CASE REPORTJUVENILE RHEUMATOID ARTHRITIS(JRA)by:

Ismafitria Idris

(070100364)

Maal Abrar

(070100374)

Supervisor:

dr. Yazid Dimyati, Sp. A (K)

DEPARTMENT OF PEDIATRICHAJI ADAM MALIK GENERAL HOSPITAL

UNIVERSITY OF SUMATERA UTARA FACULTY OF MEDICINE

MEDAN

2012

PREFACE

First of all, we would like to express our praise and gratitude to God Almighty that due to Gods grace and blessings this assignment entitled Juvenile Rheumatoid Arthritis was able to be finished in time. This assignment was written in order to fulfill the duties from the Department of Pediatric H. Adam Malik General Hospital / University of North Sumatera.

We would also like to express our gratitude to dr. Yazid Dimyati, Sp.A(K) for her valuable advices and guidance throughout the completion of this assignment. Last but not least, we thank everyone who have contributed in this assignment.

We are fully aware that this assignment is far from perfect, therefore, we accept any constructional critics and advice that can improve this assignment.Medan, 21th May 2012

WritersCONTENTSPREFACE ..ii

CONTENTS iii

CHAPTER I INTRODUCTION1

1.1. Background ................1

1.2. Objective ...................2

CHAPTER II LITERATURE REVIEW3

2.1. Definition ......3

2.2. Epidemiology.................3

2.3. Etiology...................3

2.4. Pathogenesis...4

2.5. Classification8

2.6. Clinical Presentation..9

2.7. Diagnosis...15

2.8. Laboratory Test.16

2.9. Treatments.21

2.10. Prognosis..23

CHAPTER III MEDICAL REPORT25

3.1. Case ...25

3.2. Discussion..27

3.3. Summary....28

REFERENCES........................................................................................29

ATTACHMENTS

CHAPTER I

INTRODUCTION

1 . 1. Background Juvenile rheumatoid arthritis (JRA) is a generic term for arthritis that has an onset before the age of 16 and persists for more than 6 weeks. The JRA nomenclature represents an exclusion diagnosis that includes all forms of chronic childhood arthritis of unknown origin1. Currently, 3 separate classification systems are used to categorize individuals under 16 years of age with chronic arthritis. These include the American College of Rheumatology (ACR), the European League Against Rheumatism (EULAR), and the International League of Associations for Rheumatology (ILAR) criteria. Because none of these systems are perfect models, some JRA patients fulfill criteria for more than one subtype, whereas others are difficult to classify into any of the specific subgroups. Both the ACR and EULAR criteria are based solely on the onset type as it is manifested during the first 6 months of disease, whereas the ILAR criteria also include the course type over an unknown period of time thereafter, in order to further distinguish the group of patients with oligoarticular disease1.Epidemiological studies of JRA have been hampered by a lack of standardized criteria and case ascertainment, which has resulted in wide-ranging results. For instance, the reported prevalence of JRA ranges from 0.07 to 4.01 per 1,000 children, and the annual worldwide incidence varies from 0.008 to 0.226 per 1,000 children1. JRA is the most common chronic rheumatic illness in children and is a significant cause of both short- and longterm disabilities. The heterogeneity of this disease suggests that different factors likely contribute to its pathogenesis1. 1 . 2. Objective

The objective of this case report is to familiarize ourselves with Juvenile Rheumatoid Arthritis, understand the clinical presentation, diagnosis, treatment of the disease itself and lastly to report a case of Juvenile Rheumatoid Arthritis in an 15 years old boy that was admitted to to the non-infection ward of H Adam Malik General Hospitals Pediatric Division.

CHAPTER II

LITERATURE REVIEW

2 . 1. Definition JRA is defined as persistent arthritis in 1 or more joints for at least 6 weeks if certain exclusionary conditions have been eliminated; disease onset subtype is defined by clinical symptoms in the first 6 months of disease. The course of JRA is defined by what happens after the first 6 months2, 3.

2 . 2. Epidemiology

The exact incidence and prevalence of JRA is not known. A recent meta-analysis of 34 epidemiological studies showed wide variability in both the reported incidence and prevalence of JRA. Incidence numbers varied considerably from 0,008 to 0,226/1000 children per year. Prevalence numbers varied even more widely and ranged from 0,,07 to 4,01/1000 children4.2 . 3. EtiologyJRA is an autoimmune disease. This means it is the body's own immune system that causes the damage. The immune system problems may be caused by genetics and/or environment 3, 5.Various studies seeking epidemiological evidences for etiology of arthritic manifestation thaw infectious connection to RA. For obvious reason, triggering immune response against antigenic determinant is a preparative cascaded reaction in order to eliminate invaders. There are two principal difficulties with the hypothesis that infection triggers rheumatoid arthritis: first proving a causal relation and second the limitation of the methods of detection of recent or past infection. Past or recent infection develops onset of polyarthritis persistently associated with the development of antibody response, giving satisfactory explanation for infection triggering immune response in rheumatoid phenomena6.

No particular studies documented persistence of infectious agents in joint inflammatory site, even though availability of bacterial products at the site of inflammation and triggered immune response to earlier infection and its related antibody activities and particularly of crossreactivity might be given attention in order to facilitate hypothesis to etiology of rheumatic diseases. And also from clinical concern, patients with earlier infection before develops rheumatological criteria may be no longer infectious giving opportunity to understand its connection and involvement of such infectious connection to etiopathology. Hence it could be strengthening the suggestion that rheumatoid arthritic etiology has satisfactory explanation for infection, and joint inflammation might have develops soon after or during an infection elsewhere in the body6.

2 . 4. Pathogenesis Associations of human leukocyte antigen (HLA) and non-HLA molecules in JRA

The genetic basis of JRA is complex, but it has been estimated that the sibling recurrence risk of developing the disease is around 15. To date, only 2 genetic risk factors, HLA and protein tyrosine phosphatase non-receptor 22 (PTPN22) genes, have been unequivocally confirmed as JRA susceptibility genes in multiple populations. The most well-established genetic factors for JRA are the HLA genes. Because the main function of HLA molecules is presenting antigenic peptides to T cells, HLA associations with JRA imply that this disease may be caused by an unidentified arthritogenic antigen1, 7.However, both the strength of these associations and the associated alleles vary between the JRA subtypes. Specifically, oligoarthritis has been consistently associated with HLA-A2, HLA-DRB1*11, and HLA-DRB1*08. Rheumatoid factor (RF)-positive polyarthritis is reportedly associated with HLADR4 in children, similarly to in adults. Moreover, the presence of HLA-B27 confers an increased risk of enthesitis-related arthritis. PTPN22 encodes a lymphoid-specific phosphatase (Lyp). A variant in the coding region of this gene, which is reportedly associated with a number of autoimmune diseases, has also been identified as a susceptibility locus for JRA. The effect size of PTPN22 varies somewhat between JRA subtypes but, in general, is more consistent than that of HLA genes. A few other genes, including macrophage inhibitory factor, interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-, have also been associated with JRA in different populations and subtypes. However, these discussed genes may collectively account for only a small proportion of the total genetic contribution to disease1, 7.

Inflammatory mediators of joint damage

Synovial membranes of JRA patients contain activated T and B cells, plasma cells, and activated macrophages that are recruited via an intense neovascularization process. Host tissue cells, including activated synovial fibroblasts, chondrocytes, and osteoclasts, mediate cartilage and bone destruction. It has been established that the recruitment, activation, and effector function of each of these contributor lineages are directed principally by a network of cytokines.

Figure 1. Cytokine signaling pathways involved in JRA. Interactions among macrophages, T cells, B cells, and non-hematopoietic cells including fibroblasts are important in the pathogenesis of JRA. These interactions are facilitated by the actions of cytokines that induce the production of other proinflammatory cytokines1.

Antigen-specific T cells appear to play a central role in the pathogenesis of arthritis subtypes within JRA. T-cell infiltrates are composed predominantly of T helper 1 (Th1) cells, which express an activated memory phenotype and high concentrations of chemokine receptors. Th1 cells stimulate B cells, monocytes, macrophages, and synovial fibroblasts to produce immunoglobulins and inflammatory mediators. Activated B cells produce immunoglobulins, including RF and antinuclear antibodies (ANAs). The precise pathogenic role of RF remains unknown, but it may involve the activation of complement through the formation of immune complexes. ANAs, which are mainly associated with early-onset oligoarthritis, have been reported to react against different nuclear targets, none of which are specific for JRA. Activated macrophages, lymphocytes, and fibroblasts, as well as their products including vascular endothelial growth factor (VEGF) and osteopontin, can stimulate angiogenesis. VEGF is highly expressed in synovial tissue, whereas osteopontin is raised in synovial fluid and tissue, and correlates with new vascularisation1.

TNF- and IL-1 produced by activated monocytes, macrophages, and synovial fibroblasts likely have primary roles in the pathogenesis of JRA. These cytokines are detected in synovial fluids or tissues in a majority of JRA patients, and are known to stimulate mesenchymal cells, such as synovial fibroblasts, osteoclasts, and chondrocytes, to release tissue-destroying matrix metalloproteinases. TNF- and IL-1 also inhibit synovial fibroblasts from producing tissue inhibitors of metalloproteinases. Collectively, these dual actions seem to lead to joint damage. Indeed, data from animal models strongly suggest TNF- and IL-1 play roles in JRA. For instance, transgenic mice that expressed a deregulated human TNF- gene spontaneously developed an inflammatory and destructive polyarthritis similar to JRA. Moreover, blocking TNF- with either a soluble TNF-receptor fusion protein ormonoclonal antibodies also ameliorated disease activity in mice with type II collagen-induced arthritis. Injection of IL-1 into the knee joints of rabbits has been demonstrated to result in the degradation of cartilage, whereas the injection of antibodies against IL-1 ameliorated collagen-induced arthritis in mice and decreased the damage to cartilage1.IL-6 is a multifunction cytokine that has a wide range of biological activities in various target cells and regulates immune responses, acute phase reactions, hematopoiesis, and bone metabolism. Circulating levels of IL-6 are markedly elevated in patients with JRA, and are associated with laboratory and clinical variables of disease activity. IL-6 stimulates hepatocytes and induces the production of several acute-phase proteins, such as C-reactive protein (CRP)33). Thus, elevated levels of IL-6 in serum correlate with CRP levels in JRA patients with active disease. IL-17 is produced by Th17 cells, and induces a massive tissue reaction due to the broad distribution of the receptors to this cytokine. Recent evidence suggests that IL-17-producing Th17 cells have a crucial role in autoimmune inflammation. In particular, IL-17 promotes a proinflammatory cytokine environment in the joint, stimulating macrophage production of TNF- and IL- 13, and synergizes with these cytokines to increase IL-6 and IL-8 production36, 37). In addition, IL-17 contributes directly to joint destruction by upregulating matrix metalloproteinases and stimulating osteoclastogenesis through receptor activation of nuclear factor-B ligand (RANKL) induction38-40). IL-17 is increased in JRA patients with active disease compared with levels in individuals in remission41). Data from animal models also suggest IL-17 has a role in cartilage degradation. For instance, IL- 17-deficient mice were demonstrated to be resistant to induction of collagen-induced arthritis42). Moreover, joint inflammation and cartilage and bone destruction were suppressed after administration of anti-IL-17 antibodies in mice with collagen-induced arthritis1.Anti-inflammatory mediators in JRA

The two most well-known anti-inflammatory cytokines associated with JRA are IL-10 and IL-4. IL-10 has been shown to reverse cartilage degradation mediated by antigen-stimulated mononuclear cells in adult patients with arthritis. In addition, a single nucleotide polymorphism connected to lower production of IL-10 is associated with a more severe type of arthritis. IL-4 inhibits the activation of Th1 cells, which in turn decreases the production of TNF- and IL-1 and inhibits cartilage damage1.IL-4 and IL-10 cooperate to inhibit the production of inflammatory cytokines, including IL-6 and IL-8. Higher levels of IL-4 and IL-10 mRNA within a joint are allied with a milder oligoarticular course and non-erosive disease. Foxp3+CD4+CD25+ regulatory T cells (Tregs) are important for controlling inflammatory processes68). In humans, an X-linked genetic defect in Foxp3 is the underlying cause of a condition that presents with multiple autoimmune conditions, which is named the immuno-dysregulation, polyendocrinopathy, enteropathy (IPEX) syndrome. Less serious defects in Treg function have also been put forward as a cause of failed tolerance in several human autoimmune diseases. However, there is currently no evidence suggesting defects in Treg function in JRA, although the number of synovial Tregs is significantly lower in patients with extended oligoarthritis compared with the number in patients with a milder course of the disease. Moreover, a higher number of Tregs have been found within joints of JRA patients compared with the number in peripheral blood, which indicates an enrichment of Tregs within the inflamed joints. However, it appears that high numbers of regulatory cells in the joint fail to moderate the local inflammatory process. This finding may be related to effector T cell resistance, suppression at the site of inflammation, or the attenuation of Treg function by local dendritic cell-derived cytokines, such as IL-61.

2 . 5. Classification The 3 major subtypes of JRA are based on the symptoms at disease onset and are designated systemic onset, pauciarticular onset, and polyarticular onset. Pauciarticular-onset and polyarticular-onset JRA are further divided into 2 subsets. Although the major JRA classifications are based on onset type, the course of the disease is also critical to patient prognosis. For instance, systemic-onset JRA can eventually become indistinguishable from polyarticular JRA. Patients with this pattern of onset and disease course may be particularly difficult to treat. JRA that begins as pauciarticular-onset disease, with more extensive joint involvement over time, is frequently referred to as extended pauciarticular or extended oligoarticular disease2.Table 1. Key Clinical Characteristics of JRA Onset Types2

2 . 6. Clinical PresentationArthritis

An arthritic joint exhibits a number of cardinal signs of inflammation, such as swelling, erythema, heat, pain, and loss of function. Involved joints are often warm, but are not typically erythematous. Children with arthritis may not complain of pain while at rest, but active or passive motion typically elicits pain.

Joint tenderness is usually maximal at the joint line or just over the hypertrophied, inflamed synovium. Of note, bone pain or tenderness is not characteristic of JRA and may instead indicate the possibility of a malignancy involving bone. Morning stiffness and gelling following inactivity are common manifestations of joint inflammation, but young children infrequently describe these symptoms. Often, young children do not complain of pain and instead refuse to use the affected joint entirely1, 3.

Figure 2. Swelling and flexion contracture of the right knee of a representative patient with oligoarticular disease1.

Any joint can be affected by JRA, but large joint are more frequently involved than smaller joints. However, small joints of the hands and feet are also affected, particularly in polyarticular onset disease. Of note, cricoarytenoid arthritis is unusual but may be responsible for acute airway obstruction. Inflammation of the synovial joints in the middle ear has also been detected by tympanometric studies. The temporomandibular joint and the cervical, thoracic, and lumbar spine should also be examined in the case of JRA. JRA often affects the cervical spine, and the most common changes in the upper cervical spine are anterior atlantoaxial subluxation and impaction. Subluxation of the atlantoaxial joints may also occur, rendering the affected child at risk of injury in an accident or upon attempted intubation prior to receiving general anesthesia. Scoliosis, which possibly reflects asymmetric thoracolumbar apophyseal joint inflammation, may also occur in children with JRA. Small outpouchings of symovium are not uncommon in individuals with JRA and are particularly evident at the extensor hood of the proximal interphalangeal joint and around the wrist or ankle. A synovial cyst in the antecubital area or anterior to the shoulder may be the initial or sole presentation of JRA1.Oligoarticular disease develops in at least 50% of children with JRA during the first 6 months of disease. This subtype is the only form of JRA without an adult equivalent. Oligoarticular disease affects up to 4 joints at presentation, with the knee joints mostly affected, followed by the ankles. In contrast, this subtype almost never affects the hips, and rarely the smaller joints of the hands and feet. Oligoarticular disease is characterized by asymmetric arthritis, early onset (before 6 years of age), female predilection, high frequency of positive ANAs, and a high risk of iridocyclitis1.

Polyarticular disease is defined as the presence of arthritis in 5 or more joints during the first 6 months of disease. The arthritis may be symmetrical and usually involves the large and small joints of the hands and feet, although the axial skeleton, including the cervicalspine and the temporomandibular joints, may also be affected. This subtype includes children with both RF-negative and RF-positive diseases. Both types affect girls more frequently than boys. RFnegative patients often develop polyarthritis in early childhood, whereas RF-positive patients instead develop arthritis during late childhood and adolescence1.

Figure 3. Polyarticular disease affects the joints of the wrist and hand. The proximal and distal interphalangeal joints are erythematous. There are flexion contractures of the fingers1.

Systemic extra-articular manifestations

Systemic involvement may precede the development of overt arthritis by weeks, months, or rarely years. In the right clinical setting, with characteristic fever and classic rash, the diagnosis of probable systemic onset disease may be made, and confirmation of the diagnosis can follow when persistent arthritis develops. The arthritis associated with systemic onset disease is usually polyarticular affecting both large and small joints. Asymmetric, oligoarticular arthritis is less common. The systemic pattern is prominent during the first 4-6 months of disease and rarely occurs for the first time during the later course of disease1.The most prominent feature of systemic involvement is a high spiking fever. Specifically, the temperature of an individual typically rises to 39 or higher on a daily or twice-daily basis, followed by a rapid return to the baseline temperature or below. Although this quotidian pattern is highly suggestive of systemic onset disease, patients may not present this fever pattern. Fever may occur at any time of the day, but characteristically presents in the late afternoon to evening in conjunction with the rash. Moreover, the temperature may be subnormal in the morning. During episodes of fever, an affected child commonly appears ill when chills are present, but then appears well when the fever breaks. Fever associated with systemic onset disease often responds poorlyto the commonly prescribed nonsteroidal anti-inflammatory drugs (NSAIDs), even at high doses1.

Figure 4. High intermittent fever in a representative patient with systemic onset disease1.

In the case of systemic onset disease, intermittent fever is almost always accompanied by the classic rash. The classic rash is evanescent (usually coming and going with the fever spikes) and consists of discrete, circumscribed, salmon-pink macules (2-mm to 10-mm in size) that may be surrounded by a ring of pallor or may develop central clearing. Lesions are most common on the trunk and proximal extremities, including the axilla and inguinal areas, but can also develop on the face, palms, or soles of affected individuals. The rash tends to be migratory and is strikingly evanescent: individual lesions last for up to a few hours and leave no residua. Moreover, the rash may be much more persistent in children who are systemically very ill, and may reappear with each systemic exacerbation. Such rash also occurs very rarely in children with polyarticular onset disease, and likely never occurs in those with classic oligoarthritis. Individual lesions may be elicited either by rubbing and/or scratching the skin (the so-called Koebner response), by a hot bath, or by psychological stress. The rash is occasionally pruritic but is never purpuric1.

Figure 5. Typical rash in a patient with systemic onset disease1.

Pericarditis and pericardial effusions are especially common in children with systemic onset disease. Pericarditis may precede the development of arthritis or may occur at any time during the course of disease, and is usually accompanied by a systemic exacerbation of disease. Pericarditis tends to occur in older children, but it is not related to sex, age at onset, or severity of joint disease. Most pericardial effusions are asymptomatic, although some children have dyspnea or precordial pain that may be transferred to the back, shoulder, or neck. In many cases, pericardial effusions develop insidiously, may not be accompanied by obvious cardiomegaly or electrocardiographic changes, and escape recognition except by echocardiography. Examination of affected patients may disclose diminished heart sounds, tachycardia, cardiomegaly, and a pericardial friction rub, usually at the left lower sternal border. Pneumonitis or pleural effusions may also occur with carditis, or may be asymptomatic and detected only as incidental findings on chest radiographs. Pulmonary rheumatoid nodules that are described in adult rheumatoid arthritis are rare in childhood1.Another characteristic of systemic onset disease is enlargement of lymph nodes and spleen, either alone or in combination. Marked symmetric lymphadenopathy is particularly common in the anterior cervical, axillary, and inguinal areas, and may suggest the diagnosis of lymphoma. Mesenteric lymphadenopathy may cause abdominal pain or distention and lead to an erroneous diagnosis of an acute surgical abdomen. Splenomegaly is generally most prominent within the first years after onset of systemic onset disease. The degree of splenomegaly may be extreme, but it is uncommonly associated with Feltys syndrome (splenic neutropenia). Hepatomegaly is less common than splenomegaly. Furthermore, moderate to severe enlargement of the liver is often associated with only mild derangement of function and relatively nonspecific histopathologic changes. However, massive enlargement of the liver is usually accompanied by abdominal distention and pain1. Uveitis

Chronic, anterior, nongranulomatous uveitis (iridocyclitis) develops in up to 21% of patients with oligoarticular disease and 10% of patients with polyarticular disease. However, no patients with systemic onset disease have been diagnosed as having uveitis to date. The only known independent risk factor for developing uveitis is a positive ANA test. The onset of chronic uveitis is typically insidious and often entirely asymptomatic, although up to one half of affected children have some symptoms attributable to uveitis (e.g., pain, redness, headache, photophobia, change in vision) later in the course of their disease. Uveitis may be present at the time of diagnosis, may develop during the course of JRA, or may be an initial manifestation of JRA that is usually detected in the course of routine ophthalmologic examination. JRA patients should be screened routinely to prevent delay in diagnosis of uveitis. The earliest signs of uveitis on slit-lamp examination are the presence of inflammatory cells and increased protein concentration in the aqueous humor of the anterior chamber of the eye. In addition, deposition of inflammatory cells on the inner surface of the cornea (keratopunctate deposits) may develop later during the course of disease. Complications of uveitis include posterior synechiae, cataracts, band keratopathy, glaucoma, and visual impairment1, 3.2 . 7. DiagnosisHistory

Arthritis must be present for 6 weeks before the diagnosis of juvenile rheumatoid arthritis (JRA) can be made. Disease onset is either insidious or abrupt, with morning stiffness or gelling phenomenon (ie, stiffness after long periods of sitting or inactivity) being a frequent complaint and arthralgia occurring during the day. A morning limp that improves with time may be noted, and a toddler may no longer stand in the crib in the morning or after naps3,8.

Complaints of joint pain may not be predominant in the patients history, however; children often stop using joints normally (eg, develop contractures of joints, decreased wrist range, limp) rather than complain of pain. Up to a quarter of children with oligoarticular JRA have no pain3,8.Individuals with JRA may have a history of school absences, and their ability to participate in physical education classes reflects the severity of the disease or acute flares3,8.Systemic-onset JRA is characterized by spiking fevers, typically occurring once or twice each day, at about the same time of day, with temperature returning to normal or below normal. The fever pattern is very useful because infections, Kawasaki disease, and malignancy usually do not have such a predictable pattern.

Systemic-onset JRA is usually accompanied by an evanescent rash (lasting a few hours), which is typically nonpruritic, macular, and salmon colored on the trunk and extremities. Occasionally, the rash is extremely pruritic and resistant to antihistamine treatment3,8.Physical ExaminationJRA is a clinical diagnosis. A complete physical examination is critical for the diagnosis. Physical findings are important to provide criteria for diagnosis and to detect abnormalities suggestive of alternative etiologies. The diagnosis of JRA is based on the physical finding of arthritis in at least 1 joint that has persisted for at least 6 weeks, with other causes excluded, in an individual younger than 16 years3,8.Arthritis is defined as either intra-articular swelling on examination or as limitation of joint motion in association with pain, warmth, or erythema of the joint. The hips, temporomandibular joint, and small joints in the spine do not demonstrate swelling when affected by synovitis but demonstrate the combination of loss of motion and pain. The physical findings in JRA are a reflection of the extent of joint involvement3,8.In synovitis, in which there is synovial proliferation and an increase in joint volume, the joint is held in a position of maximum comfort. Limbs with synovitis are generally held in flexion. Range of motion often is limited only at the extremes. In synovitis, the fingers may appear swollen, and the range of motion becomes painful. The wrist goes into flexion. In the knee, the parapatellar fossae often are obliterated, and a doughy synovium may be palpable. A soft, boggy swelling is appreciated in the popliteal fossa3,8.The hip is held in an attitude of flexion, abduction, and external rotation. Attempted range of motion will be painful to a varying degree. Guarding is an early sign of synovitis8.2 . 8. Laboratory TestThe diagnosis of juvenile rheumatoid arthritis (JRA) is based on the history and physical examination findings. No laboratory studies are diagnostic for JRA, and indeed, all laboratory study findings may be normal in children with this disorder. However, laboratory studies help to exclude other underlying disorders, classify the type of arthritis, and evaluate for extra-articular manifestations of JRA. Imaging of affected joints is usually indicated8. Inflammatory Markers

The erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) level is usually elevated in children with systemic-onset JRA (with a disproportionate increase in the CRP) and may be elevated in those with polyarticular disease; however, it is often within the reference range in those with oligoarticular disease. When elevated, inflammatory markers can be used to monitor disease activity8.Complete Blood Count and Metabolic PanelLymphopenia is not uncommon because of emigration of activated lymphocytes out of the circulation into synovium. However, neutropenia is uncommon and, particularly with lymphocytosis or thrombocytopenia, raises the possibility of acute lymphocytic leukemia8.A complete blood count, liver function tests (to exclude the possibility of viral or autoimmune hepatitis), and assessment of renal function with serum creatinine levels should be done before starting treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), methotrexate (MTX), or tumor necrosis factoralpha inhibitors8.

Antinuclear Antibody Testing

As many as 70% of children with oligoarticular JRA have positive ANA assays. However, a positive ANA should also raise suspicion ofsystemic lupus erythematosus(SLE). Overlap between the manifestations of the two disorders may lead to initial misdiagnosis of SLE as JRA8.A positive ANA is a marker for increased risk of anterior uveitis. Children younger than 6 years at arthritis onset with a positive ANA finding are in the highest risk category for development of uveitis and need slit lamp screening every 3-4 months. Titers do not correlate with disease activity8.Additional Laboratory Tests

In systemic-onset JRA, total protein and albumin levels are often decreased during active disease, and fibrinogen, ferritin and D-dimer levels are often elevated. Laboratory results that can help to rule out JRA include angiotensin-converting enzyme (ACE) elevation, which may be indicative of sarcoidosis, and antistreptolysin 0 (AS0) and anti-DNAse B elevations, which may indicate acute rheumatic fever or poststreptococcal arthritis8.Perform a urinalysis to exclude the possibility of infection (as a trigger for JRA or transient postinfectious arthritis). Proteinuria (>0.5 g/d or 3+ positive on dipstick testing) or cellular casts is consistent with renal involvement in SLE. In patients with systemic-onset JRA, the following test results are indicative of the development of macrophage-activating syndrome (MAS)8:

Falling ESR

Normalization or decrease in white blood cell (WBC) count

Low platelets

Elevated liver enzymes

Increased ferritin

Increased triglycerides

Low fibrinogen

Erratic fevers

Hemorrhages (disseminated intravascular coagulationlike pattern)

Radiography

When only a single joint is affected, radiography is important to exclude other diseases, such as osteomyelitis. Basic radiographic changes in JRA (see the images below) include the following8, 9:

Soft tissue swelling

Osteopenia and/or osteoporosis

Joint-space narrowing

Bony erosions

Intra-articular bony ankylosis

Periosteitis

Growth disturbances

Epiphyseal compression fracture

Joint subluxation

Synovial cysts

Figure 6. Ankylosis in the cervical spine at several levels due to long-standing juvenile rheumatoid arthritis (also known as juvenile idiopathic arthritis)8.

Figure 7. Widespread osteopenia, carpal crowding (due to cartilage loss), and several erosions affecting the carpal bones and metacarpal heads in particular in a child with advanced juvenile rheumatoid arthritis (also known as juvenile idiopathic arthritis)8.Ultrasonography

On ultrasonograms, inflamed synovium can appear as an area of mixed echogenicity lining the articular cartilage; the vascularity of the synovium can be assessed with Doppler flow studies. Serial measurements of synovial thickness and effusion volumes have been used to monitor disease progression.It can be helpful to evaluate joints that are difficult to palpate, such as the hip and shoulder. Some researchers claim that ultrasonography is more sensitive than plain radiography in the detection of cartilage erosions and effusions. Ultrasound has the advantages of no exposure to ionizing radiation; it can be done in the clinic is an awake, moving child; and it can help guide injections8, 9.

Computed Tomography and Magnetic Resonance Imaging

CT scanning is the best method for analyzing bony abnormalities, but it has been largely superseded by MRI in the overall assessment of JRA. The major disadvantage of CT scanning is that it involves a substantial radiation dose. Perform CT scanning of the long bones when considering osteoid osteoma is suspected8, 9.MRI is helpful when considering trauma in the differential diagnosis. In addition, imaging of the TMJ, sacroiliac joint, cervical spine, midfoot, hip, or shoulder is useful in diagnosing inflammatory arthritis8, 9.MRI provides the most sensitive radiologic indicator of disease activity. The modality can depict synovial hypertrophy, define soft tissue swelling, and demonstrate excellent detail of the status of articular cartilage and overall joint integrity8, 9. To improve visualization of synovial hypertrophy and improve detection of cartilaginous erosions when an inflammatory arthritis is suspected, contrast-enhanced sequences should be performed8, 9.Synovitis and a joint effusion may have similar hyperintensity on T2-weighted (T2W) and short-tau inversion recovery (STIR) images. Therefore, gadolinium-enhanced T1-weighted (T1W) MRIs are necessary to accurately define active synovitis8, 9.

Figure 8. (A) T2-weighted MRI shows high signal in both hips, which may be due to hip effusions or synovitis. High signal intensity in the left femoral head indicates avascular necrosis. (B) Coronal fat-saturated gadolinium-enhanced T1-weighted MRI shows bilateral enhancement in the hips. This indicated bilateral active synovitis, which is most pronounced on the right. Because the image was obtained with fat saturation, the hyperintensity in both hips is pathologic, reflecting an inflamed pannus8.2 . 9. TreatmentsFor all patients, the goals of therapy are to decrease chronic joint pain and suppress the inflammatory process. Accomplishing these goals will lead not only to improved short-term and long-term function but also to normal growth and development2.First-line therapy includes nonsteroidal anti-inflammatory drugs (NSAIDs). In addition, intra-articular corticosteroid injections have been shown to be safe and effective, may have beneficial effects on growth parameters, and can be administered with little psychologic trauma, even in young patients. Cognitive-behavioral pain management techniques have also been successful in reducing pain intensity in pediatric patients. Physical therapy is important not only for reducing pain but also for maintaining joint and muscle function2.

Preventing eye damage is another important goal of JRA therapy. Because of the risk of chronic uveitis in patients with JRA, careful ophthalmologic surveillance is essential. Pharmacotherapy of uveitis with methotrexate and cyclosporin A may be beneficial in decreasing the severity of this condition2. The toxicities associated with therapeutic agents pose a significant problem in effective treatment. For instance, agents that work by general immunosuppression may be associated with increased susceptibility to infection, complication of vaccine administration, or increased oncogenic risk. The distinction between symptom control and prevention of erosive disease must also be recognized. Many of the agents that are most effective at pain and symptom control, including corticosteroids and NSAIDs, have no effect on erosive disease. Even methotrexate, which is known to have disease-modifying activity, may relieve symptoms and signs without halting disease progression in some patients2.

Disease-Modifying Antirheumatic Drugs

The term disease-modifying antirheumatic drugs (DMARD) is limited to agents that retard radiologic progression of disease. Only 3 DMARDs have been proved to be effective in controlling disease activity in double-blind, placebo-controlled studies of children with JRA: methotrexate, sulfasalazine, and, more recently, etanercept2.

Diet and Activity

No specific diet helps in the treatment of JIA. However, because active JIA has been associated with decreased osteoblastic activity and a risk of osteopenia, encourage the inclusion of at least 3 servings of calcium-rich foods each day. Consider supplementation when poor calcium intake persists. Rarely, overall caloric intake is poor and supplementation is required. TMJ disease may also compromise the childs diet8.Encourage patients to be as active as possible. Bed rest is not a part of the treatment. In fact, the more active the patient, the better the long-term prognosis. Children may experience increased pain during routine physical activities. As a result, these children must be allowed to self-limit their activities, particularly during physical education classes. A consistent physical therapy program, with attention to stretching exercises, pain modalities, joint protection, and home exercises, can help ensure that patients are as active as possible8.

RehabilitationObjectives of physical therapy and rehabilitation in JRA include the following15: (a) controlling pain, (b) preventing limitation and restoring ROM in affected joints, (c) maintaining and improving muscle strength, (d) increasing and maintaining endurance for activities of daily living, (e) minimizing the effects of inflammation, and (f) ensuring normal growth and development10.To achieve these objectives, raising awareness about the disease in patients and families is one of the most essential components of treatment. A study by Andr et al16 documented that through education, physical exercises, coping strategies, and problem-solving skills, families became more involved in the treatment, better understood their childrens condition, and were able to find more efficient solutions, with a subsequent improvement in the quality of life of their children10.In JRA, home-based programs are important to support the treatment. There are three basic rules for home programs: first, the most appropriate treatment is the simplest, least painful, and least expensive; second, stretching and strengthening exercises should be customized according to the daily activities that the patient is unable to perform; and third, all treatments must be followed closely by a health care professional10.

2 . 10. Prognosis

The course of the disease is highly variable. Only approximately one quarter of patients with polyarticular onset are in remission at 5 years after disease onset, and more than two thirds develop erosions within the first 5 years of the disease. The extended oligoarthritis phenotype has a similar prognosis2.As might be expected from the high frequency of erosions in patients with polyarticular disease, polyarticular onset and polyarticular disease course both have been identified as significant risk factors for disability. Other factors that determine disability include female gender and the presence of rheumatoid factor. Lower remission rates have been observed in patients with polyarticular onset, rheumatoid factor, persistent morning stiffness, tenosynovitis, subcutaneous nodules, or antinuclear antibody. Poor outcomes are also associated with early involvement of the small joints of the hands and feet and rapid appearance of erosions2.The most challenging patients to treat are those with poor prognostic indicators. These patients are likely to require more aggressive therapy, as well as early initiation of treatment. A recent study of predictive factors that influence the outcome of patients with JRA or juvenile spondyloarthropathy found that patients who developed erosions and disability tended to have received treatment later thanthose who did not2.Table 2. Poor Prognostic Indicators for Patients With JRA2

CHAPTER III

MEDICAL REPORT3. 1. Case

DP, a 15 years and 10 months old boy, with a body weight of 25 kg, was admitted to the non-infection ward of H Adam Malik General Hospitals Pediatric Division on 4 May 2012 at 09.30 AM with a chief complaint of swelling on the joints.PERSONAL ANAMNESIS

Name

: DPAge

: 15 years and 10 months

Sex

: MaleInitial Body Weight : 25 kilogram

Body Height

: cm

Religion

: ChristianiRace

: Batak

Address

: Lingkungan IX Sikkam Kel. SibaAdmission Date: 04 May 2012

Medical Record: 51.37.45ANAMNESIS OF DISEASE:

Chief complaint: swelling of the jointsResume:

Swelling was felt by the patient since 4 month ago. Sweeling felt on the knee joints. The knee joint could not be moved by the patient. Pain and burning sensation was felt and become worsen in 4 months. The patient could not walk since 4 months ago. The knee could not be straightened. History of recurrent fever since 9 months ago, but now the patients did not have a fever. Defecation and urination was normal. Nausea and vomiting were not found.

The patient was referred from regional hospital with the diagnosis of Rheumatoid Arthritis. The patient was transfused with 1 bag blood in that hospital. PHYSICAL DIAGNOSTIC:

Status Presence:

General Condition

Sensorium: Alert, Temperature: 37( C

Disease Condition

Anemic (+), icteric (-), edema (-), dyspnea (-), cyanosis (-), edema (+)

Nutrition Status

Age

: 15 years and 10 months

Body Weight: 25 kilogram

Body Length: 104 cm

Health status/Disease status/Nutritional status: Moderate / Moderate / PoorLocalised status:Head:

Eyes: Light Reflex +/+, isocoric pupil, pale conj.palp.inf +/+,

Ears: within normal range, Nose: within normal range, Mouth: within normal rangeNeck:

Lymph node enlargement (-)

Thorax:Fusiform symmetrical, retraction (-)

HR = 120 x/i, regular, murmur (-)

RR = 24 x/I, regular, ronchi (-/-)Abdomen: Soft, peristaltic (+) normal

Liver: not palpableSpleen: not palpableExtremities: Pulse: 120 x/i, regular, pressure/volume adequate, warm acral, CRT< 3, edema pretibial: (+/+), edema on the poplitea: (+/+), blood pressure: 100/70 mmHg

Differential Diagnosis: Juvenile Rhematoid Arthritis Acute Lymphocytic Leukemia Acute Rheumatic FeverDiagnosis: Juvenile Rhematoid ArthritisTherapy:

IVFD D5 NaCl 0,45% 10 gtt/i mikro

Ibuprofen 3x400 mgTreatment/Diagnosis Plan: Complete Blood Count, RFT, LFT, Electrolyte

Allergy Immunology referral Eye Departmen referral3. 2. DiscussionDP, a 15 years and 10 months old boy, with a body weight of 25 kg, was admitted to to the non-infection ward of H Adam Malik General Hospitals Pediatric Division on 4 May 2012 at 09.30 AM with a chief complaint of swelling on the joints Swelling was felt by the patient since 4 month ago. Sweeling felt on the knee joints. The knee joint could not be moved by the patient. Pain and burning sensation was felt and become worsen in 4 months. The patient could not walk since 4 months ago. The knee could not be straightened. History of recurrent fever since 9 months ago, but now the patients did not have a fever. Defecation and urination was normal. Nausea and vomiting were not found.

On further questioning, The patient was referred from regional hospital with the diagnosis of Rheumatoid Arthritis. The patient was transfused with 1 bag blood in that hospital.

Juvenile Rheumatoid Arthritis, persistent arthritis in 1 or more joints for at least 6 weeks if certain exclusionary conditions have been eliminated 2. JRA is the most common chronic rheumatic illness1. Patients with JRA often have symptoms including arthritis, fever, rash, arthritis, enlargement of lymph nodes and spleen, and uveitis 1. In this patient, DP, experienced swelling, pain, and burning sensation of the joints which realized 4 month ago. He also has history of fever since 9 months ago. The diagnosis of juvenile rheumatoid arthritis (JRA) is based on the history and physical examination findings. No laboratory studies are diagnostic for JRA, and indeed, all laboratory study findings may be normal in children with this disorder8. From anamnesis, DP experienced symptoms of arthritis and had history of fever since 9 months ago. From physical examination, there was a swelling of the joints (knee joint). When the joint was moved, the patient complained of pain and burning sensation. From the laboratory results, the hemoglobin was 9,1 g%, LED 27 mm/h, qualitative CRP was positive, rheumatoid factor was negative, ANA was 8, and Anti ds-DNA was 15,3. For all patients, the goals of therapy are to decrease chronic joint pain and suppress the inflammatory process. Accomplishing these goals will lead not only to improved short-term and long-term function but also to normal growth and development2. First-line therapy includes nonsteroidal anti-inflammatory drugs (NSAIDs). The patient was given ibuprofen as a first line therapy. Ibuprofen inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis. The pediatric dosage is 30-50 mg/kg/d PO divided qid, not to exceed 2.4 g/d.3. 3. Summary

A case report of Juvenile Rheumatoid Arthritis in a 15 year and 10 month old boy who was admitted to the non-infection ward of H Adam Malik General Hospitals Pediatric Division on 4th May 2012 was made. The diagnosis was established from history taking, physical examination, and laboratory examination. The goals of therapy are to decrease chronic joint pain and suppress the inflammatory process. The patient still being treated in the non-infection ward of H Adam Malik General Hospitals Pediatric Division.REFERENCES

1. Hahn YS, Kim JG. 2010. Pathogenesis and Clinical Manifestations of Juvenile Rheumatoid Arthritis. Korean J Pediatr 2010;53(11):921-9302. Ilowite NT. 2002. Current Treatment of Juvenile Rheumatoid Artrhitis. Pediatrics 2002;109;1093. Abraham, Rudolph. 2006. Buku Ajar Ilmu Pediatri Rudolph.Jakarta: EGC

4. Olson JC. 2003. Juvenile Idiopathic Arthritis: An Update. Winconsin Medical Journal. Vol. 102(7): 45-505. Rudis J. 2012. Juvenile Rheumatoid Arthritis. Available from: http://pediatrics.med.nyu.edu/conditions-we-treat/conditions/juvenile-rheumatoid-arthritis6. Subramaniam S. 2009. Ethiopathogenesis of Rheumatoid Arthritis May be Misunderstood of Non-Infectious-A Review on Infectious Etiology of RA. Asian Journal of Medical Sciences 1(2): 1-97. Samee ERAE, Chennawy FE, Shambaky AYA. 2011. Clinical and Genetic Study of Juvenile Rheumatoid Arthritis. New York Science Journal, 2011;4(4)8. Sherry DD. 2011. Juvenile Idiopathic Arthritis. Available from: http://emedicine.medscape.com/article/1007276-overview9. Hekmatnia A. 2011. Imaging in Juvenile Rheumatoid Arthritis. Available from: http://emedicine.medscape.com/article/409980-overview#a2310. Cakmak A, Bolukbas N. 2005. Juvenile Rheumatoid Arthritis: Physical Therapy and Rehabilitation. Southern Medical Journal. Vol. 98(2): 212-216EKG

ECHO

Follow Up (05/5/2012) on 06.00 pm

S: pain and swelling of the joints

O: General Status: Sensorium: Alert, Temp: 37 C, BB: 25 kg, PB: 104 cm, Anemic (+), Dyspnea (-), Cyanosis (-), Edema(+), Icteric (-)

Localized Status :

Head

: Eye: light reflex: +/+ , isochoric pupil,

Pale Inferior conjunctiva palpebra : +/+

Ear/Nose/Mouth : in normal range

Neck: Lymph nodes enlargement (-),

Thorax: Simetris Fusiformis, Retraction (-)HR =116x/i, regular, murmur (-)

RR = 24x/i, regular, wheezing (-/-), ronchi (-/-)Abdomen : Soft, peristaltic (+) N

Liver: not palpable

Spleen: not palpable

Extremities: Pulse: 116 x/i regular, pressure/volume: adequate, warm acral, Capillary refill time < 3, blood pressure: 100/70 mmHg, edema pretibial (+/+), edema on the poplitea (+/+)

Anogenital : male, within normal range.

A : Juvenile Rheumatoid Arthritis

P : IVFD D5 NaCl 0,45% 10 gtt/s micro

Diet MB 1600 kkal + 50 gr protein

Ibuprofen 3x400 mg

Recommendation : Complete Blood Count, RFT, LFT, Electrolyte

ASTO, RF

ANA, anti ds-DNA

CRP

Allergy Immunology referral Eye Departmen referral

Lab Results:

Hematology

Complete Blood Count:

Hemoglobin: 9,1 g% Neutrofil: 57,8%

Erithrocyte: 4,27x106/mm3 Lymphocyte: 24 %

Leucocyte: 10,6x103/mm3 Monocyte: 7,9 %

Hematocrit: 29,9 % Eosinofil: 9,9 %

Trombosit: 488x103/mm3 Basofil: 0,4%

MCV: 70 fL

MCH 21,3 pg

MCHC: 30,4 g%

LED: 27 mm/jam

LE cell : negative

Clinical Chemistry:

Liver

Total Bilirubin: 0,19 mg/dl

Direct Blirubin: 0,1 mg/dl

Alkali Phosphatase: 92 U/L

AST/SGOT : 15 U/L

ALT/SGPT : 16 U/L

Carbohydrate Metabolism

Random Blood Glucose: 84,9 mg/dl

Kidney

Ureum : 13,7 mg/dl

Creatinin : 0,26 mg/dl

Uric Acid : 3,1 mg/dl

Electrolyte

Calcium (Ca) : 8,3 mg/dl

Sodium (Na) : 136 mEq/L

Potassium (K) : 4,3 mEq/L

Chloride (Cl) : 102 mEq/L

Immunoserology

ASTO: