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Infection-related death among persons with refractory juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA), a group of clinically heterogenous conditions with arthritis of unknown origin beginning before 16 years of age and persisting for >6 weeks, is the most common childhood chronic rheumatic disorder (1). The most severe forms are those with systemic (So-JIA) or polyarticular (poly-JIA) onset, progressing to polyarticular disease. Despite the success of conventional and new biological disease-modifying antirheumatic drugs (DMARDs), a substantial percentage (>30%) of patients will have ongoing active disease into adulthood that includes sequelae from chronic inflammation and considerable morbidity from joint damage, osteoporosis, growth retardation, psychosocial morbidity, and reduced quality of life and education or employment (2).

Rapidly evolving guidelines (3) include the window-of-opportunity concept, where biological DMARDs are used as tailored therapy, depending on the disease category, and in naive patients not previously treated with conventional DMARDs (e.g., corticosteroids) (2). In the United Kingdom, treatment guidelines are regulated by the National Institute for Clinical Excellence, which specifies indications for tumor necrosis factor-[alpha] (TNF-[alpha]), interleukin (IL) 6, T-cell activation, and IL-1 blocking agents (; uk/advice/esnm36). However, no good evidence exists to guide clinicians when they confront failure of the initial biological DMARD (4), and switching to a second (or third) (5) or combining [greater than or equal to] 2 biological DMARDs (6) raises concern about risks from severe infections and development of malignancy and new autoimmune disorders (7,8). For this small group of patients with refractory JIA, hematopoietic stem cell transplantation (HSCT) might be the only treatment option (9).

We report details of 4 patients referred for HSCT because of refractory JIA who died of overwhelming infection from central venous catheter (CVC)-related bacterial sepsis (3 patients) or disseminated viral infection (1 patient). Two died while receiving high-dose systemic corticosteroids and methotrexate and after recent exposure to anti-TNF-[alpha] agents, before they underwent stem cell collection and were not started on conditioning chemotherapy at the time of death; 2 died during HSCT (10,11).

Case Reports

Parents provided informed consent for data and tissue collection. Consent was obtained when the child started treatment with new anti-TNF-[alpha] agents (British Society for Paediatric and Adolescent Rheumatology database) or at assessment for HSCT (Newcastle upon Tyne Hospitals National Health Service [NHS] Foundation Trust, Newcastle upon Tyne, UK).

Patient 1

Patient 1, a 13-year-old girl with refractory So-JIA who was previously reported with osteoarticular tuberculosis while treated with etanercept (12) (Table 1), never achieved complete disease control (Juvenile Arthritis Disease Activity Score [JADAS]-10 score 25-30) (Table 1) (73). She was assessed for HSCT on February 17, 2004 (Table 2). After CVC insertion for treatment with weekly intravenous methylprednisolone pulses (IVMPs) and 1 dose of infliximab, routine CVC cultures grew fully sensitive coagulase-negative Staphylococcus. She was treated with systemic teicoplanin and vancomycin locks to all 3 CVC lumens for 7 days (15). On February 28, three days after antimicrobial treatment ended, she was readmitted with fever (40[degrees]C), generalized macular erythematous rash, abdominal discomfort, nausea, vomiting, and diarrhea. Alongside empirical treatment with systemic antimicrobial drugs (vancomicin and cefotaxime) and intravenous fluids, presumed adrenal insufficiency was treated with hydrocortisone, but she remained febrile (38.6[degrees]C); on February 29, she had a sudden episode of hypotension (blood pressure 70 mm Hg) requiring fluid bolus resuscitation and further hydrocortisone. On March 1, as the CVC was accessed for administration of antimicrobial drugs, she became pale and light-headed and collapsed; the CVC was removed, but she died of cardiorespiratory arrest. Multiple peripheral blood and CVC cultures taken during this period remained sterile. Autopsy showed congested lungs and pleural effusions, atrophic adrenal glands, no identifiable thymus, and no erythrophagocytosis in liver or spleen. Cultures from the CVC tip, both lungs, and the pleural fluid samples taken post mortem grew [alpha]-hemolytic Streptococcus.

Patient 2

Patient 2, a 6-year-old girl, had refractory So-JIA (Table 1) with macrophage activation syndrome (MAS), a form of hemophagocytic lymphohistiocytosis and a potentially fatal complication characterized by unremitting fever, pancytopenia, liver failure with coagulopathy, and central nervous system dysfunction (14). Several months before referral, she was brought for care again with possible MAS; symptoms and signs included fever, hepatomegaly, diarrhea, anemia, thrombocytopenia, high serum ferritin (5,670 [micro]g/L [reference 20-60 [micro]g/L]). albeit with leukocytosis and normal clotting (16). She was treated with IVMP and high-dose intravenous immunoglobulin. A previously inserted CVC was removed because of Enterobacter intermedins infection. Because her disease was never in full remission (JADAS-10 score 20-30; Table 1), she was referred on May 27, 2004, for HSCT (Table 2). On June 1 (one week after new CVC insertion), she was admitted with fever (38[degrees]C), macular erythematous rash, vomiting, swelling and pain of several joints, and cough (Table 2). Chest examination and radiographic findings were normal, and she was treated empirically with systemic antimicrobial drugs (teicoplanin and meropenem) for 1 week (15) and a 3-day course of IVMP for presumed MAS. After transient improvement during the next few days, on June 6 the child again became unwell, with fever (38.5[degrees]C), rash, hepatomegaly, and joint pain (Table 2). Empirical treatment with systemic antimicrobial drugs (teicoplanin and ceftriaxone) was restarted with another 3-day course of IVMP, but she remained febrile (38.5[degrees]C) and became restless with abdominal pain and vomiting. She was transferred to the pediatric intensive care unit (PICU), where surgical reasons for acute abdomen pain were excluded. Ciprofloxacin and ambisome were added to the treatment regimen but the child's condition rapidly progressed into multiorgan failure (Table 2), and she died on June 10. Multiple peripheral blood and CVC cultures taken during this period remained sterile. The family did not agree to autopsy. Culture from the CVC tip removed postmortem grew coagulase-negative Staphylococcus.

Patients 3 and 4

Both children received immunosuppressive conditioning with anti-T-cell globulin (rabbit, 10 mg/kg), fludarabine (150 mg/[m.sup.2]), and cyclophosphamide (120 mg/kg) (10,11). Both died during T-cell-depleted (by CD34+ positive selection; Miltenyi Biotec, San Diego, CA, USA) autologous HSCT.

Patient 3

Patient 3 was an 18-year-old woman whose So-JIA was diagnosed at 10 years of age. She had active systemic disease. MAS, and progressive polyarthritis refractory to conventional (corticosteroids, methotrexate, cyclosporine, leflunomide) and biological DMARDs, both TNF-[alpha] (infliximab, etanercept) and IL-1 (anakinra) inhibitors (JADAS-10 score over the years 22-35). She underwent HSCT in 2007 with MAS prevention (prednisolone, cyclosporine, and anakinra) during conditioning, but after uneventful engraftment, she died 2.5 months after HSCT of disseminated adenovirus (blood, feces, brain) and Epstein-Barr virus (EBV) (blood, cerebrospinal fluid) infection/reactivation. Aspergillus fumigatus was grown from a paranasal sinus washout sample in terminal stage; autopsy was not performed (10).

Patient 4

Patient 4 was a 13-year-old girl whose rheumatoid factor + poly-JIA was diagnosed at 4 years of age. She had progressive and debilitating polyarthritis refractory to conventional (corticosteroids, methotrexate) and biological (infliximab, etanercept, anakinra, rituximab) DMRADSs (JADAS-10 score over the years 24-30). She underwent HSCT in 2009. [alpha]-hemolytic Streptococcus grew from CVC culture taken during a febrile episode after receipt of anti-T-cell globulin, and she was treated empirically with meropenem and teicoplanin; unusually, she rapidly progressed into multiorgan failure requiring ventilatory, inotropic, and renal support in the PICU. Because results of initial liver function tests, including clotting, were normal, and C-reactive protein (CRP) response was adequate, the impression was of bacterial (or fungal) septicemia and renal failure. After transient improvement, she completed conditioning and HSCT and, despite renal failure, maintained stable neutrophil engraftment but remained platelet dependent. Bone marrow biopsy was hypocellular and showed some evidence of macrophage activation. Subsequently, and in parallel with acute pancreatitis, encephalopathy, and progressive enteral and liver failure, the girl manifested prolonged hyperinflammatory response (CRP 100-170 mg/L [reference 0-5 mg/L]; fibrinogen 6-10 g/L [reference 1.5-4.0 g/L]; raised neutrophil count >20 x [10.sup.9] cells/L) despite broad-spectrum antimicrobial and antifungal therapy. Multiple cultures and viral PCRs from different sites (blood, CVC, and other line tips; bone marrow and intestine biopsy; cerebrospinal fluid; maxillary sinus washing) remained negative. She died on day 43 after HSCT; autopsy confirmed multiorgan failure with severe secondary pancreatitis (11).

Possible Risk Factors for Severe Infection and Death

Treatment with Combined DMARDs, Including Biologicals

At death, patients 1 and 2 had active disease treated with high-dose systemic corticosteroids and methotrexate; because they previously had been exposed to long-term and multiple DMARDs, including anti-TNF-[alpha] biologicals (Table 1). Patients 3 and 4 underwent autologous T-cell-depleted HSCT after a severely immunosuppressive conditioning regimen.

Clinical observation of increased risk from severe infections in children with JIA, often requiring treatment in a hospital (17), recently was confirmed in a study of a large JIA cohort (18). The increased risk for concurrent immunosuppressive therapy, in addition to the underlying disease-related immune dysfunction (8,17), was supported by this study, in which high-dose systemic corticosteroids, but not methotrexate and/or anti-TNF-[alpha] agents, substantially increased susceptibility to severe infections (18). Although simultaneous use of different biological DMARDs is not common (5,6), a recently published study highlighted the exposure to multiple and often combined immunosuppressive drugs, such as corticosteroids, methotrexate, cyclosporine, cyclophosphamide, and a variety of biological antiinflammatory DMARDs, including TNF-[alpha], IL-1, and IL-6 blocking agents, as a major risk factor for severe infections and the unusually high rate of death for a selected group of children with refractory So-JIA, often complicated by MAS, and associated with pulmonary hypertension, interstitial lung disease, and alveolar proteinosis (19). It is well recognized that severe immunosuppression targeting B- and/or T-lymphocyte functions (e.g., B-cell-depleting agents, such as rituximab, T-cell activation blocking agent abatacept, anti-CD52 monoclonal antibody alemtuzumab, HSCT procedure) is often complicated with infections caused by a wide spectrum of pathogens, such as pyogenic bacteria, viruses, and fungi (7,9-11). In contrast, blocking specific inflammatory pathways (e.g., IL-1, IL-6, TNF-[alpha]) mimics some of the very rare primary immunodeficiencies of the innate immune system (20), with susceptibility to a relatively narrow range of pathogens (21,22). Infections with encapsulated pyogenic bacteria have been reported in patients with deficiencies of IL-6 function (23), whereas the essential role of TNF-[alpha] in defense against intracellular pathogens (24) was highlighted by the initially observed increased risk for mycobacterial infections associated with anti-TNF-[alpha] biologicals (7,12), prompting the introduction of effective screening and prevention measures (24). Although inconsistently reported (25), unusually prolonged, severe, and life-threatening infections with common bacterial pathogens are being seen in children with JIA treated with combined DMARDs, including anti-TNF-[alpha] agents (26,27). As observed in these patients (23,28), because of blocking of the inflammatory response mediated by TNF-[alpha], IL-1, or IL-6 cytokines, these patients might not have high fever and raised CRP, a fact of which clinicians should be aware (20-24,29). Regardless of active disease and combined immunosuppressive therapy, patients 1 and 2 (i.e.. those not undergoing HSCT) had preserved inflammatory responses (Table 2) and appropriate routine immunologic testing (data not shown).

CVC-Related Bacterial Infections

Three patients died of CVC-related bacterial sepsis with [alpha]-hemolytic Streptococcus and coagulase-negative Staphylococcus, common and fully sensitive organisms, despite timely administered appropriate antimicrobial therapy (15). Long-term CVCs are essential for patients requiring frequent blood tests and intravenous treatments. Unfortunately, CVC-related bloodstream infection is a well-recognized and potentially severe complication. Coagulase-negative Staphylococcus species are the most common pathogens causing CVC-related infections. Guidelines recommend treatment with 10-14 days of systemic antimicrobial drugs and antibiotic locks, but routine CVC removal is not recommended because most patients have a benign course and rarely develop sepsis or poor outcome (15). S. aureus, enteric gram-negative bacilli and Candida are less frequent but potentially more severe pathogens. Coagulase-negative Staphylococcus species (S. epidermidis in particular) were the most common (>50%) pathogens identified from 146 episodes of bacteremia in 64 children with primary immunodeficiencies undergoing HSCT in Great North Children's Hospital, whereas Enterococcus species, gram-negative organisms, and Candida were isolated only in few cases each (30). Most (80%) episodes were successfully treated with appropriate systemic and antibiotic locks; CVC was removed in 12 patients, and the only death resulted from overwhelming C. albicans infections despite CVC removal (30). Contrary to that study, severe and life-threatening CVC-related sepsis caused by S. epidermidis has been reported in a significant percentage of children with systemic vasculitis treated with infliximab and combined immunosuppressive and/or antiinflammatory therapies (31). Two deaths from CVC-related sepsis resulting from coagulase-negative Staphylococcus and combined Escherichia coli and Candida infection were reported from a cohort of children with inflammatory bowel disease treated with adalimumab in combination with other immunosuppressive medications (32). This high risk for severe CVC-related infections associated with active disease that requires multiple immunomodulatory therapies was also reported from a group of children with pediatric rheumatic disease-related complications admitted to PICU, with substantially high rate of death (50%), of which 44% resulted from multiorgan failure (33).

MAS versus Multiorgan Failure

Because the 3 patients we describe who died of CVC-related bacterial sepsis manifested unusually severe and rapidly progressing multiorgan failure, we considered the possibility of MAS in the differential diagnoses (14,16,33,34). MAS is a well-recognized major risk factor for death in children with JIA admitted to PICU (33,34). A recent international study of a large cohort of So-JIA patients identified the most common clinical features as fever, organomegaly, central nervous system involvement, and hemorrhage (16). The most useful laboratory parameters were thrombocytopenia; hyperferritinemia; increased liver transaminases, lactate dehydrogenase, triglycerides, and D-dimer levels; and decreased leukocyte count, erythrocyte sedimentation rate, and fibrinogen (16).

Some features that manifested near death, such as persisting fever, falling neutrophil and platelet counts, and increased serum transaminase levels (Table 2; patient 1 on March 1) suggest MAS inpatient 1 (16). Unfortunately, not all of the laboratory parameters highlighted as essential for the clinical diagnosis of MAS were available (14) (Table 2). However, the fact that she collapsed after CVC was accessed and that [alpha]-hemolytic Streptococcus grew from the CVC line tip, lung tissue, and pleural effusion samples after death favors infection as the cause of death. In patient 2, persisting fever, hepatomegaly, and high serum ferritin level suggested MAS, but increasing platelet and neutrophil counts, erythrocyte sedimentation rate, and fibrinogen and normal liver transaminase levels did not support MAS (14) (Table 2; patient 2 on June 6). Although rapid deterioration to terminal multiorgan failure was associated with falling platelet count, deranged liver function, and clotting (Table 2; patient 2 on June 10), the high neutrophil count suggested overwhelming fungal infection (which cannot be ruled out because autopsy was not performed), regardless of negative fungal cultures. In patient 4, unusually severe, progressive multiorgan failure developed after CVC-related sepsis, but normal liver function results and clotting and adequate CRP response did not support MAS. Features of macrophage activation in bone marrow biopsy were seen later in the course of progressive multiorgan failure and in parallel with unusual hyperinfiammation, suggesting possible fungal infection. However, multiple cultures from different sites remained negative, and autopsy confirmed severe pancreatitis. In patient 3, disseminated adenovirus and EBV infection/reactivation during HSCT led to bone marrow aplasia. In the terminal stage of multiorgan failure with A. fumigatus infection, results of liver function and clotting tests were normal, and inflammatory markers were raised (erythrocyte sedimentation rate 80 mm/h [Westergren method; reference 1-10 mm/h]; CRP 200 mg/L [reference 0-5 mg/L]; ferritin 11,000 |[micro]g/L [reference 20-60 |[micro]g/L|).

Deaths and Reporting Deaths

Although the death rate for JIA has decreased since the 1970s, 1 of 2 recent studies referring to the period before the use of biological DMARDs reported a standardized mortality ratio of 3.4 (95% CI 2.0-5.5) for boys and 5.1 (95% CI 3.2-7.8) for girls (35). This nationwide cohort study from Scotland (1,246 children with JIA during 1981-2000) reported 39 JIA-associated deaths, for which the most common causes were the underlying disease (9 cases), circulatory complications (8 cases), and respiratory complications (6 cases) (35). In the United States, the standardized mortality ratio for the JIA pediatric rheumatology mortality database (9,604 children with JIA during 1992-2001) was lower at 1.8 (95% CI 0.66-3.92), with 6 of 19 reported deaths occurring among children with So-JIA caused by MAS and heart failure (2 each) and infection and secondary malignancy (1 each) (36).

In addition to uncontrolled disease activity and its complications, in particular amyloidosis in the past and MAS today, several recent reviews highlighted the substantial risk for death from severe infections in children with JIA who are receiving biological DMARDs (7,8). Most of these children were treated with multiple and combined classical DMARDs before or alongside biological DMARDs. Although the range of causing pathogens is broad, pyogenic bacteria and herpes viruses were the most common (7,8). An unexpectedly high death rate (68% [17/25]) in a group of children with refractory So-JIA associated with pulmonary complications was recently reported from an international group of 25 patients (19). Although disease onset ranged from the 1980s onward and most children in the cohort had received multiple immunosuppressive and antiinflammatory drugs, 19 (76%) diagnoses were made after 2000; contrary to previous reports (35,36), 68% had been exposed to biological DMARDs (19). Strikingly, the calculated death rate for these 19 patients increased by almost 50% over the figure recently reported from the US pediatric rheumatology mortality database for the period up to 2000, before the use of biological DMARDs (36).

The regional pediatric rheumatology service at Great North Children's Hospital is closely linked to the national center providing expertise in investigating and treating children with primary immunodeficiencies for northern England and a leading center for HSCT in children with severe rheumatic diseases. This database holds -1,250 children in whom JIA has been diagnosed and who were treated and followed during 1994-2013; each year, 50-80 new patients are referred. The calculated death rate for children in this cohort is 0.032% (4 patients died during this period). Three had So-JIA and 1 rheumatoid factor + polyJIA, all with progressive polyarthritis and poorly controlled systemic disease for many years, including fever, rash, organomegaly, and high acute-phase reactants, with features of MAS in 2 So-JIA patients (14.16). All died during the early 2000s after long-term treatment with multiple and combined conventional and biological DMARDs: corticosteroids and methotrexate (all 4 children), cyclosporine and leflunomide (1 each); anti-TNF-[alpha] agents (3 etanercept, 4 infliximab); IL-1 blocking agent (2 anakinra); and B-cell-depleting (anti-CD20) monoclonal antibody (1 rituximab). Although considered in all 4, only 2 patients underwent autologous T-cell-depleted HSCT (10,11). With the expertise in pediatric rheumatology, immunology, and infectious diseases available in centers best placed to care for these most severe and often refractory cases, fatalities are rare but do occur.

Monitoring the safety and reporting the side effects, including severe infections and deaths, of new biological DMARDs is a priority of national and international patient registries and multicenter, international collaborative research consortiums, such as the Childhood Arthritis and Rheumatology Research Alliance, Pediatric Rheumatology International Trials Organisation, Pediatric Rheumatology Collaborative Study Group, and Single Hub and Access Point of Care for Pediatric Rheumatic Diseases in Europe (37,38). However, reporting of deaths is still inconsistent. In children with JIA treated with multiple DMARDs alongside anti-TNF-[alpha] biologicals, a systematic review from 2013 reported 4 deaths, 3 of which were associated with severe infections: 2 treated with etanercept (group A Streptococcus-related purpura fulminans) and 1 with adalimumab (bacterial sepsis); for 1 treated with infliximab, infection cause was not given (27). However, Hashkes et al. (8) commented on 6 deaths, all in children treated with combined DMARDs, including anti-TNF-[alpha] agents, and associated with serious infections: 3 treated with etanercept (1 each with suspected sepsis, MAS, and tuberculosis [previously treated with infliximab]); 2 with infliximab (sepsis); and 1 with adalimumab (MAS and interstitial pneumonia). Furthermore, neither Woerner and Ritz (7) nor Swart et al. (24) referred to severe infections and infection-related deaths associated with biological DMARDs from 2 clinical trials reported in 2012 (39,40). Six deaths were reported in trials of the anti-IL-6 agent tocilizumab, including 1 each from probable streptococcal sepsis and MAS (other listed causes were traffic accident, pulmonary hypertension [2 cases], and pneumothorax) (40). Two deaths were reported in a trial of long-acting anti-IL-1 agent canakinumab, both from MAS (1 was previously treated with anakinra and tocilizumab) (39). All these patients had active disease and had been treated with a combination of multiple DMARDs before or at death; some were reported as part of the So-JIA cohort associated with pulmonary complications and high death rate (19). The most recent report from the United States for 2008-2012 highlighted 7 deaths (1 from an accident) in children with JIA treated with multiple DMARDs (methotrexate and steroids), including biologicals (4 anakinra, 1 each etanercept and infliximab), of which 3 were associated with severe infections (multiorgan failure from disseminated tuberculosis, viral illness, and sepsis) (38).


Three patients with refractory JIA reported here died with evidence of CVC-related bacterial sepsis caused by common pathogens ([alpha]-hemolytic Streptococcus and coagulasenegative Staphylococcus): 2 while receiving high-dose systemic corticosteroids; and methotrexate and after recent exposure to the anti-TNF-[alpha] biological DMARD infliximab; 1 during HSCT procedure. As has been previously reported, we observed unusual severity of septic shock and rapid progression to multiorgan failure despite timely and appropriate antimicrobial treatment (31-33). Patient 4 died of disseminated adenovirus and EBV infection during HSCT procedure.

Evidence from clinical trials facilitated by multicenter international collaborative research enabled introduction of biological DMARDs in the treatment of rheumatic diseases in children and unprecedented improvement in their care during the past 20 years (1-4,41,42). However, severe infections are emerging as an important risk factor for death among children with JIA treated with combined and multiple conventional and new biological DMARDs (8,19,37,38). Accurately reporting all cases of severe infections and especially deaths in these children is of paramount importance, as was highlighted a decade ago (25). Although monitoring safety and reporting side effects of new biological DMARDs is in place and improving, we note marked inconsistency in the current literature (7,8,19,24,27,38-40).

Author affiliations: Great North Children's Hospital, Newcastle upon Tyne, UK (M. Abinun, J.P. Lane, M. Friswell, T.J. Flood, H.E. Foster); Newcastle University, Newcastle upon Tyne (M. Abinun, H.E. Foster); Leeds General Infirmary, Leeds, UK(M. Wood)



We are grateful to the Paediatric Rheumatology Teams in Liverpool and Glasgow, and the Paediatric Intensive Care Unit Team, Great North Children's Hospital, for providing excellent clinical care, and to Andrew Riordan and Athimalaipet V. Ramanan for helpful discussion.

M.W., M.F., T.J.F., H.E.F., and M.A. were involved in direct patient care. M.W., M.F., J.L., and M.A. collected the data. J.L. and M.A. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis and interpretation. M.A. wrote the manuscript. All authors read and approved the final version to be published and had input in revising it for intellectual content and style.

This work was supported by the National Institute for Health Research Financial Management Group Flexibility and Sustainability Funding (ref. FSF 121301 to M.A.).

Dr. Abinun is a senior consultant in pediatric immunology at Great North Children's Hospital and an honorary clinical senior lecturer at Newcastle University, Institute of Cellular Medicine, Primary Immunodeficiency Group. His research interests include primary immunodeficiency, autoimmune and auto inflammatory diseases, and treatment with hematopoietic stem cell transplantation.


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(35.) Tilomas E, Symmons DP, Brewster DH, Black RJ, Macfarlane GJ. National study of cause-specific mortality in rheumatoid arthritis, juvenile chronic arthritis, and other rheumatic conditions: a 20 year followup study. J Rheumatol. 2003;30:958-65.

(36.) Hashkes PJ. Wright BM. Lauer MS. Worley SE. Tang AS. Roettcher PA, et al. Mortality outcomes in pediatric rheumatology in the US. Arthritis Rheum. 2010;62:599-608.

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(42.) Wahezi DM, Ilowite NT. Juvenile idiopathic arthritis: an update on current pharmacotherapy and future perspectives. Expert Opin Phannacother. 2013;14:975-89. 6.2013.783569


This activity has been planned and implemented through the joint providership of Medscape, LLC and Emerging Infectious Diseases. Medscape, LLC is accredited by the American Nurses Credentialing Center (ANCC), the Accreditation Council for Pharmacy Education (ACPE), and the Accreditation Council for Continuing Medical Education (ACCME), to provide continuing education for the healthcare team.

Medscape, LLC designates this Journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit(s)[TM]. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 75% minimum passing score and complete the evaluation at; and (4) view/print certificate. For CME questions, see page 1866.

Release date: September 15, 2016; Expiration date: September 15, 2017

Learning Objectives

Upon completion of this activity, participants will be able to:

* Assess the prognosis and management considerations of juvenile idiopathic arthritis (JIA)

* Distinguish characteristics of fatal infections in the current case series

* Evaluate the relationship between biologic disease-modifying antirheumatic drugs (DMARDs) and the risk for serious infections

* Analyze the clinical presentation of macrophage activation syndrome

CME Editor

Karen L. Foster, MA, Technical Writer/Editor, Emerging Infectious Diseases. Disclosure: Karen L. Foster has disclosed no relevant financial relationships.

CME Author

Charles P. Vega, MD, Clinical Professor of Family Medicine, University of California, Irvine. Disclosure: Charles P. Vega, MD, has disclosed the following financial relationships: served as an advisor or consultant for Allergan, Inc.; McNeil Consumer Healthcare; served as a speaker or a member of a speakers bureau for Shire Pharmaceuticals.

Disclosures: Mario Abinun MD, PhD; Jonathan P. Lane, MBBS, Dip Clin Res; Mark Wood, MBBCh, MRCPCH; Mark Friswell, MBBCh, MRCPCH; and Terence J. Flood, MRCPi, have disclosed no relevant financial relationships. Helen E. Foster, MD, MBBS (Hons), has disclosed the following relevant financial relationships: other (unrestricted educational bursaries and honoraria) from Pfizer, BioMarin, AbbVie, Sobi, Genzyme.

CME Questions

1. You are seeing an 8-year-old girl with a history of polyarticular juvenile idiopathic arthritis (poly-JIA) that failed to improve after treatment with corticosteroids and methotrexate. She also had a poor response to infliximab. What should you consider regarding the management of JIA in this patient and its prognosis?

A. More than 70% of all patients with JIA will have ongoing active disease into adulthood

B. Patients with systemic JIA (So-JIA) and poly-JIA have the worst prognosis

C. The recommended practice after failure of a tumor necrosis factor-alpha antagonist is initiation of a biologic agent that blocks the action of interleukin

D. The recommended practice for this patient would be to combine 2 biologic agents with different mechanisms of action

2. The patient has a central venous catheter placed to facilitate treatment. One week later, she experiences a fever and malaise. Which of the following statements regarding characteristics of the 4 patients with juvenile idiopathic arthritis (JIA) and severe infection in the current study is most common?

A. Antibiotics were significantly delayed in all cases

B. There was a prolonged course of all infections with a slow progression toward death

C. Affected patients had no previous history of serious infections

D. Bacteria implicated in the infections included coagulase-negative Staphylococcus and alpha-hemolytic Streptococcus

3. What should you consider regarding the association between infections and the use of biologic disease-modifying antirheumatic drugs (DMARDs) for juvenile idiopathic arthritis (JIA)?

A. Treatment that targets B- and/or T-cell lymphocyte function results in immune dysfunction that mimics very rare and specific primary immunodeficiencies

B. Treatment that blocks specific inflammatory pathways such as interleukin-1 and tumor necrosis factor-alpha is associated with infections from a broad spectrum of organisms

C. Patients receiving biologic DMARDs may not present with high fever and elevated serum C-reactive protein levels

D. Deaths related to the use of biologic DMARDs are now well categorized in international patient registries

4. You are concerned regarding the potential for macrophage activation syndrome (MAS) in this patient. Which of the following is consistent with the clinical picture of MAS?

A. Central nervous system involvement is very uncommon

B. Triglyceride and D-dimer levels are elevated

C. Leukocyte count is elevated

D. Erythrocyte sedimentation rate is elevated
1. The activity supported the learning objectives.

Strongly Disagree                       Strongly Agree

1                   2       3      4         5

2. The material was organized clearly for learning to occur.

Strongly Disagree                       Strongly Agree

1                   2       3      4         5

3. The content learned from this activity will impact my practice.

Strongly Disagree                       Strongly Agree

1                   2       3      4         5

4. The activity was presented objectively and free of commercial bias.

Strongly Disagree                       Strongly Agree

1                   2       3      4         5

Address for correspondence: Mario Abinun, Great North Children's Hospital, Royal Victoria Infirmary, Queen Victoria Rd, Newcastle upon Tyne, NE1 4LP, LTK; email:

Mario Abinun, Jonathan P. Lane, Mark Wood, [1] Mark Friswell, Terence J. Flood, Helen E. Foster

[1] Current affiliation: Leeds General Infirmary, Leeds, UK.
Table 1. Disease characteristics and treatment at time of death
for 2 children with JIA, Newcastle upon Tyne, United Kingdom *

Characteristic                 Patient 1             Patient 2

Year of disease                1996/2004             2000/2004
onset/year of death

Age at So-JIA                    5/13                   2/6
diagnosis/at death, y

JIA symptom or
sign, ever
  Fever                           Yes                   Yes
  Rash                            Yes                   Yes
  Arthritis                       Yes                   Yes
  Lymphadenopathy                 No                     No
  Hepato/splenomegaly             Yes                   Yes
  Serositis                       No                     No
  Macrophage                      No                    Yes
     activation syndrome
Disease remission,                No                     No
JADAS-101 ([dagger])             20-35                 12-32

  Corticosteroids           Yes ([section])       Yes ([section])
  ([double dagger])
  Methotrexate              Yes ([section])       Yes ([section])
  Cyclosporin A                   No                    Yes (#)
  Intravenous                     No                    Yes
  immunoglobulins **                             ([dagger][dagger])
  Etanercept             Yes ([double dagger],           No
                           [double dagger])
  Infliximab                Yes ([section],        Yes ([section]
                          [section][section])       [paragraph]

Side effects of
  Cushingoid                      Yes                   Yes
  Cataracts                       Yes                    No
  Osteoporosis                    Yes                   Yes
  Osteoarticular                  Yes                    No
  Stunted growth                  Yes                   Yes

* JADAS, Juvenile Arthritis Disease Activity Score; JIA, juvenile
idiopathic arthritis; So-JIA, systemic JIA.

([dagger]) Linear sum of the scores of the 4 JADAS components
(0-40): physician global assessment of disease activity (measured
on a 10-cm visual analog scale; 0 = no activity and 10 = maximum
activity); parent/patient global assessment of well-being (measured
on a 10-cm visual analog scale; 0 = very well and 10 = very poor);
count of joints with active disease (0-10); erythrocyte
sedimentation rate (actual value/10; range 0-10) (13).

([double dagger]) Methylprednisolone pulses (intravenous 30 mg/kg/day;
maximum. 1 g) given as a 3-day course or a single dose (weekly or
otherwise), when indicated based on clinical decision (for treating
a disease flare). Prednisolone maintenance dose (orally 0.5-1
mg/kg/d) with adjusting and aiming for alternate day regimen
whenever possible depending on the clinical course or disease

([section]) Treatment at time of death.

([paragraph]) Subcutaneously 15 mg/m2/wk.

(#) March-December 2002.

** 2 g/kg/mo.

([dagger][dagger])December 2003-January 2004.

([double dagger][double dagger])0.4 mg/kg/wk during March-May 2000
(12) and again during May 2003-January 2004.

([section][section]) 5 mg/kg single dose, February 2004.

([paragraph][paragraph]) 6 mg/kg/mo during December 2002-December

Table 2. Laboratory parameters of inflammatory activity for 2 children
with juvenile idiopathic arthritis, Newcastle upon Tyne, United
Kingdom, 2004 *

Patient      CRP,    Ne, x [10.sup.9]      PLT, x      ESR,
no., date    mg/dL       cells/L        [10.sup.9]/L   mm/h

Patient 1
  Feb 17      100          20.2             322         35
  Feb 28      107          28.5             266         --
  Feb 29      157          15.8             140         --
  Mar 1       63           7.1               79         --

Patient 2
  May 27      122          17.2             475         45
  Jun 1       260          34.9             603         -
  Jun 6       365          37.5             710        105
  Jun 10      127          70.5             244         -

Patient        Ferr,                  TG,
no., date    [micro]g/L   Fib, g/L   mmol/L

Patient 1
  Feb 17        485         5.4       0.7
  Feb 28        --           --        --
  Feb 29        --           --        --
  Mar 1         --           --        --

Patient 2
  May 27        339         6.3       1.9
  Jun 1         2815        8.0        --
  Jun 6         7692        8.1        --
  Jun 10         -          2.9        --

Patient                             Na,
no., date    Alb, g/L   ALT, U/L   mmol/L

Patient 1
  Feb 17        34         24       142
  Feb 28        31         35       136
  Feb 29        22         48       134
  Mar 1         23        120       140

Patient 2
  May 27        44         10       135
  Jun 1         38         23       137
  Jun 6         37         50       134
  Jun 10        13        125       134

* Laboratory parameters for diagnosing macrophage activation
syndrome: Ferr >684 [micro]g/L and any 2 of the following signs:
PLT count <181 x [10.sup.9]/L, ALT >48 U/L, TG >156 mg/dL,
fibrinogen <360 mg/dL (14). See section in text on MAS versus
Multiorgan Failure. Alb, serum albumin level (reference 38-53 g/L);
ALT, serum alanine transaminase level (reference 0-40 U/L); CRP,
C-reactive protein (reference 0-5 mg/dL); ESR, erythrocyte
sedimentation rate (Westergren; reference 1-10 mm/h); Ferr, serum
ferritin level (reference 20-60 [micro]g/L); Fib, serum fibrinogen
level (reference 1.5-4.0 g/L); Na, serum sodium level (reference
135-145 mmol/L); Ne, absolute neutrophil count; PLT, absolute
platelet count; TG, serum triglyceride level (reference 0.5-1.8).
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Article Details
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Title Annotation:SYNOPSIS
Author:Abinun, Mario; Lane, Jonathan P.; Wood, Mark; Friswell, Mark; Flood, Terence J.; Foster, Helen E.
Publication:Emerging Infectious Diseases
Geographic Code:4EUUK
Date:Oct 1, 2016
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