Differential diagnosis The differential diagnoses for all subtypes of JIA are similar and t heir key features are listed in the table below. Co-morbidities Co-morbidity can arise as a result from JIA- associated lesions in extra-art icular organs, from long-term complica- tions of the conditions or their treatment. \200 Disease activity assessment and monitoring Combinations of measures are employed including joint counts, pain measures, acute phase measures, and global assessments. \200 Most complications of JIA can be avoided with early diagnosis and aggressive control of dis ease. Complications and co-morbidities include poor denti- tion, osteoporosis, and growth f ailure (disease severity and GC use associated), infections secondary to immune suppression , VZ in particular, blindness owing to anterior uveitis, amyloidosis and macrophage activat ion syndrome (haemophagocytosis) (see Plate 20). Psychosocial problems with depression, anx iety, loss of schooling/education and peer interaction can be a par- ticular problem in ado lescents. Active joint score \200\223 those joints with tenderness, and/ or pain and/or swelling, wi th swelling being the most objective of these parameters, but dif \201 cult to detect in n eck, hip, shoulder, temporomandibular joint (TMJ). The restricted joint count measures join ts with a limited range of movement and may count joints with previously active disease. Pa in may reflect current active disease or joint damage from previous disease activity and sh ould be routinely monitored. Simple methods utilize a visual ana- logue scale (e.g. as part of the CHAQ). JUVENILE IDIOPATHIC ARTHRITIS: OVERVIEW 354 Condition Features Septic arthritis Usually (but not invariably) single joint; fever and systemically unwell. Severe joint pain . Inability to weight-bear. Raised ESR and CRP. Leucocytosis. Arthrocentesis with stain, cu lture and antigen testing prudent. Tuberculous \200\223 typically chronic monoarthritis ev entually causing severe destruction. Osteomyelitis Fever. Severe bone pain extending beyond joint margins. Local swelling and/or erythema; pse udoparalysis \200\223 young infants and children stop using a limb, although they may not be able to say it hurts. Maintain a low index of suspicion in neonates or immunocompromised children, as easily missed. Bone scan or MR scan helpful. Under 18 months highly likely to extend to the joint and include a septic arthritis; radiograph changes seen late (weeks). Reactive and post- infectious arthritis Secondary to infection with enteric organisms. Asymmetric oligoarticular pattern. Viral inf ections (rubella, measles, mumps, parvovirus, varicella, hepatitis) and vaccinations can ca use a short-lived reactive arthritis responsive to NSAIDs. Rheumatic fever Diagnosis made on the presence of two major criteria (carditis, polyarthritis, chorea, eryt hema marginatum, subcutaneous nodules) or one major and two minor criteria (arthralgia, fev er) plus evidence of group A streptococcal infection (throat swab or rising titres). Raised ESR or CRP, prolonged PR interval on ECG, raised or rising ASOT or anti DNAseB antibody te sts are supportive. The arthritis is often migratory and short-lived. Lyme disease Weeks to months after infection with Borrelia burgdorferi. History of tick bite may or may not be elicited. Large joint oligoarthritis (typically knee), usually lasting days to weeks completely resolving for weeks before recurring in the same joint or elsewhere. Erythema m igrans \200\223 spreading pink rash following the bite. Lethargy and general malaise with fever. Neurological or cardiac abnormalities also occur. Diagnosis is made on serological t esting. Trauma In young infants and children a history of trauma may not be elicited. Consider non-acciden tal injury if evidence of trauma without a history or inconsistent history. Mechanical Mechanical musculokeletal pains occur after activity or later in the day. Diagnoses include : joint hypermobility syndrome, Perthe \200\231s disease, slipped capital femoral epiphysis , spondylolysis, and spondylolisthesis Pain syndromes Non-in \202 ammatory and non-mechanical pain should be considered such as pain ampli \201 cation, chronic pain syndrome (localized or generalized), Chronic regional pain syndrome ( 1 or 2). In \202 ammatory bowel disease Arthritis may be the \201 rst presenting symptom of IBD. Weight loss/faltering growth. Mo uth ulcers/anal skin tags. Family history of HLAB27 associated conditions. Systemic diseases Rickets. Haemaglobinopathies. Hemophilia. Diabetes mellitus. Hyperparathy roidism. Glycogen storage disorders. Malignancy Symptoms suggestive of malignancy include night pain, non-articular bone pain, back pain, s ystemically unwell, weight loss, pallor, bruising. Investigations: raised ESR in presence o f low/normal platelets, raised LDH, abnormal blood \201 lm. Where there is suspicion do a bone marrow aspirate or speci \201 c imaging. Differentials include leukemia, lymphoma, n euroblastoma, Ewings sarcoma, and bone tumors. Systemic lupus erythematosus (SLE). Juvenile dermatomyositis (JDM). Henoch Sch nlein purpu ra (HSP). Sarcoid: polyarthritis, rash, uveitis, hepatosplenomegaly, malaise, boggy large j oints and tendon sheath effusions with minimal pain, serum ACE positive in only 50%. Diagno sis on biopsy. Autoimmune connective tissue disease ESR and CRP are relatively insensitive to disease activity, although a persistently elevate d ESR and platelet count over 6 months is associated with later erosions. Physician global assessment score is used, measured on a 10-cm visual analog scale Parent and patient scored global assessment of overall well-being is valuable. psychological, and social factors have been developed for children. They include health-rel ated quality of life (HRQOL) measures (e.g. PedsQL), which has a generic and a rheumatology module to it. Core set outcome variables for JIA The Pediatric ACR score was developed in 1997 by Giannini to standardize assessments and allow for out- comes to be measured in clin ical trials. These variables can be routinely monitored in pediatric rheumatology clinics, as they are quick and easy to carry out. Disease damage Radiographic appearances are relatively insensitive mea- sures of change in JIA unless there is a severely aggressive RF positive polyarthritis or psoriatic JIA (JPsA) . In adults US or MR scans can show cartilage damage before the appear- ance of erosions, b ut as yet there is no evidence for this in children. Pediatric ACR score: core set outcome variables for children being treated for JIA \200 Physician global assessment of disease activity [10-cm Visual Analog Scale (VAS)]. Parent/p atient global assessment of overall well- being (10-cm VAS). Functional ability (CHAQ). Num ber of joints with active arthritis. Number of joints with limited range of motion. ESR. Function and quality of life The Child Health Assessment Questionnaire (CHAQ) is a validate d measure of function, which is not speci \201 c to chil- dren with JIA but has been shown to be sensitive to change in this group. \200 \200 \200 \200 Global measures of \200\230quality of life \200\231, which indicate an individual \200\231 s \200\230well-being \200\231, and includes physical, CHAPTER 10 Juvenile idiopathic arthritis 355 Treatment Objectives Medical management of JIA has changed in recent years with an overridi ng principle of early and aggressive treat- ment to suppress in \202 ammation and prevent progression to the complications detailed above. To this end, intra-articular glucocorticoi ds (GCs) are used early, with progression to methotrexate as the \201 rst line disease mo difying anti- in \202 ammatory drug (DMARD) and the use of biological therapy where necess ary. Naproxen, diclofenac and tolmetin (not available in UK) were compared in a single-blind cro ss-over trial in 28 children with (RF) seronegative JIA with clinical improvement in all th ree and increased adverse events in diclofenac (Leak, 1988). Meloxicam (selective COX-2 inh ibitor) has been shown to be effective in JIA, but no comparative studies have been carried out. Immunosupression Glucocorticoids Intra-articular GC injections are a well-established treat - ment in JIA and are used early to gain rapid control of joint in \202 ammation, solely i n oligoarticular disease, and as an adjuvant in polyarticular disease. \200 Multidisciplinary team A multidisciplinary team working effectively together best manages a ll children with JIA. \200 A pediatric rheumatology nurse specialist for disease and medication education, and co-ordi nation of care. Physiotherapy to help reverse the effects of the disease once it is under c ontrol (encourage full range of joint motion and strengthen atrophied muscles). Occupationa l therapy (OT) to assess and provide appli- ances where necessary to encourage independence , and school liaison to ensure teachers are aware and encour- aging activity with guidance. Orthotist (or podiatrist). Ophthalmology liaison. Dentist, orthodontist, maxillofacial sur geon where necessary. Informed musculoskeletal radiologist. Orthopedic surgery for an opini on on the role of timely joint surgery. Social worker where needed to help address impact o n family \201 nancially (Disability Living Allowance). Psychologist and play specialist t o help with issues around impact of disease on child/adolescent/family, issues of complianc e, dif \201 culties with needle phobia, imaging, joint injections, etc. Dietician to optim ize nutrition, advise, and supervise cal- cium and vitamin D supplementation. In addition, transition to adult services, addressing sexual health issues and liaison with the general practitioner are critical. Further detail in this chapter will concentrate on medical manag ement. Indications will be described further under the types of JIA, but in general, those childre n with no systemic symp- toms can have up to a maximum of 10 injections. It will depend upo n the individual and the number/type of joints to be injected as to whether this done under general or local anesthetic, but in general those under 12 should be offered a general ane sthetic. Children over 12 may manage with local anesthesia and access to entonox or sedatio n with midazolam. Triamcinolone hexacetonide at a dose of 1 mg/kg for large joints, 0.5 mg/ kg small joints, is the GC of choice having been shown to give better results than triamci- nolone acetonide, betamethasone, and methylpred- nisolone acetate. Pulsed intravenous (IV) methylprednisolone at a dose of 30 mg/kg/day on 3 consecutive days (maximum 1 g daily) and repeated 1 week later as necessary is valuable for achieving rapid control of symptoms in polyarticular or systemic onset JIA. IV GC regimes may result in less cumulative GC dosage than an oral GC regime alone. If GCs are required to maintain disease control they should b e given at the low- est possible daily (or alternate daily) dosage. If systemic GCs are req uired, a disease-modifying agent should be started for longer-term disease control. \200 \200 \200 Methotrexate Methotrexate (MTX) is the \201 rst-line disease modifying anti-rheumatic dru g (DMARD) for the vast majority of children with JIA. \200 Pain relief Non-steroidal anti-in \202 ammatory drugs (NSAIDs) NSAIDs are used for the ini tial treatment of pain, in \202 am- mation, and stiffness. \200 MTX is safe, reliable and effective in at least 60-70% of children treated for JIA, althoug h the maximal bene \201 t may not be evident for 9 \200\22312 months. Evidence suggests th at a dose of 15 mg/m2/week is opti- mal (range 10 \200\22320 mg/m2/week). Subcutaneous (sc) MTX is superior in terms of bioavail- ability and tolerance compared to oral MTX (at the h igher doses). Oral MTX may be suf \201 cient for relatively mild disease. Oral MTX is avai lable in tablet or syrup forms. Parents should be discouraged from crushing tablets and mix - ing with food because of the risk to the parent of han- dling cytotoxic medication. For s ome children refusing medication, however, this is the method of last resort. Appropriate c ounseling is required prior to commenc- ing methotrexate and immunity to chickenpox should be known. There may be time to recommend immunization with Varicella zoster (VZ) vaccine in children known to be VZ IgG negative, but this will require delaying MTX or GCs for 6 \200 \2238 weeks post-vaccination. Gastrointestinal side effects are common to all, but they are usually well tolerated in chi ldren. Gastro- protective medication may be required if symptoms occur. There are few compa rative data to aid prescribing NSAIDs, and choices are usually made on the tolerability of the formulation and dosage schedule. Ibuprofen syrup is commonly used at a dose of 10 mg/ k g/dose tds or qds (up to 6x day in systemic JIA), since it is palatable and well tolerated. The disadvantage is the dosing schedule. Naproxen was compared with piroxicam in a multice n- tre double-blind crossover study in 47 children with JIA, and no significant difference in clinical variables or patient preference was found (Williams, 1986). A dispersible formu lation of piroxicam is available and naproxen syrup can be obtained if ordered speci \201 cally. JUVENILE IDIOPATHIC ARTHRITIS: OVERVIEW 356 Children >12 years often need two doses of VZ vaccine, 4 \200\2236 weeks apart to seroconve rt, delaying treatment still further. If the child is susceptible to chicken pox, parents n eed clear instructions on consulting following a chicken pox contact for consideration of V Z immunoglobulin or acy- clovir treatment. Concurrent immunosuppression with GCs increases the risk of complicated VZ infection substantially. In \202 iximab (unlicensed in UK) may be useful in children with compliance issues or side effects to etanercept. Adalimumab is a humanized monoclonal antibody to TNFA given by sc i njection every 2 weeks. Adalimumab has showed some ef \201 cacy in polyarticular JIA in pr elimi- nary studies (Lovell, 2004). Anakinra, a recombinant IL-1 receptor antagonist, injec ted daily, is also showing promising results in JIA with response documented in 58% of pati ents after 4 months treatment. Information to be discussed before starting MTX \200 \200 Autologous stem cell transplantation This still experimental treatment is used only as a la st resort in children with an intolerably poor quality of life because of the high morbidit y and mortality associated with treatment. Intensive immunosuppression to remove autoreacti ve lymphocytes is followed by rescue therapy with haematopoietic stem cells \200\223 data are published on 34 children within nine centers in Europe. Eighteen children (53%) achieve d complete drug-free remission and a 15% mortality rate was reported. Avoid all live vaccinations. Seek advice from pediatric rheumatology team if VZ contact and non-immune. Seek advice from pediatric rheumatology team if acutely unwell with intercurre nt infection (missing a dose may be advised). Monitor FBC and LFT monthly initially, then 6 \200\2238-weekly when stable (ESR /CRP for disease monitoring). Ensure adequate contracept ion. Minimize alcohol intake. If prescribed other medications ensure prescriber is aware of MTX treatment (potential interactions). Side effects of MTX (nausea, vomiting, mouth ulcer s, anorexia, alopecia, transient rise in ALT, leucopenia) and occur in about 20% of childre n. Folic acid has been shown to bene \201 t adults, although there is no evidence for bene \201 t in children. Dose regimes include 1 mg/day (except on day of MTX) or 5mg/week, syr up or tablet formulations available. Switching from oral to sc MTX may resolve nausea. Most families learn to administer sc MTX at home. \200 \200 Surgery Orthopedic operations are required infrequently. Access to the expertise of a pedia tric orthopedic surgeon is important. Indications for surgery may include: \200 Poor jaw growth (micrognathia and overbite possibly requiring maxillofacial surgery). Joint deformity and destruction requires joint replace- ment surgery as in adults. Prognosis Available long-term outcome studies re \202 ect historical treatment regimes and make for sober reading \200\223 40% of children with JIA take their arthritis with them t o adult- hood (Packham, 2002) and between 30 \200\22356% have severe functional limitations . \200 Other DMARDS Sulphasalazine (SZP) can be bene \201 cial for ERA. Hydroxy- chloroquine conf ers little bene \201 t alone, but is used in com- bination with MTX, particularly for juve nile systemic lupus erythematosus (SLE). Anti-TNFA treatment In those children who fail to respond adequately to MTX (and have ongoing swollen joints or require ongoing GCs), or who are unable to tolerate MTX, it is now common practice to use anti-TNFA therapy. \200 Unemployment is 3 \227 higher in JIA patients compared with controls despite excellent educ ational results. Poor prognostic indicators include polyarticular/ systemic onset, poor dis ease control in the first 6 months, presence of autoantibodies (ANA and RF), and rapid deve lopment of erosive changes. Resources Assessment tools CHAQ (see www.arc.org.uk); PGALS (joint examination of young chi ldren); HRQoL; PedsQL; Pediatric ACR score. British society for pediatric and adolescent rh eumatology www.bspar.org.uk for eye screening guidelines. UK National Institute of Clinical Excellence (NICE) guid- ance for the use of etanercept in JIA advises that etaner- cept should be reserved for children with JIA where MTX has faile d (at a dose of 20 mg/m2/week by sc injec- tion for 3 months). Etanercept is the only licen sed anti-TNFA to treat JIA in children, and studies show impressive benefits [74% achieved JRA30 (Lovell, 2000)] at a standard dose of 400 g/kg twice a week. Nevertheless, long-ter m follow up of Etanercept treat- ment is lacking and all children should be registered on a Biologics Registry (in the UK \200\223 www.bsparreg.org). Side effects include injection site reactions, headaches, urticaria, abdominal pain, nausea, and vomiting. Guidelines British Society for Pediatric and Adolescent Rheumatology. UK guidelines on medi cation, link to NICE guidelines, CHAQ and scoring available. www.bspar.org.uk Pediatric Rhe umatology European Society: www.pres. org.uk NICE. Guidance on the use of etanercept for th e treatment of juvenile idiopathic arthritis, March 2002, Ref. N0070. www. nice.org.uk Arth ritis Research Campaign: http://www.arc.org.uk/ arthinfo/medpubs/6535/6535.asp www.arc.org. uk/arthinfo/emedia.asp#pGALS In \202 iximab is a chimeric monoclonal anti-TNFA, which is given by iv infusion every 4 \200\22312 weeks. \200 In a small non-randomized, open-label study of 24 JIA patients In \202 iximab was shown to have equivalent ef \201 - cacy to, but increased side effects compared with, etanercept ( Lahdenne, 2003). Patient information Pediatric Rheumatology International Trials Organization. www.printo.it / (good information for families and resource for research activity). CHAPTER 10 Juvenile idiopathic arthritis 357 Packham JC, Hall MA. Long-term follow-up of 246 adults with juve- nile idiopathic arthritis : functional outcome. Rheumatology (Oxf) 2002; 41: 428 \200\22335. Arthritis Research Campaign. www.arc.org.uk \200\223 useful patient information. ICD10 codes M08 M08.0 M08.2 M08.4 Packham JC, Hall MA. Long-term follow-up of 246 adults with juve- nile idiopathic arthritis : functional outcome. Rheumatology 2002; 41: 1428 \200\22335. Juvenile arthritis Juvenile RA Juvenile arthritis with systemic onset Pauciarticular juveni le arthritis Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumato logy classi \201 cation of juvenile arthritis: second revision, Edmonton, 2001. J Rheumato l 2004; 31: 390 \200\2232. Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet 2007 ; References Gylis-Morin VM, Graham TB, Blebea JS, et al. Knee in early juvenile rheumatoid a rthritis: MR imaging \201 ndings. Radiology 2001; 220: 696 \200\223706 369: 767 \200\22379. Symmons DP, Jones M, Osborne J, et al. Pediatric rheumatology in the United Kingdom: data f rom the British Pediatric Rheumatology Group National Diagnostic Register. J Rheumatol 1996 ; 23: 1975 \200\22380. Williams PL, Ansell BM, Bell A, et al. Multicentre study of piroxica m versus naproxen in juvenile chronic arthritis, with special refer- ence to problem areas in clinical trials of nonsteroidal anti-in \202 am- matory drugs in childhood. Br j Rheuma tol 1986; 25: 67 \200\22371. Lahdenne P, Vahasalo P, Honkanen V. In \202 iximab or etanercept in the treatment of child ren with refractory juvenile idiopathic arthritis; an open label study. Ann Rheum Dis 2003; 62: 245 \200\2237. Leak AM, Richter MR, Clemens LE, et al. A crossover study of naproxen, diclofenac and tolme tin in seronegative juvenile chronic arthritis. Clin Exp Rheumatol 1988; 6: 157 \200\22360. See also Juvenile SpA/ERA Lovell DJ, Giannini EH, Reiff A, Cawkwell GD, et al. Etanercept in children with polyarticu lar juvenile rheumatoid arthritis. N Engl J Med 2000; 342: 763 \200\223800. Lovell DJ, Ruperto N, Goodman S, et al. Preliminary data from the study of adalimumab in ch ildren with juvenile idiopathic arthritis. Arthritis Rheum 2004; 50 (Suppl): S436. OLIGOARTICULAR JUVENILE IDIOPATHIC ARTHRITIS 358 Oligoarticular juvenile idiopathic arthritis Oligoarticular JIA (oligo-JIA) is the commonest type of JIA and occurs in over 50% of JIA c ases. Some oligo-JIA cases \200\230extend \200\231 over time to involve >4 joints evolving >6 months after onset. Co-morbidities Uveitis The most serious complication for children with oligo-JIA is blindne ss from uveitis (iridocyclitis). \200 Uveitis is diagnosed in up to 30%, is associated with pos- itive ANA, and is insidious and asymptomatic. The iris and ciliary body are principally involved resulting in deposition of cells in the anterior chamber, and for- mation of synechiae or band keratopathy. Slit-lamp examination is critical early in the diagnosis of Oligo-JIA and regular check-ups are nece ssary. Most children develop uveitis within the \201 rst 5 \200\2237 years of onset of ar thritis. The course can be relapsing or chronic and does not parallel the course of arthrit is. Treatment is with topical GCs and mydriatics, and close monitoring to judge bene \201 t. In uveitis resistant to topical treatment, systemic GCs and DMARDs, usually MTX, are use d initially. Ciclosporin and azathioprine can also be used. There are anecdotal reports on the bene \201 ts of in \202 iximab in cases resistant to MTX. Epidemiology Early onset persistent oligoarthritis is characterized by onset less than 6 ye ars of age, female predominance, asym- metric arthritis, uveitis, and ANA positivity. \200 Oligo-JIA is common in European and North American Caucasians, rare in Asian, Arab, and Afr ican children. Persistent oligo-JIA is associated with HLA A2 and Class II HLA alleles DR8, DR5, and DR6. Extended oligo-JIA, by contrast, is associated with DR1. The differential di agnosis is detailed in the JIA chapter. A septic arthritis is the primary differential. Rar ely, a hae- mangioma can cause joint swelling and pain. Clinical features Key features in the history Typically children complain about a single sw ollen joint usually of the lower limb, which causes stiffness and limited movement. \200 Conditions related to growth and skeletal development See also JIA chapter. Leg length disc repancy is commonly seen in children with persistent knee in \202 ammation. A heel insert can be used in the shoe to address asymmetry and prevent secondary mechanical symptoms deve loping. Often children report less pain than expected. Thus, the differential of septic arthritis i s relatively easily made. The joint swelling is often noted by a parent before the child is thought to be in pain or complains of pain, and is sometimes revealed by an episode of min or trauma. The child is otherwise well with an unremarkable history and often no past histo ry to note. A family history of psoriasis should be sought. Any preceding infection is impo rtant, particularly an epi- sode of infection suggestive of a streptococcal sore throat, di arrhea, or tick bite. Investigations Laboratory FBC/CBC, ESR, and routine biochemistry are typically normal. ANA is present in up to 70 \200\22380% of young girls. \200 Treatment Initial treatment: intra-articular GC injection with NSAIDs. Joint injection can be safely repeated after 3 \200\2236 months and up to 3 \227 in a year in the same joint, b ut if required more frequently than this, MTX is advisable. Key features on examination Physicians often \201 nd more affected joints than parents ha ve identi \201 ed. \200 It is important to carefully examine all joints \200\223 synovial swelling, warmth, effusi on, and limitation without much tenderness are hallmark features. Knee and ankle are most c ommonly affected. Hips, neck, and TMJ are not affected initially. Look for nail dystrophy o r nail pitting, and hidden psoria- sis present in scalp or umbilicus. Look for enthesitis t en- derness or swelling (more likely ERA, especially in male >6 years) and dactylitis (psor iasis). Wrist and upper limb involvement, symmetrical joint involvement and an ESR >20 mm/h are predictive of extended oligo-JIA. Asymmetrical increased growth and muscle atrophy of the involved limb is characteristic. Involved joints mature faster than their opposite. A v algus knee is common in untreated disease. Asymmetric jaw opening can develop with unilater al temporomandibular (TMJ) involvement (usually in extended oligo-JIA). Prognosis About 50% of children with oligo-JIA will have persistent disease or functional j oint problems 10 years later (often the children whose disease extends to a polyarticular f orm). In 50% the arthritis will remit. Monitoring Very young children should be monitored regularly since they often do not recogn ize or are unable to communicate their problems. School age children should be able to aler t their parents to any problems and can be discharged when in remission. They should be exp ected to return promptly if symptoms recur. See also Juvenile idiopathic arthritis: overview CHAPTER 10 Juvenile idiopathic arthritis 359 Rheumatoid factor (RF) negative polyarticular JIA Treatment NSAIDS are commenced immediately. A short course of systemic GCs (either oral or intra-venous) is commonly used for rapid symptomatic relief with the aim to taper it quickl y. Intra-articular GCs can be used for speci \201 c joints, which are particularly symptom atic or remain trouble- some. A DMARD should be started immediately or within a few weeks o f diagnosis, since remission is highly unlikely to occur with NSAIDs alone. The only except ion would be in cases of diagnostic uncertainty where reactive arthritis is possible. Metho trexate is the DMARD of choice. Oligo-JIA denotes <5 joints and Polyarticular JIA more joints with a more symmetrical distr ibution. There is noth- ing magical about \200\2305 \200\231 joints. This group may includ e those with extended oligo-JIA who simply extended earlier than average. This classi \201 cation, therefore, results in a rather heterogeneous group. Epidemiology RF negative polyarticular JIA (RF \200\223 ve poly-JIA) makes up 25% of all J IA in Europe and the US. Mean age of onset is 6.5 years, with two peaks at toddler to pre-s chool and pre- adolescent. Girls are more frequently affected than boys (ratio about 3:1). There are no consistent HLA types associated. Prognosis Overall remission rate at 10 years is 23%, with remissions most frequently occurr ing within 5 years of onset. This is worse than oligo-JIA, but better than RF positive Poly ar- ticular JIA (Oen, 2002). Clinical features Three distinct subsets are recognized. \200 The \201 rst resembles early onset oligoarthritis with more joints affected earlier. Thus it is asymmetrical, onset <6 years, female>male, ANA positive and high risk of uveitis (se en in 20 \200\22340%). The second comprises symmetrical synovitis of large and small joints ; onset 7 \200\2239 years; elevated ESR; PIPJs are affected more than MCPJs initially; teno synovitis around wrists and ankles is common. The outcome is variable. The third is known a s \200\230dry synovitis \200\231. There is negligible joint swelling, but stiffness, \202 exion contractures, and nor- mal or slightly raised ESR. It often responds poorly to t reatment and can follow a destructive course. Monitoring It is prudent to monitor radiographs on a yearly basis in those children with ac tive disease. Joint space narrowing and erosions develop commonly in carpal bones. Cervical spine ankylosis can be seen. Complications Growth disturbance is common and proportional to the degree and duration of i n \202 ammation. Mandibular hypopla- sia secondary to TMJ involvement is common. Resources See after section Juvenile idiopathic arthritis: overview Investigations An improvement in US technology has lead to it \200\231s emer- gence as a ve ry useful investigation tool, valuable in con- firming joint effusions, synovial hypertroph y, tendon pathology, and early erosions. There are few published data on its use in childre n and young people. MR scans with gadolinium enhancement are very valuable where there is d iagnostic uncertainty. See also Juvenile idiopathic arthritis: overview RHEUMATOID FACTOR (RF) NEGATIVE POLYARTICULAR JIA K. HARRIS 360 Rheumatoid factor (RF) positive polyarticular JIA About 5% of JIA cases have multiple joints affected and are rheumatoid factor (RF) positive (RF + poly-JIA). Rheuma- toid factor (RF) needs to be seen on two occasions 3 or more mont hs apart. However, RFs occur in the healthy population (1%), thus the diagnosis should not be made on RF alone! A substantial proportion has circulating antibodies against cyclic citrullinated peptide (R avelli, 2007). Imaging Radiographs of affected joints should be taken at baseline. Treatment Good disease control is the primary aim and is critical in attempting to prevent the many complications of chronic in \202 ammation on the growing child. \200 Epidemiology There are no population-based surveys. Hospital based surveys suggest an incid ence of 0.25 \200\2231.8 per 100 000. Age of onset is around 9 \200\22312 years (female:mal e 6 \200\22312:1). There may be a higher incidence in Native North American, Canadian, Abor iginal, African American, Caribbean, and Latin American people compared with Caucasian popu lations. Osteoporosis, growth failure, poor nutrition, differential growth problems, delayed puberty are all potential con- sequences of persistent disease activity. Early use of immunosuppre ssants (particularly subcuta- neous methotrexate) is warranted. It is important to discuss sexual health, fertility, contra- ception, and planned pregnancy with adolescents. Genetics As with adult RA, RF + poly-JIA associates with HLA DR4, and its subtype DRB*0401 and DW4. Prognosis Only 6% of RF + poly-JIA patients achieved remission at 10 years (Oen, 2002). The re is a high risk of ongoing erosive disease and need for joint replacement surgery. Such c hildren need good careers advice. Clinical features Typically a symmetrical polyarthrits of the small and large joints often affecting the wrists, MCP, and PIP joints. \200 Rheumatoid nodules may be palpable around the elbow or in other areas of friction (in about 10%). Tenosynovitis, low-grade fever, hepatosplenomegaly and lymphadenopathy, serositis, a nd pericardial effusions may be seen. The differential diagnosis includes SLE and sarcoid. Uveitis is uncommon, but keratitis and dry eyes are occasionally seen. Resources See after section Juvenile idiopathic arthritis: overview References Oen K, Malleson PN, et al. Disease course and outcome of juvenile rheumatoid art hritis in a multicentre cohort. J Rheumatol 2002; 29: 1989 \200\22399. \200 Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet 2007; 369: 767 \200\22379. Investigations Laboratory As in the adult form, anemia of chronic disease, neutro- philia, thrombocytosis, and raised in \202 ammatory markers are hallmarks of the disease. \200 \200 See also Juvenile idiopathic arthritis: overview Urinalysis, U&E, LFT should be normal. ANA, ENA, dsDNA are negative and help to distinguish RF + Poly-JIA from autoimmune connective tissue diseases, all of which may be RF positive. This page intentionally left blank SYSTEMIC ONSET JIA 362 Systemic onset JIA \200 \200 \200 This life-threatening condition may be triggered by changes in medicat ion or viral infection. All types of JIA have both arthritis and the risk of joint destruction in common, but it is the extra-articular mani- festations of systemic onset JIA arthritis, which makes it uniqu e. Systemic onset JIA makes up 5 \200\22310% of all JIA. George Frederick Still described t he disease as a distinct entity in children in 1897 (Still, 1897). Hemoglobin, WBC, platelets fall. ESR is elevated. Increased triglycerides and liver transam inases. Extremely high ferritin. Classi \201 cation and diagnosis See under Juvenile idiopathic arthritis: overview Secondary amyloidosis Rare if in \202 ammation controlled. Epidemiology Incidence varies from 0.49 \200\2231.3 per 100 000 children at risk. There is some evidence that incidence is decreasing, and some evidence of seasonality (peaking in sp ring and autumn) suggesting an infectious trigger, but this is by no means clear. \200 Joint pathology High probability of arthroplasty in chronic severe form (57% after 10 years follow-up). Synovial cysts occur more commonly than other forms of JIA and lymphodema of u nknown cause may occur. Investigations Routine laboratory tests, serology and speci \201 c imaging is important wh ere Systemic-onset JIA is being considered. The disease is equally common in males and females, with an average age of onset of 5 years , but wide variability. Systemic onset JIA occurs in all ages and in adults is termed \200 \230adult onset Still disease \200\231. Abnormal results from investigations arranged when considering a diagnosis of systemic onse t JIA \200 Etiology and pathophysiology Unknown. At the outset the systemic features of fever and rash mimic infection, but no infectious agent can be found. There is only limited evidence for a genetic link in the disease. Anemia (usually of chronic in \202 ammation, may also be GI blood loss secondary to medica tion). Leukocytosis with neutrophilia. Thrombocytosis. ESR often >100 mm/h. CRP elevated. F ibrinogen, immunoglobulins, and complement C3 and C4 raised. Autoantibodies including ANA, ANCA negative. Ferritin is high [if very high consider macrophage activation syndrome (MAS) ]. LDH low/normal. If raised consider malignancy. Imaging \200\223 US of joints helpful if synovitis present. Radiographs usually normal at baseline. Transthoracic echocardiogram fo r pericarditis/ myocarditis and effusion. \200 \200 \200 \200 Clinical features Daily high spiking fevers are the most important criterion for diagnosis. Almost always fevers are present at the out- set of the illness. \200 The fever pattern is a single high spike in the afternoon or evening, falling to baseline o r below. Double temperature spikes are also seen. This typical quotidian (or double quotidi an) pattern may only become obvious once treatment with NSAIDs is started. The rash is pres ent in more than 90% of cases at the outset. It is a non- \201 xed erythematous rash, evan escent with fever and appearing as salmon-pink macules 2 \200\22310 mm in size that may coa lesce. The Koebner phenomenon is exhibited and it can resem- ble urticaria with mild prurit is. The liver is mildly enlarged and 30% of children have mild splenomegaly. There is gener alized lymphadenopathy in 50% with small, freely mobile, painless nodes. Serositis \200 \223 typically pericarditis with or without effusion is usually mild and asymptomatic. Myoc arditis occurs infrequently and there is rarely car- diac compromise. Pleuritis and periton itis can occur. Arthritis is only present at onset of the disease in about a third of patie nts (symmetrical and polyarticular). Arthritis will often develop within the \201 rst few months if not at the outset. Knees, wrists, ankles, and C-spine are commonly involved. \200 \200 Differential diagnosis Many children present systemically unwell with fevers and rash. The primary differential diagnosis then includes infec- tious disease and malignancy. \200 There are no pathognomonic laboratory test results for systemic onset JIA. Investigations a re aimed at ruling out other diagnoses. If leukemia remains a possibility, a bone marrow as pira- tion/biopsy must be performed. Kawasaki disease (fever, rash, joint pains) must be co nsid- ered in younger children, as well as other vasculitides and fever syndromes (see p. 3 44). \200 Treatment Treat with NSAIDs initially. \200 Clinical complications Macrophage activation syndrome Alternatively described as secondary haemophagocytic lymphohistiocytosis. Characterized by: \200 Ibuprofen at 60 mg/kg/day (6 divided doses), indomet- acin at 1 \200\2232 mg/kg/day (2 divi ded doses). Glucocorticoids (GCs) are used for systemic symptoms (e.g. intravenous methylpr ednisolone 30 mg/kg/day for three consecutive days, repeated as required). Fever, hepatosplenomegaly, bruising and coagulopathy, encephalopathy (dizzy, lethargy, diso rientation). CHAPTER 10 Juvenile idiopathic arthritis 363 Resources See after section Juvenile idiopathic arthritis: overview Pulse methylprednisolone may result in lower cumula- tive doses of GCs over time compared w ith high dose oral prednisolone. Oral prednisolone can be given at doses of 1 \200\2232 mg/ kg/ day in 2 \200\2233 divided doses initially. Disease modifying anti-rheumatic drugs (DMA RDs) should be started early. Subcutaneous methotrexate is the usual first line DMARD. Cycl ophosphamide and ciclosporin can be used for severe cases or where methotrexate has failed or chil- dren are intolerant of it. Anakinra, a recombinant IL-1 receptor antagonist, is un der study and preliminary reports suggest 79% of sys- temic onset JIA patients responding ( Verbsky, 2004). Anti IL-6 antibody (MRA) is theoretically bene \201 cial and requires furt her study. References Lomater C, Gerloni V, Gattinara M, Mazzotti J, Cimaz R, Fantini F. Systemic onse t juvenile rheumatoid arthritis; A retrospective study of 80 consecutive patients followed for 10 years. J Rheumatol 2000; 27: 491 \200\2236. Still GE. On a form of chronic joint disease in children. Med Chir Trans 1897; 80: 47. Verbsky JW. White AJ. Effective use of the recombinant interleukin- 1 receptor agonist anak inra in therapy resistant systemic onset juvenile rheumatoid arthritis. J Rheumatol 2004; 3 1: 2071 \200\2235. See also Juvenile idiopathic arthritis: overview Kawasaki disease Natural history and prognosis Three disease courses are described: \200 \200 Monocyclic: remits completely (11%). Polycyclic: relapses with intervals of remission some lasting several years (34%). Unremitting: about 55% who never go into remission and suffer long-term disability. JUVENILE PSA 364 Juvenile PsA Psoriatic arthritis in children has only recently been recog- nized as a distinct condition within the JIA spectrum. Juvenile PsA (JPsA), as in adults, may pre-date psoriasis by many years (may be 15 years or more) and for this reason the condition has been under-diagnosed .