Mucocutaneous \200 \200 Swelling of hands and feet, red palms and soles. Truncal rash. Musculoskeletal Acute polyarthralgia. Reddening of lips. Strawberry tongue. Diffuse injection of oral and pharyngeal mucosa. Cardiac Angina, dyspnoea. 4. Polymorphous exanthem 5. Peripheral extremities \200 Key features on examination The child is miserable. Initial stage: \200 \200 Convalescent stage: membranous desquamation from \201 ngerti ps reddening of palms and soles; indurative oedema. Mucosal \200 Bilateral conjunctival congestion, suffused without exudates. Erythema and \201 ssuring o f lips and oropharynx. Strawberry tongue. Non-purulent cervical lymphadenopathy. \200 \200 6. Acute non-purulent cervical lymphadenopathy At least \201 ve items are required for a diagnosis of KD. If coronary aneu- rysms are no ted on 2D echocardiography or coronary angiography then 4 items are suf \201 cient (from K amiya, 1984). Cutaneous \200 Indurative oedema of hands and feet, erythema palms and soles. Polymorphous exanthema, peri neal accentuation. Desquamation \201 ngers and toes in convalescent period only. \200 Epidemiology \200 In Japan the annual incidence is 150/100 000 children aged <4 years. 50% are aged <2 years. Onset age >10 years is rare. KD occurs worldwide, but is most prevalent in Japan and East Asia. In the UK the incidence is 14.6/100 000 in Indian Subcontinent Asians and 4.6/100 000 in White Caucasians. \200 \200 Musculoskeletal \200 \200 Polyarthritis (less common). Irritability and aseptic meningitis are frequent, abdominal pa in and diarrhea, hydrops of gall bladder, and hepa- tomegaly rarer. Cardiovascular \200 Heart murmurs mitral regurgitation most common. Valvular heart disease occurs in 1% patient s. Gallop rhythm. Faint heart sounds, suggestive of pericardial effusion. Pericarditis occu rs in 13% patients. Peripheral artery aneurysms (1%). Aetiopathogenesis The aetiopathogenesis is unknown. An infectious etiology has long been su spected. Cyclical epidemics have been observed especially in Japan supporting the notion th at there is an infectious cause. So far no speci \201 c organism has been identi \201 ed. \200 General investigations Investigation is directed at establishing the diagnosis, and assessi ng the extent and severity of organ involvement. \200 KD is similar to scarlet fever and toxic shock syndrome, and it has been suggested that KD is caused by toxin producing bacteria with superantigen activity. The acute phase of KD is associated with production of in \202 ammatory cytokines, including TNF-alpha, IL-1B, and y-IFN with induction of endothelial injury via ELAM-1 and ICAM-1. FBC mild anemia, leucocytosis with a left shift, throm- bocytosis in the second week of ill ness. Acute phase response (signi \201 cantly raised ESR and CRP). Elevated liver enzymes, hypoalbuminaemia. Urinalysis sterile pyuria, proteinuria. \200 \200 Pathology Coronary arteritis begins with oedema in the media with a lymphocytic and macroph age in \201 ltration. This spreads to cause a panarteritis involving all layers of the ves sel wall. Around the twelfth day the artery begins to dilate, abnormal blood \202 ow lead s to thrombus formation and Assessment of organ involvement Cardiac \200 Electrocardiography: prolonged PR/QT intervals, abnormal Q waves, low voltage, ST-T changes , dysrhythmias CHAPTER 9 Vasculitis 345 The optimal dose and timing of IVIg remains controver- sial and single doses of IVIg 2 g/kg has been show to be effective. Intravenous corticosteroids have been show in a recent RCT to confer no additional benefit when used in conjunction with IVIg. Echocardiography: \200 \200 dilatation of coronary arteries; coronary artery aneurysms are shown in 10 \200\22320% of p atients; pericardial effusion. Angiography: \200 Convalescent phase \200 coronary angiography enables accurate de \201 nition of coronary artery abnormalities and the severity of valvular lesions; angiography should be performed in patients with cardiova scular involvement because there is a risk of progression to ischaemic heart disease especi ally in patients with giant aneurysms. Aspirin 3 \200\2235 mg/kg for 6 \200\2238 weeks in those without coronary abnormalities. As pirin should be continued in patients with coronary abnormalities until they have resolved. Anti-coagulation with warfarin should be considered in those with giant aneurysms. Other t herapies. \200 Serological investigations \200 ANA, ANCA, RF all negative. \200 Complement levels are normal. Plasma exchange, TNF-alpha blockade with in \202 iximab and cytotoxic therapy have all bee n used successfully but there is not controlled trial data to support their use. Differential diagnosis Conditions to be considered/excluded: Erythema multi- forme/Steven \200\231s Johnson, scarlet fever, toxic shock syndrome, systemic JIA, measles, reactive art hritis. Follow-up \200 All children should have a repeat 2D echocardiography in the convalescent phase (4 \200\223 6 weeks) regardless of ini- tial echocardiography in accute phase. Regular 2D echocardiogra phy is required in patients with coronary aneurysms to document regression. Management shou ld be in conjunction with a pediatric cardiologist. Prognosis \200 \200 \200 Generally good. The recurrence rate is 3.3%. Mortality is very low 0.1 \200\2230.2% and is due to acute myocardial infarction. 50% of coronary aneurysms regress at 2 years. KD is now the commonest cause of acquired cardiac disease, and may cause premature adult atheroscler osis. \200 Resources Patient organizations Kawasaki disease foundation: www.kdfoundation.org Patient advice \200 ICD 10 code M30.3 Mucocutaneous lymph node syndrome (Kawasaki). Potentially serious acute vasculitis, prognosis is generally good, with a low risk of recur rence. Risk of development of coronary aneurysms. References Kamiya T. Research committee on Kawasaki disease. Tkio: Ministry of Health and Welfare, 1984. Treatment Acute phase \200 Newburger JW, Sleeper LW, McCridle BW, et al. Randomized trial of pulse corticosteroid ther apy for primary treatment of Kawasaki disease. N Engl J Med 2000; 356: 663 \200\22375. Aspirin high dose 80 \200\223100 mg/kg per day in divided doses for 14 days. Intravenous im munoglobulin (IVIg) 400 mg/kg for 4 days. When given within the \201 rst ten days the rat e of aneu- rysm formation is reduced to 5% overall, and 15% for giant aneurysms. The combin ation of high dose aspirin and IVIg has been shown in an RCT to prevent coronary artery ane urysm formation (Neuberger et al., 1986, 1991, 2000). Newburger JW, Takahashi M, Beiser AS, et al. A single infusion of gamma globulin as compare d with four infusions in the treatment of acute Kawasaki syndrome. N Engl J Med 1991; 324: 1633 \200\2239. Newburger JW, Takahashi M, Burns JC, et al. The treatment of Kawasaki syndr ome with intravenous gamma globulin. N Engl J Med 1986; 315: 341 \200\2237. RELAPSING POLYCHONDRITIS 346 Relapsing polychondritis Respiratory Dyspnoea with stridor is suggestive of tracheal involvement. Respiratory involv ement is the most serious complication of RP. Up to 50% of patients have respiratory involv ement. Relapsing polychondritis (RP) is a rare condition character- ized by in \202 ammation and destruction of cartilage. De \201 nition Relapsing polychondritis is a rare condition characterized by recurrent epi sodes of in \202 ammation and destruction of cartilage. Ophthalmic Painful red eyes with blurred vision suggest scleritis or episcleritis. Diagnostic criteria The following diagnostic criteria have been proposed. Cutaneous Skin involvement is common with purpura. Key features on examination Cartilage in \202 ammation \200 Diagnostic criteria for relapsing polychondritis \200 \200 \200 \200 The pinna becomes red, painful, swollen. In \202 ammatory episodes last a few days or week s. The pinna becomes \202 oppy and loses its rigidity. There may be inflammation of the m iddle ear and audiovestibular structures. Nasal chondritis occurs in 50% of case, presentin g with pain, erythema, swelling, stuf \201 ness. The nasal bridge is destroyed and collaps es. Recurrent chondritis of both auricles. Non-erosive seronegative in \202 ammatory polyarthr itis. Nasal chondritis. Inflammation of ocular structures (conjunctivitis, keratitis, scler itis, episcleritis, uveitis). Chondritis of the respiratory tract involving laryngeal and/o r tracheal cartilage. Cochlear and/or vestibular damage causing sensorineural hearing loss, tinnitus and/or vertigo. To establish a diagnosis of RP, patients must have one of the fol lowing: \200 \200 \200 Respiratory \200 \200 Tenderness over the trachea and thyroid cartilage. Larynx and racial in \202 ammation lead s to hoarseness, dry cough, dyspnoea, wheeze, and stridor. Damage to laryngeal and epiglott is may lead to upper airway collapse, which will require emergency tracheostomy. At least three of the above clinical criteria. One or more of the above clinical criteria i n conjunc- tion with cartilage biopsy con \201 rmation. Chondritis at two or more separate anatomical locations with response to steroids and/or dapsone. Ophthalmic There are recurrent episodes of episcleritis or scleritis, conjunctivitis, kerat itis, and uveitis. Slit lamp examination may be required. (From Michet et al., 1986). Epidemiology \200 \200 \200 \200 Cardiovascular Uncommon, but is cause of death in RP patients, the most common involvement being complete heart block, aortic valve rupture, and acute aortic regurgitation. The incidence in Rochester County, USA is 3.5/million. Males and females are affected equal ly. The peak age of onset is 50 years. More common around the Mediterranean littoral, the S ilk Route, and Japan. RP has been described in every ethnic group. Mucocutaneous \200 Skin involvement is common. Purpura, papules, aphtho- sis, pustules, Biopsy may show a leuc ocytoclastic or lymphocytic vasculitis. MAGIC syndrome is an overlap between RP and Beh et \200\231s disease. Mouth and genital ulcers with in \202 amed cartilage (MAGIC). Etiology The etiology is unknown, but like many autoimmune conditions is generally believed to result from an environ- mental trigger interacting with a genetically predisposed host. Familial cases are rare. General investigations The diagnosis is usually made on the characteristic clinical feature s. Investigation is directed at establishing the diagnosis and assessing the extent and sev erity of organ involvement. There is evidence of in \202 ammation. \200 There is an association with HLA-DR4. No infectious triggers have been identi \201 ed. The re is frequently a co- existent autoimmune disease. Antibodies to type II collagen are found. Clinical features Initial symptoms may be non-speci \201 c with fever, weight loss and fat igue. FBC anemia, leucocytosis (to exclude co-existent hematological disease). Acute phase respon se (ESR and CRP). Liver function. \200 Key features on history Cartilage in \202 ammation Auricular in \202 ammation is present in almost all patients (85%). This involves the cartilaginous part of the pinna and spares the non-cartilaginous lobe (see Plate 17). Imaging CT Fast sequence CT scanning can visual dynamic airway collapse. Musculoskeletal Joint pain is a common feature. This can involve both large and small joint s and the axial skeleton. CHAPTER 9 Vasculitis 347 Assessment of organ involvement \200 Laryngotracheal involvement requires corticosteroids at high doses (prednisolone 0.5 \200 \2231.0 mg/kg). Long- term maintenance therapy may be required to control in \202 ammation . Immunosuppression with methotrexate, azathioprine, le \202 unomide and ciclosporin has b een reported to be effective in controlling chronic in \202 ammation. The role of TNF-alph a blockade is still to be determined, but encouraging responses have been described. Acute airway obstruction refractory to medical treat- ment may require tracheostomy. Patients wit h tracheal collapse may be managed with stents. Severity of involvement of target organs should be carefully assessed. In particular eviden ce tracheal involve- ment with pulmonary function tests including inspira- tory and expirat ory \202 ow-volume curves. Biopsy of in \202 amed areas may con \201 rm the diagnosis b it is not speci \201 c. Serological investigations \200 ANCA, ANA, RF, Anticardiolipin antibodies. These are usually negative unless there is co-ex istent autoimmune disease. Complement levels are normal Cryoglobulins are not detected \200 Follow-up RP is a relapsing condition and lifelong follow-up is required. Differential diagnosis This is from other types of chondritis and perichondritis. Infection may lead to perichondritis. Wegener \200\231s granuloma- tosis and lethal midline granulom a may lead to nasal de- struction. Resources Patient organizations www.vasculitisfoundation.org Relapsing polychondritis suppo rt group. www. polychondritis.com Prognosis \200 The course is usually relapsing remitting. Mortality is low at 6% at 8 years. There is a ri sk of myelodysplasia. Most patients develop some disability with hearing or visual impairme nt, speech impediment ICD-10 coding M94.1 Relapsing polychondritis \200 References Gergely P, Poor G. Relapsing polychondritis. Best Prac Res Clin Rheumatol 2004;18: 723 \200\22338. Pathology Biopsy of the ear shows perichondritis with the presence of mononuclear cells and occasional polymorphonuclear leucocytes at the \201 brochondral junction. Michet C, McKeena CH, Luthra HS, O \200\231Fallon WM. Relapsing polychondritis. Survival an d predictive role of early disease manifestations. Annl Intern Med 1986; 104: 74 \200\2238. Staats BA, Utz JP, Michet CJ. Relapsing polychondritis. Semin Resp Crit Care Med 2002; 23: 145 \200\22354. Patient advice General Potentially serious multisystem condition, requiring immunosuppressi ve therapy and lifelong follow-up. See also Wegener \200\231s granulomatosis Behcet \200\231s syndrome Treatment \200 There are no randomized controlled trials in RP. NSAIDs only are adequate for patients with mild chondritis. THROMBOANGIITIS OBLITERANS 348 Thromboangiitis obliterans Super \201 cial thrombophlebitis \200 Thromboangiitis obliterans (TAO - Buergher \200\231s disease) is a rare thrombo-occlusive v asculopathy of medium and small arteries, characteristically occurring in young males smoke rs with distal leg ischaemia. Super \201 cial thrombophlebitis occurs in 40 \200\22360% of cases; deep venous thrombosis is suggestive of an alternative diagnosis; Migratory super \201 cial thrombophlebitis in a young per- son is very suggestive of TAO. Classi \201 cation and diagnostic criteria There are no validated diagnostic or classi \201 cation criteria. The diagnosis is very likely in young smokers with distal lower limb ischaemia. In addition, the diagnosis should be considered in patients with at least two of the following three symptoms: \200 \200 \200 Musculoskeletal Arthralgias are not uncommon (15%), transient single joint in \202 ammatio n. Wrists and knees are the most common joints. These may precede the onset of ischaemia by 10 years. The arthritis is not erosive. Super \201 cial thrombophlebitis. Arterial upper limb involvement. Raynaud \200\231s pheno menon. Neurological Neurological involvement and cerebral ischaemia is very rare. The following must be excluded \200 \200 \200 \200 \200 \200 \200 Diabetes mellitus. Atheroma. Embolism. Entrapment syndrome. Auto-immune disease. Myeloproli ferative syndrome. Hypercoagulability states. Key features on examination \200 Upper limb ischaemia. Allen \200\231s test. Place both thumbs to occlude the radial and uln ar arteries of one hand. The examiner releases the radial artery, but not the ulnar artery. If the radial artery distal to the wrist is patent, there is rapid return of color to the hand (negative test). If the artery is occluded the hand will remain pale. The procedure ca n be repeated with the ulnar artery. Trophic changes, which may progress to gangrene. Super \201 cial thrombophlebitis. The occurrence of one symptom makes the diagnosis possible (from Puechal & Fiessinger, 2007 ). \200 Epidemiology \200 General investigations Investigation is directed at establishing the diagnosis and excludin g other causes of distal arteriopathy. \200 In Europe and the USA, TAO accounts for 0.5-5% of patients with arterial disease, whilst in Japan up to 16% of such patients are affected. Males are affected much more frequently tha n women up to 10:1. Clinical onset is age <40 years. FBC is normal, but excludes are myeloproliferative disorder. Elevated acute phase response (ESR and CRP) suggests a systemic vasculitis. They are normal or only marginally elevated i n the absence of extensive trophic change. Modest hyperlipidaemia is compatible with TAO. D iabetes mellitus should be sought, as DM is an exclusion criterion for TAO. Thrombophilia s creening is necessary to exclude a hypercoagulable state. Etiology There is a strong link with smoking, most patients being heavy smokers. Rechalleng e after stopping smoking results in a recurrence of symptoms, suggesting that some compo- n ent of tobacco is a key factor. A genetic component has been proposed, as TAO is more commo n in Ashkenazi Jews than non-Ashkenazi Jews in Israel. No association with HLA has been dem onstrated. Impaired endothelium- dependent vasorelaxation in peripheral vasculature has bee n described in both affected and non-affected limbs. No clear evidence for autoimmunity has been found. \200 Serological investigations ANCA, ANA, RF, anticardiolipin antibodies, complement levels, cr yoglobulins will be negative or normal. Serology for HBV and HCV will be negative. Differential diagnosis This is from atherosclerosis and other forms of in \202 ammatory va sculopathy. Clinical features Key points on history TAO usually presents with distal limb ischaemia in a young, male smoker. Imaging Angiography There is no speci \201 c appearance of TAO. Angiography will reveal in volvement in clinically uninvolved limbs. Systemic Systemic symptoms uncommon in TAO. Ischaemia of legs \200 The artery proximal to the lesion appears smooth and non-atherosclerotic. Small- and medium -sized vessels are involved in a segmental and bilateral pattern. Claudication of the foot is an early feature; diagnosis is often not made until rest pain a nd ulceration has devel- oped; Rest pain is continuous and the patient has to sleep with fe et hanging down. Disease assessment Severity is assessed by the presence of rest pain and trophic changes. Ischaemia of arms Arm ischaemia occurs in 40 \200\22350% of cases, Allen \200\231s test is positive in 63%. CHAPTER 9 Vasculitis 349 Prognosis \200 Treatment \200 The course is relapsing and remitting with long periods of remission. Life expectancy is no rmal with up to 85% 25-year survival reported (Ohta et al., 2004) Overall, prognosis is det ermined by abstinence from smoking, with relapse being association with resumption of smoki ng. Progressive and recurrent amputations may be needed. The risk of amputation is strongly associated with continuation of smoking with 2.73 times increased risk. In smokers (Sasaki et al., 2000) Cessation of smoking is the main stay of treatment and means of support should be proved to achieve this. Local care of trophic wounds is important. Prostacycline derivatives are eff ective, but must be given continuously often for several weeks. In an RCT of 152 patients o f Iloprost IV daily compared with placebo plus aspirin, after 21 \200\22328 days of infusio n with Iloprost 85% of patients had healed lesions or abol- ished pain compared with 17% re ceiving aspirin alone (Fiessinger et al., 1990). These results were maintained to 6 months and the amputation rate was lower in the Iloprost group 6% versus 18%). Oral Iloprost appea rs to be less effective. Revascularization is rarely possible due to the diffuse distal nat ure of the vascular disease. Experimental therapies include gene transfer using VEGF gene t ransfer; stem cell transplantation. \200 Pathology \200 \200 TAO is characterized histopathologically by a cellular and in \202 ammatory thrombus forma tion primarily in distal extremities. Fibrinoid necrosis of arterial wall is not observed a nd the structure of the vessel wall is pre- served. These features distinguish TAO from the systemic arteritides and atherosclerosis, in which there is \201 brinoid necrosis in the former, and disruption of the internal elastic lamina and media in the latter. In the acut e phase arterial and venous lesions are characterized by an association of in \202 ammatio n and thrombus formation. Resources Information and support Vasculitis Foundation: www.vasculitisfoundation.org ICD-10 coding I73.1 References Fiessinger JN, Schaffer M. Trial of Iloprost versus aspirin treatment for critic al limb ischaemia of thrmoboangiitis obliterans: the TAO study. Lancet 1990; 335: 555 \200 \2237. Patient advice General \200 \200 \200 \200 Stop smoking. Attention to cardiovascular risk. Healthy balance diet. Regular exercise. Ohta T, Ishioashi H, Hosaka M, Sugimoto I. Clinical and social conse- quences of Buergher \200\231s disease. J Vasc Surg 2004; 39: 176 \200\22380. Puechal X, Fiessinger JN. Thromboangiitis obliterans or Buergher \200\231s disease: a chall enge for the rheumatologist. Rheumatology 2007; 46: 192 \200\2239. This page intentionally left blank 351 Chapter 10 Juvenile idiopathic arthritis Juvenile idiopathic arthritis: overview 352 Oligoarticular juvenile idiopathic arthritis 35 8 Rheumatoid factor (RF) negative polyarticular JIA 359 Rheumatoid factor (RF) positive pol yarticular JIA 360 Systemic onset JIA 362 Juvenile PsA 364 JUVENILE IDIOPATHIC ARTHRITIS: OVERVIEW 352 Juvenile idiopathic arthritis: overview Long-term studies have shown that juvenile idiopathic arthritis (JIA) is not as benign as p reviously thought, with approximately 50% of adults suffering from persistent in \202 amma tion and disability (Packham, 2002). There has been a shift towards early aggressive treatm ent to limit in \202 am- mation and achieve a normal lifestyle, since there is some eviden ce for a better long-term prognosis with this approach. The development of drugs such as th e anti-cytokine agents for disease resistant to conventional treatment has greatly improved disease management. Juvenile psoriatic arthritis (JPsA) Arthritis and psoriasis (Ps) or arthritis and at least two of the following: \200 Dactylitis \200 . \200 Nail pitting or onycholysis. \200 Psoriasis in a \201 rst degree relative. Exclusions: b \200\223e (see below). \200 Swelling of one or more digits, usually asymmetrical extending beyond the joint margi n. Minimum of 2 pits on any one or more nails at any time. De \201 nition JIA is de \201 ned as arthritis (swelling or limitation of motion of the j oint accompanied by heat, pain or tenderness) of unknown etiology beginning before the 16th birthday and persisting for at least 6 weeks where other known condi- tions are excluded. Historically, there have been a number of classi \201 cations, but the most recent by The International League of Associations for Rheumatology (ILAR) has widely been accepted. It w as revised in 2001. The impor- tance is primarily in classi \201 cation for research purpo ses, but is also a useful clinical tool. With further research into the genetics and cytoki nes involved in JIA, classi \201 cation will no doubt be revised further. We will deal wit h JIA as a whole in this chapter. Subsequent chapters will discuss spe- ci \201 c subtypes separately. Enthesitis-related arthritis (ERA) (See Juvenile SpA/ERA, Chapter 7 on p. 232) Arthritis an d enthesitis, or arthritis or enthesitis with at least two of the following: \200 Sacroiliac (SIJ) tenderness and/or in \202 ammatory lum- bosacral pain (at rest with morni ng stiffness, improves on movement). The presence of HLA-B27 antigen. Onset of arthritis in a male >6 years of age. Acute (symptomatic) anterior uveitis. History of AS, ERA, sacroili itis with in \202 ammatory bowel disease, reactive arthritis or acute anterior uveitis in a 1st degree relative. \200 \200 \200 Exclusions: a, d, e (see below). Enthesitis: tenderness at the insertion of a tendon, liga- ment, joint capsule, or fascia to bone. The ILAR classi \201 cation of JIA Systemic onset arthritis (systemic onset JIA) Arthritis with or preceeded by daily fever of at least 2 weeks duration that is documented to be quo tidian* for at least 3 days, and accompanied by one or more of the following: \200 \200 \200 \200 Undifferentiated arthritis Arthritis that doesn \200\231t ful \201 l inclusion criteria fo r any cate- gory or is excluded by ful \201 lling criteria for >1 category. Exclusion crit eria (a) Ps/history of Ps in the patient or 1st degree relative. (b) Arthritis in HLA-B27+ male starting after 6th Evanescent, non- \201 xed, erythematous rash. Generalized lymph node enlargement. Hepatome galy and/or splenomegaly. Serositis**. birthday. (c) AS, enthesitis-related arthritis, sacroiliitis with in \202 am- matory bowel disease, Reiter \200\231s syndrome or acute anterior uveitis or a history of one of these disorders in a \201 rst degree relative. Exclusions: a \200\223d (see below). *Quotidian fever is de \201 ned as a fever that rises to >39 C once a day and returns to <37 C between fever peaks. **Pericarditis and/or pleu ritis and/or peritonitis. (d) The presence of IgM RF on at least two occasions Oligoarthritis (oligoarticular JIA) Arthritis affecting one to four joints during the first 6 months of disease. Two subcategories are recognized: \200 more than 3 months apart. (e) The presence of systemic JIA in the patient. Epidemiology JIA has an incidence in the UK of 1 in 10 000 and a preva- lence of 1 in 1000 (similar to that of diabetes) with a female predominance (Symmons, 1996). It is described i n all races and geographic areas, but large regional variations exist. The etiology remains unknown. Persistent oligoarthritis: affects no more than four joints throughout the disease course. Extended oligoarthritis: affects a total of more than four joints after the \201 rst 6 mo nths of disease. Exclusions: a \200\223e (see below). Polyarticular JIA (RF negative) Arthritis affecting \201 ve or more joints during the \201 rst 6 months of disease. Tests for rheumatoid factor (RF) are negative. Exclusions: a \200\223e (see below). Etiology and pathophysiology There is good evidence that T-cells play an important role wit h recruitment to the joint by up-regulation of adhesion molecules on synovial endothelium a nd retention in the joint of activated cells. \200 \200 The pattern of cytokine expression is of the Th1 type. Pro-in \202 ammatory cytokine level s in the joint are high. From T-cells: TNFA, Interferon G, IL2, macrophage inhibi- tory fac tor (MIF). From monocytes: TNFA, IL1, IL6, IL8, IL12. Polyarticular JIA (RF positive) Arthritis affecting five or more joints during the first si x months of disease; two or more tests for RF at least 3 months apart are positive. Exclusi ons: a-e (see below). CHAPTER 10 Juvenile idiopathic arthritis 353 Regulatory T-cells and anti-in \202 ammatory cytokines (IL4, IL10 and TGFB) appear reduced . A number of HLA class I and class II antigens are found in association with sub-types of JIA. HLA-A2 with early onset oligoarthritis in girls. Twin and sibling studies lend weight to genetic susceptibility. Disability accumulates from a multitude of effects but speci \201 c musculoskeletal disabi lity can arise from leg length discrepancy (overgrowth of growth plates around affected joi nts), postural scoliosis (secondary to leg length discrepancy) and joint contractures ( \201 xed loss of extension commonly). Investigations No investigation is diagnostic of JIA. The diagnosis is made clinically with consistent investigation \201 ndings. Environmental The notion that an infectious agent triggers JIA is attractive, but as yet un proven. There appears to be interaction be- tween microbes and the immune system triggering JIA in a susceptible child. Laboratory \200 FBC/CBC: hemoglobin may be low (normocytic nor- mochromic, or microcytic commonly). White c ell count normal/mildly raised (with normal differential). Platelets commonly mildly raised . Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are often mildly raised . Antinuclear antibody (ANA) if consistently raised suggests an increased risk of associate d iritis. RF, dsDNA and HLA B27 are helpful in classi \201 cation. Serology for suspected viral or bacterial triggers if his- tory suggestive of reactive arthritis and for Varicella zoster titres to check immunity (as may subsequently consider immunosuppressants). Clinical features Key features in the history It goes without saying that the history will be taken from both the child (if old enough), and the parent or carer. \200 Sensitivity is required in the young person who might want to consult with you on his or he r own, and/or with their parent/carer. The child or young person \200\231s functioning at h ome and at school is critical to the assessment. What can they do for themselves? What do t hey need help with that they used to be able to do? Do they use any aids or appliances? Thi s can be assessed using the Children \200\231s Health Assessment Questionnaire (CHAQ), whic h is helpful in clinical assessment and is critical for research purposes and in assessing response to therapy (see p. 4). \200 Imaging \200 Radiographs of affected joints are usually normal in early arthritis. They can show joint e ffusions, peri-articular osteoporosis, soft tissue swelling or surprises, such as evidence of trauma, osteomyelitis, malignancy. Ultrasound (US) examination can show joint effusion a nd synovitis (especially where clinical examination is dif \201 cult, such as the hips). M agnetic resonance (MR) shows joint anatomy and shows early changes in cartilage. Gadolinium enhance- ment may be more sensitive in detection of synovitis compared with routine T2-wei ghted sequences. In young children, good preparation by a play specialist is essential to o btain good images. A general anesthetic may be necessary. Key features on examination \200\230Every joint, every time \200\231. \200 Since children may not be able to express where there is pain and stiffness, it is critical that every joint is examined on every contact with the clinician. All too often a child is subjected to a knee aspiration for presumed sepsis, when careful examination would have re vealed toe dactylitis or a swollen ankle. It is helpful in the infant/small child to examin e the ankle from behind, whilst the child is standing. Examine small children on their pare nts lap with ready access to distracting toys. Perform a PGALS (pediatric gait, arms, legs, spine) examination for screening and hone in on affected joints for detailed examination ( DVD available from ARC) (see p. 11). Perform a careful systematic examination at the initia l assessment (rash, nail changes, mouth ulcers, hepat- osplenomegaly, respiratory, or cardi ac \201 ndings, weak- ness, scalp/hair changes, etc.). Other Arthrocentesis should be performed if septic arthritis is suspected. Straw colored \202 uid with a high white cell count, but no organism cultured is typical of JIA. 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.