International Journal of Rheumatic Diseases 2014
ORIGINAL ARTICLE
Biologic agents therapy for Saudi children with rheumatic diseases: indications and safety Sulaiman M. AL-MAYOUF,1 Abdullatif ALENAZI,1 and Hind ALJASSER2 1
Sections of Rheumatology, Department of Pediatrics, Pharmacy Services, King Faisal Specialist Hospital and Research Center, and Clinical Pharmacy, Department of Pediatrics, Pharmacy Services, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
2
Abstract Objective: To report the indications and safety of biologic agents in childhood rheumatic diseases at a tertiary hospital. Methods: Children with rheumatic diseases treated with biologic agents at King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, from January 2001 to December 2011 were included. All patients were reviewed for: demographic characteristics, diagnosis, concomitant treatment and indications of using biologic agents, age at start of therapy and side effects during the treatment period. Results: In all, 134 children (89 female) with various rheumatic diseases were treated with biologic agents. Mean age at starting biologic treatment was 9.3 (4.25–14) years and mean therapy duration was 14.7 (3–88) months. Juvenile idiopathic arthritis (JIA) was the most frequent diagnosis (70.1%) followed by systemic lupus erythematosus (12.7%) and vasculitis (4.5%). All patients received concomitant therapy (corticosteroids and disease-modifying antirheumatic drugs). In total, 273 treatments with biologic agents were used, (95 etanercept, 52 rituximab, 47 adalimumab, 37 infliximab, 23 anakinra, 10 tocilizumab and nine abatacept). Therapy was switched to another agent in 57 (42.5%) patients, mainly because of inefficacy (89.4%) or adverse event (10.6%). A total of 95 (34.8%) adverse events were notified; of these, the most frequent were infusion-related reactions (33.7%) followed by infections (24.2%) and autoantibody positivity (10.6%). One patient developed macrophage activation syndrome. Conclusion: Biologic agents were used in children with a range of rheumatic diseases. Of these, the most frequent was JIA. Off-label use of biologic agents in our cohort is common. These agents seem safe. However, they may associated with various adverse events. Sequential therapy seems well tolerated. However, this should be carefully balanced and considered on an individual basis. Key words: adverse events, biologic agents, childhood rheumatic diseases, Saudi Arabia, sequential therapy.
INTRODUCTION Rheumatic diseases in children encompass several disease categories, each of which has distinct clinical signs Correspondence: Sulaiman M Al-Mayouf, Associate Professor Alfaisal University, Consultant and Section Head, Rheumatology, Department of Pediatrics, King Faisal Specialist Hospital and Research Center, PO Box 3354, Riyadh 11211, Saudi Arabia. Email: [email protected]
and symptoms. These diseases primarily include juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), juvenile dermatomyositis (JDM) and systemic vasculitis; classification criteria for most of these diseases are available.1–5 Children with rheumatic diseases are usually treated with disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate, sulfasalazine and leflunomide.6–8 However, not all patients respond to these treatments and some DMARDs are associated with toxicities that limit
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
S. M. Al-Mayouf et al.
long-term use or diminish compliance; such patients are therefore candidates for treatment with biologic agents. Biologic agents have emerged as effective therapies for treating a wide spectrum of rheumatic diseases.9,10 However, available data on the use of biologic agents in children with rheumatic diseases rely on some randomized controlled trials but especially on many of observational studies and case reports.11–16 In contrast, limited information, particularly from Middle East, exists on the long-term safety of these agents that are being used in children with rheumatic diseases and it is not known whether the use of sequential biologic agents over time leads to a cumulative risks of complications.17,18 Our aim is to evaluate the indications and safety of administering biologic agents in children with rheumatic diseases who were followed in the pediatric rheumatology clinic at King Faisal Specialist Hospital and Research Center (KFSH-RC).
METHODS Children with rheumatic diseases treated with biologic agents at KFSH-RC, Riyadh, from January 2001 to December 2011 were included. To make sure that all patients who received biologic agents were included, we used our own data and contacted pharmacy services to retrieve all children who had received biologic agents. All patients were reviewed for: demographic data, concomitant medications and indications of using biologic agents, time of starting and discontinuation of the medication and adverse events, including unusual manifestations not attributable to the primary disease. Adverse events were categorized into major and minor adverse events. Major adverse events were defined as resulting in death, life-threatening (patient was at immediate risk of death from the event), resulting in significant disability, infection requiring intravenous antibiotics or hospitalization, malignancy and autoimmune disorders. Minor events included other events such as local reaction, mild infection. All collected data were handled anonymously and confidentiality of the patients was protected and all collected data were acquired through routine clinical care. The proposal was approved by the Research Affairs Council at KFSHRC (#2111 083).
STATISTICAL ANALYSIS Descriptive statistics were used to describe the data. The results are expressed as mean standard deviation (SD) for continuous variables and frequencies and per-
2
centages for categorical variables. Student’s t-test and Chi-square test or Fisher exact test were used whenever appropriate to compare the data.
RESULTS In total, 134 children (89 female) with various rheumatic diseases were treated with 273 biologic agents; 77 patients used one biologic agent, 57 patients used two or more sequential treatments. Table 1 shows the demographic features of the patients and the number of biologic agents. Mean age was 9.3 (4.25–14) years; mean therapy duration was 14.7 (3–88) months. Table 2 shows the spectrum of diagnoses and their frequencies; JIA was the most prevalent diagnosis (70.1%) followed by SLE (12.7%) and vasculitis (4.5%). All patients received corticosteroids and DMARDs as concomitant therapy. All JIA patients used methotrexate and 17 patients were also treated with sulfasalazine. Ten patients with SLE used cyclophosphamide, while other SLE patients were treated with mycophenolate mofetil (four patients) and azathioprine (three patients). Table 1 Demographic features of the patients and the number of biologic agents Number of patients (F:M) Mean age at diagnosis, years (range) Mean age at starting biologic therapy, years (range) Mean disease duration, months (range) Mean therapy duration, months (range) Total of biologic agents No. patients used one biologic agent No. patients used two sequential biologic agents No. patients used < 2 sequential agents No. patients used three biologic agents No. patients used 4 biologic agents No. patients used 5 biologic agents No. patients used 6 biologic agents
134 (89 : 45) 7 (3.5–13) 9.3 (4.25–14.0)
62 (8–108) 14.7 (3–88) 273 77 19
38 10 15 10 3
International Journal of Rheumatic Diseases 2014
Biologic therapy in childhood rheumatic diseases
Table 2 Spectrum and frequency of diagnoses and biologic agents Diagnosis
Frequency
JIA Polyarticular 39 Systemic onset 42 Familial JIA 6 Spondyloarthropathy Psoriatic 2 Ankylosing IBD 2 associated arthritis 3 SLE 17 Auto inflammatory syndromes CINCA 3 MWS 2 Sarcoidosis 2 JDM 5 Vasculitis Unclassified 1 Vasculitis 5 Others Uveitis 1 MCTD 1 MAS 2 Devic’s NMO 1
Etanercept
Adalimumab
Infliximab
Anakinra
Rituximab
Tocilizumab
Abatacept
39 37 7
20 23 3
13 14 0
2 13 0
11 14 4
0 9 0
8 1 0
2 2 0 0
0 0 0 0
0 0 3 1
0 0 0 0
0 0 0 16
0 0 0 0
0 0 0 0
1 0 1 2
0 0 0 0
0 0 1 1
3 2 0 0
0 0 2 3
0 0 0 0
0 0 0 0
1 1
0 1
1 3
1 0
1 0
1 0
0 0
1 1 0 0
0 0 0 0
0 0 0 0
0 0 0 2
0 0 0 1
0 0 0 0
0 0 0 0
JIA, juvenile idiopathic arthritis; IBD, inflammatory bowel disease; CINCA, chronic infantile neurological, cutaneous and articular; MWS, Muckle– Wells syndrome; JDM, juvenile dermatomyositis; MCTD, mixed connective tissue disease; MAS, macrophage-activation syndrome; Devic’s NMO, neuromyelitis optica.
All patients had laboratory assessment before initiating the biologic treatment, particularly anti-tumor necrosis factor (anti-TNF) agents; the assessment comprised chest X-ray, tuberculin skin test (TST), antinuclear antibodies and rheumatoid factor. Only one patient had positive TST. However, other assessments for tuberculosis, including chest X-ray, were negative despite that particular patient receiving tuberculosis prophylactic therapy (isoniazid) for 6 months. In total, 273 treatments with biologic agents were used; 95 etanercept, 52 rituximab, 47 adalimumab, 37 infliximab, 23 anakinra, 10 tocilizumab and nine abatacept. Seventy-seven, (57.5%) patients commenced the biologic agents for the first time due to active disease despite 3 months conventional (DMARDs) therapy, while 57 (42.5%) patients used it because of failure of the previous biologic treatment. Sixteen (12%) patients were able to stop their biologic treatment because of disease control (duration of benefit 14–56 months). However, after a few months (6–9 months) seven patients (four etanercept, one adalimumab, one anakinra, one infliximab) were restarted again on biologic agents because of disease
International Journal of Rheumatic Diseases 2014
relapse and they were still on the same treatment. In contrast, 57 (42.5%) patients discontinued biologic treatment either due to inefficacy (51 patients) or due to adverse events (six patients). Of those patients in whom the first biologic agent was considered as being treatment failure, the biologic agent was switched for another agent. Nineteen patients used two sequential agents, while 38 patients tried more than two agents (Table 1). Thirty-nine patients experienced a range of adverse events. Ninety-five (34.8%) adverse events associated with biologic treatment were notified; these events were categorized into three groups: infusion-related reaction, infection and others. Table 3 shows the frequency and type of the adverse events per biologic agent. Twenty-seven events (28.4%) were considered as major events and 68 events (71.6%) were minor events. The most frequent events were infusion-related reactions (33.7%); 18 events related to intravenous infusion. Ten patients developed anaphylaxis-like reaction (eight infliximab, one rituximab, one tocilizumab) requiring therapy termination while other reactions were mild and were managed by slowing the infusion
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S. M. Al-Mayouf et al.
Table 3 Adverse events in children with rheumatic disease treated with biologic agents Etanercept No. of patients Total adverse events Infusion related Local reaction Infections Diarrhea Fever Autoimmune diseases Autoantibody positivity High LFT Leukopenia Others
95 30 1 7 4 1 1 5 2 3 1 5
Adalimumab 47 16 0 4 4 2 0 0 5 0 1 0
Infliximab 37 16 8 0 3 0 1 0 2 1 1 0
Anakinra 23 11 0 3 5 1 1 0 1 0 0 0
Rituximab; 52 16 5 0 6 0 0 1 0 0 1 3
Tocilizumab
Abatacept
Total
10 4 3 0 1 0 0 0 0 0 0 0
9 2 1 0 0 0 0 0 0 0 1 0
273 95 18 14 23 4 3 6 10 4 5 8
LFT, liver function test.
rate; in contrast, 14 local reactions were related to subcutaneous infusion in form of local reaction, such as pain and redness at site of injection. Infection was the second most frequent adverse event (24.2%). Most of the events were mild, in the form of upper respiratory tract infection, urinary tract infection and soft tissue infection; most of these were managed by oral antibiotics. Four patients had diarrhea with no isolated organisms and three patients were found to have fever without an infection focus. Five patients were hospitalized because of pneumonia and treated with intravenous antibiotics. One patient had severe soft tissue fungal infection after the first dose of rituximab; she required hospitalization and intravenous antifungal therapy and two patients (etanercept, adalimumab) developed varicella and were treated with intravenous acyclovir. Four patients (two rituximab and two anakinra) developed septic shock due to Gram-negative sepsis; the two patients treated with anakinra passed away. Six patients developed other autoimmune diseases during the biologic treatment period; two patients developed uveitis and one each developed lupus-like, sarcoidosis, psoriasis and diabetes mellitus. On the other hand, 10 patients developed autoantibody (antinuclear antibody and rheumatoid factor) positivity. None of the patients developed malignancy. However, one patient developed macrophage activation syndrome after the first dose of rituximab infusion. Another eight events were noticed during the treatment period (two patients had headache and one each developed alopecia areata, plastic bronchitis, depression, pancreatitis, pityriasis alba and peri-orbital swelling).
4
DISCUSSION The use of biologic agent therapy for childhood rheumatic diseases is rapidly expanding. Four agents are now available and approved for treating JIA: etanercept, adalimumab, abatacept and tocilizumab.12–14,16 Obviously, use of biologic agents becomes an important therapeutic option for standard care of JIA. However, available data on the use of biologic agents in children with rheumatic diseases other than JIA rely on observational studies and case reports. It is worth mentioning that the usual practical indications for off-label use of biologic agents in childhood rheumatic diseases are either life-threatening conditions or severe refractoriness or intolerance to conventional therapy.11,19 In the current study, JIA was the most frequent diagnosis and as expected the approval agents (etanercept, adalimumab) for JIA were the most often used biologic agents. However, the off-label use of biologic agents in our cohort was common, taking into consideration the range of diseases, including SLE, JDM and other infant diseases, besides using unapproved biologic agents for JIA such as rituximab and infliximab. It not unusual that children with rheumatic diseases who need continuous treatment and have failed the current anti-TNF therapy due to either loss of the initial clinical response or toxicity, switch to a second antiTNF agent or other biologic agent with different mechanisms of action, although the exact risk of switching is not known.20,21 Fifty-seven patients (42.5%) in our cohort switched to another biologic agent; 20 patients used two agents sequentially and 37 patients attempted more than two
International Journal of Rheumatic Diseases 2014
Biologic therapy in childhood rheumatic diseases
agents (up to six agents); we believed that this group reflected the more severe end of our cohort; most of them were unresponsive to the previous biologic therapy and only 10.6% were intolerant to the first biologic agent. It is not known for how long these agents should be used. However, patients usually stay on therapy until they achieve remission; unfortunately, in many instants patients need to restart the therapy again because of disease flare. We had only 16 (12%) patients who were able to stop their biologic treatment because of disease control; seven patients resumed it because of disease relapse. There have been several published reports on favorable safety and tolerability profiles of different biologic agents in children with rheumatic diseases; however, the available data of long-term safety is limited, especially from the Middle East.22,23 Most of the reported adverse events are mild, such as infusion-related reactions and upper respiratory tract infection; yet serious events like malignancy, opportunistic infections and autoimmune events have been reported.17,23 In this study, 95 adverse events associated with biologic treatment were notified; most of these were infusion-related reactions and were considered minor events. Nonetheless, 10 patients developed anaphylaxis-like reaction necessitating therapy withdrawal. Most of the infections were mild. However, few patients had serious infection and required hospitalization and intravenous antimicrobial therapy. Unfortunately, two patients died because of Gram-negative septic shock. The first rituximab-treated patients who developed serious infections were treated with high doses (750 mg/m2); later we changed the dose to 350 mg/m2 for the next patients; fortunately, we did not see more grave infections. Autoimmune events, including a new autoimmune disease or autoantibody positivity, are identified adverse events in patients treated with biologic agents.24 However; it is hard to make a strong causative link to these agents as patients with autoimmune diseases may develop another disease over time. For example; patients with JIA might develop uveitis or psoriasis during the disease course. Six of our patients developed autoimmune diseases and 10 patients with negative baseline autoantibody testing converted to autoantibody positivity. These findings highlight a need for careful monitoring of children who are receiving biologic agents for treatment of rheumatic diseases, taking into account the increased risk of remote autoimmunity events during treatment.
International Journal of Rheumatic Diseases 2014
There is a major concern about the increased risk of malignancy in JIA patients treated with anti-TNF agents. However, the underlying disease and the concomitant immunosuppressive therapy may result in the occurrence of malignancy; thus, it is hard to draw a definite direct relationship. Nevertheless, recent data indicated that short-term risk of cancer is low.25–27 None of our patients developed malignancy but one patient with active systemic onset JIA proved to have macrophage activation syndrome after rituximab. We believe that it is probably a consequence of the disease and not a real adverse event from the medication. In conclusion, to the best of our knowledge, this is the first study from the Middle East discussing the long-term safety of biologic agents in children with rheumatic diseases. Knowing that our institution is the main tertiary pediatric rheumatology clinic in the country, these results show the range of biologic agents used in children with a range of rheumatic diseases. Off-label use of biologic agents in our cohort was common. These agents seem relatively safe. However, they may be associated with various adverse events. Sequential therapy seems well tolerated. However, it should be carefully balanced and considered on an individual basis. Our study has limitations; taking into consideration the nature of this work, we could not discuss the efficacy of these agents and it is not yet possible to make definite recommendations for the off-label use of biologic agents in children, especially in juvenile diseases.
REFERENCES 1 Petty RE, Southwood TR, Manners PJ et al. (2004) International League of Associations for Rheumatology Classification of Juvenile Idiopathic Arthritis: second revision, Edmonton, 2001. J Rheumatol 31, 390–2. 2 Tan E, Cohen A, Fries J et al. (1982) The 1982 revised criteria for the classification of the systemic lupus erythematosus. Arthritis Rheum 25, 1271–7. 3 Ozen S, Pistorio A, Iusan S et al. (2010) EULAR/PRINTO/PRES criteria for Henoch-Sch€ onlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: final classification criteria. Ann Rheum Dis 69, 798–806. 4 Duffy C (2004) Health outcomes in pediatric rheumatic diseases. Curr Opin Rheumatol 16, 102–8. 5 Ruperto N, Pistorio A, Ravelli A et al. (2011) Criteria to define response to therapy in paediatric rheumatic diseases. Eur J Clin Pharmacol 67, 125–31.
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6 Silverman E, Mouy R, Spiegel L et al. (2005) Leflunomide or methotrexate for juvenile rheumatoid arthritis. N Engl J Med 352, 1655–66. 7 Giannini E, Cawkwell G (1995) Drug treatment in children with juvenile rheumatoid arthritis. Past, present, and future. Pediatr Clin North Am 42, 1099–125. 8 Packham J, Hall M (2002) Long-term follow-up of 246 adults with juvenile idiopathic arthritis: functional outcome. Rheumatology (Oxford) 41, 1428–35. 9 Furst D, Keystone E, Braun J et al. (2010) Updated consensus statement on biological agents for the treatment of rheumatic diseases (2011). Ann Rheum Dis 70 (Suppl. 1), i2–36. 10 Ramos-Casals M, Brito-Zer on P, Mu~ noz S, Soto M, BIOGEAS Study group (2008) A systematic review of the offlabel use of biological therapies in systemic autoimmune diseases. Medicine 87, 345–64. 11 Breda L, Del Torto M, De Sanctis S, Chiarelli F (2011) Biologics in children’s autoimmune disorders: efficacy and safety. Eur J Pediatr 170, 157–67. 12 Lovell D, Giannini E, Reiff A et al. (2000) Etanercept in children with polyarticular juvenile rheumatoid arthritis. N Engl J Med 342, 763–9. 13 Ruperto N, Lovell DJ, Quartier P et al. (2008) Abatacept inchildren with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial. Lancet 372, 383–91. 14 Lovell D, Ruperto N, Goodman S et al. (2008) Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. N Engl J Med 359, 810–20. 15 Tynj€al€a P, V€ah€asalo P, Tarkiainen M et al. (2011) Aggressive combination drug therapy in very early polyarticular juvenile idiopathic arthritis (ACUTE-JIA): a multicentre randomised open-label clinical trial. Ann Rheum Dis 70, 1605–12. 16 Quartier P, Allantaz F, Cimaz R et al. (2011) A multicentre, randomised, double-blind, placebo-controlled trial with the interleukin-1 receptor antagonist anakinra in patients with systemic-onset juvenile idiopathic arthritis (ANAJIS trial). Ann Rheum Dis 70, 747–54.
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17 Hashkes P, Uziel Y, Laxer R (2010) The safety profile of biologic therapies for juvenile idiopathic arthritis. Nat Rev Rheumatol 6, 561–71. 18 Alexeeva E, Valieva S, Bzarova T et al. (2011) Efficacy and safety of repeat courses of rituximab treatment in patients with severe refractory juvenile idiopathic arthritis. Clin Rheumatol 30, 1163–72. 19 Brik R, Gepstein V, Shahar E, Goldsher D, Berkovitz D (2007) Tumor necrosis factor blockade in the management of children with orphan diseases. Clin Rheumatol 26, 1783–5. 20 Tynj€al€a P, V€ah€asalo P, Honkanen V, Lahdenne P (2009) Drug survival of the first and second course of anti-tumor necrosis factor agents in juvenile idiopathic arthritis. Ann Rheum Dis 68, 552–7. 21 Dhingra N, Morgan J, Dick A (2009) Switching biologic agents for uveitis. Eye 23, 1868–70. 22 Gartlehner G, Hansen R, Jonas B, Thieda P, Lohr K (2008) Biologics for the treatment of juvenile idiopathic arthritis: a systemic review and clinical analysis of the evidence. Clin Rheumatol 27, 67–76. 23 Gerloni V, Pontikaki I, Gattinara M, Fantini F (2008) Focus on adverse events of tumor necrosis factor alpha blockade in juvenile idiopathic arthritis in an open monocentric long-term prospective study of 163 patients. Ann Rheum Dis 67, 1145–52. 24 Prinz J (2011) Autoimmune-like syndromes during TNF blockade: does infection have a role? Nat Rev Rheumatol 29, 429–34. 25 Diak P, Siegel J, La Grenade L, Choi L, Lemery S, McMahon A (2010) Tumor necrosis factor alpha blockers and malignancy in children: forty-eight cases reported to the Food and Drug Administration. Arthritis Rheum 62, 2517– 24. 26 Simard J, Neovius M, Hagelberg S, Askling J (2010) Juvenile Idiopathic Arthritis and Risk of Cancer: a nationwide cohort study. Arthritis Rheum 62, 3776–82. 27 McCroskery P, Wallace C, Lovell D et al. (2010) Summary of worldwide pediatric malignancies reported after exposure to etanercept. Pediatr Rheum Online J 8, 18.
International Journal of Rheumatic Diseases 2014
ORIGINAL ARTICLE
Biologic agents therapy for Saudi children with rheumatic diseases: indications and safety Sulaiman M. AL-MAYOUF,1 Abdullatif ALENAZI,1 and Hind ALJASSER2 1
Sections of Rheumatology, Department of Pediatrics, Pharmacy Services, King Faisal Specialist Hospital and Research Center, and Clinical Pharmacy, Department of Pediatrics, Pharmacy Services, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
2
Abstract Objective: To report the indications and safety of biologic agents in childhood rheumatic diseases at a tertiary hospital. Methods: Children with rheumatic diseases treated with biologic agents at King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, from January 2001 to December 2011 were included. All patients were reviewed for: demographic characteristics, diagnosis, concomitant treatment and indications of using biologic agents, age at start of therapy and side effects during the treatment period. Results: In all, 134 children (89 female) with various rheumatic diseases were treated with biologic agents. Mean age at starting biologic treatment was 9.3 (4.25–14) years and mean therapy duration was 14.7 (3–88) months. Juvenile idiopathic arthritis (JIA) was the most frequent diagnosis (70.1%) followed by systemic lupus erythematosus (12.7%) and vasculitis (4.5%). All patients received concomitant therapy (corticosteroids and disease-modifying antirheumatic drugs). In total, 273 treatments with biologic agents were used, (95 etanercept, 52 rituximab, 47 adalimumab, 37 infliximab, 23 anakinra, 10 tocilizumab and nine abatacept). Therapy was switched to another agent in 57 (42.5%) patients, mainly because of inefficacy (89.4%) or adverse event (10.6%). A total of 95 (34.8%) adverse events were notified; of these, the most frequent were infusion-related reactions (33.7%) followed by infections (24.2%) and autoantibody positivity (10.6%). One patient developed macrophage activation syndrome. Conclusion: Biologic agents were used in children with a range of rheumatic diseases. Of these, the most frequent was JIA. Off-label use of biologic agents in our cohort is common. These agents seem safe. However, they may associated with various adverse events. Sequential therapy seems well tolerated. However, this should be carefully balanced and considered on an individual basis. Key words: adverse events, biologic agents, childhood rheumatic diseases, Saudi Arabia, sequential therapy.
INTRODUCTION Rheumatic diseases in children encompass several disease categories, each of which has distinct clinical signs Correspondence: Sulaiman M Al-Mayouf, Associate Professor Alfaisal University, Consultant and Section Head, Rheumatology, Department of Pediatrics, King Faisal Specialist Hospital and Research Center, PO Box 3354, Riyadh 11211, Saudi Arabia. Email: [email protected]
and symptoms. These diseases primarily include juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), juvenile dermatomyositis (JDM) and systemic vasculitis; classification criteria for most of these diseases are available.1–5 Children with rheumatic diseases are usually treated with disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate, sulfasalazine and leflunomide.6–8 However, not all patients respond to these treatments and some DMARDs are associated with toxicities that limit
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
S. M. Al-Mayouf et al.
long-term use or diminish compliance; such patients are therefore candidates for treatment with biologic agents. Biologic agents have emerged as effective therapies for treating a wide spectrum of rheumatic diseases.9,10 However, available data on the use of biologic agents in children with rheumatic diseases rely on some randomized controlled trials but especially on many of observational studies and case reports.11–16 In contrast, limited information, particularly from Middle East, exists on the long-term safety of these agents that are being used in children with rheumatic diseases and it is not known whether the use of sequential biologic agents over time leads to a cumulative risks of complications.17,18 Our aim is to evaluate the indications and safety of administering biologic agents in children with rheumatic diseases who were followed in the pediatric rheumatology clinic at King Faisal Specialist Hospital and Research Center (KFSH-RC).
METHODS Children with rheumatic diseases treated with biologic agents at KFSH-RC, Riyadh, from January 2001 to December 2011 were included. To make sure that all patients who received biologic agents were included, we used our own data and contacted pharmacy services to retrieve all children who had received biologic agents. All patients were reviewed for: demographic data, concomitant medications and indications of using biologic agents, time of starting and discontinuation of the medication and adverse events, including unusual manifestations not attributable to the primary disease. Adverse events were categorized into major and minor adverse events. Major adverse events were defined as resulting in death, life-threatening (patient was at immediate risk of death from the event), resulting in significant disability, infection requiring intravenous antibiotics or hospitalization, malignancy and autoimmune disorders. Minor events included other events such as local reaction, mild infection. All collected data were handled anonymously and confidentiality of the patients was protected and all collected data were acquired through routine clinical care. The proposal was approved by the Research Affairs Council at KFSHRC (#2111 083).
STATISTICAL ANALYSIS Descriptive statistics were used to describe the data. The results are expressed as mean standard deviation (SD) for continuous variables and frequencies and per-
2
centages for categorical variables. Student’s t-test and Chi-square test or Fisher exact test were used whenever appropriate to compare the data.
RESULTS In total, 134 children (89 female) with various rheumatic diseases were treated with 273 biologic agents; 77 patients used one biologic agent, 57 patients used two or more sequential treatments. Table 1 shows the demographic features of the patients and the number of biologic agents. Mean age was 9.3 (4.25–14) years; mean therapy duration was 14.7 (3–88) months. Table 2 shows the spectrum of diagnoses and their frequencies; JIA was the most prevalent diagnosis (70.1%) followed by SLE (12.7%) and vasculitis (4.5%). All patients received corticosteroids and DMARDs as concomitant therapy. All JIA patients used methotrexate and 17 patients were also treated with sulfasalazine. Ten patients with SLE used cyclophosphamide, while other SLE patients were treated with mycophenolate mofetil (four patients) and azathioprine (three patients). Table 1 Demographic features of the patients and the number of biologic agents Number of patients (F:M) Mean age at diagnosis, years (range) Mean age at starting biologic therapy, years (range) Mean disease duration, months (range) Mean therapy duration, months (range) Total of biologic agents No. patients used one biologic agent No. patients used two sequential biologic agents No. patients used < 2 sequential agents No. patients used three biologic agents No. patients used 4 biologic agents No. patients used 5 biologic agents No. patients used 6 biologic agents
134 (89 : 45) 7 (3.5–13) 9.3 (4.25–14.0)
62 (8–108) 14.7 (3–88) 273 77 19
38 10 15 10 3
International Journal of Rheumatic Diseases 2014
Biologic therapy in childhood rheumatic diseases
Table 2 Spectrum and frequency of diagnoses and biologic agents Diagnosis
Frequency
JIA Polyarticular 39 Systemic onset 42 Familial JIA 6 Spondyloarthropathy Psoriatic 2 Ankylosing IBD 2 associated arthritis 3 SLE 17 Auto inflammatory syndromes CINCA 3 MWS 2 Sarcoidosis 2 JDM 5 Vasculitis Unclassified 1 Vasculitis 5 Others Uveitis 1 MCTD 1 MAS 2 Devic’s NMO 1
Etanercept
Adalimumab
Infliximab
Anakinra
Rituximab
Tocilizumab
Abatacept
39 37 7
20 23 3
13 14 0
2 13 0
11 14 4
0 9 0
8 1 0
2 2 0 0
0 0 0 0
0 0 3 1
0 0 0 0
0 0 0 16
0 0 0 0
0 0 0 0
1 0 1 2
0 0 0 0
0 0 1 1
3 2 0 0
0 0 2 3
0 0 0 0
0 0 0 0
1 1
0 1
1 3
1 0
1 0
1 0
0 0
1 1 0 0
0 0 0 0
0 0 0 0
0 0 0 2
0 0 0 1
0 0 0 0
0 0 0 0
JIA, juvenile idiopathic arthritis; IBD, inflammatory bowel disease; CINCA, chronic infantile neurological, cutaneous and articular; MWS, Muckle– Wells syndrome; JDM, juvenile dermatomyositis; MCTD, mixed connective tissue disease; MAS, macrophage-activation syndrome; Devic’s NMO, neuromyelitis optica.
All patients had laboratory assessment before initiating the biologic treatment, particularly anti-tumor necrosis factor (anti-TNF) agents; the assessment comprised chest X-ray, tuberculin skin test (TST), antinuclear antibodies and rheumatoid factor. Only one patient had positive TST. However, other assessments for tuberculosis, including chest X-ray, were negative despite that particular patient receiving tuberculosis prophylactic therapy (isoniazid) for 6 months. In total, 273 treatments with biologic agents were used; 95 etanercept, 52 rituximab, 47 adalimumab, 37 infliximab, 23 anakinra, 10 tocilizumab and nine abatacept. Seventy-seven, (57.5%) patients commenced the biologic agents for the first time due to active disease despite 3 months conventional (DMARDs) therapy, while 57 (42.5%) patients used it because of failure of the previous biologic treatment. Sixteen (12%) patients were able to stop their biologic treatment because of disease control (duration of benefit 14–56 months). However, after a few months (6–9 months) seven patients (four etanercept, one adalimumab, one anakinra, one infliximab) were restarted again on biologic agents because of disease
International Journal of Rheumatic Diseases 2014
relapse and they were still on the same treatment. In contrast, 57 (42.5%) patients discontinued biologic treatment either due to inefficacy (51 patients) or due to adverse events (six patients). Of those patients in whom the first biologic agent was considered as being treatment failure, the biologic agent was switched for another agent. Nineteen patients used two sequential agents, while 38 patients tried more than two agents (Table 1). Thirty-nine patients experienced a range of adverse events. Ninety-five (34.8%) adverse events associated with biologic treatment were notified; these events were categorized into three groups: infusion-related reaction, infection and others. Table 3 shows the frequency and type of the adverse events per biologic agent. Twenty-seven events (28.4%) were considered as major events and 68 events (71.6%) were minor events. The most frequent events were infusion-related reactions (33.7%); 18 events related to intravenous infusion. Ten patients developed anaphylaxis-like reaction (eight infliximab, one rituximab, one tocilizumab) requiring therapy termination while other reactions were mild and were managed by slowing the infusion
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Table 3 Adverse events in children with rheumatic disease treated with biologic agents Etanercept No. of patients Total adverse events Infusion related Local reaction Infections Diarrhea Fever Autoimmune diseases Autoantibody positivity High LFT Leukopenia Others
95 30 1 7 4 1 1 5 2 3 1 5
Adalimumab 47 16 0 4 4 2 0 0 5 0 1 0
Infliximab 37 16 8 0 3 0 1 0 2 1 1 0
Anakinra 23 11 0 3 5 1 1 0 1 0 0 0
Rituximab; 52 16 5 0 6 0 0 1 0 0 1 3
Tocilizumab
Abatacept
Total
10 4 3 0 1 0 0 0 0 0 0 0
9 2 1 0 0 0 0 0 0 0 1 0
273 95 18 14 23 4 3 6 10 4 5 8
LFT, liver function test.
rate; in contrast, 14 local reactions were related to subcutaneous infusion in form of local reaction, such as pain and redness at site of injection. Infection was the second most frequent adverse event (24.2%). Most of the events were mild, in the form of upper respiratory tract infection, urinary tract infection and soft tissue infection; most of these were managed by oral antibiotics. Four patients had diarrhea with no isolated organisms and three patients were found to have fever without an infection focus. Five patients were hospitalized because of pneumonia and treated with intravenous antibiotics. One patient had severe soft tissue fungal infection after the first dose of rituximab; she required hospitalization and intravenous antifungal therapy and two patients (etanercept, adalimumab) developed varicella and were treated with intravenous acyclovir. Four patients (two rituximab and two anakinra) developed septic shock due to Gram-negative sepsis; the two patients treated with anakinra passed away. Six patients developed other autoimmune diseases during the biologic treatment period; two patients developed uveitis and one each developed lupus-like, sarcoidosis, psoriasis and diabetes mellitus. On the other hand, 10 patients developed autoantibody (antinuclear antibody and rheumatoid factor) positivity. None of the patients developed malignancy. However, one patient developed macrophage activation syndrome after the first dose of rituximab infusion. Another eight events were noticed during the treatment period (two patients had headache and one each developed alopecia areata, plastic bronchitis, depression, pancreatitis, pityriasis alba and peri-orbital swelling).
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DISCUSSION The use of biologic agent therapy for childhood rheumatic diseases is rapidly expanding. Four agents are now available and approved for treating JIA: etanercept, adalimumab, abatacept and tocilizumab.12–14,16 Obviously, use of biologic agents becomes an important therapeutic option for standard care of JIA. However, available data on the use of biologic agents in children with rheumatic diseases other than JIA rely on observational studies and case reports. It is worth mentioning that the usual practical indications for off-label use of biologic agents in childhood rheumatic diseases are either life-threatening conditions or severe refractoriness or intolerance to conventional therapy.11,19 In the current study, JIA was the most frequent diagnosis and as expected the approval agents (etanercept, adalimumab) for JIA were the most often used biologic agents. However, the off-label use of biologic agents in our cohort was common, taking into consideration the range of diseases, including SLE, JDM and other infant diseases, besides using unapproved biologic agents for JIA such as rituximab and infliximab. It not unusual that children with rheumatic diseases who need continuous treatment and have failed the current anti-TNF therapy due to either loss of the initial clinical response or toxicity, switch to a second antiTNF agent or other biologic agent with different mechanisms of action, although the exact risk of switching is not known.20,21 Fifty-seven patients (42.5%) in our cohort switched to another biologic agent; 20 patients used two agents sequentially and 37 patients attempted more than two
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Biologic therapy in childhood rheumatic diseases
agents (up to six agents); we believed that this group reflected the more severe end of our cohort; most of them were unresponsive to the previous biologic therapy and only 10.6% were intolerant to the first biologic agent. It is not known for how long these agents should be used. However, patients usually stay on therapy until they achieve remission; unfortunately, in many instants patients need to restart the therapy again because of disease flare. We had only 16 (12%) patients who were able to stop their biologic treatment because of disease control; seven patients resumed it because of disease relapse. There have been several published reports on favorable safety and tolerability profiles of different biologic agents in children with rheumatic diseases; however, the available data of long-term safety is limited, especially from the Middle East.22,23 Most of the reported adverse events are mild, such as infusion-related reactions and upper respiratory tract infection; yet serious events like malignancy, opportunistic infections and autoimmune events have been reported.17,23 In this study, 95 adverse events associated with biologic treatment were notified; most of these were infusion-related reactions and were considered minor events. Nonetheless, 10 patients developed anaphylaxis-like reaction necessitating therapy withdrawal. Most of the infections were mild. However, few patients had serious infection and required hospitalization and intravenous antimicrobial therapy. Unfortunately, two patients died because of Gram-negative septic shock. The first rituximab-treated patients who developed serious infections were treated with high doses (750 mg/m2); later we changed the dose to 350 mg/m2 for the next patients; fortunately, we did not see more grave infections. Autoimmune events, including a new autoimmune disease or autoantibody positivity, are identified adverse events in patients treated with biologic agents.24 However; it is hard to make a strong causative link to these agents as patients with autoimmune diseases may develop another disease over time. For example; patients with JIA might develop uveitis or psoriasis during the disease course. Six of our patients developed autoimmune diseases and 10 patients with negative baseline autoantibody testing converted to autoantibody positivity. These findings highlight a need for careful monitoring of children who are receiving biologic agents for treatment of rheumatic diseases, taking into account the increased risk of remote autoimmunity events during treatment.
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There is a major concern about the increased risk of malignancy in JIA patients treated with anti-TNF agents. However, the underlying disease and the concomitant immunosuppressive therapy may result in the occurrence of malignancy; thus, it is hard to draw a definite direct relationship. Nevertheless, recent data indicated that short-term risk of cancer is low.25–27 None of our patients developed malignancy but one patient with active systemic onset JIA proved to have macrophage activation syndrome after rituximab. We believe that it is probably a consequence of the disease and not a real adverse event from the medication. In conclusion, to the best of our knowledge, this is the first study from the Middle East discussing the long-term safety of biologic agents in children with rheumatic diseases. Knowing that our institution is the main tertiary pediatric rheumatology clinic in the country, these results show the range of biologic agents used in children with a range of rheumatic diseases. Off-label use of biologic agents in our cohort was common. These agents seem relatively safe. However, they may be associated with various adverse events. Sequential therapy seems well tolerated. However, it should be carefully balanced and considered on an individual basis. Our study has limitations; taking into consideration the nature of this work, we could not discuss the efficacy of these agents and it is not yet possible to make definite recommendations for the off-label use of biologic agents in children, especially in juvenile diseases.
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