REVIEW URRENT C OPINION
Infection risk and biologics: current update Dinny Wallis
Purpose of review The management of inflammatory arthritis has been revolutionized by the use of biologic therapy. However, an important safety issue has been identified with regard to the risk of serious and opportunistic infections with biologic therapy. This review aims to summarize the most recent data available in the field. Recent findings The risk of infection in inflammatory arthritis is partly determined by the nature of the underlying disease, comorbidities and other immunosuppressive treatments, in particular glucocorticoids. Data are conflicting with regard to the absolute risk of infection with biologic agents, as a result of differing study methodologies, classification of outcomes and patient populations. There appear to be some differences in risk of infection between biologic agents, which relate to their varying modes of action. Summary Long-term observational data about the risk of infection and biologic therapy continue to emerge, although there are inherent limitations with this type of data. The process of determining the risk of infection for an individual patient should incorporate a range of factors, which may contribute to the infection risk. Keywords biologics, infection, rheumatoid arthritis, spondylitis, tumour necrosis factor inhibitor
INTRODUCTION The treatment of rheumatic diseases has been revolutionized by the introduction of biologic drugs. An expanding list of biologic drugs is now in use in clinical practice. These agents, which are immunosuppressive or immunomodulatory, have been reported to have an association with serious or opportunistic infection, in particular tuberculosis (TB). However, the interpretation of this association is confounded by the use of other immunosuppressive drugs as well as the risk of infection related to the underlying disease. The purpose of this review is to summarize the current understanding of infection risk in relation to biologic therapy in inflammatory arthritis.
DISEASE-RELATED INFECTION RISK Rheumatoid arthritis (RA) is known to be associated with a heightened risk of infection when compared with the general population, in particular septic arthritis, osteomyelitis and skin and soft tissue infections [1]. Disease severity indices, comorbidities and the use of glucocorticoids are all predictors of infection [2]. Early work investigating the risk of infection with disease modifying drugs (DMARDs) suggested that there was a higher risk of infection in patients on methotrexate than those not on methotrexate [3], but later studies [2,4,5] have not www.co-rheumatology.com
supported these findings. A recent 5-year prospective, multicentre observational study in the United States [6 ] investigated the effect of disease activity and disability on the risk of infection in 4084 RA patients with a mean follow-up of 3.17 years. A correlation was identified between increased disease activity or disability and an increased risk of serious infection. Patients with mild, moderate or severe disease activity experienced a 2.7-fold, 4.3-fold or 4.8-fold increase in serious infection risk, respectively. The association remained significant after adjusting for disease duration, comorbidities, glucocorticoids and previous serious infection. A similar effect was found for disability. &
TRENDS IN INFECTION IN RHEUMATOID ARTHRITIS Modern management of RA is underpinned by tighter control of disease activity and hence more Department of Rheumatology, Royal Hampshire County Hospital, Hampshire Hospitals NHS Foundation Trust, Winchester, UK Correspondence to Dr Dinny Wallis, Department of Rheumatology, Royal Hampshire County Hospital, Hampshire Hospitals NHS Foundation Trust, Romsey Road, Winchester, SO22 5DG UK. Tel: +44 1962 863535; e-mail: [email protected] Curr Opin Rheumatol 2014, 26:404–409 DOI:10.1097/BOR.0000000000000072 Volume 26 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Infection risk and biologics: current update Wallis
KEY POINTS A number of long-term observational studies and metaanalyses have identified an association with biologic agents and increased risk of infection in inflammatory arthritis. The risk of infection is influenced by underlying disease activity, comorbidities and concomitant immunosuppressive medication. The infection rate and in some cases, types and sites of infection may vary between agents with differing mechanisms of action.
aggressive therapy. The question might be raised of whether this change has had any effect on the risk of infection. A recent retrospective cohort study [7 ] in the United States compared the rates and types of infection in a cohort of 609 patients diagnosed with RA in 1955–1994 to outcomes in 464 patients from the same geographical area who were diagnosed in 1995–2007. Rates of smoking and comorbidities were similar in the two cohorts, except for diabetes, which occurred more frequently in the later cohort. The overall rate of serious infections declined from 9.6 per 100 patient years in the earlier cohort to 6.6 per 100 patient years in the later cohort, but the rate of serious gastrointestinal infection increased, mostly explained by a higher rate of Clostridium difficile infection. The rate of subsequent infection in those patients with a history of serious infection also increased in the later cohort. Importantly, the effect of disease activity on infection risk was not assessed, and the follow-up time of the later cohort was substantially shorter than the earlier cohort, which could influence the rates of infection. Other time-varying factors, which were not assessed, could contribute to the findings, for example vaccination strategies and antibiotic resistance. &
TUMOUR NECROSIS FACTOR INHIBITORS IN RHEUMATOID ARTHRITIS Tumour necrosis factor (TNF) plays an essential part in the host immune system. Early randomized controlled trials of the TNF inhibitors (TNFi) etanercept, infliximab and adalimumab did not report a higher rate of infection in the treatment groups than in the placebo groups, but subsequent observational studies, meta-analyses and reviews have raised concerns about infection. However, the data are inconsistent [8–13]. Differing inclusion criteria, along with an increasing awareness of the risk of infection, which affected patient selection for biologic treatment, have made it difficult to compare data from different
biologic registries. Although there is no head-tohead comparison of the anti-TNF agents with regard to infection risk, recent observational data from 2356 patients in the Dutch RA registry [14 ] have identified a trend for lower risk of infection for etanercept than with infliximab or adalimumab. This might partly be explained by the different mode of action of etanercept, which is a soluble TNF receptor fusion protein, as compared with the monoclonal antibodies. The unadjusted incidence rate of a first serious infection per 100 patient year was 1.66 for etanercept, 2.61 for adalimumab and 3.86 for infliximab. The adjusted model confirmed a lower infection rate for etanercept. However, patients were not randomly assigned to treatments, and the risk of infection at baseline may have differed in the three groups. A recent retrospective cohort study [15 ] (Safety Assessment of Biologic Therapy) used four administrative data systems in the United States to investigate nonviral opportunistic infections in RA, inflammatory bowel disease and spondylitis. In RA, 24 384 new users of TNFi were compared with 11 828 patients treated with traditional DMARDs. The adjusted risk of nonviral opportunistic infection was not increased significantly in new users of TNFi, although infliximab was associated with an increased risk when compared with either traditional DMARDs or etanercept. Pneumocystis and mycobacterial infections accounted for almost half of the opportunistic infections occurring among new users of TNFi and most occurred within 6 months of TNFi initiation. The study relied on the use of administrative databases, which could result in misclassification of outcomes (for example, active TB versus latent TB) and underreporting of events, but these errors are likely to be seen across all treatment groups and probably do not affect the conclusions. Skin and soft tissue infections have been reported to occur three times more frequently in RA patients than in the general population [1]. The German biologics register (Rheumatoid Arthritis Observation of Biologic Therapy, RABBIT) identified a trend for increased rates of herpes zoster (shingles) infection with TNFi compared with traditional DMARDs [16], whereas the Spanish Registry of adverse events to biological therapy in rheumatic diseases (BIOBADASER) registry found that RA patients on TNFi were more likely to be hospitalized for chickenpox and shingles than patients on DMARDs [17]. Most recently, a report from the British Society for Rheumatology Biologics Registers (BSRBR) demonstrated a significantly increased risk of shingles in TNFi-treated patients (1.6 per 100 patient year) compared with the DMARD cohort (0.8 per 100 patient year) [18 ]. The hazard risk for serious skin and soft
1040-8711 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
&
&
www.co-rheumatology.com
405
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Infection and autoimmunity
tissue infections and for shingles varied over time, with a higher risk early on in therapy. However, this analysis did not include steroid use, and there were important differences between the biologic and DMARD-treated groups, with biologic-treated patients having higher disease activity.
RITUXIMAB IN RHEUMATOID ARTHRITIS Rituximab is a CD20-directed cytolytic antibody that targets CD20-positive B cells. The overall risk of infection with rituximab appears to be less than with the TNF inhibitors. An observational study [19] of patients switching biologic agents demonstrated that the risk of infection in those switching to rituximab was no different than that for patient switching to infliximab, adalimumab, etanercept or abatacept. Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection caused by the JC virus and, among rheumatology patients, is particularly seen in patients with systemic lupus erythematosus (SLE). PML has been the subject of Food and Drug Administration (FDA) alerts with regard to several immunosuppressive agents, including rituximab, natalizumab and efalizumab. However, the rarity of the disease and confounding nature of the underlying illnesses and other therapies make it difficult to define the exact association of these therapies with PML. A recent review of the experience of PML in association with autoimmune rheumatic disease in the FDA Adverse Event Reporting System database found 34 cases of PML among patients with predominantly SLE (n ¼ 17) or RA (n ¼ 10) [20 ]. Fifteen patients had received a biologic agent in recent months, which in 14 cases, was rituximab. Nineteen patients had received only synthetic DMARDs prior to the onset of PML. In six cases, PML occurred in patients treated with TNFi, of whom five had also received rituximab and one had received cyclophosphamide. After reviewing the available data, the authors conclude that the paucity of confirmed cases of PML in patients exposed to TNFi therapy suggests a causal relationship is unlikely, but that a signal continues to emerge with regard to rituximab and PML.
the role of IL-6, it is plausible that inhibiting its function may lead to susceptibility to infections. A meta-analysis of six early clinical trials of tocilizumab, including 601 patients, demonstrated a serious infection rate of 6.22 per 100 patient years [22]. A systematic review of 41 clinical trials of tocilizumab [23] found that the rate of serious infection in the 6-month control studies with tocilizumab 8 mg/kg in combination with DMARD was 5.3 per 100 patient years compared with 3.9 per 100 patient years in the placebo with DMARD group. In patients treated as monotherapy, the rate was lower at 3.6 per 100 patient years. There were fewer infections in patients treated with the lower dose of 4 mg/kg tocilizumab. No cases of TB were seen in any of the five phase 3 trials, but the usual recommendations for screening of TB apply to toclizumab given the paucity of data in this respect. A recent randomized controlled trial (RCT) of tocilizumab in patients who had failed to respond to DMARDs demonstrated infection rates of 7.8 per 100 patient year in the tocilizumab arm compared with 1.2 per 100 patient year in the placebo arm over 24 weeks [24]. A short-term (24 week) study [25] in 2013, which investigated the safety and efficacy of subcutaneous versus intravenous (i.v.) tocilizumab in moderate-to-severe RA (n ¼ 1262) found that the most common adverse event was infection. The serious infection rate was 1.4% in both groups. The effective suppression of CRP in patients treated with tocilizumab might contribute to delay in identification of infection, although this effect is also seen with glucocorticoids and other immunosuppressants.
&&
TOCILIZUMAB IN RHEUMATOID ARTHRITIS Tocilizumab, a human antiinterleukin-6 (IL-6)-receptor antibody, has been approved for the treatment of RA. IL-6 induces the hepatic acute-phase response and mediates the production of C-Reactive Protein (CRP) during infection as well as playing roles in B-cell proliferation, antibody production, T-cell differentiation and cytotoxicity [21]. Considering 406
www.co-rheumatology.com
ABATACEPT Abatacept, which modulates T-cell activation, was shown to increase the rate of serious infection in clinical trial data at 12 months, but not in a metaanalysis of five trials [26]. One observational study [19] has reported that the rate of infection was lower with abatacept than with rituximab, infliximab, etanercept or adalimumab, but the large AIM (Abatacept in Inadequate responders to Methotrexate) trial reported that the risk of infection with abatacept is similar to that seen with TNFi [27]. A recent retrospective analysis of a US claims database found that for 4332 RA patients switching to a second biologic, the risk of serious infection was not significantly different among patients switching to rituximab, abatacept, etanercept and adalimumab but significantly higher for those switching to infliximab [28]. Pooled data from eight trials of i.v. abatacept in RA [29] found no difference in the infection rate between abatacept-treated and placebo-treated patients during the short-term Volume 26 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Infection risk and biologics: current update Wallis
(
Infection risk and biologics: current update Dinny Wallis
Purpose of review The management of inflammatory arthritis has been revolutionized by the use of biologic therapy. However, an important safety issue has been identified with regard to the risk of serious and opportunistic infections with biologic therapy. This review aims to summarize the most recent data available in the field. Recent findings The risk of infection in inflammatory arthritis is partly determined by the nature of the underlying disease, comorbidities and other immunosuppressive treatments, in particular glucocorticoids. Data are conflicting with regard to the absolute risk of infection with biologic agents, as a result of differing study methodologies, classification of outcomes and patient populations. There appear to be some differences in risk of infection between biologic agents, which relate to their varying modes of action. Summary Long-term observational data about the risk of infection and biologic therapy continue to emerge, although there are inherent limitations with this type of data. The process of determining the risk of infection for an individual patient should incorporate a range of factors, which may contribute to the infection risk. Keywords biologics, infection, rheumatoid arthritis, spondylitis, tumour necrosis factor inhibitor
INTRODUCTION The treatment of rheumatic diseases has been revolutionized by the introduction of biologic drugs. An expanding list of biologic drugs is now in use in clinical practice. These agents, which are immunosuppressive or immunomodulatory, have been reported to have an association with serious or opportunistic infection, in particular tuberculosis (TB). However, the interpretation of this association is confounded by the use of other immunosuppressive drugs as well as the risk of infection related to the underlying disease. The purpose of this review is to summarize the current understanding of infection risk in relation to biologic therapy in inflammatory arthritis.
DISEASE-RELATED INFECTION RISK Rheumatoid arthritis (RA) is known to be associated with a heightened risk of infection when compared with the general population, in particular septic arthritis, osteomyelitis and skin and soft tissue infections [1]. Disease severity indices, comorbidities and the use of glucocorticoids are all predictors of infection [2]. Early work investigating the risk of infection with disease modifying drugs (DMARDs) suggested that there was a higher risk of infection in patients on methotrexate than those not on methotrexate [3], but later studies [2,4,5] have not www.co-rheumatology.com
supported these findings. A recent 5-year prospective, multicentre observational study in the United States [6 ] investigated the effect of disease activity and disability on the risk of infection in 4084 RA patients with a mean follow-up of 3.17 years. A correlation was identified between increased disease activity or disability and an increased risk of serious infection. Patients with mild, moderate or severe disease activity experienced a 2.7-fold, 4.3-fold or 4.8-fold increase in serious infection risk, respectively. The association remained significant after adjusting for disease duration, comorbidities, glucocorticoids and previous serious infection. A similar effect was found for disability. &
TRENDS IN INFECTION IN RHEUMATOID ARTHRITIS Modern management of RA is underpinned by tighter control of disease activity and hence more Department of Rheumatology, Royal Hampshire County Hospital, Hampshire Hospitals NHS Foundation Trust, Winchester, UK Correspondence to Dr Dinny Wallis, Department of Rheumatology, Royal Hampshire County Hospital, Hampshire Hospitals NHS Foundation Trust, Romsey Road, Winchester, SO22 5DG UK. Tel: +44 1962 863535; e-mail: [email protected] Curr Opin Rheumatol 2014, 26:404–409 DOI:10.1097/BOR.0000000000000072 Volume 26 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Infection risk and biologics: current update Wallis
KEY POINTS A number of long-term observational studies and metaanalyses have identified an association with biologic agents and increased risk of infection in inflammatory arthritis. The risk of infection is influenced by underlying disease activity, comorbidities and concomitant immunosuppressive medication. The infection rate and in some cases, types and sites of infection may vary between agents with differing mechanisms of action.
aggressive therapy. The question might be raised of whether this change has had any effect on the risk of infection. A recent retrospective cohort study [7 ] in the United States compared the rates and types of infection in a cohort of 609 patients diagnosed with RA in 1955–1994 to outcomes in 464 patients from the same geographical area who were diagnosed in 1995–2007. Rates of smoking and comorbidities were similar in the two cohorts, except for diabetes, which occurred more frequently in the later cohort. The overall rate of serious infections declined from 9.6 per 100 patient years in the earlier cohort to 6.6 per 100 patient years in the later cohort, but the rate of serious gastrointestinal infection increased, mostly explained by a higher rate of Clostridium difficile infection. The rate of subsequent infection in those patients with a history of serious infection also increased in the later cohort. Importantly, the effect of disease activity on infection risk was not assessed, and the follow-up time of the later cohort was substantially shorter than the earlier cohort, which could influence the rates of infection. Other time-varying factors, which were not assessed, could contribute to the findings, for example vaccination strategies and antibiotic resistance. &
TUMOUR NECROSIS FACTOR INHIBITORS IN RHEUMATOID ARTHRITIS Tumour necrosis factor (TNF) plays an essential part in the host immune system. Early randomized controlled trials of the TNF inhibitors (TNFi) etanercept, infliximab and adalimumab did not report a higher rate of infection in the treatment groups than in the placebo groups, but subsequent observational studies, meta-analyses and reviews have raised concerns about infection. However, the data are inconsistent [8–13]. Differing inclusion criteria, along with an increasing awareness of the risk of infection, which affected patient selection for biologic treatment, have made it difficult to compare data from different
biologic registries. Although there is no head-tohead comparison of the anti-TNF agents with regard to infection risk, recent observational data from 2356 patients in the Dutch RA registry [14 ] have identified a trend for lower risk of infection for etanercept than with infliximab or adalimumab. This might partly be explained by the different mode of action of etanercept, which is a soluble TNF receptor fusion protein, as compared with the monoclonal antibodies. The unadjusted incidence rate of a first serious infection per 100 patient year was 1.66 for etanercept, 2.61 for adalimumab and 3.86 for infliximab. The adjusted model confirmed a lower infection rate for etanercept. However, patients were not randomly assigned to treatments, and the risk of infection at baseline may have differed in the three groups. A recent retrospective cohort study [15 ] (Safety Assessment of Biologic Therapy) used four administrative data systems in the United States to investigate nonviral opportunistic infections in RA, inflammatory bowel disease and spondylitis. In RA, 24 384 new users of TNFi were compared with 11 828 patients treated with traditional DMARDs. The adjusted risk of nonviral opportunistic infection was not increased significantly in new users of TNFi, although infliximab was associated with an increased risk when compared with either traditional DMARDs or etanercept. Pneumocystis and mycobacterial infections accounted for almost half of the opportunistic infections occurring among new users of TNFi and most occurred within 6 months of TNFi initiation. The study relied on the use of administrative databases, which could result in misclassification of outcomes (for example, active TB versus latent TB) and underreporting of events, but these errors are likely to be seen across all treatment groups and probably do not affect the conclusions. Skin and soft tissue infections have been reported to occur three times more frequently in RA patients than in the general population [1]. The German biologics register (Rheumatoid Arthritis Observation of Biologic Therapy, RABBIT) identified a trend for increased rates of herpes zoster (shingles) infection with TNFi compared with traditional DMARDs [16], whereas the Spanish Registry of adverse events to biological therapy in rheumatic diseases (BIOBADASER) registry found that RA patients on TNFi were more likely to be hospitalized for chickenpox and shingles than patients on DMARDs [17]. Most recently, a report from the British Society for Rheumatology Biologics Registers (BSRBR) demonstrated a significantly increased risk of shingles in TNFi-treated patients (1.6 per 100 patient year) compared with the DMARD cohort (0.8 per 100 patient year) [18 ]. The hazard risk for serious skin and soft
1040-8711 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
&
&
www.co-rheumatology.com
405
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Infection and autoimmunity
tissue infections and for shingles varied over time, with a higher risk early on in therapy. However, this analysis did not include steroid use, and there were important differences between the biologic and DMARD-treated groups, with biologic-treated patients having higher disease activity.
RITUXIMAB IN RHEUMATOID ARTHRITIS Rituximab is a CD20-directed cytolytic antibody that targets CD20-positive B cells. The overall risk of infection with rituximab appears to be less than with the TNF inhibitors. An observational study [19] of patients switching biologic agents demonstrated that the risk of infection in those switching to rituximab was no different than that for patient switching to infliximab, adalimumab, etanercept or abatacept. Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection caused by the JC virus and, among rheumatology patients, is particularly seen in patients with systemic lupus erythematosus (SLE). PML has been the subject of Food and Drug Administration (FDA) alerts with regard to several immunosuppressive agents, including rituximab, natalizumab and efalizumab. However, the rarity of the disease and confounding nature of the underlying illnesses and other therapies make it difficult to define the exact association of these therapies with PML. A recent review of the experience of PML in association with autoimmune rheumatic disease in the FDA Adverse Event Reporting System database found 34 cases of PML among patients with predominantly SLE (n ¼ 17) or RA (n ¼ 10) [20 ]. Fifteen patients had received a biologic agent in recent months, which in 14 cases, was rituximab. Nineteen patients had received only synthetic DMARDs prior to the onset of PML. In six cases, PML occurred in patients treated with TNFi, of whom five had also received rituximab and one had received cyclophosphamide. After reviewing the available data, the authors conclude that the paucity of confirmed cases of PML in patients exposed to TNFi therapy suggests a causal relationship is unlikely, but that a signal continues to emerge with regard to rituximab and PML.
the role of IL-6, it is plausible that inhibiting its function may lead to susceptibility to infections. A meta-analysis of six early clinical trials of tocilizumab, including 601 patients, demonstrated a serious infection rate of 6.22 per 100 patient years [22]. A systematic review of 41 clinical trials of tocilizumab [23] found that the rate of serious infection in the 6-month control studies with tocilizumab 8 mg/kg in combination with DMARD was 5.3 per 100 patient years compared with 3.9 per 100 patient years in the placebo with DMARD group. In patients treated as monotherapy, the rate was lower at 3.6 per 100 patient years. There were fewer infections in patients treated with the lower dose of 4 mg/kg tocilizumab. No cases of TB were seen in any of the five phase 3 trials, but the usual recommendations for screening of TB apply to toclizumab given the paucity of data in this respect. A recent randomized controlled trial (RCT) of tocilizumab in patients who had failed to respond to DMARDs demonstrated infection rates of 7.8 per 100 patient year in the tocilizumab arm compared with 1.2 per 100 patient year in the placebo arm over 24 weeks [24]. A short-term (24 week) study [25] in 2013, which investigated the safety and efficacy of subcutaneous versus intravenous (i.v.) tocilizumab in moderate-to-severe RA (n ¼ 1262) found that the most common adverse event was infection. The serious infection rate was 1.4% in both groups. The effective suppression of CRP in patients treated with tocilizumab might contribute to delay in identification of infection, although this effect is also seen with glucocorticoids and other immunosuppressants.
&&
TOCILIZUMAB IN RHEUMATOID ARTHRITIS Tocilizumab, a human antiinterleukin-6 (IL-6)-receptor antibody, has been approved for the treatment of RA. IL-6 induces the hepatic acute-phase response and mediates the production of C-Reactive Protein (CRP) during infection as well as playing roles in B-cell proliferation, antibody production, T-cell differentiation and cytotoxicity [21]. Considering 406
www.co-rheumatology.com
ABATACEPT Abatacept, which modulates T-cell activation, was shown to increase the rate of serious infection in clinical trial data at 12 months, but not in a metaanalysis of five trials [26]. One observational study [19] has reported that the rate of infection was lower with abatacept than with rituximab, infliximab, etanercept or adalimumab, but the large AIM (Abatacept in Inadequate responders to Methotrexate) trial reported that the risk of infection with abatacept is similar to that seen with TNFi [27]. A recent retrospective analysis of a US claims database found that for 4332 RA patients switching to a second biologic, the risk of serious infection was not significantly different among patients switching to rituximab, abatacept, etanercept and adalimumab but significantly higher for those switching to infliximab [28]. Pooled data from eight trials of i.v. abatacept in RA [29] found no difference in the infection rate between abatacept-treated and placebo-treated patients during the short-term Volume 26 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Infection risk and biologics: current update Wallis
(
