Lupus Erythematosus
For a variety of reasons, patients with systemic lupus erythematosus (SLE) may be at increased risk for infection (see Chap. 21). Defects in innate immunity related to opsonization functions known to also predispose to SLE include deficiencies in early components of the classic complement pathway (C1q, C2, and C4) and mannose-binding lectin [27, 28]. Lymphopenia is a common disease manifestation and a demonstrated risk factor for infectious complications in lupus . Autoreactive T cell clones and/or autoantibodies may potentially target molecules required for appropriate production of granulocytes  or the ability of B cells to appropriately mature, proliferate, and secrete high-affinity antibodies capable of neutralizing microbial pathogens . Autoimmunity with SLE features may be the presenting feature of patients with common variable immune deficiency or immunoglobulin IgG subclass deficiency . Although therapies required to suppress autoreactive inflammatory disease are becoming increasingly selective and targeted (one example being belimumab), many of the current therapies required to effectively manage moderate to severe SLE activity result in some degree of nonselective immune suppression impacting innate and/or acquired immune functions.
Due primarily to their direct effects on the function of phagocytic cells as well as the production and survival of T lymphocytes, chronic corticosteroid therapy constitutes one of the major risk factors for infection-related morbidity and mortality in SLE patients. For patients who require ongoing treatment with corticosteroids, the dosing of steroids during intercurrent bacterial infection should be the lowest deemed sufficient to avoid SLE-related acute organ damage. In the setting of overwhelming confirmed microbial sepsis deemed life-threatening, it is usually prudent to decrease the dose of steroids to that required to avoid adrenal crisis, even if this entails a risk of SLE-related organ damage. The exception may be in the setting of active lupus-related CNS or pulmonary disease (notably diffuse alveolar hemorrhage) where corticosteroid dosing at high levels may be necessary to avoid imminent demise or brain injury. High-dose intravenous immunoglobulin (IVIG) (2.0 g/kg/day) is often effective in ameliorating acute lupus-related CNS vascular injury [33, 34] or alveolar hemorrhage  and should be considered as an alternative to high-dose steroid therapy when these entities require treatment in the setting of serious bacterial infection.
Dosing with cyclophosphamide or azathioprine, both of which may impact the numbers and production of phagocytic cells, is best withheld in the setting of bacterial infection. Moreover, should lupus patients develop significant granulocytopenia (<500/mcl) during treatment with either of these agents, prophylactic use of levofloxacin (500 mg/day) is recommended to decrease the risk of gram-negative sepsis until the absolute neutrophil count recovers to >500/mcl . Treatment with recombinant granulocyte colony-stimulating factor (rCSF) can be considered if serious intercurrent bacterial infection occurs in this setting, but use of rCSF is otherwise not recommended due to increased risk of lupus flare associated with its use . Since mycophenolate and mycophenolic acid target primarily the proliferation of lymphoid cells with minimal, if any, impact on the proliferation of phagocytic cells, it may not be necessary to withhold treatment with these agents during episodes of bacterial infection. Antimalarials (chloroquine, hydroxychloroquine, quinacrine), dapsone, and thalidomide have no significant impact on host responses to microbial pathogens and can be continued as needed to suppress lupus activity during episodes of infection. Since belimumab primarily impacts the maturation, proliferation, and survival of autoreactive B cells and has no known effects on phagocytic cell function, it is usually not necessary to withhold scheduled dosing with this biologic during periods of intercurrent infection. Provided patients who may be hypogammaglobulinemic (due to immunosuppression or underlying associated immunodeficiency) are receiving appropriate immunoglobulin replacement treatment in the setting of acute infectious complications, it may also not be necessary to withhold dosing with B cell-depleting agents such as rituximab or obinutuzumab if needed for managing acute disease complications such as immune thrombocytopenia or hemolytic anemia. However, temporizing measures using a course of high-dose IVIG (2 g/kg) may be a more prudent intervention for treating acute exacerbations of immune cytopenias in lupus patients with intercurrent serious microbial infection [38, 39].
Patients with Sjogren’s syndrome may require immunosuppressive therapy for pulmonary complications such as acute interstitial lung disease or organizing pneumonia or neurologic complications such as transverse/longitudinal myelitis. Although corticosteroids and cytotoxic agents are often employed in the initial acute management of these complications, early initiation of steroid-sparing therapy with agents such as mycophenolate with minimal impact on phagocytic cell function may help mitigate infection risk. For patients with intercurrent infection who still have acute myelitis or other central nervous system disease, temporizing measures with use of high-dose IVIG may permit prompt lowering of the employed use of corticosteroids and holding of cytotoxic therapy without increasing the risk of clinical relapse . For patients who develop infection in the setting of active interstitial lung disease or organizing pneumonia, lowering the dose of corticosteroids and use of IVIG with rituximab or mycophenolate may be an effective therapeutic alternative with minimal impact on host defenses required to clear intercurrent infection [41, 42, 43].
Immunosuppressive therapy is being utilized more frequently in the management of patients with systemic sclerosis who have evidence of alveolitis or who have early active skin disease with dermal edema. Cyclophosphamide is used most commonly for patients with active interstitial lung disease and evidence of active alveolitis on high-resolution CT scan, with concomitant improvements also noted in selected patients with active skin disease. Notably, improvements have also been noted in both lung and skin manifestations among patients treated with mycophenolate . Although not yet assessed in randomized trials, a number of small case series have reported improvements in both lung and skin manifestations following treatment with high-dose (2 g/kg) IVIG . As such, for patients with active lung and skin disease who have ongoing infection complications that would best preclude use of cyclophosphamide, consideration can be given to using IVIG as a suitable alternative for managing acute lung inflammation and/or transitioning to mycophenolate for long-term management of these disease complications.
Polymyositis and Dermatomyositis
The standard management of inflammatory myopathies entails initial use of corticosteroids, most often in divided doses, with early initiation of steroid-sparing immunosuppressive therapy such as mycophenolate, azathioprine, methotrexate, or calcineurin inhibitors. Given the negligible effects of mycophenolate or calcineurin inhibitors on phagocytic cell proliferation and function, it may not be necessary to withhold these medications during treatment for routine bacterial infections. However, withholding mycophenolate and other immune suppressants is advisable in the setting of infection with opportunistic infections, whereby host T cell responses are critical in effecting clearance of the infecting pathogen. IVIG has demonstrated efficacy in both the acute and chronic management of polymyositis as well as dermatomyositis (including associated acute lung inflammation) and would be a preferred option for managing critical weakness and/or pneumonitis in patients with these disorders who have infection complications requiring attenuation of corticosteroid and other immunosuppressive therapy .
Given the intensity of immune suppression often required to induce remission in patients with systemic vasculitis , infectious complications are not uncommon occurrences in patients with these disorders. Moreover, compromise of vascular integrity in patients with disease-involving vessels which supply the dermis and gastrointestinal tract may engender septic complications. Disease management may be further complicated by the propensity of intercurrent infection to trigger flares of disease. These considerations require careful vigilance for infection as well as careful attention to organ-specific disease activity when managing patients with systemic vasculitis.
Infectious complications in patients with granulomatosis and polyangiitis (GPA) or microscopic polyangiitis (MPA) are of particular concern not only from the standpoint of sepsis-associated morbidity but also the possibility of disease flare triggered by neutrophil degranulation of target antigen (proteinase-3 and myeloperoxidase). Flares of ANCA-associated vasculitis and pauci-immune glomerulonephritis occurring in the context of bacteremia are well documented [47, 48, 49]. Vigilance for development of bacterial infection as well as antimicrobial prophylaxis is therefore a critical component of disease management strategies in patients with ANCA-associated vasculitis . Daily dosing with trimethoprim-sulfamethoxazole (160–800 mg) has been shown to decrease flares of GPA and is recommended as an adjunct treatment to immune suppression in patients with GPA as well as MPA . Use of trimethoprim-sulfa would be of even greater importance to prevent infection with Pneumocystis jirovecii pneumonia in patients who may develop CD4+ T cell counts <300/mm3 as a consequence of sustained treatment with immune suppression regimens impacting T cells. Leucopenia in association with immunosuppressive therapy is a significant risk factor for sepsis and poor outcomes in ANCA-associated glomerulonephritis . Accordingly, for patients receiving cyclophosphamide as part of their induction treatment or patients managed with azathioprine, prophylactic use of levofloxacin is recommended during periods of severe neutropenia that may occur as a complication of treatment with these immune suppressants . Use of recombinant granulocyte colony-stimulating factor can be considered if intercurrent serious infection occurs but is otherwise best avoided due to potential increased risk of vasculitis flares that may be associated with its use .
Since B cell depletion treatments with rituximab, use of cyclophosphamide, or use of azathioprine in the management of ANCA vasculitis may engender hypogammaglobulinemia, it is important to check immunoglobulin levels when patients with ANCA vasculitis develop septic complications. Administration of immunoglobulin replacement therapy (0.4 g/kg) should be considered for patients with bacterial infection and serum IgG levels less than 500 mg/dL. Continuation of immunoglobulin replacement at 3–4-week intervals is recommended until the infection has resolved; longer treatment duration for patients with sustained hypogammaglobulinemia may decrease the likelihood of recurring infection .
Giant Cell Arteritis
The primary treatment for giant cell arteritis (GCA) is chronic corticosteroid therapy, placing affected patients at risk for routine as well as opportunistic infection. Optimal disease management of GCA during episodes of infection depends upon when in the course of disease septic complications occur. Should bacterial infection develop within the first month of diagnosis when patients with ophthalmic artery involvement may be at risk for visual loss, it may be necessary to continue prescribed steroid treatment in the setting of bacterial infection. Subsequent to this initial phase of treatment, temporary attenuation of corticosteroid dosing to doses required to avoid adrenal insufficiency can usually safely be undertaken until the infection has resolved.
Similar considerations as were discussed in RA management apply to the more recent use in GCA of anti-IL-6 therapy with tocilizumab, shown to increase the likelihood of GCA remission and lower the cumulative dose of corticosteroid required for management. Should infectious complications occur, treatment with anti-IL-6 therapy is best withheld until infection has resolved, with use of the lowest dose of corticosteroid deemed appropriate to manage the GCA at the time infection occurs. Due to the association of tocilizumab therapy with intestinal perforations and homeostatic role of IL-6 in maintenance of mucosal integrity, tocilizumab or other anti-IL6 therapies are best not resumed in patients with sepsis arising from the gastrointestinal tract [13, 14].
Optimal management of polyarteritis nodosa (PAN ) varies depending upon whether the disease has been demonstrated to develop in the context of infection with viral pathogens such as hepatitis B (HBV), parvovirus B19, or cytomegalovirus. Induction strategies for HBV-associated PAN often entail combinations of a limited (2-week) course of corticosteroids and plasma exchange with antiviral therapy to induce remission , and CMV-associated polyarteritis is best managed with corticosteroids, ganciclovir, and either IVIG or anti-CMV immunoglobulin . IVIG alone may be sufficient to effect resolution of parvovirus B19-associated PAN . PAN syndromes in the absence of confirmed viral disease are most often managed with corticosteroids in combination with cyclophosphamide. Should septic complications occur during the prescribed treatment program, use of high-dose IVIG as a temporary alternative to cytotoxic therapy may serve to suppress vasculitis [58, 59]. However, for patients with neurologic or visceral complications of non-viral-associated PAN, the effects of IVIG are often just transient, and it is usually necessary to resume cytotoxic therapy to achieve disease remission.
Similar to PAN, optimal management of cryoglobulin syndromes is based upon the disease process that has engendered the development of the cryoprecipitating immunoglobulins. Induction strategies entail combinations of plasma exchange with B cell depletion or alternative cytotoxic therapy for type I cryoglobulins associated with monoclonal gammopathies and type III cryoglobulin-associated autoimmune disease. Use of antiviral therapies with or without a brief course of corticosteroid therapy and plasma exchange constitute the most common strategies for management of severe or life-threatening type II cryoglobulins associated with hepatitis C infection. Rituximab may be added after viral clearance for persistent autoimmune manifestations (see Chap. 26). Should septic complications occur in the course of any of the above cryoglobulin syndromes, high-dose IVIG (2 g/kg) is an effective treatment strategy that can be employed to suppress vasculitis manifestations until intercurrent bacterial infection resolves. Bacterial infections occurring as a complication of plasma exchange may be due in part to associated hypogammaglobulinemia, and IVIG replacement therapy (0.4 g/kg) should be administered to such patients. However, administration of IVIG is not recommended in patients who have cryoglobulins associated with rheumatoid factor activity, as severe disease exacerbations have been reported when IVIG is administered in this setting [60, 61].
Management of Autoimmune Disorders in the Setting of Immune Deficiency
Immune deficiency may occur as a consequence of prescribed immunosuppressive therapy, genetic defects impacting development of mature immune responses, autoimmune responses targeting cells and/or molecules involved in the immune response, or viruses targeting immune effector cells. Since underlying immune deficiency may be an important consideration in the overall management strategy of autoimmune disease, assessment of underlying immune competence should be included in the initial if not ongoing assessment of individuals presenting with autoimmune manifestations.
Immune Deficiency Occurring as a Consequence of Autoimmune Disease Treatment
Attenuating the dose of prescribed immunosuppressive therapy as disease activity permits
Use of prophylactic interventions (Table 33.1)
Alternative therapeutic approaches that are least likely to compromise phagocytic cell functions as have been discussed for patients with autoimmune disease and intercurrent infection
Risk mitigation in the setting of immunosuppressive treatment
Levofloxacin 500 mg/day
Trimethoprim-sulfa 160/800 mg q.o.d.
Dapsone 100 mg daily
Corticosteroids (prolonged use)
<500 mg/dL (<700 mg/dL with infection)
IVIG 0.4 g/kg every 3–4 weeks
Immune Deficiency Occurring as a Consequence of Autoimmunity
Immune deficiency developing as a consequence of autoimmunity poses a significant therapeutic challenge, as the cell line(s) affected may be further impacted by therapies normally required to manage the underlying autoimmune process. Lymphopenia, neutropenia, and pancytopenia not uncommonly occur in the context of SLE. Autoimmune neutropenia and aplastic anemia occurring in the setting of lupus have been effectively managed with therapies primarily targeting autoreactive T lymphocytes, including cyclosporine, tacrolimus, or anti-thymocyte globulin. Severe peripheral lymphopenia is a hallmark of lupus activity, but the underlying mechanisms giving rise to lymphopenia are not well understood and the extent to which the noted lymphopenia increases infection risk in SLE has not been well defined.
In the presence or absence of lymphopenia, hypogammaglobulinemia may occur in patients with established SLE . For patients in whom low immunoglobulin levels are noted to antedate SLE manifestations, the underlying immunopathology may comprise part of the spectrum of common variable immune deficiency (discussed below). Alternatively, hypogammaglobulinemia may develop in the absence of significant immunosuppressive therapy well into the course of SLE [63, 64]. In such cases, it is hypothesized that autoimmune responses develop that target B cells directly or growth factors or cytokines requisite for B cell maturation and survival. Notably, it has been observed that in patients who develop spontaneous B cell depletion, preceding lupus manifestations may remit . For patients who otherwise continue to have active disease manifestations requiring immune suppression, institution of immunoglobulin replacement therapy may permit proceeding as needed with usual SLE standard of care interventions .
Immune Deficiency Occurring as the Primary Disorder Underlying Autoimmunity
Primary immune deficiencies associated with autoimmunity
AIHA, ITP, SLE, (multiple)
Low serum IgA
JIA, RA, SLE
FcR, TLR signaling
CD40, CD40 ligand
Low serum IgG
T cell co-stimulation
Low serum IgG
RA, IBD, uveitis
C1q, C2, C4
C1q, C2, C4A/C4B
Adenosine deaminase deficiency
Th, T reg, variable low IgG
Th, T reg, variable low IgG
Th, T reg
AIHA, ITP, IBD, vasculitis, glomerulonephritis
Th, T reg
AIHA, ITP, IBD, thyroiditis
T reg, low serum IgG
AIHA, ITP, enteritis, arthritis, myasthenia gravis, encephalitis, cerebellitis
Th, T reg, variable low IgG
AIHA, ITP, enteritis, pneumonitis
Common variable immune deficiency (CVID) is the disorder in which autoimmunity is most commonly linked to immune deficiency. The prevalent immunologic phenotype is hypogammaglobulinemia with low levels of IgG and inability to generate sufficient IgG antibodies in response to pneumococcal or other polysaccharide bacterial antigens. Levels of IgA and/or IgM in CVID may also be attenuated. The mechanisms underlying the immune deficiency are variable; those most well described are failures of immunoglobulin class switch due to mutations in the transmembrane activator, calcium-modulator, and cyclophilin ligand interactor (TACI) receptor, but these account for less than 20% of affected patients . While most patients with CVID have a history of recurring bacterial infections dating to childhood, many patients noted to have clinical and immunologic features consistent with CVID do not develop recurring infections or hypoglobulinemia until the third, fourth, fifth, or even later decades of life , begging the question as to whether the immune deficiency in such patients develops as a consequence of autoreactive responses targeting the normal production of mature neutralizing antibodies.
Preventative strategies are employed to minimize infectious complications associated with CVID and to permit management of associated autoimmunity with less infection risk. Milder variants associated with recurring respiratory infections can be successfully managed with rotating antibiotic therapy targeting respiratory pathogens. For patients with more severe levels of hypogammaglobulinemia (less than 500 mg/dL) and/or those demonstrating failure to mount sufficient titers of neutralizing antibodies in response to administered vaccine antigens, intravenous (every 3–4 week) or weekly subcutaneous infusions of immunoglobulin replacement therapy are recommended. Although complete selective IgA deficiency is uncommon in CVID, assessment for this is advised to minimize risk of anaphylaxis with IVIG administration. For CVID patients with significant intercurrent infection complications or undergoing major surgery, an additional dose of IVIG (0.4 g/kg) is recommended.
Immune thrombocytopenia, autoimmune hemolytic anemia, neuromyelitis optica, anti-GAD65 dystonias, ANCA vasculitis, or other CVID-associated autoimmune complications associated with defined autoantibodies frequently respond favorably to rituximab in combination with scheduled IVIG replacement therapy [68, 69, 70, 71]. A similar therapeutic approach may be effective in managing the granulomatous interstitial lung disease that is not uncommonly associated with CVID [72, 73]. Lupus-related musculoskeletal and cutaneous syndromes that develop on a background of CVID can frequently be managed effectively with antimalarials, weekly methotrexate, and/or dapsone, without requiring significant corticosteroid use. As these drugs do not significantly impact B cell proliferation, the use of background immunoglobulin replacement therapy may not be required in patients who have these lupus-related features in association with milder variants of CVID. The use of immunosuppressive therapies that do impact B cell populations is otherwise best undertaken in CVID patients on a background of immunoglobulin replacement therapy.
Patients with CVID with or without known autoimmunity have been observed to have higher than normal levels of B lymphocyte stimulator (BLyS, BAFF), a known survival factor for autoreactive B cells . Whether and to what extent elevated levels of BLyS/BAFF contribute to autoimmunity in CVID remain an active area of investigation. The noted elevations in BLyS/BAFF in patients with CVID suggest that presently available biologic reagents which neutralize the effects of BLyS/BAFF may be potentially useful in suppressing autoimmune complications in this population of patients.
Selective IgA Deficiency (sIgAD) is commonly associated with a variety of autoimmune disorders, and case-control cohort studies have demonstrated greater prevalence of autoantibodies in IgA deficient patients [75, 76]. The immunopathologic mechanisms underlying noted increases in autoimmunity in sIgAD individuals remain poorly understood, but associations with deficiencies in the population of Treg cells and class-switched memory B cells have been observed in sIgAD cohorts with autoimmunity . Since the vast majority of patients with sIgAD in the absence of IgG or IgG subclass deficiency do not have increased prevalence of serious infections, management of autoimmune and rheumatic disease in sIgAD patients can proceed as would be custom for patients who are not IgA deficient.
X-linked agammaglobulinemia (XLA) , associated with mutations in Bruton’s tyrosine kinase (btk) resulting in absence of circulating CD19+/CD20+ B cells and hypogammaglobulinemia, is rarely associated with autoimmune disease. In addition to being critical to normal B cell maturation, btk also mediates monocyte Fc receptor as well as toll-like receptor (TLR)-associated signal transduction, and in a variety of murine models of autoimmune inflammation, btk inhibitors have a profound ameliorative effect on tissue inflammation as well as titers of autoantibodies [78, 79]. The paucity of autoimmune complications in patients with btk deficiency is therefore not surprising and selective btk inhibitors are now being evaluated in clinical trials of patients with lupus. However, should autoimmune complications occur in a patient with XLA, treatment with indicated immunosuppressive therapy can proceed on a background of immunoglobulin replacement therapy.
Hyper IgM syndromes occur most commonly in the setting of CD40 or CD40 ligand deficiency, whereby there are observed failures of Ig class switching, establishment of effective cell memory, and T cell-driven monocyte activation. Laboratory correlates include low levels of IgG and IgA but normal to elevated levels of serum IgM, normal levels of circulating B cells but only expressing IgM or IgD, and absence of circulating memory B cells . Clinical features include frequent respiratory infections and opportunistic infections (histoplasmosis, cryptosporidium, pneumocystis). Given the pivotal role of CD40-CD40 ligand interactions in T cell co-stimulation, it is therefore not surprising that autoimmune complications are seen rarely in patients with deficiency in CD40-mediated signaling and that interruptions in CD40-CD40L signaling can ameliorate autoimmune manifestations in lupus-prone mice.
In a small minority of cases (<5%), hyper IgM syndrome occurs due to deficiencies in either activation-induced cytidine deaminase (AICDA) or uracil nucleoside glycosylase (UNG). Both enzymes are required for B cell class switching, and deficiency of either results in low serum levels of IgG and IgA, with normal to high serum levels of IgM and normal levels of circulating B cells expressing IgM [81, 82]. However, unlike CD40/CD40L deficiency, T cell number and functions are essentially intact, and a variety of autoimmune complications have been reported in individuals deficient in AICDA or UNG including autoimmune hepatitis, RA, IBD, uveitis, and diabetes mellitus. Provided they are administered on a background of scheduled immunoglobulin replacement therapy, standard treatments can be employed to manage AICDA- and UNG-associated autoimmune complications.
Complement (C1q, C2, C4) and mannose-binding lectin (MBL) deficiencies are associated with increased risk of pyogenic infection with encapsulated organisms. Early complement components as well as MBL also opsonize and facilitate the removal by macrophages of nucleosome products of cellular apoptosis, rather than by plasmacytoid dendritic cells in a manner that renders epitopes in the nucleosomes becoming potentially immunogenic . Deficiencies in C1q, C2, C4, and MBL have all been associated with increased risk of systemic or cutaneous lupus, presumably due to associated impairment in the noninflammatory, non-immunogenic disposal of apoptotic nucleosomes [28, 84]. Management of lupus-related autoimmune disease in patients with early complement or MBL deficiency can proceed with standard lupus therapies. However, it is prudent to monitor for treatment-associated lymphopenia, neutropenia, and hypogammaglobulinemia in affected patients, entertaining a lower threshold for instituting immunoglobulin replacement therapy or prophylactic antibiotic use in patients further immunocompromised (Table 33.1).
Adenosine deaminase deficiency ( ADA ) , Wiskott-Aldrich syndrome ( WAS ) , and DiGeorge (22q11 deletion) syndrome s are combined immune deficiencies associated with defects primarily in T cell function, with variable defects in humoral immunity arising secondarily. Autoimmunity occurs in these syndromes likely due in large part to impairments in the function and/or numbers of T regulatory lymphocytes.
The elevated levels of adenosine and deoxyadenosine associated with ADA are toxic primarily to T lymphocytes, engender feedback inhibition of ribonucleotide reductase with decreased de novo purine synthesis, and inhibit phagocytic cell migration. The primary observed immunologic abnormalities in ADA are very low levels of circulating T cells with variable degrees of hypogammaglobulinemia; immune cytopenias are the most commonly observed autoimmune complications. The noted autoimmunity observed in ADA likely occurs as a consequence of imbalances in the proportions of affected regulatory versus helper/cytotoxic T cells .
WAS develops primarily due to loss of function mutations of the WASp protein involved in the cytoskeletal functions of hematopoietic cells. The immunodeficiency develops due to loss of formation of lipid rafts required for the formation of the immunologic synapse between T lymphocytes and antigen-presenting cells. This WASp-associated cytoskeletal defect also likely accounts for the failure of T regs to form synapses with effector T cells, with attendant failure to suppress effector functions of autoreactive T lymphocytes . As a consequence, autoimmune manifestations including immune cytopenias, vasculitis, IBD, and/or nephritis occur commonly in patients with WAS.
Individuals with DiGeorge syndrome due to deletions of 22q11 have impaired thymic development with low numbers of circulating T lymphocytes. Reported autoimmune complications include immune cytopenias, endocrinopathies, and inflammatory enteropathies . Autoimmunity in DiGeorge syndrome likely occurs as consequence of impaired development of a sufficiently diverse T regulatory cell repertoire .
Although management of autoimmune complications in patients with primary immune deficiencies is challenging, the majority of affected patients can be effectively managed with standard therapies employed in the treatment of nonimmune deficient individuals. It is nonetheless important to recognize the presence of primary immune deficiency in patients presenting with autoimmunity so as to appropriately choose and minimize the risk of infection that may be heightened as a consequence of employed immunosuppressive therapy. The development of an autoimmune disorder at an unusually early age for that condition, the presence of autoimmunity affecting multiple organ systems, or atypical immune syndromes that cannot be attributed to specific rheumatologic diagnosis should prompt investigation for possible primary immune deficiency. Assessment of immunoglobulin levels, responses to pneumococcal vaccination, and flow cytometry studies to quantify numbers of circulating B cells and T cell subset populations may serve as useful initial screening assessments for many of the immune deficiencies associated with autoimmunity.
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