Alterations in immune function with biologic therapies for autoimmune disease

Alterations in immune function with biologic therapies for autoimmune disease

Current perspectives Alterations in immune function with biologic therapies for autoimmune disease Minyoung Her, MD,a and Arthur Kavanaugh, MDb Busa...

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Current perspectives

Alterations in immune function with biologic therapies for autoimmune disease Minyoung Her, MD,a and Arthur Kavanaugh, MDb

Busan, South Korea, and San Diego, Calif

Autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease, psoriasis, and others, are characterized by dysregulation of various aspects of normal immunity and inflammation. Biologic agents targeting key components of the dysregulated immune response have dramatically improved patient outcomes and transformed treatment paradigms for a number of systemic inflammatory autoimmune diseases. Despite their excellent efficacy, because they do affect normal immune responsiveness, biologic agents can potentially be associated with a variety of adverse effects. Important potential adverse effects related to the use of biologic agents include immunosuppression, which might result in outcomes such as infection, and autoimmunity, that could result in paradoxical inflammation or even autoimmune disease. In this article the current clinical evidence and immunologic mechanisms of the adverse effects related to biologic agents are discussed. (J Allergy Clin Immunol 2016;137:19-27.) Key words: Biologic agents, adverse effect, infection, autoimmunity, paradoxical inflammation

Discuss this article on the JACI Journal Club blog: Biologic agents have revolutionized the treatment of a number of systemic inflammatory autoimmune diseases, including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), psoriasis, psoriatic arthritis, ankylosing spondylitis (AS), and others. Agents targeting specific immune cells (eg, B and T cells) or secreted mediators, such as proinflammatory cytokines (eg, TNF, IL-1, IL-6, IL-17, IL-12, and IL-23), have been developed and brought to the clinic. Specific biologic agents approved for several autoimmune diseases include a soluble TNF receptor IgG Fc fusion protein (etanercept), several anti–TNF-a mAbs (infliximab, adalimumab, and golimumab), and a pegylated

From athe Division of Rheumatology, Busan Paik Hospital, Inje University, Busan, and b the Division of Rheumatology, Allergy, and Immunology, University of California, San Diego. Disclosure of potential conflict of interest: A. Kavanaugh has conducted sponsored research for Amgen, AbbVie, BMS, Celgene, Eli Lilly, Genentech, Janssen, Novartis, Pfizer, Regeneron, and UCB. M. Her declares no relevant conflicts of interest. Received for publication September 11, 2015; revised October 21, 2015; accepted for publication October 28, 2015. Corresponding author: Arthur Kavanaugh, MD, Center for Innovative Therapy, Division of Rheumatology, Allergy, and Immunology, University of California, San Diego, 9500 Gilman Dr, Mail Code 0943, La Jolla, CA 92037. E-mail: [email protected] The CrossMark symbol notifies online readers when updates have been made to the article such as errata or minor corrections 0091-6749

Abbreviations used ANA: Antinuclear antibody AS: Ankylosing spondylitis DMARD: Disease-modifying antirheumatic drug IBD: Inflammatory bowel disease ILD: Interstitial lung disease NTM: Nontuberculous mycobacteria RA: Rheumatoid arthritis SLE: Systemic lupus erythematosus TNFi: TNF inhibitor

antibody fragment (certolizumab pegol), an anti–IL-6 receptor mAb (tocilizumab), an IL-1 receptor antagonist (anakinra), an anti–IL-17A mAb (secukinumab), and an anti–IL-12/IL-23 mAb (ustekinumab, Table I and Fig 1).1 The anti-CD20 chimeric mAb rituximab is a B-cell–targeting agent initially developed to treat lymphoma that subsequently showed efficacy in patients with autoimmune diseases, including RA, systemic lupus erythematosus (SLE), and Wegener granulomatosis. Another B cell–targeting agent (targeting B cell–activating factor; ie, belimumab) and a T cell–targeting agent (abatacept) have been shown to be efficacious in the treatment of SLE and RA, respectively.2 Success with available biologic agents has driven research interest in identifying novel biologic agents targeting other pathways. All of these agents target cytokines or cells dysregulated in patients with autoimmune diseases. However, these targets are also key components of normal immune homeostasis and involved in an array of normal physiologic responses. Therefore blocking particular cytokines or cells might result in adverse events. A mechanistic classification of adverse effects potentially related to the use of biologic agents has been proposed: a, high cytokine levels and cytokine release syndrome (or cytokine storm); b, hypersensitivity, acute infusion reaction, inject-site reaction, or anti-drug antibodies; g, immune imbalance syndrome (immune deviation), impaired immune function (immunodeficiency and immunosuppression), autoimmunity, or allergic/atopic disorder; d, cross-reactivity; and ε, nonimmunologic function.3,4 Because biologic agents are large protein molecules, they can be intrinsically immunogenic and might be expected to lead to immunologic side effects.4 However, the immune deviation phenomenon of biologic agents is more target related than agent related.5 Infection is perhaps the prototypical manifestation of immunodeficiency, and paradoxical inflammation or the presence of autoantibodies is most typical of autoimmunity. In this article the clinical manifestations and underlying immunologic mechanisms of biologic agents’ side effects, particularly immune deviation, will be reviewed. Because TNF 19



TABLE I. Biologic agents for RA and other rheumatic diseases Target

Cytokine TNF-a

IL-1 receptor IL-6 receptor IL-12/IL-23 IL-17 Lymphocyte T cell CD28 B cell CD20 BAFF



FDA approval

Etanercept Infliximab Adalimumab Golimumab Certolizumab pegol Anakinra Tocilizumab Ustekinumab Secukinumab

Soluble TNF receptor IgG Fc fusion protein Chimeric anti–TNF-a mAb Fully human anti–TNF-a mAb Fully human anti–TNF a mAb Humanized Fab9 fragment linked to pegylated molecules Recombinant IL-1 receptor antagonist Humanized anti–IL-6 receptor mAb Fully human anti–IL-12/IL-23 mAb Fully human anti–IL-17A mAb



CTLA-4:Ig G Fc fusion protein


Rituximab Belimumab

Chimeric anti-CD20 mAb Fully human mAb for soluble BAFF


BAFF, B-cell activating factor; CAPS, cryopyrin-associated periodic syndrome; CD, Crohn disease; CLL, chronic lymphocytic leukemia; CTLA, cytotoxic T lymphocyte antigen; Fab9, antigen biding prime; FDA, US Food and Drug Administration; GPA, granulomatosis with polyangiitis (Wegener granulomatosis); JIA, juvenile idiopathic arthritis; MPA, microscopic polyangiitis; NHL, non-Hodgkin lymphoma; PsO, psoriasis; PsA, psoriatic arthritis; UC, ulcerative colitis.

inhibitors (TNFis) are the most widely used biologic agents, with millions of patients with various autoimmune diseases having been treated worldwide since their clinical introduction in 1998, and given the wealth of data from many clinical trials and post-marketing surveys on TNFis, these agents have been a focus, and adverse effects potentially related to their use will be reviewed in detail.

IMMUNODEFICIENCY Infection Immunity against microorganisms depends on various components of the innate and adaptive immune responses.6 Because biologic agents act on this network in various ways, it is not unexpected that infection is one of the more common side effects observed with the use of these agents. However, autoimmune diseases themselves increase affected patients’ susceptibility to infection, an observation most clear among those patients with the most active ongoing inflammatory disease activity. Although use of biologic agents in patients with autoimmune disease might enhance this susceptibility, it could also be reasoned that by controlling disease activity, biologic agents could obviate some of the disease-related infectious proclivity. Some proinflammatory cytokines, particularly TNF-a, play important roles in host immunity and inflammatory responses. An increased incidence of bacterial infections, particularly pulmonary and soft tissue infections, are seen among patients treated with TNFis.7,8 Interestingly, the association of TNFis with serious infections requiring hospitalization has not been consistently observed. In some studies the use of biologic agents results in no increased risk,9-11 whereas others have reported an increased risk.12,13 In an analysis of data from 4 large US administrative databases (the Safety Assessment of Biologic Therapy project), TNFi use was not more commonly associated with hospitalization than use of conventional disease-modifying antirheumatic drugs (DMARDs) in patients with various autoimmune disease, such as RA, AS, IBD, and psoriasis.11 In a meta-analysis of 44 randomized controlled trials involving 11,700 subjects receiving TNFis and 5,901 subjects receiving

placebo or traditional DMARDs, patients with RA receiving anti-TNF mAbs other than etanercept (adalimumab, certolizumab pegol, and infliximab) experienced a higher risk of serious infection than those receiving placebo or traditional DMARDs.12 In another meta-analysis of 42,330 patients with RA from 106 randomized trials, a standard or higher dose of biological drugs (pooled analysis of etanercept, adalimumab, infliximab, golimumab, certolizumab pegol, anakinra, tocilizumab, abatacept, and rituximab) was associated with an increase in serious infections compared with use of traditional DMARDs in patients with RA, although low-dose biological drug treatment was not associated.13 Age of greater than 60 years; the presence of comorbidities, such as chronic kidney disease or impaired lung function; concomitant glucocorticoid use; and a previous serious infection were noted to be key factors increasing the risk of serious infection across many clinical trials.6,11,14 Questions regarding the difference in the risk of infection among different TNFi treatments have been raised. In Dutch15 and Italian16 registries, mAbs (infliximab or adalimumab) were associated with a higher infection rate than etanercept, but these results were not consistent with analysis of a British registry.17 In several analyses the increased risk of infection associated with use of a biologic agent was greatest during the initial 6 months of treatment and then decreased over time.17 This suggests that persons inherently at risk of infection related to specific biologic agents tend to express that risk early, and the apparent attenuation of such risk over time has been attributed to this ‘‘depletion of susceptibles’’ effect.18,19 Importantly, safety issues, such as infection, appear to correlate with the systemic inflammatory burden of the underlying disease, as well as comorbid diseases and concomitant medication. Thus in a longer-term analysis of data from adalimumab studies in patients with various autoimmune conditions, serious opportunistic infections and the discontinuation rate for adalimumab because of serious infectious events tended to be higher in patients with IBD and RA compared with those with psoriasis or AS.20 An important consideration is that the use of combinations of biologic agents, such as TNFis and IL-1 inhibitor (etanercept



FIG 1. Biologic agents for rheumatic diseases and their targets. ACPA, Anti-citrullinated peptide antibody; APC, antigen-presenting cell; APRIL, a proliferation-inducing ligand; BAFF, B-cell activating factor; BAFF-R, BAFF receptor; BCMA, B-cell maturation protein; MHCII, MHC class II; RANK, receptor activator of nuclear factor kB; RANKL, RANK ligand; RF, rheumatoid factor; TACI, transmembrane activator and CAML interactor; TCR, T-cell receptor.

and anakinra)21 or TNFis and T-cell costimulatory inhibitor (etanercept and abatacept),22 appeared to increase the risk of serious infections even further. Interestingly, combination biologic agent treatment was not associated with greater clinical efficacy, and at present, such an approach is not recommended. Regarding biologic agents other than TNFis, in a meta-analysis of clinical trials with rituximab or abatacept in patients with RA, there was no significant increase in serious infections.23 In a study of US veterans with RA that evaluated the infection risk of biologic agents, among 3,152 patients with RA contributing 4,158 biologic treatment episodes, rates of hospitalization for bacterial infection in rituximab- or abatacept-treated patients were comparable with those in etanercept-treated patients.8 The rate of hospitalization was increased for infliximab.

Intracellular infections, including tuberculosis Among various infections, mycobacterial infection rose to great interest in the early years of biologic agents. The relationship between mycobacterial infections and TNFis has since been well established from clinical trials and clinical data and also supported by animal studies.24-26 In patients with mycobacterial infection, inhaled mycobacteria are first engulfed by alveolar macrophages, and then the mycobacteria proliferate within the macrophages and dendritic cells and induce release of various cytokines.27 The human immune system has various ways of protecting against mycobacterial infection. TH1 immunity is critical to the defense against mycobacteria.27 Key factors of immunity against mycobacteria are CD41 T cells and IFN-g and TNF-a secreted by these cells. In addition to CD41 T cells and IFN-g, CD81


FIG 2. Involvement of TNF in immunity against mycobacterial infection and the effect of TNFis on mycobacterial infection. NO, Nitric oxide; T reg, regulatory T cell. 1, TNF recruits inflammatory cells with chemokines and activates macrophages. TNFis lead to increased bacterial burden and decreased chemokine levels in animal models.28 2, TNF and IFN-g synergize to stimulate nitric oxide production in macrophages to kill mycobacteria.24 3, After infliximab treatment in an in vivo study, the number of CD81 T cells expressing cytotoxic granules decreased, and the antimicrobial activity against mycobacteria decreased.29 4, TNF is essential for the formation and maintenance of granulomas. Blocking TNF disrupts granuloma structure and enables mycobacterial dissemination.28

T cells, TH17 cells, regulatory T cells, IL-1, and other mediators are involved in immunity against mycobacteria.24 CD81 T cells have a cytotoxic effect, which acts through cytotoxic granules, FAS/FAS ligand, and TNF, which kills mycobacteria.24 Granuloma formation is the key feature of mycobacterial infection and indicates that the host immune system has responded to contain the microorganism. TNF plays an important role in immunity for intracellular organisms, notably against mycobacteria (Fig 2).24,28,29 In animal studies several knockout mice (TNF, IL-1, or IL-6) died rapidly from mycobacterial infections.25,30,31 TNF recruits inflammatory cells with chemokines and activates macrophages.24,27 TNF is essential for the formation and maintenance of granulomas. In TNF2/2 mice initial cell recruitment was delayed, and T-cell migration to the infected macrophages was disturbed.32 TNF or TH1/TH17 in granulomas is associated with bacterial burden in the granuloma, and they are involved in the sterilization of granulomas.31,33 TNF and IFN-g synergize to stimulate nitric oxide production in macrophages.24,34 The main mechanism by which TNFis disturb immunity in patients with mycobacterial infection is inhibition of the


maintenance and formation of granulomas. Blocking TNF disrupts granuloma structure and enables bacterial dissemination.26 TNFis might be involved in the destruction of mycobacteria immunity in several ways. TNFis lead to increased bacterial burden and dissemination of bacteria in latent tuberculosis animal models.28 TNFis impair the antimicrobial activity of T cells against mycobacterial infection.29 After TNFi treatment in an in vivo study, the number of CD81 T cells expressing cytotoxic granules, particularly granulysin, decreased, and antimicrobial activity of PBMCs against mycobacterial agents also decreased.29 The incidence of tuberculosis is already increased in patients with RA, but it is further increased in patients treated with TNFis. The progression of tuberculosis with the use of biologic agents is quite different from that of idiopathic tuberculosis. Thus tuberculosis associated with the use of TNFis more commonly exhibits extrapulmonary manifestations and dissemination.35 Importantly, proper screening for latent tuberculosis substantially decreases the incidence of mycobacterial infection in patients treated with TNFis. The incidence of tuberculosis might also be affected by the structure of a TNFi. In some studies anti-TNF mAb was associated with tuberculosis 3 to 10 times more often than soluble TNF-a IgG Fc fusion protein.35,36 Differences in tuberculosis rates might relate to pharmacologic differences, such as the binding kinetics of the drug to TNF, the specificity and potency in neutralizing TNF, apoptosis and reverse signaling, and the permeability of the biologic agents.37 Alternatively, there could be a dose effect contributing. Although the role of IL-6 in tuberculosis remains unclear, cases of tuberculosis in patients with RA treated with the anti–IL-6 receptor mAb tocilizumab have been reported in clinical trials and postmarketing surveys.38,39 Although the number of reports of tuberculosis associated with tocilizumab is lower than for TNFis, screening for latent tuberculosis is also recommended before the use of tocilizumab, as well as other biologic agents.40 According to clinical trials and registry studies, anakinra, rituximab, and abatacept do not appear to increase the risk of tuberculosis.41 However, coming mostly after the lessons learned with TNFis, screening for latent tuberculosis became standard for clinical trials of biologic agents. TH17 and IL-17 are also involved in immunity against mycobacteria, and they play a role in the recruitment of antigen-specific IFN-g–secreting TH1 cells.42 In animal models IL-23 was required for long-term control of mycobacteria and B-cell follicle formation in the infection.43 Although no cases of latent tuberculosis reactivation have been observed in patients with isoniazid chemoprophylaxis in clinical trials of ustekinumab,44 one case of activated latent tuberculosis occurred in a patient treated with ustekinumab without isoniazid chemoprophylaxis.45 More studies are needed to evaluate the possibility of a relationship between ustekinumab and tuberculosis. With increasing reports of nontuberculous mycobacteria (NTM) in patients treated with TNFis, the concerns regarding NTM infection have increased. In a study of a North American population, the rates of tuberculosis or NTM were 5 to 10 times higher in patients treated with TNFis than in TNFi-naive patients with RA or the general population.46 Compared with the disseminated manifestation in TNFi-associated tuberculosis, NTM infection associated with TNFis predominantly presented as a lung infection. Because most patients with NTM secondary


to TNFi use had underlying RA, a relationship between NTM secondary to TNFis and underlying RA was suggested.46,47 However, more studies are needed. In addition to mycobacterial infection, susceptibility to other intracellular infections, such as Pneumocystis jirovecii, listeriosis, Legionella species, coccidioidomycosis, histoplasmosis, and aspergillosis, has been reported. Because TNF activates macrophages to kill intracellular organisms,48 use of TNFis could lead to intracellular infections. In a recent meta-analysis of 70 trials including 32,504 patients with RA, the risk of opportunistic infection was higher with biologic agents than with conventional DMARDs or placebo.49 In a meta-analysis of patients with IBD from 22 randomized trials in which 4,135 patients were allocated to a TNFi treatment group and 2,919 patients were assigned to a placebo group, TNFi use doubled the risk of opportunistic infections.50

Viral infection Among the opportunistic infections that occur with the use of biologic agents, herpes zoster is of particular interest because of the possibility of complications and long-term disabilities, including postherpetic neuralgia. The association of herpes zoster with TNFis has not been consistently observed.51 In an analysis of retrospective data from 4 large US administrative databases (the Safety Assessment of Biologic Therapy project), 33,324 patients with inflammatory diseases, including RA, treated with TNFis were included.52 The TNFi-treated patients were not at higher risk of herpes zoster than those receiving nonbiologic treatments.52 In another meta-analysis of RA, the relative risk of herpes zoster in patients with RA with a total follow-up of 163,077 patient years was evaluated. The pooled risk of herpes zoster among the TNFi-treated patients was significantly increased by up to 61%. However, the absolute incidence of herpes zoster was low in both groups,53 with 1.19 per 100 patient years in the TNFi group and 0.93 per 100 patient years in the conventional DMARD group.53 Old age; concomitant immunosuppressive agents, particularly glucocorticoids; and RA activity are risk factors.54 Of note, an increased risk of herpes zoster infection, particularly among Asian patients, has been noted among patients with RA treated with the oral small-molecule Janus kinase inhibitor tofacitinib.55 Rituximab has been associated with progressive multifocal leukoencephalopathy caused by the polyomavirus JC, but most cases predominantly occurred in patients with lymphoproliferative disease. Progressive multifocal leukoencephalopathy is rare but commonly fatal.56 AUTOIMMUNITY Autoantibody and autoimmune disease Biologic agent–induced autoimmune manifestations range from the isolated presence of an autoantibody, such as antinuclear antibody (ANA), to full-blown autoimmune diseases, such as SLE, vasculitis, antiphospholipid syndrome, sarcoidosis, demyelinating disorder, inflammatory ocular diseases, and psoriasis.57 These autoimmune diseases can be organ specific (interstitial lung disease [ILD], uveitis, optic neuritis, peripheral neuropathies, and demyelinating disease including multiple sclerosis, psoriasis, and IBD) or systemic (SLE, vasculitis,


sarcoidosis, antiphospholipid syndrome, inflammatory myopathies and so on).57 From analysis of a Spanish registry and a literature search through 2009, more than 800 cases of autoimmune diseases secondary to biologic agents use have been reported.58,59 Vasculitis and lupus have been the most frequently reported autoimmune diseases trigged by TNFis.58,59 Vasculitis manifests predominantly as cutaneous vasculitis,59,60 but more systemic forms, such as glomerulonephritis and Henoch-Schonlein purpura, have also been reported.56 Purpura is a common clinical manifestation, and leukocytoclastic vasculitis was the most common histochemical finding in skin biopsy specimens.61 Autoantibodies, particularly ANA but also anti–doublestranded (ds) DNA antibodies, are not infrequently found among patients treated with TNFis. In a review of 180 patients with IBD treated with infliximab or adalimumab, a positive ANA result was detected in approximately half of the patients treated with TNFis for IBD, and anti-dsDNA antibodies, which are traditionally considered less sensitive but more specific for the diagnosis of SLE, were found in 10% to 15% of patients.62 Importantly, only 9% of patients had actual clinical lupus symptoms, and only 1% had severe lupus symptoms requiring cessation of TNFis.62 According to data from a French registry, the incidence of lupus was 0.19% among 7,700 patients exposed to infliximab and 0.18% among 3,800 patients exposed to etanercept for inflammatory arthritis.63 Other autoantibodies, such as antiphospholipid antibody, have also been detected, with 7% to 11% of patients treated with TNFi having antiphospholipid antibody.6 However, these patients were unlikely to have antiphospholipid syndrome.6 Lupus manifests differently in patients receiving biologic agents than it does in patients with idiopathic lupus. Among the manifestations of SLE, generalized nonspecific symptoms and lupus-like cutaneous manifestation, including malar rash, oral ulcers, discoid rash, and photosensitivity, were common in patients with biologic agent–related SLE.59 Severe clinical manifestations, such as renal lupus or central nervous system lupus, were significantly less common in patients with biologic agent–induced lupus.57 Usually lupus-like symptoms and vasculitis were resolved by the cessation of the suspected biologic agent.58 Biologic agent–induced lupus also showed some different immunologic features compared with drug-induced lupus secondary to small-molecule synthetic drugs. For example, a greater proportion of positive anti-dsDNA antibodies and hypocomplementemia and a lower incidence of anti-histone antibodies were observed in patients with TNFi-induced lupus than in those with traditional drug-induced lupus.64,65 The isolated presence of autoantibodies does not portend progress in clinical autoimmune disease. This might relate in part to the characteristics of the autoantibodies produced secondary to biologic agent use. For example, lower-affinity IgM antibodies rather than higher-affinity IgG antibodies were more commonly induced by biologic agents. Several hypotheses have been proposed to explain TNFi-induced autoantibodies and autoimmune diseases. TNFis can induce inflammatory cell apoptosis, causing release of antigenic material and thereby provoking antibody production.66,67 Another hypothesis is cytokine shift, particularly involving TNF and interferons. TNFis can interfere with TH1/TH2 responses, suppress TH1 cell responses, and favor TH2 cells and interferon, which are involved in SLE pathogenesis.6,65 SLE is a TH2 cell disease characterized


by increases in levels of IL-6, IL-10, and type 1 interferons (eg, IFN-a, IFN-b, and IFN-v). Type 1 interferons induce the activation and maturation of dendritic cells, and activated dendritic cells present autoantigens to B cells.68 The level of circulating plasmacytoid dendritic cells increased in TNF2/2 mouse models, and after concomitant exposure to endogenous Toll-like receptor 7 ligand, lupus developed with an increased production of autoantibody and type I interferons.69 Infection has been proposed as another cause of TNFi-induced SLE.65 Infection is a well-known side effect of TNFis. Bacterial DNA, with its immunostimulatory motifs, might help trigger autoantibody production in infection.70 Demyelinating diseases observed in conjunction with TNFi treatments primarily include optic neuritis, but multiple sclerosis and transverse myelitis have also been reported.57,71 Compared with the benign courses of other autoimmune diseases, ILD secondary to biologic agents tends to result in poor outcomes.72 ILD caused by biologic agents has predominantly been reported in patients treated with TNFis, but several cases have been reported with tocilizumab.73 There is one case report of abatacept aggravating ILD in patients with underlying RA and ILD.74 Controversy remains regarding the role of TNF in ILD because it has been shown to act through profibrotic and antifibrotic effects in animal models.73 Although ILD can develop in rituximab-treated patients treated in the context of connective tissue disease, ILD associated with rituximab primarily develops in patients with hematologic malignancies and can be fatal.75 The number and diversity of biologic-induced autoimmune diseases continue to increase.

Paradoxical inflammation Paradoxical inflammation is an intriguing side effect of biologic agents. Thus inflammation secondary to TNFis can present with the same types of clinical manifestations for which these drugs are effectively used, including arthritis, uveitis, psoriasis, and colitis.61,76 Considering the potential clinical manifestations of the underlying diseases, the occurrence of psoriatic skin lesions, uveitis, and IBD in the context of spondyloarthropathy or vasculitis and lupus manifestation in patients with RA might not be entirely surprising and could be viewed as an unmasking of previously subclinical involvement rather than an adverse drug effect. However, these reactions also occur in quite distinct conditions, such as psoriasiform lesions in patients with RA. Initially, paradoxical manifestations were probably underreported because physicians perhaps did not consider the possibility that drugs effective for autoimmune disease might cause the same disease in other patients. With greater recognition of these manifestations, there have been increasing reports. The well-documented paradoxical manifestations associated with biologic agents are psoriatic skin lesions. These lesions have been observed in patients treated with TNFis who have underlying diseases, such as RA, spondyloarthropathy, and IBD. Skin lesions are a common side effect of biologic agents and have been reported in approximately 20% of patients with IBD being treated with TNFis.77,78 Various skin lesions, such as xerosis cutis, psoriasis, eczema, and other lesions, have been reported. The prevalence of paradoxical psoriatic lesions with TNFi use has varied from 1.6% to 10% in patients with IBD and 0.6% to 5.3% in patients with RA.76,78 The most commonly


involved sites are the palmoplantar region and scalp, and the typical sites of idiopathic psoriasis, such as the extensor surface, are involved less frequently in biologic agent–induced psoriasis.79 Some researchers have questioned whether biologic agent–induced psoriasis is truly psoriasis. Some studies have shown that the clinical and histological findings of biologic agent–induced psoriasis are indistinguishable from those of true psoriasis.80 Other studies have shown a difference between biologic agent–induced psoriatic skin lesions and idiopathic psoriasis. Plaque-type psoriasis was found to occur in more than 90% of patients with classic psoriasis,81 whereas plaque-type and palmoplantar pustulosis are both common in biologic agent–induced psoriasis. Palmoplantar pustulosis has been observed in up to approximately 40% to 50% of patients treated for biologic agent–induced psoriasis.82,83 The presence of eosinophils and plasma cells in skin lesions seems to be a meaningful clue of biologic agent–induced psoriasis, but these findings have not been consistent in all skin lesions.84 Although TNFi cessation and topical agents have successfully treated biologic agent–induced psoriasis, approximately 40% of patients have responded well to topical agents while continuing TNFis.85,86 Switching to another TNFi has anecdotally been reported to lead to a recurrence of psoriatic lesions. As a result, and with the growing availability of therapeutic agents with other mechanisms of action, it has become fairly common practice at present not to use other TNFis in such cases.79 The immunologic mechanism of biologic agent–induced psoriasis might be explained at least in part by a cytokine shift of TNF and interferon similar to the situation with biologic agent–induced lupus. In the early phase of psoriatic skin lesions, plasmacytoid dendritic cells and IFN-a produced by dendritic cells are involved in the pathogenesis of psoriasis.87,88 Plasmacytoid dendritic cells, which have a unique ability to secrete large amounts of IFN-a, are a rare cell type in the peripheral blood but might accumulate in the skin in patients with psoriasis.87 TNF-a prevents the generation of plasmacytoid dendritic cells and IFN-a release by plasmacytoid dendritic cells exposed to viruses.89 Therefore it has been inferred that TNFis might induce sustained production of IFN-a, thereby driving psoriasiform skin lesions.76,90 According to histochemical findings, expression of myxovirus-resistant A protein, which specifically induces type 1 interferons, is greater in patients with biologic agent–induced psoriasis than in those with true psoriasis.90,91 IFN-a induces chemokine receptor CXCR3 on T cells, which facilitates immunity in skin cells.92 Some evidence suggests TH17 cell involvement in patients with TNFi-induced psoriasis. In a mouse model of psoriasis, after TNFi treatment, the psoriatic lesions were aggravated by enhancing TH17 function and decreasing expansion of regulatory T cells.93 According to the histologic findings of a patient who had psoriatic skin lesions after TNFi treatment, there was infiltration of IL-17 A/IL-22–secreting TH17 cells, IFN-g–secreting TH1 cells, and IFN-a–expressing cells.94 In severe cases of TNFi-induced psoriatic skin lesions, the anti–IL-12/IL-23 mAb ustekinumab has successfully been used to treat the lesions.94 Although several case reports of rituximab-induced psoriasis have been reported, a causative relationship between rituximab and psoriasis has not been supported.95 TNFis have shown good efficacy in treating an inflammatory ocular disease, such as uveitis, both in idiopathic disease and



among patients with AS, psoriatic arthritis, or Behcet disease. The role of TNFis in paradoxically provoking inflammatory ocular disease is not clear. Because some patients have inflammatory ocular disease in the absence of articular activity after TNFi treatment, the pathogenesis pathways of articular manifestation and ocular manifestation are different.59 In a review of uveitis associated with TNFis, including 31 patients from a French registry and 121 cases from a PubMed search, etanercept was the most frequently used medication, and spondyloarthropathy was the most common underlying disease.96 IBD is a rare paradoxical manifestation. Paradoxical IBD primarily occurs in patients with spondyloarthropathy who are also receiving etanercept, which is not approved for IBD, and typically presented as Crohn disease or Crohn-like disease.97




19. 20.

CONCLUSION Biologic agents target specific aspects of the immune response. Interrupting the pathways of immunity and inflammation can result in untoward effects. The effect on normal immunity related to use of biologic agents can manifest as immunodeficiency, such as infection, or as autoimmunity, such as paradoxical inflammation or autoimmune disease. Awareness of the most recent clinical information and understanding of the immunologic mechanisms of side effects secondary to biologic agents will improve the use of biologic agents and improve outcomes for patients. REFERENCES 1. Rosman Z, Shoenfeld Y, Zandman-Goddard G. Biologic therapy for autoimmune diseases: an update. BMC Med 2013;11:88. 2. Burmester GR, Feist E, Dorner T. Emerging cell and cytokine targets in rheumatoid arthritis. Nat Rev Rheumatol 2014;10:77-88. 3. Pichler WJ. Adverse side-effects to biological agents. Allergy 2006;61:912-20. 4. Aubin F, Carbonnel F, Wendling D. The complexity of adverse side-effects to biological agents. J Crohns Colitis 2013;7:257-62. 5. Lee SJ, Kavanaugh A. Adverse reactions to biologic agents: focus on autoimmune disease therapies. J Allergy Clin Immunol 2005;116:900-5. 6. Boyman O, Comte D, Spertini F. Adverse reactions to biologic agents and their medical management. Nat Rev Rheumatol 2014;10:612-27. 7. Wallis RS. Biologics and infections: lessons from tumor necrosis factor blocking agents. Infect Dis Clin North Am 2011;25:895-910. 8. Curtis JR, Yang S, Patkar NM, Chen L, Singh JA, Cannon GW, et al. Risk of hospitalized bacterial infections associated with biologic treatment among US veterans with rheumatoid arthritis. Arthritis Care Res (Hoboken) 2014;66:990-7. 9. Leombruno JP, Einarson TR, Keystone EC. The safety of anti-tumour necrosis factor treatments in rheumatoid arthritis: meta and exposure-adjusted pooled analyses of serious adverse events. Ann Rheum Dis 2009;68:1136-45. 10. Thompson AE, Rieder SW, Pope JE. Tumor necrosis factor therapy and the risk of serious infection and malignancy in patients with early rheumatoid arthritis: a meta-analysis of randomized controlled trials. Arthritis Rheum 2011;63:1479-85. 11. Grijalva CG, Chen L, Delzell E, Baddley JW, Beukelman T, Winthrop KL, et al. Initiation of tumor necrosis factor-alpha antagonists and the risk of hospitalization for infection in patients with autoimmune diseases. JAMA 2011;306:2331-9. 12. Michaud TL, Rho YH, Shamliyan T, Kuntz KM, Choi HK. The comparative safety of tumor necrosis factor inhibitors in rheumatoid arthritis: a meta-analysis update of 44 trials. Am J Med 2014;127:1208-32. 13. Singh JA, Cameron C, Noorbaloochi S, Cullis T, Tucker M, Christensen R, et al. Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis. Lancet 2015;386:258-65. 14. Strangfeld A, Eveslage M, Schneider M, Bergerhausen HJ, Klopsch T, Zink A, et al. Treatment benefit or survival of the fittest: what drives the timedependent decrease in serious infection rates under TNF inhibition and what does this imply for the individual patient? Ann Rheum Dis 2011;70:1914-20. 15. van Dartel SA, Fransen J, Kievit W, Flendrie M, den Broeder AA, Visser H, et al. Difference in the risk of serious infections in patients with rheumatoid arthritis treated with adalimumab, infliximab and etanercept: results from the Dutch
















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