1249 106 Pediatric Rheumatologic Disease MARLA GUZMAN, TIMOTHY HAHN, ALEXANDRA AMINOFF, AND KRISTEN HAYWARD • Approximately 1 child in 250 has a rheumatologic disease • A child may present to the inte[.]
106 Pediatric Rheumatologic Disease MARLA GUZMAN, TIMOTHY HAHN, ALEXANDRA AMINOFF, AND KRISTEN HAYWARD • • • The field of pediatric rheumatology encompasses a diverse set of fascinating but poorly understood disorders Although the exact pathophysiology of many rheumatologic conditions remains elusive, most are thought to be immune mediated in etiology Recent advances in immunology have allowed for important breakthroughs in identification of genetic and environmental contributions to these diseases as well as in increasingly effective treatments In particular, options for pharmacologic therapy of rheumatologic diseases have increased markedly since the early 2000s Biological medications that modulate the immune system are also being used in an increasing array of conditions outside traditional rheumatologic disorders, which have applications in cancer therapeutics, transplantation, and even in response to certain infections It is estimated that approximately child in 250 has a rheumatologic condition Although most patients are managed in the outpatient setting, children with rheumatologic disorders have the potential to become acutely ill and suffer life-threatening complications The exact number of children with rheumatologic disease who require intensive care management is unknown, but early diagnosis and rapid treatment can significantly decrease morbidity and mortality.1,2 Patients may present to the intensive • • • • Approximately child in 250 has a rheumatologic disease A child may present to the intensive care unit (ICU) with a lifethreatening manifestation of an undiagnosed rheumatologic disease or with severe complications of a known rheumatologic disorder Suspicion for rheumatologic disease should be high when children present with persistent fevers of unknown origin, multisystem involvement, joint involvement, or unexplained high inflammatory markers Diagnosing rheumatologic diseases is challenging, as few clinical features are pathognomonic and few diagnostic tests are confirmatory A thorough history and physical examination are essential Infectious and oncologic processes may mimic rheumatologic diseases and must be excluded Macrophage activation syndrome is a severe “cytokine storm” due to immune dysregulation in the setting of rheumatologic diseases, infections, and malignancy Early recognition and • • PEARLS aggressive treatment are essential, as it can lead to severe morbidity and death High-dose corticosteroid therapy is frequently used at diagnosis and for severe disease flares to bring inflammation under control quickly Corticosteroids are typically not sufficient to maintain long-term disease control and have many associated risks Thus, additional immunosuppressive therapy is employed to induce and maintain remission Immunosuppressive therapy used to treat rheumatologic diseases can lead to complications, including infections, liver disease, renal disease, and cytopenias Adrenal insufficiency following chronic corticosteroid use can occur if corticosteroid treatment is stopped abruptly Therapy for rheumatologic disease may be initiated in the ICU, which often includes high-dose corticosteroids; cyclophosphamide, anticytokine, and anticellular biological therapies; intravenous immunoglobulin; and plasmapheresis care unit (ICU) with severe manifestations of new-onset rheumatologic disease, severe complications of a known disorder, or complications secondary to immunosuppressive therapy This chapter provides an overview of the most common pediatric rheumatologic diseases followed by a discussion of the conditions and complications most likely to be encountered in the intensive care setting Rheumatologic Diseases: Overview Most rheumatologic diseases have historically been classified as autoimmune disorders Classical autoimmune diseases are characterized by adaptive immune dysfunction leading to loss of normal self-tolerance, inappropriate generation of autoantibodies, and resultant tissue injury.3 Over the past several decades, research has also begun to demonstrate the importance of innate immune pathways in the generation and propagation of immune-mediated pathophysiology Increasingly, rheumatologists are conceptualizing an immune-mediated disease spectrum with variable contributions of autoinflammatory and autoimmune responses (Fig 106.1) While certain rare monogenic diseases provide examples “pure” 1249 1250 S E C T I O N X I Pediatric Critical Care: Immunity and Infection Malignancy Surveillance Host defense Immunodeficiency Recognition and tolerance Autoinflammatory disease Defect in innate immune system Immune-mediated disease spectrum Monogenic autoinflammatory syndromes Large vessel vasculitis Systemic onset juvenile arthritis Rheumatoid arthritis Systemic lupus erythematosus ANCA vasculitis ALPS IPEX APECED Autoimmune disease Defect in adaptive immune system • Fig 106.1 Overlap in immunologic functions and disease pathologies ALPS, Autoimmune lymphopro- liferative syndrome; APECED, autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy; IPEX, Immune dysregulation, polyendocrinopathy, enteropathy, X-linked autoinflammatory or autoimmune processes, most rheumatologic diseases likely involve a complex interplay of aberrant innate and adaptive immune responses Similarly, a broader understanding of the role of tolerance and inflammation in host responses to infection and malignancy indicates that rheumatologic diseases are but one manifestation of a larger continuum of immune dysregulation Patients with defects in one immune function often demonstrate difficulty with other aspects of immunity Thus, patients with immunodeficiency and predisposition to infection often also develop autoimmune phenomenon Patients with malignancies such as leukemia and lymphoma may generate abnormal autoantibodies and/or inflammatory cytokine profiles Additionally, patients with underlying immune-mediated diseases have increased predisposition to development of malignancy due to effects of long-standing inflammation These considerations have important ramifications for diagnosis, treatment and management of rheumatologic diseases Rheumatologic diseases in children present in highly variable ways and can be difficult to diagnose and treat Given that immune-mediated diseases may present with systemwide involvement, these conditions require a thorough history and physical examination for accurate diagnosis Symptoms that should raise suspicion for an underlying immune-mediated disease include unexplained fevers or constitutional symptoms, multiorgan dysfunction, or persistent inflammation unresponsive to usual first-line therapies While laboratory tests may be helpful to support a certain disease, almost all rheumatologic diagnoses rely heavily on clinical criteria By definition, immune-mediated diseases are diagnoses of exclusion; given the overlapping nature of immune roles, exclusion of ongoing infectious insults or underlying malignancy as sources of persistent inflammation is an essential first step in establishing a disease as immune mediated Thus, laboratory tests are often more prognostic than diagnostic and suspicion for rheumatologic disease cannot be easily confirmed or eliminated by laboratory testing alone Arthritis is often considered the hallmark feature of rheumatologic diseases Almost any rheumatologic disease can potentially present with joint involvement However, certain rheumatologic diseases may present without overt joint inflammation In a patient who does have arthritis, it is important to assess for extraarticular manifestations Fig 106.2 provides one conceptual framework for categorization of rheumatologic diseases A full discussion of all of these disorders is beyond the scope of this chapter An overview of the clinical presentation, diagnosis, and treatment of representative diseases is presented next Rheumatologic Diseases: Clinical Presentation, Diagnosis, and Treatment Juvenile Idiopathic Arthritis Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatologic disease, representing a heterogeneous collection of chronic arthritides that are organized into subtypes based on clinical features (Fig 106.3).4 Most children with JIA are managed as outpatients, but the disease and its complications occasionally require intensive care An important distinction exists between systemic JIA (sJIA) and the other subtypes of JIA with regard to pathophysiology, presentation, clinical course, and treatment Advances in our understanding of the immunopathogenesis of sJIA indicate that this disorder closely resembles other so-called autoinflammatory diseases in which systemic inflammation is driven by defects in innate immune pathways.5–7 While adaptive immune cells are also involved in the pathogenesis, these disorders often lack detectable autoantibodies that are characteristic of more classic autoimmune diseases sJIA, which accounts for about 10% to 20% of children with JIA, is the JIA subtype that most often presents to the ICU sJIA is often complicated by severe multisystem disease, including a life-threatening cytokine storm known as macrophage activation syndrome (MAS), discussed later in the chapter Systemic Juvenile Idiopathic Arthritis Key Points sJIA presents with quotidian fevers, evanescent rash, lymphadenopathy, and serositis Arthritis may not be present at onset The most serious complication of sJIA is MAS, a form of secondary CHAPTER 106 Pediatric Rheumatologic Disease 1251 Pediatric Chronic Arthritis Predominant joint involvement Joints + systemic disease JIA Autoinflammatory syndromes sJIA MAS Sarcoidosis Behcet disease Periodic fever (monogenic inflammatory) syndromes Primary vasculitis Takayasu arteritis Kawasaki disease Polyarteritis nodosa ANCA-associated vasculitis Henoch-Schönlein purpura Systemic autoimmune diseases SLE Sjögren JDM Systemic sclerosis Mixed connective tissue disease • Fig 106.2 Concept map for rheumatologic disorders in childhood ANCA, Antineutrophil cytoplasmic antibody; JDM, juvenile dermatomyositis; MAS, macrophage activation syndrome; sJIA, systemic juvenile idiopathic arthritis; SLE, systemic lupus erythematosus Juvenile idiopathic arthritis (JIA) Oligoarticular ≤4 joints at disease onset Persistent Oligo JIA Extended Oligo JIA Polyarticular ≥4 joints at disease onset Rheumatoid factor negative Rheumatoid factor positive Systemic JIA Arthritis, prolonged fevers, rash, LAD, serositis, hepatosplenomegaly Psoriatic arthritis Arthritis, enthesitis, dactylitis, nail changes, personal or family history of psoriasis Undifferentiated Overlapping features or not otherwise classified Enthesitis-related arthritis Juvenile equivalent of adult spondyloarthropathy All categories of JIA require: • Presence of persistent joint inflammation (>6 weeks) • Exclusion of infection, malignancy, or other identifiable causes • Fig 106.3 Overview of juvenile idiopathic arthritis (JIA) classification categories and subtypes LAD, Lymphadenopathy hemophagocytic lymphohistiocytosis (HLH) sJIA can mimic malignancy and severe sepsis Severe hyperferritinemia can help diagnose sJIA but is not specific or sensitive as a single diagnostic criterion Treatment involves targeted therapy with interleukin-1 (IL-1) and IL-6 inhibitors Clinical Presentation The classic features of sJIA include daily high fevers, a characteristic evanescent rash, and arthritis.8 The fevers (39°C) typically occur daily in a spiking quotidian pattern with return to normal temperature for at least weeks The rash is typically a nonpruritic, salmon-colored, macular rash that can be subtle It usually occurs with fever spikes and is rapidly migratory, often disappearing completely when the temperature normalizes Arthritis can be present in any number of joints, with some patients having minimal joint involvement and others with extensive polyarticular joint disease While a complete joint examination is essential, arthritis may not be a prominent feature early in disease and can lag behind other manifestations of inflammation, such as pericardial effusion or serositis Other clinical features may include diffuse lymphadenopathy and hepatosplenomegaly Cardiac involvement in sJIA occurs in up to 10% of patients at onset and typically presents as pericarditis with or without pericardial effusion.9 Pericarditis is often recurrent but usually benign and rarely causes cardiac tamponade Pleuritis is the most common pulmonary complication, but parenchymal disease can occur as well Patients with severe disease are at risk of developing interstitial lung disease, alveolar proteinosis, bronchiolitis obliterans, and pulmonary hypertension.10,11 Interstitial lung disease can rarely occur in non-sJIA, particularly in rheumatoid factor–positive polyarticular JIA or secondary to drug toxicity (methotrexate) Laboratory Studies Laboratory findings consistent with sJIA include anemia (with hemoglobin levels often between 6–8 g/dL); elevated white blood cell (WBC) counts, sometimes in the leukemoid range; and 1252 S E C T I O N X I Pediatric Critical Care: Immunity and Infection elevated platelet counts Cytopenias should prompt consideration of malignancy or MAS C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are usually markedly elevated However, in the setting of MAS, the ESR may fall owing to declining fibrinogen levels Consumptive pathophysiology may also result in inappropriately “normal” WBC and platelet counts or frank cytopenias Hyperferritinemia is commonly seen both at onset and during flares of disease activity and is a marker for increased risk of MAS.12,13 Antinuclear antibodies (ANAs), rheumatoid factor, and anticyclic citrullinated peptide (anti-CCP) antibodies are all typically negative Unfortunately, there is no one laboratory test that can confirm or refute a diagnosis of sJIA, which is a diagnosis of exclusion by definition A thorough evaluation for alternative etiologies is essential Underlying malignancies, including leukemia and lymphoma, may present with fevers, rashes, and diffuse lymphadenopathy If more than two cell lines are decreased, hematology/oncology consultation for bone marrow biopsy and/or lymph node biopsy is often indicated, especially prior to treatment with corticosteroids Infectious disease consultation to evaluate for pathogens that present with prolonged fevers, including Epstein-Barr virus (EBV) and cytomegalovirus (CMV), rickettsial diseases, infectious endocarditis, and other more rare entities should also be performed before sJIA can be diagnosed Management Children with active sJIA should be treated aggressively Patients with life-threatening disease are often managed with high-dose pulse intravenous (IV) methylprednisolone (30 mg/kg per day, maximum dose 1000 mg) administered over hour for consecutive days Subsequent maintenance prednisone is given IV or by mouth until disease control is achieved and appropriate steroid-sparing medications have been started Biological response modifiers, such as IL-1 inhibitors (anakinra, canakinumab, and rilonacept) and the IL-6 inhibitor (tocilizumab), should be started shortly after diagnosis for patients with severe disease and often provide good control of both systemic features (fevers, serositis, rash) and arthritis.14 These agents are used in consultation with a pediatric rheumatologist to induce remission and maintain disease control as corticosteroids are weaned Anakinra, in particular, is often preferentially used in ICU settings due to efficacy in treating MAS and a short half-life, which allows flexibility with dose adjustments and minimal short-term immunosuppressive effects Given the immediate and long-term complications of high-dose corticosteroid therapy, anti-lL-1 monotherapy is being increasingly used in many centers for initial treatment of sJIA Systemic Lupus Erythematosus Key Points Systemic lupus erythematosus (SLE) is a systemic autoimmune condition that can affect almost any organ system A positive ANA has good sensitivity but poor specificity for SLE; diagnosis relies on clinical criteria Pulmonary, cardiac, renal, and central nervous system (CNS) manifestations can be severe and lifethreatening, requiring critical care and aggressive immunosuppressive medications Infections are a major cause for morbidity and mortality in SLE patients due to immunocompromise from active disease and/or treatments CRP levels are often normal in active SLE: an elevated CRP in a patient with SLE should raise suspicion for acute infection SLE is a systemic autoimmune disease characterized by loss of immunologic tolerance and development of multiple autoantibodies targeting self-antigens The hallmark of SLE is tissue injury from immune complex deposition, which results in activation of complement and recruitment of downstream inflammatory cells and chemical mediators.15 The tendency for immune complexes to deposit in tissues with a large supply of small blood vessels—such as the skin, joints, and kidneys—helps explain the predilection for involvement of these systems in many SLE patients However, autoantibodies can also cause tissue damage through direct mechanisms; thus, almost any organ system may be affected in this disease Although the exact pathogenesis is still under study, evidence suggests that immune dysregulation—as well as genetic, environmental, and hormonal factors—all contribute to the development of this disease.15 Adolescent females are most likely to be affected; however, males and younger children can also develop SLE Onset of SLE prior to age 10 years is rare and suggests the possibility of an underlying genetic etiology There are multiple sets of classification criteria for SLE (eTable 106.1),16–18 which were initially developed in adults for research purposes to define a more homogenous group of patients However, these criteria are often applied clinically to support a diagnosis of SLE in children These various criteria schemes vary in terms of estimated sensitivity and specificity for pediatric SLE.19,20 Generally, if four criteria are met and other confusable infectious or neoplastic diagnoses have been eliminated, a diagnosis of SLE is highly likely SLE presentation can be extremely variable— any organ may be affected and the disease can be mild to life threatening If the diagnosis is suspected, it is important to perform serologic testing for SLE-specific autoantibodies as well as a thorough evaluation of all organ systems to look for potential involvement Clinical Presentation Mucocutaneous Manifestations Malar rash, discoid rash, photosensitivity, painless oral ulcerations (especially over the hard palate), and nasal ulcerations are classic skin and oropharyngeal findings However, almost any kind of rash, including bullous lesions, may be seen Skin biopsy with immunofluorescence staining to demonstrate immune complex deposition (the SLE band test) can be helpful Musculoskeletal Manifestations Arthritis is common, occurring in about 65% of patients with SLE.21 A musculoskeletal examination should be performed to look for joint tenderness, contracture, or effusion Myositis is less common but can also occur Avascular necrosis can occur, which may be due to the disease itself or to corticosteroid treatment Pulmonary Manifestations Pulmonary involvement is a common finding in many patients.22 Included here are clinically significant pulmonary manifestations in SLE Pleuritis and Pleural Effusion Pleuritis is included in the SLE classification criteria and may be severe Patients typically have pleuritic chest pain, respiratory distress, and orthopnea Pleural effusions can be large enough to compromise lung function Most respond to treatment of the underlying inflammatory disease, but occasionally aspiration and drainage of effusions are necessary Pulmonary Hemorrhage Although relatively rare, pulmonary hemorrhage is one of the most serious pulmonary complications, with a mortality rate 1252.e1 eTABLE a 106.1 Comparison of Proposed Criteria Schema for Systemic Lupus Erythematosus Classification Skin and mucosa ACR Criteriab SLICC Criteriac Malar rash Acute cutaneous lupus or subacute cutaneous lupus Discoid rash Chronic cutaneous lupus Oral or nasopharyngeal ulceration Palate, tongue, or nasal ulcers Photosensitivity Nonscarring alopecia Joints Nonerosive arthritis involving two or more peripheral joints Synovitis involving two or more joints Serositis Pleuritis, pericarditis Pleurisy, pleural effusions or pleural rub, typical pericardial pain, pericardial effusion or pericardial rub Renal disorder Persistent proteinuria 0.5 g/day or cellular casts (red cell, hemoglobin, granular, tubular, or mixed) Urine protein/creatinine (or 24-h urine protein) representing 500 mg of protein/24 h or red blood cell casts Neurologic disorder Seizures or psychosis Seizures, psychosis, mononeuritis multiplex, myelitis, peripheral or cranial neuropathy, acute confusional state Hematologic disorder Hemolytic anemia Hemolytic anemia Leukopenia ,4000/mL or lymphopenia ,1500/mL Thrombocytopenia ,100,000/mL Leukopenia (,4000/mm) or lymphopenia (,1000/mm) Thrombocytopenia (,100,000/mm) An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay ANA above laboratory reference range Anti-dsDNA, anti-Sm, or positive finding of antiphospholipid antibodies Anti-dsDNA Anti-Sm Antiphospholipid antibody: lupus anticoagulant, false-positive RPR Medium- or high-titer anticardiolipin (IgA, IgG, or IgM) or anti-b2 glycoprotein (IgA, IgG, or IgM) Low complement (C3, C4, CH-50) Positive direct Coombs test in the absence of hemolytic anemia Immunologic criteria a All criteria should be in the absence of other identifiable causes, such as offending medications, infection, metabolic derangements, etc ACR criteria: For the purpose of identifying patients in clinical studies, a person is defined as having SLE if any or more of the 11 criteria are present, serially or simultaneously, during any interval of observation c SLICC criteria: A person is defined as having SLE if at least out of 17 criteria are met (at least one clinical criterion and one immunologic criterion) or biopsy-proven lupus nephritis with a positive ANA or positive dsDNA Criteria are cumulative and not have to be present concurrently ACR, American College of Radiology; ANA, antinuclear antibody; anti-Sm, anti-Smith; dsDNA, double-stranded DNA; Ig, immunoglobulin; RPR, rapid plasma reagin; SLE, systemic lupus erythematosus; SLICC, Systemic Lupus Collaborating Clinics Data from Tan EM, Cohen AS, Fries JF, et al The 1982 revised criteria for the classification of systemic lupus erythematosus Arthritis Rheum 1982;25:1271-1277; Hochberg MC Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus Arthritis Rheum 1997;40:1725; and Petri M, et al Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus Arthritis Rheum 2012;64(8):2677-2686 b ... Rheumatologic Diseases: Clinical Presentation, Diagnosis, and Treatment Juvenile Idiopathic Arthritis Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatologic disease, representing... MAS, macrophage activation syndrome; sJIA, systemic juvenile idiopathic arthritis; SLE, systemic lupus erythematosus Juvenile idiopathic arthritis (JIA) Oligoarticular ≤4 joints at disease onset... course, and treatment Advances in our understanding of the immunopathogenesis of sJIA indicate that this disorder closely resembles other so-called autoinflammatory diseases in which systemic inflammation