Key Points
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Rheumatologic disorders are perpetuated by ongoing immune activation resulting from failure to clear triggering antigens combined with aberrant control mechanisms.
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The resulting chronic inflammation leads to local granuloma formation, scarring and fibrosis, as well as systemic symptoms such as fever, malaise, disrupted growth and elevated acute-phase reactants.
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Rheumatologic diseases are monitored by physical and laboratory examination of specific and nonspecific effects on involved organ systems.
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Early, aggressive therapy is aimed at preventing irreversible tissue damage and minimizing immunologic evasion of medication efficacy through epitope spreading and antibody affinity maturation.
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Therapy is seldom curative, so chronic treatment must be guided by optimizing medication benefits and minimizing their risks, especially those related to immunosuppression.
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The expanding therapeutic armamentarium against rheumatologic diseases is improving outcomes by targeting of pathogenic cells and cytokines using biologic response modifiers and small molecule inhibitors.
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Specific approaches to the most common pediatric rheumatologic disorders – juvenile arthritis, systemic lupus erythematosus and dermatomyositis – include agents providing symptomatic relief as well as more potent antiinflammatory and immunosuppressive disease modifying agents.
‘Rheumatology’ derives from the Greek word rheuma , meaning ‘river’ or ‘flow’. It reflects the ancient belief that articular pain is caused by the settling of bad humors in the joints. In the almost two millennia since Galen introduced this term, understanding of how arthritis and related maladies develop has changed dramatically. What has not changed, however, is the broad spectrum of conditions falling within the purview of rheumatology.
Rheumatologic disorders are often equated with autoimmunity. In fact, while the former term is overly general and imprecise, the latter implies that we know more about the pathogenesis of these conditions than we really do. Most chronic inflammatory disorders are indeed marked by ongoing immune activation, but it is not clear that the process is either initiated or perpetuated by autoreactivity. Even where this may be the case, such as diseases marked by self-reacting lymphocytes or autoantibodies, an autoantigen is seldom identified. At the very least, exogenous factors such as infection or injury are often central to disease development. Accordingly, this chapter will focus on the most common pediatric inflammatory diseases, but it will stress the inflammatory and immunologic factors relevant to their diagnosis and treatment, rather than theoretical aspects of tolerance and self-recognition. The newest family of inflammatory disorders, autoinflammatory diseases, is addressed in Chapter 14 , and connective tissue diseases and pain syndromes are not addressed because their care is driven more by empirical clinical experience than by immunologic principles.
Inflammation
Inflammation is the way the body reacts to infection, injury or irritation. Although its cardinal signs – dolor, calor, rubor and tumor – are stereotypical and recognizable, the process itself is complex and protean. Further, the inflammatory response must operate within very tight constraints. It must have a rapid onset of action, lest an invading organism proliferate overwhelmingly before control is achieved. It must be restricted physically in order to minimize damage to distant, uninvolved tissues. And it must be limited temporally so that ongoing tissue destruction does not progress after the inciting trigger resolves. In view of the difficulty of achieving such tight regulation, it is not surprising that harmful pathology is a not-infrequent side-effect of inflammation.
Inflammation associated with rheumatologic diseases typically involves both the innate and the adaptive immune systems. Initially, cells at the point of contact with foreign antigens or disrupted tissue are activated when they recognize pathogen-associated molecular patterns (PAMPs) that are generally not present on normal host cells. Pattern recognition receptors on macrophages and dendritic cells lead to cellular activation and release of intercellular mediators, resulting in the manifestations of inflammation. Thus, complement breakdown products and bradykinin augment regional blood flow by dilating local vessels, leading to warmth and redness. These and other chemicals also cause pain and swelling and increase vascular permeability, allowing proteins to exude into local tissues. These substances, in turn, attract phagocytes and stimulate degranulation, releasing additional inflammatory mediators including chemokines and cytokines, attracting and activating lymphocytes and recruiting components of the adaptive immune system.
Among the cytokines most important to the inflammatory response are IL-1, IL-6 and TNF-α, which together are responsible for many of the characteristic systemic signs and symptoms including fever, anorexia and malaise. These cytokines also elicit the hepatic acute-phase response, down-regulating so-called ‘housekeeping proteins’ such as albumin and up-regulating synthesis of mediators of ‘fight and flight’ such as C-reactive protein (CRP, an opsonin for certain organisms), fibrinogen (facilitator of blood clotting) and ferritin (which deprives bacteria of free iron) ( Figure 12-1 ).
Another important class of inflammatory mediators is the arachidonic acid metabolites, including leukotrienes and prostaglandins. Released by inflammatory cells, these mediators contribute to acute erythema and swelling by inducing vasodilation and capillary leak. Prostaglandin E 2 is of particular importance because it also sensitizes local nerve endings to pain and, with IL-1, mediates fever via effects on the hypothalamus.
As important as the initiation and augmentation of the inflammatory response may be, its timely disengagement and resolution are at least as essential for good health. Much of this restoration of normal homeostasis is passive, a consequence of the short half-life of most inflammatory mediators. In addition, active controls are involved, such as antiinflammatory cytokines (e.g. IL-10) and antiinflammatory molecules (e.g. soluble TNF receptor, IL-1 receptor antagonist and resolvins). Finally, the disappearance of perpetuating mediators starves activated cells of essential growth factors, leading to programmed death (apoptosis) of accumulated inflammatory cells. In most situations, these controls are sufficient to allow the inflammatory response to fade and for damage to be repaired through healing, fibrosis and scarring.
Rheumatologic disorders are typically chronic conditions in which the usual control mechanisms fail to stem the inflammatory response. Many factors may lead to such ongoing inflammation. For example, the stimulus triggering inflammation may be recurrent or impossible to eliminate (i.e. uric acid crystals in gout or a modified self-antigen in diabetes). In the majority of rheumatologic diseases, however, the cause is not clear, with neither the triggering stimulus nor potential aberrations in control mechanisms fully understood. In such cases, persistent inflammation may result in granuloma formation, scarring and/or fibrosis locally, as well as malaise, fever, anorexia, weight loss and elevation of acute-phase reactants systemically. While the specific manifestations of various rheumatologic conditions vary, these hallmarks are typical of all forms of systemic inflammation.
Assessing Systemic Inflammation
As noted, cytokines and other mediators released by immune cells account for the clinical picture of systemic inflammation. Another clinical manifestation of inflammation is stunting of growth, apparently as a result of interference with normal anabolic hormones even in the setting of adequate dietary intake. The onset of a chronic inflammatory disease often can be pinpointed by careful review of the growth chart.
The blood tests most often used to assess the degree of systemic inflammation are the erythrocyte sedimentation rate (ESR) and the CRP. CRP is a product of the hepatic acute-phase response and rises within 48 hours of an inflammatory stimulus ( Figure 12-2 ). An elevated ESR is a rapidly quantifiable physical manifestation of elevation of a variety of acute-phase reactants, especially fibrinogen. This and other positively charged proteins tend to intercalate between negatively charged erythrocytes, facilitating the formation of red blood cell stacks (rouleaux) that sediment more rapidly than free-floating cells. Since the levels of these proteins take days to weeks to respond to an inflammatory stimulus, the ESR rises more slowly than the CRP in acute inflammation and remains elevated longer after the inflammation resolves. Nevertheless, ready availability and extensive experience with the ESR make it a useful, if nonspecific, clinical tool.
Humoral mediators are responsible for many other manifestations of acute inflammation such as leukocytosis, appearance of immature (‘band’) forms of white blood cells, and thrombocytosis. In additional, prolonged inflammation typically causes normocytic anemia (the anemia of chronic disease) and, in response to some inflammatory stimuli, elevated levels of serum immunoglobulins from B cell stimulation.
Principles of Antiinflammatory Therapy ( Box 12-1 )
Ideal therapy would target only aberrant manifestations of the inflammatory response while preserving basic regulatory and effector functions of immunity. Unfortunately, the aberration in the immune system responsible for specific inflammatory diseases is generally unknown, available agents do not distinguish between harmful and beneficial immune activity, and many drugs also have nonimmunologic side-effects. The result is that the risks of immune suppression are often considerable, and they must be balanced against the benefits of controlling inflammation when deciding upon therapy. Practical aspects of these considerations generally follow several basic principles:
- 1.
The least toxic medications should be used for the briefest period of time. Unfortunately, most rheumatologic disorders are managed without expectation of cure. For unknown reasons, varying percentages of different conditions will remit over time, but rarely can such remissions be ascribed to the effects of treatment. At best, conditions may be stabilized as inflammation is controlled, ultimately minimizing the need for continuous immunosuppression. Thus, with antiinflammatory therapy likely to be needed indefinitely, minimizing the amount and intensity of antiinflammatory treatments is essential for avoiding complications due to effects on tumor surveillance and resistance to infections. While such risks are increased by combination immunosuppression, particularly the addition of steroids to other agents, in many cases disease activity also contributes to a patient’s risk of developing opportunistic infections and malignancies. Thus, managing rheumatologic diseases remains very much an art rather than a science.
- 2.
Early, aggressive therapy offers the greatest chance of achieving a good outcome :
- a.
Rheumatologic disorders not only cause inflammation and the signs and symptoms with which it is associated, but over time they tend to cause irreversible tissue damage as well. While such damage occurs at varying rates in different conditions and different individuals, achieving disease control rapidly enough to avoid such damage is generally the best way to avoid chronic ill-effects of rheumatologic disorders. Often such damage occurs early in the disease course – for example, up to 50% of people with rheumatoid arthritis develop erosive changes within two years of disease onset. As a result, earlier ideas of gradual intensification of therapy (the so-called ‘reverse pyramid’) have fallen out of favor. Instead, early initiation of optimally effective treatment, with subsequent tapering once disease control is achieved, is now preferred.
- b.
The centrality of involvement of the immune system in the pathogenesis of rheumatologic disorders means that disease activity is not static. Rather, as long as a tissue is being targeted, the immune system is evolving to optimize the inflammatory attack. Affinity and avidity of antibodies increase over time (affinity maturation), and target epitopes are honed and extended (epitope spreading) to minimize immune evasion due to antigenic variation. Thus, there may be a ‘window of opportunity’ early in the course of inflammatory disorders during which autoimmunity may be controlled. Over time, however, with broadening of the inflammatory response, such restoration of regulation may become increasingly difficult and require progressively more intense immunosuppression.
- a.
- 3.
The complexity and unpredictability of the immune process driving inflammation in rheumatologic disorders necessitates an individualized approach to therapy. The many factors involved in the initiation and perpetuation of rheumatologic conditions – including host genetic and epigenetic factors, co-morbid medical conditions, variations in triggering events, and pharmacogenetic idiosyncrasies affecting response to medications – do not lend themselves to standardized protocols of treatment. Rather, the concept of ‘treat to target’ is now the preferred paradigm: therapeutic response is measured on an ongoing basis, and types and doses of medications are adjusted based on a patient’s response rather than being continued for an arbitrary period of time before changes are made. No single approach is universally effective in all patients, and not all therapeutic regimens are equally beneficial. Thus careful monitoring as well as thorough familiarity with both theoretical and experimental effects of treatments are necessary to optimally treat rheumatologic conditions.
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The least toxic medications should be used for the briefest period of time.
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Early, aggressive therapy offers the greatest chance of achieving a good outcome:
- a.
Irreversible damage, which occurs early in the disease course, is avoided
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Evolution of the immune response increases resistance to therapy over time.
- a.
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The uniqueness of the individual immune response necessitates a ‘treat to target’ approach.
With these principles as a background, a general overview of the current panoply of antiinflammatory agents is offered below. Following that is a discussion of the most common pediatric rheumatologic conditions, including specific information on their diagnosis and natural history, and empirical approaches to treatment.
Therapeutic Strategies ( Box 12-2 )
Inadequate understanding of fundamental disease mechanisms has limited treatment options for rheumatologic diseases. Since the initial use of corticosteroids almost 60 years ago, clinicians could offer little more than broad immunosuppression plus supportive care (e.g. physical therapy for rheumatoid arthritis) to mitigate end-organ damage. More recently, rapid advances in molecular immunology have brought us tantalizingly near to the Holy Grail of immunomodulation – the possibility of targeting only disease-mediating cells, leaving other facets of immunity unaffected. Although this possibility remains largely theoretical, new targeted approaches for reducing long-term disability and total exposure to immunosuppressive therapy are improving quality of life and long-term outcomes faster than ever before.
- 1.
Inhibitors of arachidonic acid metabolism
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Nonsteroidal antiinflammatory drugs (NSAIDs)
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Cyclooxygenase (COX)-2 inhibitors
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Immunomodulators
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Disease-modifying antirheumatic drugs (DMARDs)
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Calcineurin inhibitors
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Targeted molecular therapies
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Monoclonal antibodies
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Cytokines
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Costimulatory molecules
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Receptor antagonists
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Small molecules
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Protease inhibitors
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Interfering RNA
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- a.
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Immunosuppressants
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Antimetabolites
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Cytoxic agents
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Corticosteroids
- a.
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Immune reconstitution
- a.
Stem cell transplant
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Bone marrow transplant
- a.
Systemic Immunosuppression
The mainstay of treatment for systemic rheumatologic diseases remains immunosuppressive medications. These ameliorate the clinical and serologic effects of disease activity by targeting effectors of the immune response. Adverse effects of immunosuppression result from interference with protective immunity as well as pathologic autoimmunity and include the ongoing risk of infection and the cumulative potential for developing a malignancy due to diminished immune surveillance.
Corticosteroids, perhaps the least discriminating tool in the armamentarium, are used in doses ranging from daily low-dose oral regimens to ‘pulsed’ high-dose intravenous therapy. Traditional disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, leflunomide, hydroxychloroquine and sulfasalazine are mildly immunosuppressive and cause minimally increased risks of infection. Their benefits are likely mediated through antiinflammatory and immunomodulatory effects rather than through immunosuppression per se. More potent immunosuppressive agents such as azathioprine, cyclosporin A, mycophenolate mofetil and cyclophosphamide are often necessary for treating more severe conditions such as vasculitis and systemic lupus erythematosus (SLE).
Plasmapheresis is an important treatment utilized to remove pathogenic antibodies and other humoral factors from the circulation. It is employed when urgent measures are needed to stabilize a patient before longer-term interventions take effect, for example cases of acute hemorrhage from the pulmonary-renal syndromes, granulomatosis with polyangiitis (Wegener’s granulomatosis) and Goodpasture syndrome. Intravenous immunoglobulin (IVIG) has immunomodulatory properties without the risks of immunosuppression, particularly useful in patients whose inflammatory condition is a result of an immunodeficiency (e.g. granulomatous common variable immunodeficiency). Inexplicably, IVIG is superior to any other therapy in arresting acute inflammation and preventing target-organ damage in cases of Kawasaki disease, an inflammatory vasculitis of childhood. While IVIG can also remove activated complement fragments that mediate inflammation in dermatomyositis, its role in other inflammatory disorders is far less prominent.
Targeted Molecular Therapies
During the past decade, a new generation of drugs targeting cytokines and lymphocyte receptors has dramatically altered the therapeutic landscape of rheumatology. These so-called ‘biologic response modifiers’ (BRMs) are recombinant monoclonal antibodies and receptor antagonists that inhibit specific targets. The impact of BRMs is perhaps most clearly evidenced by the fact that, as of 2007, eight of the 20 best-selling biotechnology drugs in the USA were therapeutic monoclonal antibodies. Biologic drugs are discussed further in Chapter 17 .
Novel Therapeutic Targets
Novel targeted therapies for autoimmune diseases will broaden attempts to exploit cytokines and lymphocyte cell surface molecules involved in mediating inflammation and lymphocyte activation. Not only monoclonal antibodies but small molecule inhibitors and interfering RNA are being investigated. The first such agent approved for a rheumatologic indication was tofacitinib, a Janus kinase (JAK) inhibitor, which was approved for treatment of rheumatoid arthritis in 2012. Protein kinase inhibitors interfere with phosphorylation of serine, threonine or tyrosine residues in proteins. This step is needed for proliferation or activation, so inhibitors of protein kinases may have therapeutic effects in rheumatologic and malignant disorders. Such agents are immunosuppressive and so risk of infections remains a serious concern, as with biologic agents. Their major advantage at present is the fact that they are not digested by enzymes of the gastrointestinal tract so they may be taken orally, unlike monoclonal antibodies.
Small molecule protein kinase inhibitors developed for the treatment of malignancies may have utility in autoimmune diseases. For example, patients with systemic sclerosis (SSc) demonstrate increased activity of the platelet derived growth factor receptor (PDGFR), possibly due to stimulatory autoantibodies. Studies have focused attention on imatinib (Gleevec®), a drug that inhibits multiple tyrosine kinases including PGDFR, as a possible therapy for SSc. This kinase inhibitor has already had dramatic effects on the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors.
Proteasome inhibition and pharmacologic regulation of autophagy, a cellular recycling pathway in which cellular targets are delivered to lysosomes for degradation, represent additional autoimmune disease targets of interest. Bortezomib, a proteasome inhibitor approved for the treatment of multiple myeloma, inhibits degradation of pro-apoptotic factors, permitting activation of programmed cell death in rapidly dividing cells. This leads to depletion of short- and long-lived plasma cells and reduces autoantibody production, a possible explanation for the ability of bortezomib to protect lupus-prone mouse strains from the development of nephritis. Hydroxychloroquine, a drug used to treat malaria for more than half a century, also blocks acidification of phagolysosomes. It is known to prolong remissions in SLE and may exert beneficial effects in other autoimmune diseases by modulating autophagy-mediated antigen presentation. Future work may lead to therapies that capitalize on immune cell requirements for cellular recycling and unfolded protein response pathways in order to inhibit autoreactive responses without causing significant immunosuppression.
The ultimate approach to therapy of intractable immune activation or immune dysregulation is ‘resetting’ of the immune system in an attempt to restore normal regulatory controls. Treatment of severe autoimmunity with stem cell transplantation remains experimental, largely because of the significant morbidity and mortality that still accompany this approach. Nonetheless, this approach has been used in cases of severe systemic juvenile rheumatoid arthritis (JRA), SSc, and SLE resistant to conventional therapy. For example, a recent report documented sustained clinical remission in seven patients with severe refractory SLE treated with immunoablation and autologous hematopoietic stem cell transplantation. Further, after transplantation, the patients demonstrated evidence of normalization of naïve lymphocyte populations and generation of thymic derived regulatory T cells. Safer methods for reconstituting the bone marrow compartment, such as autologous stem cell reconstitution protocols, could provide a therapeutic alternative for the most difficult to treat patients.
Approaches to Specific Conditions
The final section of this chapter addresses specific therapeutic approaches to the three most common pediatric rheumatologic disorders. This represents a snapshot of a rapidly evolving discipline. Each new biologic agent or small molecule inhibitor has the potential to disrupt the existing paradigm by introducing dramatic improvements in the therapeutic risk-benefit ratio. The rapidity of such changes cannot be overstated. For example, within the past 15 years identification of the genetic basis of familial Mediterranean fever led to the description of an entire new class of disorders, the autoinflammatory conditions. In short order, this was followed by the introduction of biologic therapy as an almost miraculous, specific approach to conditions that had previously been untreatable, debilitating and often fatal. In view of this unprecedented rate of change, clinicians caring for children with rheumatologic conditions require guidelines to help navigate the rapidly expanding and increasingly complex rheumatologic armamentarium. These are offered below.
Juvenile Idiopathic Arthritis (JIA)
Juvenile arthritis is the most common rheumatologic disorder of childhood, affecting as many as one in 1,000 children under the age of 16 years. From the first published case of arthritis developing in a child in 1864, descriptions have tended to include a variety of patterns that likely represent numerous different subtypes of juvenile arthritis.
Unfortunately, with the pathogenesis of juvenile arthritis poorly understood, most classification schemes have categorized patients based on the number and pattern of joints involved, the populations being studied and the interests of the committee members categorizing them. Not surprisingly, genetic and immunologic data demonstrate significant overlap and imprecision when classification is based solely on such phenotypic patterns. Current classifications thus leave much room for improvement. Nonetheless, whether a child is said to have psoriatic arthritis (based on the 1977 criteria of the International Leagues of Associations for Rheumatology), pauciarticular juvenile rheumatoid arthritis (based on the 1986 American College of Rheumatology criteria) or enthesitis-related arthritis (according to the 1993 International League of Associations for Rheumatology proposed classification of the idiopathic arthritides of childhood), management and therapy are largely similar across classification systems and disease subtypes.
Pauciarthritis
Arthritis involving fewer than five joints, known as oligoarticular or pauciarticular arthritis, is the most common form. The knee is most often affected, followed by the ankle, wrist and elbow. There are two peaks of onset: one between the ages of 1 and 5 years and the other between 12 and 16 years. Most patients present with a gradual onset of stiffness, swelling and diminished mobility, most prominent early in the day or after prolonged inactivity.
The extent to which children complain of pain varies, with younger children often limping but denying discomfort.
The degree of debility caused by arthritis is generally proportional to the number of joints involved. Pauciarthritis usually does not cause systemic symptoms such as fatigue, malaise, fevers or significant elevation of acute-phase reactants. Involved joints may grow more rapidly, however, due to increased blood flow and nutrient delivery to inflamed tissues, so asymmetric involvement persisting for more than a few months may lead to limb-length discrepancies and significant muscle atrophy.
In addition, pauciarthritis is associated with a significantly increased risk of developing chronic, asymptomatic anterior uveitis. This occurs in up to 30% of children with pauciarthritis who are antinuclear antibody (ANA) positive, with up to one third of children diagnosed with anterior chamber inflammation before arthritis develops. About 50% of children with uveitis develop it roughly coincident with the onset of arthritis; onset more than 7 years after the diagnosis of arthritis is very rare. Early detection of the uveitis is important in preventing sequelae; 20% or more of those in whom diagnosis is delayed develop decreased visual acuity or even blindness. Unfortunately, chronic anterior uveitis is usually asymptomatic, so children with pauciarticular JIA should have slit lamp examinations by a pediatric ophthalmologist on a regular basis so that undetected inflammation does not cause irreversible ocular changes.
Polyarthritis
Polyarthritis affects five or more joints, both large and small, though typically in a symmetric pattern. Diagnosis requires clear evidence of joint inflammation (decreased function, swelling, stiffness and/or warmth), not merely pain. It is thus important to perform both a thorough history and a careful physical exam to distinguish arthritis from arthralgias. The more joints involved, the more likely the child is to have systemic features of disease, including malaise, fatigue and laboratory abnormalities.
About 10% of children with polyarthritis test positive for rheumatoid factor. This subtype of juvenile arthritis most closely resembles adult rheumatoid arthritis. In long-term follow-up studies, the presence of rheumatoid factors in serum correlates with more aggressive disease and a greater possibility of joint damage and disability. So-called ‘seropositive’ arthritis is also marked by antibodies to cyclic citrullinated peptide (CCP), another predictor of more aggressive and destructive arthritis.
Some cases of arthritis include prominent inflammation of the entheses (insertion sites of tendons and ligaments into bone), most often the Achilles tendon at the heel or the patellar tendon at the tibial tuberosity. Furthermore, the history frequently reveals other members of the family with ankylosing spondylitis, psoriasis, inflammatory bowel disease (IBD) or Reiter’s disease. These individuals, in particular those with a strong family history, may be HLA-B27 positive. Neck, back and hip involvement is common in these so-called ‘spondyloarthropathies’, though sacroiliitis (often manifesting as lumbosacral pain) may not be present at disease onset. Such axial involvement typically becomes symptomatic by mid-adolescence.
Systemic Onset Juvenile Idiopathic Arthritis
The third type of JIA, systemic-onset JIA or Still’s disease (SoJIA) , is the least common form. Systemic complaints, particularly fever, often precede development of arthritis, so pediatricians are most likely to consider this diagnosis in children with a fever of unknown origin (FUO). SoJIA fevers are typically prolonged, minimally responsive to antipyretics, and hectic. Temperatures may reach 104° to 105° F once or twice a day, often at the same hour of the day, while dipping below normal between fevers, especially just before sunrise. Patients may experience chills and toxicity with the fevers, while such symptoms tend to improve during afebrile intervals. Appetite is frequently decreased, often accompanied by weight loss. Family history as well as a thorough review of systems and physical exam should focus on constitutional symptoms, delayed growth, poor weight gain, rashes, nail pits, oral lesions, nailbed capillary changes, clubbing, weakness and intestinal symptoms.
A diagnostic rash occurs in 90% of patients with systemic-onset JIA ( Figure 12-3 ). The rash consists of evanescent 3- to 5-mm erythematous macular or barely papular lesions occurring most commonly on the trunk and proximal extremities. It may be asymptomatic or occasionally pruritic and is typically most prominent during fever elevations. Uncommonly, the rash can involve the face and hands and feet, but fixed lesions persisting for more than 24 hours in a location should stimulate a search for an alternative diagnosis. The rash is more likely to be atypical for the first several weeks of illness before evolving into the classic salmon pink exanthem. Similarly, early in the course of the illness a child may complain of joint pain, with frank arthritis not becoming evident for weeks or months. Less specific findings may include lymphadenopathy, hepatosplenomegaly or serositis with pericardial effusions.
