Immunodeficiency secondary to biologics.

Biologics are widely used in the treatment of autoimmune, autoinflammatory, atopic, and neoplastic diseases, with unprecedented success. They may, however, cause immunosuppression, potentially increasing the risk of severe and/or opportunistic infections. Nevertheless, this secondary immunodeficiency (SID) is poorly documented. Randomized controlled trials conducted during drug development are often underpowered to detect uncommon events. Also, most observational studies reporting infections are biased because patients often require concomitant use of other immunosuppressive drugs such as glucocorticoids. In addition, the underlying disease can intrinsically predispose to infections. With these caveats in mind, SID and infectious complications reported with selected biologics are summarized in Table I. We discuss immunodeficiency caused by some of the most frequently used biologic agents.Table IExamples of commonly used biologic treatments and associated secondary immunodeficiencyMolecular targetExampleLicensed indications∗Compilation of all indications from this drug class; specific indications vary by drug.Associated immunologic effectsAssociated infection risk†Nonexhaustive list.Anticytokines Autoimmune and autoinflammatory diseasesBAFF (BlyS)BelimumabSLENot well reportedIL-1AnakinraCanakinumabRilonaceptRheumatoid arthritis sJIAPeriodic fever syndromes (CAPS, TRAPS, HIDS/MKD, FMF)Neutropenia (rare)Generally well toleratedModerate increased risk of infections (mild-to-moderate in severity), includingRTIIL-6TocilizumabSarilumabRheumatoid arthritis sJIAPolyarticular JIAGiant cell arteritisCytokine release syndromeSevere COVID-19NeutropeniaSignificant increased risk of infections, includingSevere bacterial infectionsVZVTB/non-TB mycobacteriaHepatitis B reactivationPJPIL-12 and IL-23 (p40 subunit)UstekinumabPlaque psoriasisPsoriatic arthritisCrohn diseaseGenerally well toleratedHepatitis B reactivationTB (theoretic)IL-17ASecukinumabIxekizumabBrodalumabPlaque psoriasisPsoriatic arthritisAnkylosing spondylitisNeutropeniaMinor increased risk of infections (mild- moderate in severity), includingURTICandidiasis (mucocutaneous)TB (theoretic)IFN-γEmapalumabpHLHNot well reportedTNF-αAdalimumabCertolizumab pegolEtanerceptGolimumabInfliximabRheumatoid arthritisJIAPsoriatic arthritisAnkylosing spondylitisCrohn diseaseUlcerative colitisPlaque psoriasisHidradenitis suppurativaUveitisNeutropeniaSignificant increased risk of infections, includingSevere bacterial infectionsVZVTB/non-TB mycobacteriaOther granulomatous infectionsHepatitis B and hepatitis C reactivationInvasive fungal infectionsPJP Atopic diseasesTSLPTezepelumabAsthmaWell toleratedHelminth infections (theoreticl)IL-4 & IL-13 (IL4-receptor α)DupilumabAtopic dermatitisAsthmaCRSwNPEoEEosinophiliaWell toleratedHelminth infections (theoreticl)IL-5MepolizumabBenralizumabReslizumabAsthmaEGPAHESWell toleratedHelminth infections (theoreticl)IL-13TralokinumabAtopic dermatitisEosinophiliaWell toleratedHelminth infections (theoreticl)Surface molecules T cellsCD25BasiliximabRenal transplant rejectionNot well reportedCD52AlemtuzumabMultiple sclerosisLymphopenia (on-target effect)NeutropeniaMajor increased risk of infections, includingSevere bacterial infectionsCMV, EBVHSV, VZV, HPVHepatitis B and hepatitis C reactivationTBInvasive fungal infection, candidiasisListeriosis, toxoplasmosisPJP, PML, BKV B cellsCD20RituximabObinutuzumabOcrelizumabOfatumumabRheumatoid arthritisGPA, MPANHL, CLLPemphigus vulgarisMultiple sclerosisB-cell depletion (on-target effect)Late-onset neutropeniaHypogammaglobulinemiaImpaired vaccine responsesSignificant increased risk of infections, includingSevere bacterial infectionsHepatitis B and hepatitis C reactivationCMV, VZVEnteroviral infectionPJP, PMLSevere COVID-19CD38DaratumumabMultiple myelomaDecreased plasma cells (on-target effect)HypogammaglobulinemiaLymphopeniaNeutropeniaIncreased risk of VZV infection T-cell costimulationCD80, CD86AbataceptBelataceptRheumatoid arthritisJIARenal transplant rejectionGenerally well toleratedAssociated with PTLD (belatacept only) Leukocyte movement inhibitionIntegrin α4NatalizumabMultiple sclerosisCrohn diseaseMajor increased risk of PMLIntegrin α4β7VedolizumabCrohn diseaseUlcerative colitisNo cases of PML reportedOther circulating proteins ComplementC5EculizumabPNH aHUSMyasthenia gravisSignificant increased risk of invasive Neisseria infections IgEIgEOmalizumabAsthmaChronic idiopathic urticariaWell toleratedHelminth infections (theoretic)aHUS, Atypical hemolytic uremic syndrome; BAFF, B-cell–activating factor; BKV, BK virus; BLys, B lymphocyte stimulator; CAPS, cryopyrin-associated periodic syndrome; CLL, chronic lymphocytic leukemia; CMV, Cytomegalovirus; CRSwNP, chronic rhinosinusitis with nasal polyposis; EGPA, eosinophilic granulomatosis with polyangiitis; EoE, eosinophilic esophagitis; FMF, familial Mediterranean fever; GPA, granulomatosis with polyangiitis; HES, hypereosinophilic syndrome; HIDS, hyperimmunoglobulin D syndrome; HPV, human papillomavirus; HSV, herpes simplex virus; JIA, juvenile idiopathic arthritis; MKD, mevalonate kinase deficiency; MPA, microscopic polyangiitis; NHL, non-Hodgkin lymphoma; pHLH, primary hemophagocytic lymphohistiocytosis; PJP, Pneumocystis jirovecii pneumonia; PML, progressive multifocal leukoencephalopathy; PNH, paroxysmal nocturnal hemoglobinuria; PTLD, posttransplant lymphoproliferative disorder; RTI, respiratory tract infection (including bronchitis, pneumonia); sJIA, systemic-onset juvenile idiopathic arthritis; TRAPS, TNF receptor associated periodic syndrome; TSLP, thymic stromal lymphopoietin; URTI, upper respiratory tract infection; VZV, varicella-zoster virus.∗ Compilation of all indications from this drug class; specific indications vary by drug.† Nonexhaustive list. Open table in a new tab aHUS, Atypical hemolytic uremic syndrome; BAFF, B-cell–activating factor; BKV, BK virus; BLys, B lymphocyte stimulator; CAPS, cryopyrin-associated periodic syndrome; CLL, chronic lymphocytic leukemia; CMV, Cytomegalovirus; CRSwNP, chronic rhinosinusitis with nasal polyposis; EGPA, eosinophilic granulomatosis with polyangiitis; EoE, eosinophilic esophagitis; FMF, familial Mediterranean fever; GPA, granulomatosis with polyangiitis; HES, hypereosinophilic syndrome; HIDS, hyperimmunoglobulin D syndrome; HPV, human papillomavirus; HSV, herpes simplex virus; JIA, juvenile idiopathic arthritis; MKD, mevalonate kinase deficiency; MPA, microscopic polyangiitis; NHL, non-Hodgkin lymphoma; pHLH, primary hemophagocytic lymphohistiocytosis; PJP, Pneumocystis jirovecii pneumonia; PML, progressive multifocal leukoencephalopathy; PNH, paroxysmal nocturnal hemoglobinuria; PTLD, posttransplant lymphoproliferative disorder; RTI, respiratory tract infection (including bronchitis, pneumonia); sJIA, systemic-onset juvenile idiopathic arthritis; TRAPS, TNF receptor associated periodic syndrome; TSLP, thymic stromal lymphopoietin; URTI, upper respiratory tract infection; VZV, varicella-zoster virus. TNF-α inhibitors, the best studied biologics, may induce an increased risk of severe bacterial infections. Because TNF-α plays a role in the recruitment of antigen-specific T cells and monocytes at the site of mycobacterial infection,1Yasui K. Immunity against Mycobacterium tuberculosis and the risk of biologic anti-TNF-alpha reagents.Pediatr Rheumatol Online J. 2014; 12: 45Crossref PubMed Scopus (24) Google Scholar TNF-α inhibitors also increase the risk of tuberculosis (TB) and non-TB mycobacterial infection.1Yasui K. Immunity against Mycobacterium tuberculosis and the risk of biologic anti-TNF-alpha reagents.Pediatr Rheumatol Online J. 2014; 12: 45Crossref PubMed Scopus (24) Google Scholar Such infection likely occurs via reactivation of latent disease because most cases occur shortly after treatment initiation; hence the rationale for TB screening recommendations before treatment. Despite the central role of IL-1 in driving inflammatory responses to pathogens, IL-1 inhibitors are generally very well tolerated. Although there is a slight increase in rate of viral and bacterial infections (mostly respiratory tract infections), opportunistic infections do not occur,2Dinarello C.A. Simon A. van der Meer J.W. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases.Nat Rev Drug Discov. 2012; 11: 633-652Crossref PubMed Scopus (1266) Google Scholar unlike with other biologics. Further, anakinra (an IL-1 receptor antagonist) has been administered in patients with chronically active infections, such as those with chronic hidradenitis suppurativa, without exacerbation. Use of IL-6 inhibitors has been associated with an increased rate of infections similar to that associated with TNF-α inhibitors,3Pawar A. Desai R.J. Solomon D.H. Santiago Ortiz A.J. Gale S. Bao M. et al.Risk of serious infections in tocilizumab versus other biologic drugs in patients with rheumatoid arthritis: a multidatabase cohort study.Ann Rheum Dis. 2019; 78: 456-464Crossref PubMed Scopus (107) Google Scholar although with a lower risk of TB and non-TB mycobacterial infection. Given the role of IL-6 in acute-phase responses, delay in diagnosis of infection is a potential risk. In addition to its role in inflammation, IL-6 is important for terminal B-cell differentiation, which may explain the higher risk of infections with use of IL-6 inhibitors than with IL-1 antagonists. Although rituximab (an anti-CD20 mAb) spares antibody-secreting plasma cells, a subset of patients experience de novo or worsened preexisting hypogammaglobulinemia, which may be symptomatic.4Labrosse R. Barmettler S. Derfalvi B. Blincoe A. Cros G. Lacombe-Barrios J. et al.Rituximab-induced hypogammaglobulinemia and infection risk in pediatric patients.J Allergy Clin Immunol. 2021; 148 (e8): 523-532Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Reactivation of hepatitis B virus and opportunistic infections such as severe cytomegalovirus disease, Pneumocystis jiroveci pneumonia, and progressive multifocal leukoencephalopathy (PML) have also been reported with rituximab use,5Mikulska M. Lanini S. Gudiol C. Drgona L. Ippolito G. Fernandez-Ruiz M. et al.ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (agents targeting lymphoid cells surface antigens [I]: CD19, CD20 and CD52).Clin Microbiol Infect. 2018; 24: S71-S82Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar although the latter occurs mainly in adults. These infections are uncommon, occurring primarily in individuals with antibody deficiencies, suggesting that cellular immunity is affected or that humoral immunity is essential to controlling these pathogens. For progressive multifocal leukoencephalopathy, an additional possible mechanism is that pre-B cells, which are part of the JC virus reservoir, are mobilized from the bone marrow after CD20+ mature B-cell depletion and transmit the latent infection in the brain.6Durali D. de Goer de Herve M.G. Gasnault J. Taoufik Y. B cells and progressive multifocal leukoencephalopathy: search for the missing link.Front Immunol. 2015; 6: 241Crossref PubMed Scopus (43) Google Scholar Management of secondary immunodeficiency should be tailored to each patient. As a general rule though, all patients taking biologics should benefit from active monitoring and prompt treatment of infections. Vaccination should be up to date before initiation of biologics, with special considerations for specific drugs (eg, meningococcal vaccination before eculizumab (an anti-C5 mAb). Antibiotic prophylaxis can be indicated depending on the patient’s background and disease and/or in patients treated with multiple immunosuppressive drugs and/or biologics. Specific biologics may require targeted prophylaxis, such as Pneumocystis jirovecii pneumonia prophylaxis in patients with low CD4+ T-cell counts5Mikulska M. Lanini S. Gudiol C. Drgona L. Ippolito G. Fernandez-Ruiz M. et al.ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (agents targeting lymphoid cells surface antigens [I]: CD19, CD20 and CD52).Clin Microbiol Infect. 2018; 24: S71-S82Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar and antimeningococcal prophylaxis in patients treated with eculizumab. In patients treated with B-cell–depleting biologics, immunoglobulin replacement therapy may be indicated depending on the Ig levels or on clinical condition (Fig 1).7Otani I.M. Lehman H.K. Jongco A.M. Tsao L.R. Azar A.E. Tarrant T.K. et al.Practical guidance for the diagnosis and management of secondary hypogammaglobulinemia: a work group report of the AAAAI Primary Immunodeficiency and Altered Immune Response Committees.J Allergy Clin Immunol. 2022; 149: 1525-1560Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar An important aspect of management is to rule out a preexisting inborn errors of immunity (IEIs) in patients with infections secondary to biologics.4Labrosse R. Barmettler S. Derfalvi B. Blincoe A. Cros G. Lacombe-Barrios J. et al.Rituximab-induced hypogammaglobulinemia and infection risk in pediatric patients.J Allergy Clin Immunol. 2021; 148 (e8): 523-532Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar,7Otani I.M. Lehman H.K. Jongco A.M. Tsao L.R. Azar A.E. Tarrant T.K. et al.Practical guidance for the diagnosis and management of secondary hypogammaglobulinemia: a work group report of the AAAAI Primary Immunodeficiency and Altered Immune Response Committees.J Allergy Clin Immunol. 2022; 149: 1525-1560Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar In the vast majority of cases, these agents are well tolerated and infections should prompt clinicians to consider an underlying IEI, because indications of biologics such as autoimmunity or inflammation are frequently observed in patients with IEIs. For example, chronic granulomatous disease can be diagnosed after infections following administration of infliximab for inflammatory bowel disease, and common variable immunodeficiency can be diagnosed in patients with persistent hypogammaglobulinemia after administration of rituximab for autoimmunity.4Labrosse R. Barmettler S. Derfalvi B. Blincoe A. Cros G. Lacombe-Barrios J. et al.Rituximab-induced hypogammaglobulinemia and infection risk in pediatric patients.J Allergy Clin Immunol. 2021; 148 (e8): 523-532Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar The greatest lesson learned during the COVID-19 pandemic is one of humility. Although there was an urgent need for recommendations for each biologic and physicians were frequently implored by patients regarding the associated risks, we realized that many things were unknown. Consequently, many patients were left without answers, or worse, with contradictory opinions. Perhaps surprisingly, the data showed that most biologics, with rituximab being a notable exception, did not increase the risk of severe COVID-198MacKenna B. Kennedy N.A. Mehrkar A. Rowan A. Galloway J. Matthewman J. et al.Risk of severe COVID-19 outcomes associated with immune-mediated inflammatory diseases and immune-modifying therapies: a nationwide cohort study in the OpenSAFELY platform.Lancet Rheumatol. 2022; 4: e490-e506Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar and with some studies showing a protective effect.9Peng J. Fu M. Mei H. Zheng H. Liang G. She X. et al.Efficacy and secondary infection risk of tocilizumab, sarilumab and anakinra in COVID-19 patients: a systematic review and meta-analysis.Rev Med Virol. 2022; 32: e2295Crossref Scopus (28) Google Scholar In addition, targeting IL-6 reduced mortality in hospitalized patients.10Godolphin P.J. Fisher D.J. Berry L.R. Derde L.P.G. Diaz J.V. Gordon A.C. et al.Association between tocilizumab, sarilumab and all-cause mortality at 28 days in hospitalised patients with COVID-19: a network meta-analysis.PLoS One. 2022; 17e0270668Crossref Scopus (11) Google Scholar Considering the mechanism of action of anticytokine biologics, in particular, those targeting the TH2 pathway, there is a theoretic risk of susceptibility to parasitic infections and other tropical diseases, a phenomenon that should be closely followed with the increased use of biologics in developing countries in which these diseases are endemic. Large natural history studies and international registries are greatly needed to better assess the risks and anticipate complications of biologics, and clinical immunologists are well positioned to study these effects because pathways modulated by these drugs are well known to them. With the exponential increase in the use of immunosuppressive drugs, including biologics, SIDs have become more frequent than IEIs, yet they remain largely underexplored. Our perspective is that SIDs should be addressed by using tools similar to those used for IEIs, with tailored approaches of assessment, prophylaxis, and treatment based on the specific pathway targeted by the biologic, the underlying disease, and the genetic predisposition of the patient, as well as use of biologic testing (Fig 1). SIDs may be the next big field of our specialty, and clinical immunologists should get more involved in their assessment and care.