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Immunosuppressants, infection, and inflammation
Clinical Immunology 113 (2004) 137 – 139 www.elsevier.com/locate/yclim
Case Discussion
Immunosuppressants, infection, and inflammation Daniel J. Lovell, Theoklis E. Zaoutis, and Kathleen Sullivan * Division Immunologic Infectious Disease, Children’s Hospital of Philadelphia, Philadelphia, PA 19104 USA Received 10 March 2004; accepted 12 March 2004 Available online 26 June 2004
Case A 3-year-old girl abruptly developed fever with swollen, painful wrists and knees. She initially responded to naproxen but several months later developed numerous swollen joints, low-grade fevers, and fatigue. A diagnosis of polyarticular juvenile rheumatoid arthritis (JRA) was made and 10 mg/m2/wk of methotrexate was added to the naproxen to control her joint pain. She had no response to this regimen, and in fact, she developed new joint involvement. Furthermore, radiologic evaluations demonstrated additional cartilage destruction. A recommendation was made to increase the methotrexate dose, add therapy with a TNF alpha inhibitor, or add cyclosporine. The family is extremely concerned about the level of immunocompromise these agents would induce because the child has a history of recurrent infections and has been hospitalized twice for pneumonia.
Recommendations of Dr. Daniel Lovell, MD, MPH In consideration of this case, it is important to stress that this child has worsening, destructive arthritis that if left uncontrolled, will result in additional joint damage. She has demonstrated two significant poor prognostic factors for severity of the arthritis (wrist involvement and demonstration of radiologic joint damage). In a recent study of radiologic joint damage in juvenile arthritis, the most significant predictor of worsening joint damage after 24 months was the presence of any radiologic joint damage at the onset of the study [1]. Given these facts, the question at hand must be what (not if) additional therapy should be used to treat this child with polyarticular JRA. * Corresponding author. Division Immunologic Infectious Disease, Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104. Fax: +1-215-590-3044. E-mail address: [email protected] (K. Sullivan). 1521-6616/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.clim.2004.03.010
Early trials of cyclosporine in JRA at transplant doses (approximately 10 mg/kg/day) demonstrated a high frequency of adverse events with few children being able to continue the medication for even 1 year [2]. A recent international registry of cyclosporine use in children with JRA (n = 344) demonstrated that at a mean dose of 3.5 mg/ kg/day, over 60% discontinued due to lack of clinical improvement (E.H. Giannini, personal communication). Therefore, cyclosporine seems a poor choice for this child. Both methotrexate [3] and the TNF alpha inhibitor, etanercept [4], have demonstrated efficacy in children with severe polyarticular JRA in randomized, placebo controlled trials (RCT). The dose of methotrexate used in this child was the dose found efficacious in approximately 70% of the subjects enrolled in the randomized RCT [3]. One small open study demonstrated that for children not responding to this dose, escalation of the methotrexate dose to as much as 1 mg/ kg body weight (maximum of 50 mg/week) will often bring the disease into control [5]. However, a large randomized prospective trial [6] comparing two higher doses of parenteral methotrexate (15 versus 30 mg/m2/week) in children with polyarticular JRA that had failed to respond to 10 mg/m2/ week orally, the overall response rate using the ACR Pediatric 30 definition of response, was similar at both doses. Methotrexate was well tolerated in this study with only 5% and 12% discontinuing therapy due to adverse events, respectively. This study suggests that if methotrexate is used in this child, the maximal dose should be 15 – 20 mg/m2/week. Methotrexate is unquestionably the best-studied therapy in both children and adults with chronic arthritis. Extensive use in children with JRA for over 20 years has failed to produce convincing evidence of significant immunosuppression or increased frequency of serious infections. In the aforementioned RCT of methotrexate in polyarticular JRA [3], the rate of serious infections was similar in the placebo and the methotrexate. These data suggest that methotrexate does not significantly increase the rate of severe infections. The data from the only RCT utilizing etanercept in children [4] with severe polyarticular JRA did not demon-
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D.J. Lovell et al. / Clinical Immunology 113 (2004) 137–139
strate a significantly increased rate of nonserious upper respiratory infections nor serious infections in the etanercept versus placebo arms (0.14 vs. 0.16 nonserious events/patient month, respectively, P = 0.82). However, during the RCT and open extension study [7], two of three subjects who developed varicella had courses complicated by aseptic meningitis although all demonstrated full recovery and normal development of varicella-specific antibodies. Another patient developed a severe infection with invasive group A beta hemolytic Streptococcus. In RCTs of etanercept in adults with RA, the overall rate of severe infections has not been statistically different in the etanercept and placebo arms [8]. However, data from open label studies in adults with RA suggest an increased rate of a several infections including tuberculosis with anti-TNF therapies [8]. In my opinion, in this child, given the severity of the current arthritis and the presence of several poor prognostic indicators, more aggressive therapy is certainly warranted. Given the history of recurrent infections, it would be wise to evaluate the child for immunodeficiency. The next step I would suggest is the use of parenteral methotrexate at 15– 20 mg/m2/week for 3– 6 months, and if the child continued to demonstrate active articular disease by either symptoms or joint exam, I would perform TB testing (and treatment of latent TB, if appropriate) and begin etanercept at a dose of 0.4 mg/kg/dose (maximum of 25 mg/dose) twice weekly. With either methotrexate or etanercept, the standard precautions used for any immunosuppressed subject should be observed (e.g., avoidance of live virus vaccines, varicella exposure or infection precautions, holding medication for febrile illnesses, increased index of suspicion for evolution of severe infections). Given the history of recurrent infections, the more conservative approach of substituting etanercept for methotrexate instead of adding it to existing methotrexate would be appropriate.
Recommendations of Dr. Theoklis Zaoutis, MD Immunosuppressive agents have improved the outcomes of autoimmune disorders and solid organ transplantation in children. The goal of immunosuppressive therapy is to optimize disease control while limiting side effects such as an increased risk of infection. Immunosuppressive medications commonly used in clinical practice include corticosteroids, cytotoxic drugs (cyclophosphamide, azathioprine, mycophenolate mofetil [MMF]), calcineurin inhibitors (cyclosporine A, tacrolimus, rapamycin), and the folic acid analogue (methotrexate) [9 – 12]. Newer agents include monoclonal antibodies against TNF alpha (113). Corticosteroids, cyclosporine, tacrolimus, and rapamycin inhibit T-cell activation, proliferation, and function [9]. The infectious disease effects of these agents are predicated on the same mechanisms involved in their therapeutic action; they promote infection with organisms in which cell-mediated immunity is the dominant host defense. Patients re-
ceiving these agents are susceptible to herpes group viruses, fungi, mycobacteria, Strongyloides stercoralis, and infection with such intracellular organisms as Listeria monocytogenes, and Salmonella species. The calcineurin inhibitors, in particular, promote the occurrence of cytomegalovirus infection (CMV) and Epstein– Barr virus (EBV) lymphoproliferative disease [9]. Rapamycin is similar to tacrolimus in structure and likely has similar infectious disease effects, although some studies have suggested a lower incidence of CMV infection. Interestingly, rapamycin has potent in vitro fungicidal activity against Cryptococcus neoformans, Candida albicans, Aspergillus species, and other molds. The clinical significance of rapamycin’s antifungal activity is unclear [10]. The use of cyclophosphamide, azathioprine, and MMF results in a decrease in the number of functional T and B cells [10,11]. Patients receiving cyclophosphamide are at higher risk for bacterial infections and it is the most potent drug in suppressing the immune response specific for varicella zoster virus. The effect of azathioprine on the risk of infection is not as strong as cyclophosphamide. However, azathioprine can also cause neutropenia leading to an increased risk of bacterial infections [10,11]. MMF, a recently developed immunosuppressive drug, was initially used for organ transplantation but is emerging as an alternative for the treatment of lupus nephritis. MMF has a similar infectious diseases profile to other immunosuppressive medications discussed above but may predispose to a higher risk of invasive CMV disease and other herpes viruses such as varicella zoster and herpes simplex [10]. In contrast to the other immunosuppressive agents, methotrexate is relatively safe and has a much lower risk of infection associated with its use. Methotrexate inhibits folate metabolism, antibody synthesis, leukotriene production, and interleukin-1 activity. Cellular effects include inhibition of neutrophil and NK cell function. Most patients do not exhibit overt signs of immunosuppression although methotrexate may be associated with a modest increase in the rate of bacterial respiratory and skin infections. Methotrexate is useful for the treatment of many immunemediated disorders because of its excellent risk/benefit ratio [12]. Infliximab and etanercept are biological products that inhibit TNF alpha, one of the major pro-inflammatory cytokines. Infliximab is a monoclonal antibody that binds to TNF alpha. Etanercept is a human TNF alpha receptor that binds to TNF alpha with greater affinity than do natural receptors, and subsequently renders the bound TNF alpha biologically unavailable. Since TNF alpha plays an important role in host defense against infection; inhibition of its activity could therefore be expected to increase the risk of infection. Treatment with TNF alpha antagonists has been associated with serious bacterial, fungal, mycobacterial, and bacterial infection. Use of infliximab is associated with a marked increase in the occurrence of tuberculosis. Patients
D.J. Lovell et al. / Clinical Immunology 113 (2004) 137–139
in whom infliximab therapy is being considered should be evaluated for the presence of latent tuberculosis infection. The risk of tuberculosis is higher with infliximab than with etanercept [13].
References [1] S. Magni-Manzoni, F. Rossi, A. Pistorio, et al., Prognostic factors for radiographic progression, radiographic damage and disability in juvenile idiopathic arthritis, Arthritis Rheum. 48 (2003) 3509 – 3517. [2] M. Ostensen, H.M. Hoyerraal, E. Kass, Tolerance of cyclosporine A in children with refractory juvenile rheumatoid arthritis, J. Rheumatol. 15 (1988) 1536 – 1538. [3] E.H. Giannini, E.J. Brewer, N. Kuzimina, et al., Methotrexate in resistant juvenile rheumatoid arthritis. Results of the USA-USSR double-blind, placebo-controlled trial, N. Engl. J. Med. 326 (1992) 1043 – 1049. [4] D.J. Lovell, E.H. Giannini, A. Reiff, et al., Etanercept in children with polyarticular juvenile rheumatoid arthritis, N. Engl. J. Med. 342 (2000) 763 – 769. [5] C.A. Wallace, D.D. Sherry, Preliminary report of higher dose methotrexate treatment in juvenile rheumatoid arthritis, J. Rheumatol. 19 (1992) 1604 – 1607.
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[6] N. Ruperto, K.J. Murray, V. Gerloni, et al., A randomized trial of parenteral methotrexate in intermediate versus higher doses in children with juvenile idiopathic arthritis who failed standard dose, Arthritis Rheum. (2004) (in press). [7] D.J. Lovell, et al., for the Pediatric Rheumatology Collaborative Study Group, Long-term efficacy and safety of etanercept in children with polyarticular-course juvenile rheumatoid arthritis: interim results from an ongoing multicenter, open-label, extended-treatment trial, Arthritis Rheum. 48 (2003) 218 – 226. [8] T. Ellerin, R.H. Rubin, M.E. Weinblatt, Infections and anti-tumor necrosis factor alpha therapy, Arthritis Rheum. 48 (2003) 3013 – 3022. [9] J.M. Smith, T.L. Nemeth, R.A. McDonald, Current immunosuppressive agents: efficacy, side effects, and utilization, Pediatr. Clin. North Am. 50 (2003) 1283 – 1300. [10] S. Husain, N. Singh, The impact of novel immunosuppressive agents on infections in organ transplant recipients and the interactions of these agents with antimicrobials, Clin. Infect. Dis. 35 (2002) 53 – 61. [11] I. Kang, S. Hwan Park, Infectious complications in SLE after immunosuppressive therapies, Curr. Opin. Rheumatol. 15 (2003) 528 – 534. [12] K.S. Kanik, J.M. Cash, Does methotrexate increase the risk of infection or malignancy, Rheum. Dis. Clin. North Am. 23 (1997) 955 – 967. [13] M.A. Gardam, E.C. Keystone, R. Menzies, et al., Anti-tumor necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management, Lancet Infect. Dis. 3 (2003) 148 – 155.
Case Discussion
Immunosuppressants, infection, and inflammation Daniel J. Lovell, Theoklis E. Zaoutis, and Kathleen Sullivan * Division Immunologic Infectious Disease, Children’s Hospital of Philadelphia, Philadelphia, PA 19104 USA Received 10 March 2004; accepted 12 March 2004 Available online 26 June 2004
Case A 3-year-old girl abruptly developed fever with swollen, painful wrists and knees. She initially responded to naproxen but several months later developed numerous swollen joints, low-grade fevers, and fatigue. A diagnosis of polyarticular juvenile rheumatoid arthritis (JRA) was made and 10 mg/m2/wk of methotrexate was added to the naproxen to control her joint pain. She had no response to this regimen, and in fact, she developed new joint involvement. Furthermore, radiologic evaluations demonstrated additional cartilage destruction. A recommendation was made to increase the methotrexate dose, add therapy with a TNF alpha inhibitor, or add cyclosporine. The family is extremely concerned about the level of immunocompromise these agents would induce because the child has a history of recurrent infections and has been hospitalized twice for pneumonia.
Recommendations of Dr. Daniel Lovell, MD, MPH In consideration of this case, it is important to stress that this child has worsening, destructive arthritis that if left uncontrolled, will result in additional joint damage. She has demonstrated two significant poor prognostic factors for severity of the arthritis (wrist involvement and demonstration of radiologic joint damage). In a recent study of radiologic joint damage in juvenile arthritis, the most significant predictor of worsening joint damage after 24 months was the presence of any radiologic joint damage at the onset of the study [1]. Given these facts, the question at hand must be what (not if) additional therapy should be used to treat this child with polyarticular JRA. * Corresponding author. Division Immunologic Infectious Disease, Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104. Fax: +1-215-590-3044. E-mail address: [email protected] (K. Sullivan). 1521-6616/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.clim.2004.03.010
Early trials of cyclosporine in JRA at transplant doses (approximately 10 mg/kg/day) demonstrated a high frequency of adverse events with few children being able to continue the medication for even 1 year [2]. A recent international registry of cyclosporine use in children with JRA (n = 344) demonstrated that at a mean dose of 3.5 mg/ kg/day, over 60% discontinued due to lack of clinical improvement (E.H. Giannini, personal communication). Therefore, cyclosporine seems a poor choice for this child. Both methotrexate [3] and the TNF alpha inhibitor, etanercept [4], have demonstrated efficacy in children with severe polyarticular JRA in randomized, placebo controlled trials (RCT). The dose of methotrexate used in this child was the dose found efficacious in approximately 70% of the subjects enrolled in the randomized RCT [3]. One small open study demonstrated that for children not responding to this dose, escalation of the methotrexate dose to as much as 1 mg/ kg body weight (maximum of 50 mg/week) will often bring the disease into control [5]. However, a large randomized prospective trial [6] comparing two higher doses of parenteral methotrexate (15 versus 30 mg/m2/week) in children with polyarticular JRA that had failed to respond to 10 mg/m2/ week orally, the overall response rate using the ACR Pediatric 30 definition of response, was similar at both doses. Methotrexate was well tolerated in this study with only 5% and 12% discontinuing therapy due to adverse events, respectively. This study suggests that if methotrexate is used in this child, the maximal dose should be 15 – 20 mg/m2/week. Methotrexate is unquestionably the best-studied therapy in both children and adults with chronic arthritis. Extensive use in children with JRA for over 20 years has failed to produce convincing evidence of significant immunosuppression or increased frequency of serious infections. In the aforementioned RCT of methotrexate in polyarticular JRA [3], the rate of serious infections was similar in the placebo and the methotrexate. These data suggest that methotrexate does not significantly increase the rate of severe infections. The data from the only RCT utilizing etanercept in children [4] with severe polyarticular JRA did not demon-
138
D.J. Lovell et al. / Clinical Immunology 113 (2004) 137–139
strate a significantly increased rate of nonserious upper respiratory infections nor serious infections in the etanercept versus placebo arms (0.14 vs. 0.16 nonserious events/patient month, respectively, P = 0.82). However, during the RCT and open extension study [7], two of three subjects who developed varicella had courses complicated by aseptic meningitis although all demonstrated full recovery and normal development of varicella-specific antibodies. Another patient developed a severe infection with invasive group A beta hemolytic Streptococcus. In RCTs of etanercept in adults with RA, the overall rate of severe infections has not been statistically different in the etanercept and placebo arms [8]. However, data from open label studies in adults with RA suggest an increased rate of a several infections including tuberculosis with anti-TNF therapies [8]. In my opinion, in this child, given the severity of the current arthritis and the presence of several poor prognostic indicators, more aggressive therapy is certainly warranted. Given the history of recurrent infections, it would be wise to evaluate the child for immunodeficiency. The next step I would suggest is the use of parenteral methotrexate at 15– 20 mg/m2/week for 3– 6 months, and if the child continued to demonstrate active articular disease by either symptoms or joint exam, I would perform TB testing (and treatment of latent TB, if appropriate) and begin etanercept at a dose of 0.4 mg/kg/dose (maximum of 25 mg/dose) twice weekly. With either methotrexate or etanercept, the standard precautions used for any immunosuppressed subject should be observed (e.g., avoidance of live virus vaccines, varicella exposure or infection precautions, holding medication for febrile illnesses, increased index of suspicion for evolution of severe infections). Given the history of recurrent infections, the more conservative approach of substituting etanercept for methotrexate instead of adding it to existing methotrexate would be appropriate.
Recommendations of Dr. Theoklis Zaoutis, MD Immunosuppressive agents have improved the outcomes of autoimmune disorders and solid organ transplantation in children. The goal of immunosuppressive therapy is to optimize disease control while limiting side effects such as an increased risk of infection. Immunosuppressive medications commonly used in clinical practice include corticosteroids, cytotoxic drugs (cyclophosphamide, azathioprine, mycophenolate mofetil [MMF]), calcineurin inhibitors (cyclosporine A, tacrolimus, rapamycin), and the folic acid analogue (methotrexate) [9 – 12]. Newer agents include monoclonal antibodies against TNF alpha (113). Corticosteroids, cyclosporine, tacrolimus, and rapamycin inhibit T-cell activation, proliferation, and function [9]. The infectious disease effects of these agents are predicated on the same mechanisms involved in their therapeutic action; they promote infection with organisms in which cell-mediated immunity is the dominant host defense. Patients re-
ceiving these agents are susceptible to herpes group viruses, fungi, mycobacteria, Strongyloides stercoralis, and infection with such intracellular organisms as Listeria monocytogenes, and Salmonella species. The calcineurin inhibitors, in particular, promote the occurrence of cytomegalovirus infection (CMV) and Epstein– Barr virus (EBV) lymphoproliferative disease [9]. Rapamycin is similar to tacrolimus in structure and likely has similar infectious disease effects, although some studies have suggested a lower incidence of CMV infection. Interestingly, rapamycin has potent in vitro fungicidal activity against Cryptococcus neoformans, Candida albicans, Aspergillus species, and other molds. The clinical significance of rapamycin’s antifungal activity is unclear [10]. The use of cyclophosphamide, azathioprine, and MMF results in a decrease in the number of functional T and B cells [10,11]. Patients receiving cyclophosphamide are at higher risk for bacterial infections and it is the most potent drug in suppressing the immune response specific for varicella zoster virus. The effect of azathioprine on the risk of infection is not as strong as cyclophosphamide. However, azathioprine can also cause neutropenia leading to an increased risk of bacterial infections [10,11]. MMF, a recently developed immunosuppressive drug, was initially used for organ transplantation but is emerging as an alternative for the treatment of lupus nephritis. MMF has a similar infectious diseases profile to other immunosuppressive medications discussed above but may predispose to a higher risk of invasive CMV disease and other herpes viruses such as varicella zoster and herpes simplex [10]. In contrast to the other immunosuppressive agents, methotrexate is relatively safe and has a much lower risk of infection associated with its use. Methotrexate inhibits folate metabolism, antibody synthesis, leukotriene production, and interleukin-1 activity. Cellular effects include inhibition of neutrophil and NK cell function. Most patients do not exhibit overt signs of immunosuppression although methotrexate may be associated with a modest increase in the rate of bacterial respiratory and skin infections. Methotrexate is useful for the treatment of many immunemediated disorders because of its excellent risk/benefit ratio [12]. Infliximab and etanercept are biological products that inhibit TNF alpha, one of the major pro-inflammatory cytokines. Infliximab is a monoclonal antibody that binds to TNF alpha. Etanercept is a human TNF alpha receptor that binds to TNF alpha with greater affinity than do natural receptors, and subsequently renders the bound TNF alpha biologically unavailable. Since TNF alpha plays an important role in host defense against infection; inhibition of its activity could therefore be expected to increase the risk of infection. Treatment with TNF alpha antagonists has been associated with serious bacterial, fungal, mycobacterial, and bacterial infection. Use of infliximab is associated with a marked increase in the occurrence of tuberculosis. Patients
D.J. Lovell et al. / Clinical Immunology 113 (2004) 137–139
in whom infliximab therapy is being considered should be evaluated for the presence of latent tuberculosis infection. The risk of tuberculosis is higher with infliximab than with etanercept [13].
References [1] S. Magni-Manzoni, F. Rossi, A. Pistorio, et al., Prognostic factors for radiographic progression, radiographic damage and disability in juvenile idiopathic arthritis, Arthritis Rheum. 48 (2003) 3509 – 3517. [2] M. Ostensen, H.M. Hoyerraal, E. Kass, Tolerance of cyclosporine A in children with refractory juvenile rheumatoid arthritis, J. Rheumatol. 15 (1988) 1536 – 1538. [3] E.H. Giannini, E.J. Brewer, N. Kuzimina, et al., Methotrexate in resistant juvenile rheumatoid arthritis. Results of the USA-USSR double-blind, placebo-controlled trial, N. Engl. J. Med. 326 (1992) 1043 – 1049. [4] D.J. Lovell, E.H. Giannini, A. Reiff, et al., Etanercept in children with polyarticular juvenile rheumatoid arthritis, N. Engl. J. Med. 342 (2000) 763 – 769. [5] C.A. Wallace, D.D. Sherry, Preliminary report of higher dose methotrexate treatment in juvenile rheumatoid arthritis, J. Rheumatol. 19 (1992) 1604 – 1607.
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[6] N. Ruperto, K.J. Murray, V. Gerloni, et al., A randomized trial of parenteral methotrexate in intermediate versus higher doses in children with juvenile idiopathic arthritis who failed standard dose, Arthritis Rheum. (2004) (in press). [7] D.J. Lovell, et al., for the Pediatric Rheumatology Collaborative Study Group, Long-term efficacy and safety of etanercept in children with polyarticular-course juvenile rheumatoid arthritis: interim results from an ongoing multicenter, open-label, extended-treatment trial, Arthritis Rheum. 48 (2003) 218 – 226. [8] T. Ellerin, R.H. Rubin, M.E. Weinblatt, Infections and anti-tumor necrosis factor alpha therapy, Arthritis Rheum. 48 (2003) 3013 – 3022. [9] J.M. Smith, T.L. Nemeth, R.A. McDonald, Current immunosuppressive agents: efficacy, side effects, and utilization, Pediatr. Clin. North Am. 50 (2003) 1283 – 1300. [10] S. Husain, N. Singh, The impact of novel immunosuppressive agents on infections in organ transplant recipients and the interactions of these agents with antimicrobials, Clin. Infect. Dis. 35 (2002) 53 – 61. [11] I. Kang, S. Hwan Park, Infectious complications in SLE after immunosuppressive therapies, Curr. Opin. Rheumatol. 15 (2003) 528 – 534. [12] K.S. Kanik, J.M. Cash, Does methotrexate increase the risk of infection or malignancy, Rheum. Dis. Clin. North Am. 23 (1997) 955 – 967. [13] M.A. Gardam, E.C. Keystone, R. Menzies, et al., Anti-tumor necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management, Lancet Infect. Dis. 3 (2003) 148 – 155.