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Juvenile idiopathic arthritis

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Key words: definition, pathogenesis, criteria, diagnosis, symptoms, treatment, prognosis

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  • Ny. Amiruddin
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  • Selamat sore Prof. Anak saya sarjana lulusan th.2016 dari TK kena asma setelah sms tambah alergi sampai sekarang. sudah ke klinik dgn dokter ahlinya, begitu disuntik kasih obat+salep+kompres sembuh. beberapa bulan kambuh lagi korengan ditangan_kaki seterusnya, sudah berpuluh puluh kali ke klinik tapi tdk bisa sembuh. Suami sy Pensiunan PNS, Sy PNS Jg. Dana Sebagian besar untuk berobat anak saya. Mohon maaf apakah profesor bisa membantu menyembuhkan anak saya. saya sedih takut masa depan anak sy. anaknya pintar seperti dosen. karena sakit sdh lama sekarang emosinya tinggi, cape sakit katanya ingin mati sj. terima kasih profesor.
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Juvenile idiopathic arthritis

  1. 1. Juvenile Idiopathic Arthritis Prof Ariyanto Harsono MD PhD SpA(K)
  2. 2. Introduction Juvenile rheumatoid arthritis (JRA), is the most common chronic rheumatologic disease in children and is one of the most common chronic diseases of childhood. The etiology is unknown, and the genetic component is complex, making clear distinctions between the various subtypes difficult. A new nomenclature, juvenile idiopathic arthritis (JIA), is being increasingly used to provide better definition of subgroups. Prof Ariyanto Harsono MD PhD SpA(K) 2
  3. 3. Criteria and classification Three groups have developed sets of criteria to classify children with arthritis: the American College of Rheumatology (ACR), the European League Against Rheumatism (EULAR), and the International League of Associations for Rheumatology (ILAR). The ACR criteria define juvenile rheumatoid arthritis (JRA) by age limit (< 16 y) and the duration of disease (>6 weeks). The organization recognizes the following 3 subtypes: Polyarticular Pauciarticular Systemic Prof Ariyanto Harsono MD PhD SpA(K) 3
  4. 4. Classification ACR 1977 ILAR 1997 Nomenclature Juvenile Rheumatoid Arthritis Juvenile Idiopathic Arthritis Minimum Duration >6wk >6wk Age of onset <16yr <16yr ≤ 4 joints in first 6 mo after presentation Pauciarticular juvenile rheumatoid arthritis Oligoarticular juvenile idiopathic arthritis: (A) Persistent < 4 joints for course of disease; (B) Extended >4 joints after 6 mo >4 joints in first 6 mo after presentation Polyarticular juvenile rheumatoid arthritis Polyarticular juvenile idiopathic arthritis- rheumatoid factor negative Polyarticular juvenile arthritis-rheumatoid factor positive Fever, rash, arthritis Systemic juvenile rheumatoid arthritis Systemic juvenile idiopathic arthritis Other categories included Exclusion of other forms Psoriatic juvenile idiopathic arthritis Enthesitis-related arthritis Undifferentiated: (A) Fits no other category; (B) Fits more than 1 category Inclusion of psoriatic arthritis, inflammatory bowel disease, juvenile ankylosing spondylitis No Yes Prof Ariyanto Harsono MD PhD SpA(K) 4
  5. 5. Signs and symptoms History findings in children with JIA may include the following:  Arthritis present for at least 6 weeks before diagnosis (mandatory for diagnosis of JIA)  Either insidious or abrupt disease onset, often with morning stiffness or gelling phenomenon and arthralgia during the day  Complaints of joint pain or abnormal joint use  History of school absences or limited ability to participate in physical education classes  Spiking fevers occurring once or twice each day at about the same time of day  Evanescent rash on the trunk and extremities  Psoriasis or more subtle dermatologic manifestations Prof Ariyanto Harsono MD PhD SpA(K) 5
  6. 6. Physical findings are important to provide criteria for diagnosis and to detect abnormalities suggestive of alternative etiologies, as well as to indicate disease subtypes. Such findings include the following: Arthritis: Defined either as intra-articular swelling on examination or as limitation of joint motion in association with pain, warmth, or erythema of the joint; physical findings in JIA reflect the extent of joint involvement Synovitis: Characterized by synovial proliferation and increased joint volume; the joint is held in a position of maximum comfort, and range of motion often is limited only at the extremes Prof Ariyanto Harsono MD PhD SpA(K) 6
  7. 7. Types of JIA include the following: Systemic-onset juvenile idiopathic arthritis Oligoarticular juvenile idiopathic arthritis Polyarticular juvenile idiopathic arthritis Psoriatic arthritis Enthesitis-related arthritis Undifferentiated arthritis Prof Ariyanto Harsono MD PhD SpA(K) 7
  8. 8. Arthritis must be present for 6 weeks before the diagnosis of juvenile idiopathic arthritis (JIA) 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 naps. Prof Ariyanto Harsono MD PhD SpA(K) 8
  9. 9. 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 JIA have no pain. Individuals with JIA may have a history of school absences, and their ability to participate in physical education classes reflects the severity of the disease or acute flares. Prof Ariyanto Harsono MD PhD SpA(K) 9
  10. 10. Systemic-onset JIA 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 JIA 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 treatment. Prof Ariyanto Harsono MD PhD SpA(K) 10
  11. 11. Children with psoriatic arthritis may have typical psoriasis but dermatological manifestations may be subtle; careful attention should be paid to looking for nail pits. Dactylitis is characteristic of psoriatic arthritis. Enthesitis-related arthritis frequently presents as evening and post-exercise pain. Attention should be given to buttock pain and back pain that improves with activity (inflammatory back pain). These children cannot lie in bed all morning but have to get up due to back pain. Prof Ariyanto Harsono MD PhD SpA(K) 11
  12. 12. Physical Examination JIA 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 JIA 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 years. Prof Ariyanto Harsono MD PhD SpA(K) 12
  13. 13. No diagnostic serologic tests for JIA are recognized, aside from rheumatoid factor assay for subclassification of polyarticular disease. Other tests, such as antinuclear antibody and HLA-B27 assays, may help further define diagnosis and risk of complications. 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 JIA are a reflection of the extent of joint involvement. Prof Ariyanto Harsono MD PhD SpA(K) 13
  14. 14. 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 fossa. Prof Ariyanto Harsono MD PhD SpA(K) 14
  15. 15. 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 synovitis. Cutaneous erythema is extremely rare in JIA. Its presence should alert one to look for another diagnosis. Prof Ariyanto Harsono MD PhD SpA(K) 15
  16. 16. Systemic-onset JIA A definite diagnosis of systemic-onset JIA must await the development of arthritis. This may occur at onset of the fever and rash or may lag by months or, rarely, years. Prof Ariyanto Harsono MD PhD SpA(K) 16
  17. 17. Physical examination findings include the following:  The child appears systemically ill  Arthralgia is often present  The child may have generalized myalgia  Evanescent, salmon-pink, macular rash (often linear) is found, predominantly on the trunk and the extremities; this rash, seen in the image below, is associated with fever spikes Systemic juvenile idiopathic arthritis (JIA) rash Prof Ariyanto Harsono MD PhD SpA(K) 17
  18. 18.  Hepatosplenomegaly is often present  Lymphadenopathy is sometimes present, especially the axillary lymph nodes  Muscle tenderness to palpation may be observed  Serositis, including pleural and pericardial effusions, may be present, as is noted in the image below Child with pericardial effusion due to systemic onset juvenile idiopathic arthritis Prof Ariyanto Harsono MD PhD SpA(K) 18
  19. 19. Chest pain or shortness of breath may be a sign of pericarditis or pleuritis Friction rub may occur in pericarditis but can be absent with a large pericardial effusion S3, basilar rales, and hepatomegaly suggestive of heart failure may rarely be observed when myocarditis occurs in individuals with systemic- onset JIA Prof Ariyanto Harsono MD PhD SpA(K) 19
  20. 20. Oligoarticular JIA Characteristics of oligoarticular JIA include the following:  In individuals with oligoarticular JIA, 4 or fewer joints (and in many cases, only 1 joint) are affected  Large, weight-bearing joints, such as the knees and ankles, are typically affected, as seen in the Eighteen-month-old girl with arthritis in her right knee. Note the flexion Prof Ariyanto Harsono MD PhD SpA(K) 20
  21. 21. Children appear to be well, despite ambulating with a limp In cases of asymmetrical arthritis, chronic inflammation-related hyperemia in a knee or ankle may lead to overgrowth of that limb with subsequent leg-length discrepancy Prof Ariyanto Harsono MD PhD SpA(K) 21
  22. 22.  Muscle atrophy, often of extensor muscles (eg, vastus lateralis, quadriceps when the knee is affected), may occur  Flexion contractures in the knees and, less commonly, the wrists are found  Involvement of a few small joints in the hands is atypical and suggests eventual development of polyarticular JIA or psoriatic arthritis. Dactylitis, or diffuse tenosynovitis of a finger or toe, also called a "sausage digit," is more typical of psoriatic arthritis or enthesitis-related arthritis. Prof Ariyanto Harsono MD PhD SpA(K) 22
  23. 23. Anterior uveitis (seen in the image below) is present in as many as 20% of children with oligoarticular and polyarticular JIA, especially those who are antinuclear antibody (ANA) positive. The uveitis is typically asymptomatic at onset and must be screened for with an ophthalmologic slit lamp examination. Generally, children who were 6 years of age or younger at onset (especially of oligoarticular and psoriatic arthritis) and have a positive ANA test are screened by slit lamp exam every 3 months for 4 years or more and then every 6 months until at least 7 years after diagnosis. Thereafter they are screened yearly for life. Prof Ariyanto Harsono MD PhD SpA(K) 23
  24. 24. Children who are at lesser risk (ie, have polyarticular disease and are ANA negative), are screened every 6 months for 7 years and then yearly. Children with systemic JIA are at very low risk and are screened yearly. Acute anterior uveitis is one of the diagnostic criteria for enthesitis-related arthritis. These children with are screened initially and if symptomatic. Older children with RF-positive polyarticular JIA should probably be screened yearly. There are few data on these children regarding their risk for uveitis. Prof Ariyanto Harsono MD PhD SpA(K) 24
  25. 25. Sequelae of chronic anterior uveitis. Note the posterior synechiae (weblike attachments of the pupillary margin to the anterior lens capsule) of the right eye secondary to chronic anterior uveitis. This patient has a positive antinuclear antibodies (ANAs) and initially had a pauciarticular course of her arthritis. She now has polyarticular involvement but no active uveitis. Prof Ariyanto Harsono MD PhD SpA(K) 25
  26. 26. Polyarticular Juvenile Idiopathic Arthritis In polyarticular juvenile idiopathic arthritis, 5 or more joints are affected in the first 6 months after disease onset, weight-bearing joints are affected, rheumatoid nodules may be seen in patients with RF-positive disease, and symmetrical involvement of small joints in the hands is often found, as seen in the images below. Prof Ariyanto Harsono MD PhD SpA(K) 26
  27. 27. Patient with active polyarticular arthritis. Note swelling (effusions) of all proximal interphalangeal (PIP) joints in addition to boney overgrowth. Also note lack of distal interphalangeal joint (DIP) involvement. The patient has interosseus muscle wasting (observed on the dorsum of the hands), and subluxation and ulnar deviation of the wrists are present. Prof Ariyanto Harsono MD PhD SpA(K) 27
  28. 28. Decreased extension of the cervical spine is often asymptomatic. It is indicative of arthritis of the cervical spine and can lead to subluxation, typically of the C2 vertebra on C3. Fusion of the posterior elements of the vertebra may occur. Flexion and extension views of C-spine in child with poorly controlled polyarticular juvenile idiopathic arthritis (JIA). Prof Ariyanto Harsono MD PhD SpA(K) 28
  29. 29. Psoriatic Arthritis Psoriatic arthritis in children is usually mild. Onset of arthritis precedes that of psoriasis in approximately half of children.  Characteristics of psoriatic arthritis include the following:  Monoarticular arthritis (50% of children)  DIP joint involvement (50%)  Tenosynovitis (30%)  Nail involvement(71%) - pitting is the most common but least specific finding  Disordered bone growth with resultant shortening (47%)  Sacroiliitis (28%) Prof Ariyanto Harsono MD PhD SpA(K) 29
  30. 30. Enthesitis-Related Arthritis Enthesitis-related arthritis, or pediatric spondyloarthropathy, is characterized by periods of inflammation of tendons and ligaments, particularly at the area of insertion into bone (entheses). Often, children and adolescents with spondyloarthropathy present with arthritis, making the distinction between subtypes difficult. Furthermore, children occasionally develop a disease that appears to be a combination of the 2 diseases. Prof Ariyanto Harsono MD PhD SpA(K) 30
  31. 31. Pain and tenderness at the enthesis is the most common manifestation, but swelling may also be seen. In children, the initial manifestations involve mainly the peripheral joints (eg, dactylitis) with asymmetric oligoarticular arthritis of the lower limbs; axial involvement (eg, sacroiliitis) tends to appear later in the disease course. Prof Ariyanto Harsono MD PhD SpA(K) 31
  32. 32. Diagnostic criteria for enthesitis-related JIA are the presence of both arthritis and enthesitis, or the presence of arthritis or enthesitis along with any 2 of the following 5 manifestations:  Sacroiliac tenderness and/or inflammatory lumbosacral pain  Positive human leukocyte antigen B27 (HLA-B27) test  Onset of arthritis in a male 6 years old or older  Acute symptomatic anterior uveitis  Presence in a first-degree relative of ankylosing spondylitis, enthesitis-related arthritis, inflammatory bowel disease with sacroiliitis, reactive arthritis, or acute anterior uveitis  Although enthesitis can be observed in persons with oligoarticular and polyarticular JIA, the eventual development of arthritis into a predominant enthesitis is more characteristic of spondyloarthropathy. The radiographic changes observed in adults (eg, sclerosis of the sacroiliac joints, bamboo spine) are rare in childhood and adolescence. Prof Ariyanto Harsono MD PhD SpA(K) 32
  33. 33. Diagnosis Diagnosis of JIA is based on the history and physical examination findings. When physical findings do not document definite arthritis, further evaluation is warranted. However, laboratory studies help to exclude other underlying disorders, classify the type of arthritis, and evaluate for extra-articular manifestations of JIA. Laboratory studies that may be considered include the following:  Inflammatory markers: Erythrocyte sedimentation rate (ESR) or CRP level  Complete blood count (CBC) and metabolic panel  Liver function tests and assessment of renal function with serum creatinine levels  Antinuclear antibody (ANA) testing  Rheumatoid factor (RF) and anti–cyclic citrullinated peptide (CCP) antibody  Additional studies: Total protein, albumin, fibrinogen, ferritin, D-dimer, angiotensin-converting enzyme (ACE), antistreptolysin 0 (AS0), anti-DNAse B, urinalysis  When only a single joint is affected, radiography is important to exclude other diseases. Basic radiographic changes in JIA include the following: Prof Ariyanto Harsono MD PhD SpA(K) 33
  34. 34. o Soft tissue swelling o Osteopenia or osteoporosis o Joint-space narrowing o Bony erosions o Intra-articular bony ankylosis o Periosteitis o Growth disturbances o Epiphyseal compression fracture o Joint subluxation o Synovial cysts Prof Ariyanto Harsono MD PhD SpA(K) 34
  35. 35. Inflammatory Markers The erythrocyte sedimentation rate (ESR) or C- reactive protein (CRP) level is usually elevated in children with systemic-onset JIA (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 activity. Other markers of inflammation include thrombocytosis, leukocytosis, complement, and, in a reverse fashion, albumin and hemoglobin. Prof Ariyanto Harsono MD PhD SpA(K) 35
  36. 36. Lymphopenia 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 leukemia. Prof Ariyanto Harsono MD PhD SpA(K) 36
  37. 37. Complete Blood Count and Metabolic Panel 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 factor–alpha inhibitors. Prof Ariyanto Harsono MD PhD SpA(K) 37
  38. 38. Antinuclear Antibody Testing As many as 70% of children with oligoarticular JIA have positive ANA assays. However, a positive ANA should also raise suspicion of SLE. Overlap between the manifestations of the two disorders may lead to initial misdiagnosis of SLE as JIA. 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 activity. Prof Ariyanto Harsono MD PhD SpA(K) 38
  39. 39. Radiography When only a single joint is affected, radiography is important to exclude other diseases, such as osteomyelitis. Basic radiographic changes in JIA (see the images below) include the following:  Soft tissue swelling  Osteopenia and/or osteoporosis  Joint-space narrowing  Bony erosions  Intra-articular bony ankylosis  Periosteitis  Growth disturbances  Epiphyseal compression fracture  Joint subluxation Prof Ariyanto Harsono MD PhD SpA(K) 39
  40. 40. Ankylosis in the cervical spine at several levels due to long- standing juvenile rheumatoid arthritis (also known as juvenile idiopathic arthritis). Prof Ariyanto Harsono MD PhD SpA(K) 40
  41. 41. 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). The main limitation of conventional radiography is that it does not allow direct examination of the articular cartilage, synovium, and other important noncalcified structures in a joint. Prof Ariyanto Harsono MD PhD SpA(K) 41
  42. 42. 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 JIA. 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 suspected. 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 arthritis. Prof Ariyanto Harsono MD PhD SpA(K) 42
  43. 43. (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 pannus. Prof Ariyanto Harsono MD PhD SpA(K) 43
  44. 44. 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 integrity. To improve visualization of synovial hypertrophy and improve detection of cartilaginous erosions when an inflammatory arthritis is suspected, contrast-enhanced sequences should be performed. 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 synovitis. Note that gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD).Prof Ariyanto Harsono MD PhD SpA(K) 44
  45. 45. 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.[28] 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 injections. Prof Ariyanto Harsono MD PhD SpA(K) 45
  46. 46. Pathogenesis The etiology and pathogenesis of JIA are not completely understood. Genetic susceptibility plays a major role, but there is significant overlap between loci associated with JIA and those associated with other autoimmune diseases. JIA is a genetically complex disorder in which multiple genes are important for disease onset and manifestations. The IL2RA/CD25 gene has been implicated as a JIA susceptibility locus, as has the VTCN1 gene. Associations have been found between specific HLA alleles and clinical subtypes of JIA (eg, HLA-A(*)02:06 with susceptibility to JIA accompanied by uveitis, and HLA-DRB1(*)04:05 with polyarticular JIA, in a Japanese cohort). Prof Ariyanto Harsono MD PhD SpA(K) 46
  47. 47. Humoral and cell-mediated immunity are involved in the pathogenesis of JIA. T lymphocytes have a central role, releasing proinflammatory cytokines (eg, tumor necrosis factor–alpha [TNF-α], interleukin [IL]-6, IL-1) and favoring a type-1 helper T-lymphocyte response. A disordered interaction between type 1 and type 2 T- helper cells has been postulated. Studies of T-cell receptor expression confirm recruitment of T-lymphocytes specific for synovial nonself antigens. Evidence for abnormalities in the humoral immune system include the increased presence of autoantibodies (especially antinuclear antibodies), increased serum immunoglobulins, the presence of circulating immune complexes, and complement activation. Prof Ariyanto Harsono MD PhD SpA(K) 47
  48. 48. Chronic inflammation of synovium is characterized by B-lymphocyte infiltration and expansion. Macrophages and T-cell invasion are associated with the release of cytokines, which evoke synoviocyte proliferation. A study by Scola et al found synovium to contain messenger ribonucleic acid (mRNA) for vascular endothelial growth factor and angiopoietin 1, as well as for their receptors, suggesting that induction of angiogenesis by products of lymphocytic infiltration may be involved in persistence of disease. Prof Ariyanto Harsono MD PhD SpA(K) 48
  49. 49. Some pediatric rheumatologists view systemic-onset JIA as an autoinflammatory disorder, such as familial Mediterranean fever (FMF) or cryopyrin-associated periodic fever syndromes, rather than a subtype of JIA. This theory is supported by work demonstrating similar expression patterns of a phagocytic protein (S100A12) in systemic- onset JIA and FMF, as well as the same marked responsiveness to IL-1 receptor antagonists. FMF is associated with mutations in the MEFV gene; these mutations are associated with activation of the IL-1b pathway, resulting in inflammation. A study by Ayaz et al found an increased frequency of MEFV mutations in Turkish children who were diagnosed with systemic JIA; this study has not been replicated in other populations. Prof Ariyanto Harsono MD PhD SpA(K) 49
  50. 50. Prognosis Advances in treatment over the last 20 years— especially the introduction of early use of intra- articular steroids, methotrexate, and biologic medications—have dramatically improved the prognosis for children with arthritis. Almost all children with JIA lead productive lives. However, many patients, particularly those with polyarticular disease, may have problems with active disease throughout adulthood, with sustained remission attained in a minority of patients. Prof Ariyanto Harsono MD PhD SpA(K) 50
  51. 51. Early hip or wrist involvement, symmetrical disease, the presence of RF, and prolonged active systemic disease have been associated with poor long-term outcomes. Compared with adults with RF-positive rheumatoid arthritis, however, children are at less risk for rheumatoid lung involvement and vasculitis. The anti – cyclic citrullinated peptide antibodies (CCP) antibodies test may be more specific than the RF test, but it is not as well studied in children. Children with systemic-onset disease tend to either respond completely to medical therapy or develop a severe polyarticular course that tends to be refractory to medical treatment, with disease persisting into adulthood. Most children with oligoarticular disease demonstrate eventual permanent remission, although a small number progress to persisting polyarticular disease. Prof Ariyanto Harsono MD PhD SpA(K) 51
  52. 52. Undifferentiated Arthritis Undifferentiated JIA is diagnosed if the patient’s manifestations either do not fulfill the criteria for any one category or fulfill the criteria for more than one. Most often, children in the latter category fulfill the criteria for polyarticular RF-negative JIA and either enthesitis-related JIA or psoriatic JIA. Prof Ariyanto Harsono MD PhD SpA(K) 52
  53. 53. Complications of Disease Systemic-onset juvenile idiopathic arthritis The complications that may occur in systemic-onset JIA are pericarditis, hemolytic anemia, macrophage activation syndrome (MAS), and endarteritis. Patients with pericarditis often present with orthopnea and respond to intravenous (IV) corticosteroid treatment. MAS is a rare, but important, complication, in which all 3 bloodlines become rapidly decreased. Hypofibrinogenemia, thrombocytopenia, and elevated aspartate aminotransferase levels and markedly elevated ferritin levels are hallmarks. Hypotension, central nervous system (CNS) disease, and marked hepatosplenomegaly may be noted as complications of a release of massive amounts of cytokines. Prof Ariyanto Harsono MD PhD SpA(K) 53
  54. 54. Children with limited arthritis Complications of oligoarticular JIA and psoriatic arthritis include joint contractures, uveitis, and leg-length discrepancy. Uveitis is almost always asymptomatic and more frequent in young girls who have positive levels of antinuclear antibody. Evaluation with a slit-lamp every 4 months by a pediatric ophthalmologist can detect early disease to prevent permanent eye damage and even blindness. Leg-length discrepancy may complicate unilateral knee involvement. In young children, it may result from neovascularization of growth plates, so the involved limb is longer. In early puberty, unilateral arthritis can lead to premature fusion of the epiphysis, in which case the short limb is on the affected side. The problem may not be detected in patients with a knee flexion contracture until the contracture is corrected. Both flexion contractures and leg-length discrepancies are much less frequent with early intervention. Prof Ariyanto Harsono MD PhD SpA(K) 54
  55. 55. Children with widespread arthritis Complications of polyarticular JIA include skeletal abnormalities such as increased size of epiphyses, accelerated bone age, narrowed joint spaces, swan- neck and/or boutonniere deformities, joint subluxation, and cervical spine involvement. Difficulty extending the spine may create a problem for intubation prior to surgery, so anesthesiologists need to be informed of the patient's diagnosis. Cervical spine radiography (in flexion and extension) may help to screen for potential difficulties during induction of anesthesia. High-level subluxation is a potential complication Prof Ariyanto Harsono MD PhD SpA(K) 55
  56. 56. Enthesitis-related arthritis Complications of enthesitis-elated arthritis are rare but can include restrictive lung disease and aortic insufficiency. These children are at risk for symptomatic iritis with acute photophobia and conjunctivitis but only rarely does it lead to visual impairment. Prof Ariyanto Harsono MD PhD SpA(K) 56
  57. 57. Differential Diagnosis • Behcet Syndrome • Infectious Mononucleosis • Kawasaki Disease • Lyme Disease • Pediatric Acute Lymphoblastic Leukemia • Pediatric Kawasaki Disease • Pediatric Sarcoidosis • Pericarditis, Viral • Somatoform Disorder: Pain • Systemic Lupus Erythematosus Prof Ariyanto Harsono MD PhD SpA(K) 57
  58. 58. Differential Diagnosis of Arthritis Prof Ariyanto Harsono MD PhD SpA(K) 58
  59. 59. Treatment The ultimate goals in managing rheumatoid arthritis are to prevent or control joint damage, to prevent loss of function, and to decrease pain. These goals are particularly important in juvenile idiopathic arthritis (JIA), in which the rate of progression and the onset of debility can be rapid. JIA is a chronic disease characterized by periods of remission and flare. Treatment is aimed at inducing remission with the least toxicity from medications with hopes of inducing a permanent remission. The success of therapy is monitored best with repeated physical examinations and history. The number of joints involved and the duration of morning stiffness should demonstrate continued decrease, with elimination reflecting success. Surgery may be indicated in patients who are unresponsive to medical therapy. Prof Ariyanto Harsono MD PhD SpA(K) 59
  60. 60. A team-based approach to the treatment of JIA can be helpful. Management may include 1 or all of the following areas: Pharmacologic therapy with nonsteroidal anti- inflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDs), biologic agents, or intra-articular and oral corticosteroids Psychosocial interventions Measures to enhance school performance (eg, academic counseling) Improved nutrition Physical therapy Occupational therapy Prof Ariyanto Harsono MD PhD SpA(K) 60
  61. 61. American College of Rheumatology (ACR) criteria for complete remission are as follows: No inflammatory joint pain No morning stiffness No fatigue No synovitis No progression of damage, as determined in sequential radiographic examinations No elevation of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels Prof Ariyanto Harsono MD PhD SpA(K) 61
  62. 62. The ACR issued recommendations for the treatment of JIA on the basis of the following 5 treatment groups: History of arthritis in 4 or fewer joints History of arthritis in 5 or more joints Active sacroiliac arthritis Systemic arthritis without active arthritis Systemic arthritis with active arthritis Prof Ariyanto Harsono MD PhD SpA(K) 62
  63. 63. History of arthritis in 4 or fewer jointsAccording to ACR guidelines, the treatment group that comprises patients who have developed active arthritis in only 4 or fewer joints total throughout their disease course includes patients in the International League of Associations for Rheumatology (ILAR) categories of persistent oligoarthritis, as well as patients with psoriatic arthritis, enthesitis-related arthritis, and undifferentiated arthritis. In this treatment group, escalation of therapy typically proceeds from NSAIDs to intra-articular glucocorticoid injections to methotrexate to TNF-α inhibitors. NSAIDs alone may be adequate for patients with involvement of a single joint and other indications of low disease activity (eg, normal inflammatory marker levels); response should be evident within 2 months. For other patients, NSAIDs may be used as adjunctive treatment, as needed. Intra-articular injections of triamcinolone can be used for any joint involved with active arthritis, and should provide clinical relief for at least 4 months. If so, the injections can be repeated as needed. Prof Ariyanto Harsono MD PhD SpA(K) 63
  64. 64. Methotrexate can be instituted in patients who fail to show adequate response to NSAIDs and/or joint injections. Alternatively, methotrexate is recommended as initial treatment for patients in this treatment group who have high disease activity and features indicating poor prognosis. In patients with enthesitis-related JIA, sulfasalazine rather than methotrexate is recommended for patients who have an inadequate response to joint injection or an adequate trial of NSAIDs. Patients in this treatment group who fail to respond adequately to joint injections and to 3-6 months (depending on disease characteristics and severity) of methotrexate are candidates for TNF-α treatment. The same is true of patients with enthesitis-related JIA who receive sulfasalazine. Prof Ariyanto Harsono MD PhD SpA(K) 64
  65. 65. History of Arthritis in 5 or More Joints This group comprises patients who have developed active arthritis in 5 or more joints total throughout throughout their disease course. Patients need not currently have active involvement in 5 or more joints. According to ACR guidelines, this group includes patients with the ILAR categories of extended oligoarthritis, rheumatoid factor (RF) negative and RF-positive polyarthritis, psoriatic arthritis, enthesitis-related arthritis, and undifferentiated arthritis. Prof Ariyanto Harsono MD PhD SpA(K) 65
  66. 66. Treatment in this group places less emphasis on initial NSAIDs. After 1 month of NSAID treatment in patients with low disease activity, or 1-2 months in those with moderate disease activity but without poor prognostic features (ie, hip or cervical spine involvement, positive RF or anti-cyclic citrullinated peptide antibodies (CCP), radiographic signs of joint damage), it is appropriate to escalate to methotrexate, plus adjunctive NSAIDs and joint injection as needed. In patients with moderate disease activity and poor prognostic features, as well as in patients with high disease activity, treatment may start with methotrexate. Leflunomide may be used as an alternative to methotrexate, after a failed NSAID trial, or as initial treatment in patients with high disease activity and poor prognostic features. Prof Ariyanto Harsono MD PhD SpA(K) 66
  67. 67. The US Food and Drug Administration (FDA) has approved the interleukin (IL)-6 inhibitor tocilizumab for the treatment of polyarticular JIA in children 2 years of age and older with active disease. Tocilizumab can be used alone or in combination with methotrexate. Escalation to a TNF-α inhibitor follows if 3-6 months (depending on disease characteristics and severity) of methotrexate or leflunomide provides inadequate control. Patients who show inadequate response after 3-4 months (depending on disease characteristics and severity) of TNF-α inhibitor treatment can be switched to a different TNF-α inhibitor or to abatacept. If these agents prove inadequate, patients may be started on rituximab; this agent may be most appropriate in patients with RF-positive polyarticular JIA. Prof Ariyanto Harsono MD PhD SpA(K) 67
  68. 68. Active Sacroiliac Arthritis This group includes all patients with clinical and imaging evidence of active sacroiliac arthritis. It may include patients from any of the ILAR JIA categories. Use of a TNF-α inhibitor is recommended more readily for patients in this group. A TNF-α inhibitor may be started after failure of an adequate trial of NSAIDs or after 3-6 months (depending on disease characteristics and severity) of methotrexate or sulfasalazine proves inadequate. Prof Ariyanto Harsono MD PhD SpA(K) 68
  69. 69. Systemic Arthritis with Active Systemic Features and without Active Arthritis This group includes all patients who fulfill the ILAR criteria for systemic arthritis and who have active fever of systemic JIA with or without other systemic features, but without active arthritis. A 2-week trials of NSAIDs may be used in patients who have fever and less severe disease, and have had significant active systemic disease for less than 6 months; after that, patients should be started on systemic glucocorticoids, with adjunct NSAIDs as needed. Prof Ariyanto Harsono MD PhD SpA(K) 69
  70. 70. Patients with high systemic disease activity (eg, significant serositis) may be started on steroids as a first step. There is virtually no published evidence regarding steroid doses or administration routes in this setting. Patients who sustain or develop active fever while on systemic steroid therapy can be started on anakinra. This agent may be a first choice in patients who have had significant active systemic disease for at least 6 months. Prof Ariyanto Harsono MD PhD SpA(K) 70
  71. 71. The FDA has approved tocilizumab for the treatment of systemic JIA. Clinical trials in children with JIA showed significantly fewer disease flares when treated with tocilizumab compared with placebo (26% vs 48%). Additionally, a higher success rate of steroid reduction/discontinuance was achieved in the tocilizumab group (24%) compared with placebo (3%). Prof Ariyanto Harsono MD PhD SpA(K) 71
  72. 72. Systemic Arthritis with Active Arthritis and without Active Systemic Features This category includes all patients who fulfill the ILAR criteria for systemic arthritis and who have active arthritis, but who do not have active systemic features. Most of these patients are started on NSAIDs while their diagnostic assessment progresses. NSAID therapy, with intra-articular joint injections as needed, may be adequate for patients with low disease activity who do not have hip involvement or radiographic signs of joint damage. After up to 1 month, however, methotrexate can be added for patients with any degree of disease severity who continue to have active arthritis. After 3 months of methotrexate therapy, the next step in escalation is to anakinra or a TNF-α inhibitor, although etanercept is less effective in systemic arthritis than in other forms of JIA. Patients who show inadequate response to TNF-α inhibitor treatment can be started on abatacept. 72
  73. 73. Treatment of Macrophage Activation Syndrome MAS) is a rare but important complication of systemic- onset JIA in which numbers of all 3 bloodlines become rapidly decreased. Hypofibrinogenemia, thrombocytopenia, and elevated aspartate aminotransferase levels are hallmarks. MAS often responds to cyclosporin A, and some case reports have detailed a response to anakinra. Treatment of MAS is a medical emergency and should be performed by physicians familiar with this complication. Prof Ariyanto Harsono MD PhD SpA(K) 73
  74. 74. Treatment of Uveitis Uveitis is often asymptomatic. Patients are typically young girls who have positive levels of ANA. Treatment with topical corticosteroid medication and with mydriatic agents (to prevent closed-angle glaucoma) often can prevent progression of disease to development of calcium deposition in the lens (band keratopathy) and adhesions of the iris to the lens (posterior synechiae), in which an irregular pupillary margin develops. Such complications may herald a chronic active disease in which vision is threatened. Immunosuppressive agents, such as methotrexate or cyclosporine, may help control chronic uveitis. Infliximab can be effective in some patients who are resistant to immunosuppressive agents. Prof Ariyanto Harsono MD PhD SpA(K) 74
  75. 75. Long-Term Monitoring A complete blood cell count and measurement of liver enzymes and serum creatinine should be part of routine follow-up in JIA patients. For JIA patients receiving NSAIDs on a long-term daily basis, these tests, plus urinalysis, should be done twice yearly; in patients taking these agents 3-4 days per week, testing should be repeated annually. In JIA patients taking methotrexate, these tests should be conducted approximately 1 month after initiation of routine use and approximately 1-2 months after any increase in dose. If prior results were normal and the patient is on a stable dose, the tests can be repeated approximately every 3-4 months. In JIA patients taking TNF inhibitors, these tests should be repeated approximately every 3-6 months. Tuberculosis screening should be repeated approximately once yearly. Prof Ariyanto Harsono MD PhD SpA(K) 75
  76. 76. Reference • Sherry DD. Juvenile Idiopathic Arthritis. http://emedicine.medscape.com/article/1007 276-overview . Accessed Nov 9, 2014. Prof Ariyanto Harsono MD PhD SpA(K) 76
  77. 77. Thank you Prof Ariyanto Harsono MD PhD SpA(K) 77

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