Ghai Essential Pediatrics8th

infection (usually by Shigella, Chlamydia or Yersinia), in absence of clinical symptoms and (iii) exclusion of other arthritides.

A small proportion of children with acute lymphocytic leukemia show bone and joint pains. Bone pain (more marked at night), rather than joint swelling, is the predominantcomplaintinaffectedchildren.Thehemogram shows lymphocytic predominance and thrombocytopenia, in contrast to a polymorphonuclear predominance and thrombocytosischaracteristicofjuvenileidiopathicarthritis. A bone marrow examination is required to confirm the diagnosis. X-linked agammaglobulinernia (Bruton disease) maysometimespresentasanunusual'aseptic' arthritis(due toMycoplasma infection), butaccompanying respiratory and other infections are also usually present.

Arthritis can sometimes be the presenting complaint of hemophilia.

Legg-Calve-Per/hes Disease

Thisis characterizedbyanavascularnecrosisof the femoral head, occurring usually in boys 5-10 yr of age. It is now believed to be a manifestation of an underlying hyper­ coagulable state {hypofibrinolysis or a deficiency ofprotein C or protein S). Familial occurrence can occur and the condition is bilateral in 10% patients. Affected children present with a limp. Initial X-rays may be normal. Isotope bone scans and magnetic resonance imaging are required to confirm the diagnosis. Subsequent X-rays show a characteristic sequential progression: (i) widening of joint space, (ii) fragmentation of epiphysis with patchy areas of increasedlucency ordensity, (iii)abnormalitiesof shape of femoral head and neck and (iv) deformed head. Treatment options include femoral varus osteotorniesor containment splints.

Juvenile Idiopathic Arthritis

The term Juvenile Idiopathic Arthritis (JIA) was proposed by the Pediatric Standing Committee of the International

League of Associations for Rheumatology {ILAR). It refers to a group of conditions characterized by chronic inflammatory changesof the joints. It is definedasarthritis of one or more joints with onset below the age of 16 yr and persisting for at least 6 weeks. It has the following subtypes:

i.Systemic

ii.Oligoarthritis: (a) persistent (b) extended

iii.Polyarthritis: rheumatoid factor negative

iv.Polyarthritis: rheumatoid factor positive

v.Psoriatic arthritis

vi.Enthesitis related arthritis

vii.Undifferentiated arthritis: (a) fits no other category;

(b) fits more than one category

JIA is not a rare disease; its estimatedprevalenceranging from 0.4 to 1.3 per 1000 children below16 yr ofage. It is the commonestrheumatologicaldisorderof childhoodandone of the most common causesof disability, chronic morbidity andschoolabsenteeism. While the Westernstudies suggest that JIA is more common in girls, in India the female predominanceis not marked.

Etiology

The immune systemisintimately involved in the evolution of the disease. There also appears to be a major histocom­ patibilitycomplex(MHC) associatedgeneticpredisposition. For instance HLA DRS and DR8 are linked to early onset oligoarthritis (seen more in girls), B27 to late onset oligo­ arthritis (seen more in boys) and DR4, Dw4 and DRl to rheumatoidfactorpositivepolyarthritis. JIAdoesnotappear to be a homogeneous disease entity and the different subtypesmay,in fact, represent separate clinical conditions.

The etiopathogenesis of JIA remains an enigma. Several environmental triggers (e.g. infection with rubella virus, parvovirus B19,M. tuberculosis,M. pneumoniae and enteric organisms; physical trauma; psychological stress) are linked to the onset of JIA, but their exact role is not clear. Lymphocyte subset analysis shows increased numbers of

activated T cells in children with polyarthritis and oligoarthritis, while children with systemic disease have low numbers of natural killer cells. Cytokines like tumor necrosis factor-a (TNF-a), IL-6 and IL-1 have to have an important role to play in the pathogenesis of the disease. A number of autoantibodies (for instance, antinuclear antibody) may be seen in the sera of children with JIA. The classical IgM rheumatoid factor is almost never detectable in preschool children withJIA. Older girls with polyarticular small joint disease of the hands (especially involving the metacarpophalangeal and proximal interphalangeal joints) may, however, be RF positive.

Clinical Subtypes

Three major types of onset are described according to the presentation during the first 6 months of disease, viz. systemic (with feverandrash), oligoarthritis (4orfewer joints involved) and polyarthritis (more than 4 joints involved).

SystemiconsetJIA About5-15%ofpatients withJIA may have acute onset disease with prominent systemic features. These systemic features can sometimes precede joint manifestations by weeks or months. Trus condition should, therefore, be considered in the differential diagnosis of any child with prolonged fever. The illness can occur at any age and is more common in boys.

The illness usually begins as an intermittent fever with a characteristic twice daily peak (quotidian fever). Fever is prominent in the evening hours. It is accompanied by a characteristic evanescent maculopapular rash (with central clearing), which is prominent on the trunk. This rash may be difficult to recognize in individuals with dark skins. Affected children show marked irritability, which decreases with subsidence of fever. Serosal involvement (in the form of pericarditis or pleuritis) may be prominent. Hepatosplenomegaly and lymphadenopathy are common at presentation and can lead to diagnosticconfusion. There is a moderate neutrophilic leukocytosis and an elevated erythrocyte sedimentation rate along with thrombocytosis. The rheumatoid factor is negative.

0/igoarthritis Oligoarthritis is the most frequent type of JIA accounting for approximately 60-70%of patients. Four or fewer joints (usually large) are affected during the first 6 months of the disease. The involvement is often asymmetrical. Joint swelling, rather than joint pain, is the usual complaint. Two suhtypPs are dPscrihed: persistPnt (if number of affected joints continues to be 4 or less) and extended (if number of affected joints exceeds 4 during the disease course).

Oligoarthritis is more common in young girls, typically 3-5 yr of age. ThP knPPS and ankles are commonly affected. Small joints of the hands and feet are not involved. Asymptomatic and potentially blinding, iridocylitis can be seen in 25%patients.

Polyarthritis Polyarthritis occurs in 25-30%of patients and is more common in girls.Joint pain, out of proportion to the degree of joint swelling, is the usual complaint. Fever and malaise can be significant. Two subtypes are known:

Rheumatoidfactor negative. This subtype may occur at any age in rhildhoocl. The knees, wrists and hips are the joints usually affected. Small joints of hands and feet are less commonly involved and rheumatoid nodules are not seen. Joint disease in this subtype ofJIA is far less severe than that seen in patients who are rheumatoid factor positive.

Rheumatoidfactor positive. The age at onset is late childhood or early adolescence. The arthritis is symmetrical, additive, severe and deforming and typically involves the small joints of the hand, especially the metacarpophalangeal and the proximal interphalangeal. Cervical spine and temporomandibular joints can also be affected. This subtype is the only category of JIA which is somewhat similar phenotypically to adult onset rheumatoid arthritis. Rheumatoid nodules are present in some patients and they usually manifest severe disease.

Psoriatic arthritis Psoriatic arthritis is said to be present when there is arthritis in association with psoriasis or any 2 of the following features: dactylitis, nail pitting and psoriasis in a first degree relative. Arthritis may precede, accompany or follow the occurrence of psoriasis in children. Simultaneous occurrence of small and large joint arthritis or involvement of the distal interphalangeal joint are important clinfral clues to the condition.

Enthesitis-relatedarthritis Truscondition is more common in boys, typically older than 8 yr. Large joints of lower extre­ mities are commonly affected. Many children are HLA B27 positive, and a proportion of these may go on to develop ankylosing spondylitis later as adults. However, sacroiliitis and spondylitis are usually not significant till late adole­ scence. Self limiting acute symptomatic iritis may occur in some patients but it does not progress onto the chronic iridocyclitis seen in the oligoarthritis of young girls. A family history of ankylosing spondylitis, psoriasis, Reiter disease and low back pain may be obtained in these children.

Laboratory Investigations

The clinici,m should recognize the differing patterns of joint invnlvPmPnt in various types of JIA. This 'pattern recognition' is often the most important diagnostic clue. Laboratory investigations may be of little or no help in arriving at a diagnosis.

Synovi,11 fluid aspirntion for microscopy and culture is inrlir,1tPrl in rhilrlrPn with rnonoarthritis because septic arthritis may need to be excluded in such cases (Table 21.2). Complete blood counts should be requested along with an erythrocyte sedimentation rate. Acute lymphocytic leukemia can sometimes have an arthritic presentation and

such children may be mistakenly diagnosed as having JIA. Bone marrow aspiration is therefore necessary if use of glucocorticoidsis being contemplated for treatment ofJIA.

C-reactiveproteinmeasurementis asurrogatemarkerof disease activity and are helpful on followup. Plain radiographs of affected joints are obtained at the time of initial diagnosis and may be repeated for assessment of erosive disease.It should be noted that screening for rheu­ matoid factor is not a usefultestfor diagnosis of arthritis in young children, but it is an important prognostic factor in situations where it is positive.

Treatment

ManagementofJIA is multidisciplinary.Physiotherapyand occupational therapy should be tailored to the specific needs of an individual child, in order to prevent defor­ mities and facilitate 'mainstreaming' and rehabilitation. Physical therapy helps in relieving pain, maintenance of posture and joint mobility, improves muscle strength and prevents fixed flexion deformities. Patient should be assessed by an ophthalmologist so that uveitis can be detected early and treated appropriately. Children with oligoarthritis need regular ophthalmological followup as uveitis can develop later.

Medical therapy. NSAIDs are the mainstay of symptomatic management. The conventional NSAIDs inhibit both isoforms of the enzyme cyclo-oxygenase,i.e.COX-1 (cons­ titutive; mediates physiologic prostaglandin production necessary for gastrointestinal mucosa! integrity and adequacy of renal blood flow) and COX-2 (inducible; mediatespathologicprostaglandin production, especially at sites of inflammation). The NSAIDs commonly used in children are naproxen and ibuprofen. Indomethacin is believedtobeofparticularuseinenthesitis relatedarthritis. Doses of commonly used NSAIDs aregiven inTable 21.3.

The development of Reye syndrome is a distinct possibility while a child is receiving NSAIDs, especially if there is an intercurrent viral illness. All children with NSAIDsmustbealsomonitoredfor gastrointestinaladverse effects.The recently introduced selective COX-2 inhibitors (e.g. rofecoxib, valdecoxib) have lower gastrointestinal adverseeffects,butarenotrecommendedforuseinchildren.

Tabl 21.3: Doses of commonly used NSA1Ds

The analgesic dose is usually half the anti-inflammatory dose

Rheumatological Disorders --

Although the mechanism of action of all NSAIDs is the same, idiosyncratic responses are well known and a given patient may respond to one NSAID and not to the other. Response to therapy is usually slow and this fact must be explained to the parents. Treatment must continue for at least 4-6 weeks before a decision to switch over to another NSAID is made.

Diseasemodifyinganti-rheumaticdrugs(DMARDs)need tobestartedinalmostallchildrenwithpolyarthritis.Weekly methotrexate (15-25 mg/m2 /weekgivensubcutaneouslyor orally)hassimplifiedthemanagementofsevereformsofJIA. Childrenseemtotoleratemethotrexatebetterthanadultsand have fewer adverse effects. Once the child is in stable remission (usuallyachievedafterseveralmonths),thedrug can be tapered to the minimum effective dose and then stopped. Methotrexateshouldalwaysbegivenunderclose medical supervision. Periodic testing of liver functions is mandatory. Development of hepatic fibrosis, a dreaded adverseeffect,isuncommon.Hydroxychloroquineisauseful adjunct and is often used along with methotrexate. Leflunomide,aninhibitorofpyrimidinesynthesis,hasbeen used in adults withrheumatoid arthritis, but experiencein children islimited.

Intra-articular injections of glucocorticoids (usually triamcinolone) are the preferred therapy for children with oligoarthritis who do not respond to an initial trial of NSAIDs. In addition, local steroid instillation (along with mydiatrics) may be required for patients with iridocyclitis. Systemic glucocorticoids (usually prednisolone 1-2 mg/ kg/day; occasionally methylprednisolone 10-30 mg/kg) are necessary for severe unremitting arthritis, systemic manifestations (e.g.pericarditis, myocarditis,vasculitis)and rapidly progressive disease. Prednisolone, when used in this manner, is usually given as bridge therapy for a few weekswhileawaiting the clinical response of methotrexate.

Newer modalities of treatment include recently intro­ duced biologicals. These include anakinra (IL-1 receptor antagonist); canakinumab (monoclonal antibody to IL-1); tocilizumab (monoclonal antibody to IL6 receptor); inflixi­ mab, golimumabandadalimumab(monoclonalantibodies to TNFa); etanercept (recombinant soluble TNF receptor p75 fusion protein) and abatacept (inhibitor of T cell activation). Both etanercept and infliximab are powerful biological agents against TNFa. Whileetanercepthas been used in children with polyarticular JIA not responding to methotrexate, infliximab has been more commonly used in adults with spondyloarthropathy. Tocilizumab h;i<; fnun<l favour in children with severe forms of systemic onset disease. While these agents are effective in children with difficultforms of arthritis,longtermsafety oftheseproducts in children is still unclear.

Course

Oligoarthritis usually has a good prognosis but localized deformitiescandevelopduetoasymmetricgrowthof limbs. Children with enthesitis related arthritis can develop

spondylitis andsacroiliitis later, especiallyif they are HLA B27 positive.

Children with rheumatoid factor positive polyarthritis have a disease pattern similar to adults and show erosive and deforming arthritis. Response to therapy is not predictable. The prognosis is relatively better for sero­ negative polyarthritisas remissions are obtainedmoreoften and residual joint lesions may be minimal.

The course of systemic onset disease can be extremely variable and the response to therapy is not always satis­ factory. Approximately 50% patients undergo remission with minor residual joint involvement while others may develop progressive arthritis or have recurrent episodes of systemic disease. The presence of HLA DR4 is associated with severe, persistent arthritis.

Inappropriately treated or untreated patients with JIA may developflexion contractures ofhips,knees and elbows, resulting in permanent disability. Neck stiffness is an especially debilitating problem and can result in torticollis. Temporomandibularjoint involvement results in restricted openingofthemouthand mayrequiresurgicalintervention.

Complications

Anemia, due to chronic ongoing inflammation, is almost always present in children with persistent active arthritis and serialhemoglobin levels mirror disease activity rather closely. Blood loss induced by NSAIDs can also be a contributory factor for the anemia. Chronic anterior uveitis may be clinically silent and potentially blinding. Girls below 6 yr of age with oligoarthritis and who have anti­ nuclear antibodies are at the highest risk of developing this complication.

Childrenwithsystemiconsetdiseaseareespecially prone to develop macrophage activation syndrome, a potentially life-threateningcomplication manifesting as sudden onset icterus, bleedingtendency,leukopenia,thrombocytopenia, elevated triglycerides and raised ferritin levels. Prompt administration ofintravenousmethylprednisolonepulses is often curative.

Growth disturbances, limb length discrepancies and joint contractures can be seen in children with long­ standing disease. Growth failure may occur secondary to severe inflammation or treatment with glucocorticoids. Treatmentwithrecombinanthumangrowthhormonemay be an option in children with growth disturbances. Secondary amyloidosis is a rare complication, presents with asymptomatic proteinuria and hypoalbuminemia, and is often irreversible.

SYSTEMIC LUPUS ERYTHEMATOSUS

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by inflammation of blood vessels and connective tissues resulting in multisystem involve­ ment. The clinical manifestations are variable and the course unpredictable.Childhood SLEisusuallymore severe and has a poorer prognosis than adult SLE. The hallmark

of SLE is thepresenceofantinuclearantibodies.The female predominance characteristic of adult SLE is usually not apparent in young children.

Diagnosis

The diagnosis of SLE is facilitated by the classification criteriagivenbyAmerican College ofRheumatology (Table 21.4).Presence offour of thesecriteria,eitherat presentation or sequentially, gives a sensitivity and specificity of96% in adults. However, SLE is a clinical diagnosis, the criteria provide helpful guidelines for arriving at a diagnosis. In many patients, especially children, treatment is initiated even when they do not fulfil the requisite criteria.

Table 21.4: ACR 1997 criteria for classification of systemic lupus erythematosus

Malar rash Discoid rash Photosensitivity

Oral or nasal mucocutaneous ulcerations Nonerosive arthritis

Nephritis (proteinuria >0.5 g/day or cellular casts) Encephalopathy (seizures or psychosis)

Pleuritis or pericarditis Cytopenia

Positive immunoserology (antibodies to dsDNA/Smith nuclear antigen) or positive finding of antiphospholipid antibodies (IgG/IgM anticardiolipin antibodies or lupus anticoagulant or VDRL)

Positive antinuclear antibody test

The malar rash, which is virtually pathognomonic of SLE, may not be apparent initially. It involves the cheek, bridge of nose and lower eyelids but spares the nasolabial folds (Fig. 21.1). Discoid lesions are rare in childhood onset SLE. Oral ulcerations may involve the buccal mucosa or palate and are characteristically painless. Some children may have prominent frontal alopecia (Fig. 21.2). Arthritis is usually mild and always non-erosive.

Renal involvement is adreadedcomplicationof SLE and oneofthecommonestcausesofmortalityinchildren.Lupus nephritis can be classified as follows: Class I: Minimal mesangial; Class II: Mesangial proliferative; Class III: Focal proliferative; Class IV: Diffuse proliferative; Class V: Membranous; Class VI: Advancedsclerosing. Class III and Class IV lesions require the most aggressive forms of therapy.

Neurological features may include psychosis, seizures andchorea. Theremaybenocorrelation betweentheseverity of clinical involvement and findings on neuroimaging. Hematologic abnormalities include a Coombs' positive hemolytic anemia, leukopenia, lymphopenia and throm­ bocytopenia. In addition, there may be coagulation abnormalities due to secondary antiphospholipid antibody syndrome. Cardiac manifestations include pericarditis, myocarditis, or verrucous (Libman-Sacks) endocarditis.

Fig. 21.1: Malar rash in SLE

Fig. 21.2: Frontal alopecia in SLE

Serology

Almostall patientswithSLE have demonstrable antinuclear antibodies. Presence of anti-double stranded DNA anti­ bodiesis highlyspecificof SLE. Thetitersof these antibodies usually correlate with disease activity. Anti-histone antibodies are characteristic of drug-induced lupus (e.g. following phenytoin, isoniazid, hydralazine) but in such cases anti-dsDNAantibodiesare usually absent andserum complement (C3) level is notdecreased.Anti-Ro antibodies are believed to play a role in the development of congenital heart block characteristic of neonatal lupus syndromes. These heart blocks are permanent. Anti-Sm antibodies are a marker for CNS lupus.

Treatment

Glucocorticoids and hydroxychloroquine form the main stay of therapy of lupus. Prednisolone is started in doses of 1-2 mg/kg/day and gradually tapered over several months, according to disease activity. Arthritis usually responds to NSAIDs. Sunscreen lotions (with sun

Rheumatological Disorders -

protectionfactorof 15-20) mustbeprescribedforall children with lupus and applied 3-4 times/day, even on cloudy days.

Life-threatening complications (e.g. class IV lupus nephritis, mycocarditis, encephalopathy) may warrant use of intravenous pulses of methylprednisolone (30 mg/kg/ day) for 3-5 days. Rituximab, a monoclonal antibody to CD20, has also been found to be effective in such situations. Use of monthly pulses of IV cyclophosphamide (500 mg/ m2) has considerably improved the longterm outcome in childrenwithsevereforms oflupus nephritis. Once remis­ sion is achieved, the patient can be treated with longterm azathioprine. Mycophenolate mofetil is being increasingly used for the therapy of severe forms of lupus nephritis in children.

Low dose prednisolone (2.5-5 mg/day) and hydroxy­ chloroquine (5-6 mg/kg/day) may need to be continued for several years depending on the clinical response.

Infections must betreatedaggressivelywith appropriate antimicrobials and the steroid dose hiked up during such episodes. With appropriate therapy, the longterm outlook of SLE in children is quite encouraging.

Antiphospholipid Antibody (APLA) Syndrome

The APLA syndrome is a common accompaniment of systemic lupus erythematosus but can be seen in association with other rheumatological disorders as well. The syndrome can, at times, arise de nova when it is known asprimaryAPLA syndrome. It is acommoncauseof hyper­ coagulable states in children and can manifest with arterial and venous thrombosis, livedo reticularis and thromb­ ocytopenia. Thepresentation can sometimes be catastrophic and may result in fatality. Laboratory diagnosis is suggested by a typical coagulation profile (normal pro­ thrombin andprolonged partial thromboplastintimes) and confirmed by the detection of anticardiolipin antibodies (IgM and IgG) and the lupus anticoagulant test. Treatment is with longterm oral anticoagulation.

JUVENILE DERMATOMYOSITIS

Juvenile dermatomyositis CTDM) is a multisystem disease characterized by nonsuppurative inflammation of striated muscle and skin and a systemic vasculopathy. Unlike adults,pure polymyositis (i.e. inabsenceof dermatological changes) is uncommon in children. The diagnosis can be made on the basis of the following criteria:

i.Characteristic heliotrope discoloration over the upper eyelids (Fig. 21.3)

ii.Symmetrical proximal muscle weakness

iii.Elevated levels of muscle enzymes (AST, ALT, CK, aldolase)

iv.Electromyographicevidence of myopathy

v.Musclebiopsy showing myonecrosis, myophagocytosis and perifascicular atrophy

Fig. 21.3: Heliotrope rash in juvenile dermatomyositis

A definite diagnosis of JDM can be made if a child fulfils the first criterion along with any three of the remaining four; it is considered probable if two of the four criteria are met and possible if only one of the four criteria is met in addition to the first criterion. Other typical dermatological changes include Gottron papules (collodion patches) over the dorsal aspects of metacarpophalangeal and inter­ phalangealjointsof fingersortoesare usuallynotinvolved (Fig. 21.4); edema over eyelids; photosensitivity; a trw1cal rash and calcinosis. From the clinical point of view a child with characteristic dermatological findings along with proximal muscle weakness can be confidently diagnosed as having JDM andstartedon treatment irrespective of the biopsyfindings. Magnetic resonance imaging (MRI) shows characteristic hyperintense signalson T2 weighted images suggestive of muscle edema and inflammation while the Tl weighted images may show fibrosis, atrophy and fatty

Fig. 21.4: Gottron papules in juvenile dermatomyositis

infiltration.Typicalfindingson MRI mayprecludetheneed for a muscle biopsy.

Treatment is with intravenous methylprednisolone (30 mg/kg/day) for 3-5 pulses followed by oral predni­ solone(1.5-2mg/kg/day).Prednisoloneisthengradually tapered depending on the clinical response. Weekly methotrexate(15-25mg/m2/weekgivensubcutaneouslyor orally) is now increasingly being used as first-line therapy in combination with prednisolone. The usual duration of therapy is 18-24 months. Rapid tapering of steroids may resultindiseaserelapse.Thelongtermprognosisisexcellent.

SCLERODERMA

Scleroderma refers to hardening of the skin. It can be classified as follows:

i.Systemic scleroderma (e.g. diffuse cutaneous, limited cutaneous)

ii.Overlap syndromes

iii.Localized scleroderma (e.g. morphea, linear scleroderma, eosinophilic fasciitis)

iv.Chemically induced scleroderma (e.g. with polyvinyl chloride, pentazocine, bleomycin)

v.Pseudosclerodermas(e.g.phenylketonuria, scleredema, progeria and porphyria cutanea tarda)

Diffuse cutaneoussystemic scleroderma is usually asso­ ciated withwidespreadvisceralinvolvement including the gastrointestinaltract,heart,lungsandkidneys.Itisbelieved thatfetomaternalgraft-versus-hostreactionsareinvolvedin thepathogenesisofthiscondition.Onsetofdiseaseisinsidious andmaybedifficulttorecognizeinthe initialstages.Thechild presents with skin tightening (edema, atrophy and acro­ sclerosis), Raynaud phenomenon (i.e. blanching, cyanosis and erythema), soft tissue contractures, arthralgias and myalgias,dysphagia(regurgitation, reflux and aspiration), dyspnea (interstitial fibrosis, low diffusing capacity) and characteristicsubcutaneouscalcifications.Inaddition,many childrenhaveabnormalitiesofnailfoldcapillarieswhichcan be seen as capillary dropouts and dilated loops with a magnifying glassorthe+40lensoftheophthalmoscope.Onset of hypertension and proteinuria usually indicate renal involvementandshouldbeacauseforconcern.

Systemicsclerodermaisrareinchildren butcanresultin severedisability.Investigationsshowpresenceofantinuclear antibodies (withnucleolarpatternonimmunofluorescence) and antibodies to Scl-70 (DNA-topoisomerasel) or centro­ mere.Noformofdrugtherapyhasbeenfoundtobecurative. Penicillamineandcolchicine can produce beneficial results in some patients, especially if used early in the course of di ease. Pulsedexamethaso11etherapyhasalso beenshown to be effective. Monthly pulses of IV cyclophosphamide (followed by maintenance daily azathioprine or weekly methotrexate)can belife-savinginpatientswithinterstitial lung disease. Nifedipine is useful for management of Raynaudphenomenonwhileenalaprilcanresultincontrol ofbloodpressureandstablizationofrenalfunction.Thelatter is also thedrug of choice for scleroderma renal crises. With appropriate management, 10yr survival rates of up to 90% have been reported inchildren.

Scleredema is a benign, self limiting condition charac­ terized by nonpitting indurated edema over face, neck, shoulders and chest, but always excluding the hands and feet.

MIXED CONNECTIVE TISSUE DISEASE (MCTD)

MCTDis a multisystemic overlap syndrome characterized by features of rheumatoidarthritis, systemic scleroderma, SLE and dermatomyositis occurring in conjunction with

high titers of anti-ribonucleuprutem (1<.NP) antibodies (specific for Ul RNP). Nephritis is usually less common and less severe than in SLE. Many children show good response to low-dose glucocorticoids and NSAIDs. Oral weekly methotrexate is also a useful therapeutic option. Treatmentmust be individualized and should focus on the particular disease component which is predominating in a given child.

VASCULITIDES

The vasculitides are best classified according to the size of the vessel involved:

i.Large vessel (i.e. aorta and major branches) vasculitis e.g. Takayasu arteritis, giant cell arteritis (not seen in children)

ii.Medium vessel (i.e. coronary, renal, hepatic, mesenteric) vasculitis, e.g. Kawasaki disease, polyarteritis nodosa

iii.Small vessel (i.e. arterioles, capillaries, venules) vas­ culitis, e.g. Henoch-Schonlein puqrnra, Wegener's granulomatosis, microscopic polyangiitis, Churg­ Strauss syndrome, cutaneous leukocytoclastic angiitis.

Takayasu Arteritis

This is characterized by a segmental inflammatory panarteritis resulting in stenosis and aneurysms of aorta and its major branches causing weak arterial pulses. It is believed to be the commonest cause of renovascular hypertension in India. It is classified according to the site of involvement: Type I: aortic arch; Type II: descending aorta; Type III: aortic arch and descending aorta; Type IV: aorta and pulmonary artery. Many children with Takayasu arteritis show a strongly positive tuberculin reaction. The classification criteria for childhood Takayasu arteritis are given in Table 21.5.

Diagnosis is confirmed by angiography. Treatment involves longterm immunosuppressiun with prednisolune and methotrexate (used in weekly du es). Mycuphenolate mofetil has also been found to be useful. Angioplasty procedures are now being increasinglyperformed even in small children and have shown promising results. Cyclo­ phosphamide or azathioprine may be required in children who fail to show an adequate response to steroids. Hyper­ tension must be managed appropriately.

Kawasaki Disease

Kawasaki disease is an acute febrilemucocutaneuus lymph

Table 21.5: Classification criteria for childhood Takayasu artentis

Angiographic abnormalities (conventional, CT or MRI) of the aorta or its main branches, plus at least one of the following 4 features:

i.Decreased peripheral artery pulse(s) and/or claudication of extremities

ii.Blood pressure difference >10 mm Hg

iii.Bruits over aorta and/or its maior brdnches

iv.Hypertension (based on childhood nonnative data)

Rheumatologlcal Disorders ---'

nude syndrome mainly affecting infants and young children. More than 80% of cases areseenin children below the age of 5 yr. It is a common vasculitic disorder of childhood and has replaced acute rheumatic fever as the leading cause of acquired heart disease in children in many countries. The condition has been reported from all parts of the world. In India this condition is now being increasingly recognized but the vast majority of patients still continue to remain undiagnosed probably because of lack of awareness amongst pediatricians.

It is important to remember that the diagnosis of KO is based entirely on the recognition of a temporal sequence of characteristic clinical findings (Figs 21.5 to 21.8) and that there is no specific laboratory test. The diagnostic criteria for KO are as follows:

A Fever lasting for at least 5 days

B.Presence of any 4 of the following 5 conditions:

i.Bilateral nonpurulent conjunctiva! injection (no discharge)

Fig. 21.5: Rf::d uacked l1 s 1n Kawasaki disease

Fig. 21.6: Strawberry tongue in Kawasaki disease

Fig. 21.7: Swelling on dorsum of hands in Kawasaki disease

Fig. 21.8: Periungual desquamation in Kawasaki disease

ii. Changes ofmucosae oforopharynx (e.g. injectedpharynx, injected lips, strawberry tongue)

iii.Changes of peripheral extremities (acute stage: edema, erythema of hands or feet; convalescent stage: desquamation, which usually begins periungually)

iv.Polymorphous rash (never vesicular)

v.Cervical lymphadenopathy (at least 1 node 1.5 cm; usually unilateral)

C.Illness not explained by any other known disease process.

It shouldbe noted that the above clinical features evolve sequentially over a period of few days and all need not be present atoneparticularpoint of time. Thispartlyexplains the difficulty that the clinician experiences in arriving at a correct diagnosis.Most childrenhave high grade fever and are extremely irritable. In fact it is this irritability which often provides the first clinical clue to the diagnosis. Kawasaki disease must be considered in the differential diagnosis of all children below 5 yr of age who have fever without apparent focus lasting more than 5 days. Beau linesmay beseenduringtheconvalescentphase(Fig. 21.9). Thebasiclesionis a necrotizing vasculitis of medium-sized muscular arteries (especially coronaries), which may result

Fig. 21.9: Beau line in Kawasaki disease

in aneurysms, dilatations, and stenoses in untreated patients.

Treatmentis with asingle dose of intravenous immuno­ globulin (2 g/kg) and aspirin in anti-inflammatory doses (75-80 mg/kg) until the child becomes afebrile. Low dose aspirin (3-5mg/kg/day)isthencontinuedfor afewweeks foritsantiplatelet activity. In appropriately treatedchildren, the longterm prognosis is excellent with less than 3% patients developing coronary artery abnormalities as com­ pared to 15-25% in the untreated category.

Polyarteritis Nodosa

Polyarteritis nodosa (PAN) is rare in childhood.The clinical manifestations can be variable because of multisystemic involvementandincludefever,hypertension (seen in 80%), abdominal pain, arthritis, myalgia, skin involvement (especially livedo reticularis, Fig. 21.10). Neurological involvement (seizures, encephalopathy) and peripheral neuropathy (mononeuritis multiplex). Pathological diagnosis consists of demonstration of fibrinoid necrosis in medium sizedarteries with segmentalinvolvement and a predilection for bifurcation of vessels. On angiography, aneurysms may be demonstrable in the renal arteries or celiacaxis (Fig.21.11). The diagnostic criteriafor childhood PAN have been recently revised (Table 21.6). Treatment consists of longterm immunosuppression (initially with cyclophosphamide and prednisolone, followed by azathioprine).

Henoch-Schonlein Purpura

Henoch-Schonlein purpura (HSP) is one of the most common vasculitic disorder of childhood and is char­ acterized by the presence of a nonthrombocytopenic (and usually) palpable purpura, transient arthralgia (occa­ sionally arthritis) and abdominal symptoms. The criteria for diagnosis of childhoodHSP are given in Table 21.7.

The illnessbegins with a purpuric rash more prominent over theextensor aspects oflowerextremities andbuttocks. It may be macular, maculopapular or even urticaria! to

Fig. 21.10: Livedo reticularis in polyarteritis nodosa

Fig. 21.11: Microaneurysms in polyarteritis nodosa

Table 21.6: Classification criteria for childhood polyarteritis nodosa

A childhood illness characterized by the presence of either a biopsy showing small and mid-size artery necrotizing vasculitis or angiographic abnormalities (aneurysms or occlusions)*, plus at least 2 of the following:

i.Skin involvement

ii.Myalgia or muscle tenderness

iii.Systemic hypertension (based on childhood normative data)

iv.Abnormal urinalysis and/or impaired renal function

v.Mononeuropathy or polyneuropathy

vi.Testicular pain or tenderness

vii.Signs or symptoms suggesting vasculitis of any other major organ systems (gastrointestinal, cardiac, pulmo­ nary or central nervous system)

Rheumatological Disorders -

Table 21.7: Classification criteria for childhood Henoch­ Schonlein purpura

Palpablepurpura inthepresenceof at leastone of the following

4features:

i.Diffuse abdominal pain

ii.Any biopsy showing predominant IgA deposition

iii.Arthritis or arthralgia

iv.Renal involvement (any hematuria and/or proteinuria)

begin with and can be difficult to diagnose in the first few days of the illness. Glomerulonephritis is seen in appro­ ximately one-third, but only 10% patients have azotemia or nephrotic rangeproteinuria.Clinically, it may manifest as isolated hematuria, hypertension or a nephritic/ nephrotic syndrome. Thisisthe only longterm complication of HSP. Significant renal involvement is uncommon in children below 6 yr of age.

Gastrointestinal manifestations usually occur in the first 7-10 days of the illness. Affected children may be erro­ neously diagnosed as having a 'surgical abdomen' and even subjected to unnecessary surgery. Abdominal pain is usually intermittent, colicky and periumbilical. Vomiting occurs in about 60% of patients but hematemesis and malena are relatively less common.

Mostclinicalfeaturesof HSP are selflimitingand resolve in a few days. Rare manifestations include CNS vasculitis, coma, Guillain-Barre syndrome, pulmonary hemorrhage, carditis and orchitis.

Laboratory Investigations

HSP is a clinical diagnosis and none of the laboratory fea­ tures are pathognomonic. There may be a nonspecific increase intotalserum IgA levels. Manychildrenmayhave microscopic hematuria and proteinuria. Skin biopsy from the involved sites may show the characteristic leuko­ cytoclastic vasculitis. On indirect immunofluorescence there are deposits of IgA and C3 in skin as well as renal biopsies. Ultrasoundexaminations mayneedto be repeated at frequent intervals for evolving abdominal findings.

Treatment

Management is generallysupportive with maintenance of hydration andpainrelief.Prednisolone (1-1.5 mg/kg/day) is often given in childrenwith gastrointestinal involvement and is usually continued for 2-3 weeks depending on the clinical response. There is, however, no clear evidence that steroids alter the natural course of the disease.

HSP nephritis is a serious complication and can result in chronicrenalfailure if not managedappropriately. There is evidence to suggest that longterm treatmentwith predni­ solone andazathioprinecanresult in prolongedremissions.

Prognosis

• Should include conventional angiography if magnetic resonance angiography is negative

The disease usually runs its entire course in 4 weeks and majorityof the children have no permanent sequelae even

when the short-termmorbidityisquitesignificant. Children older than 6 yr with significant renal involvement (espe­ ciallychildrenwithrapidly progressive glomerulonephritis and fibrous crescents) need to be followed up and the longterm prognosis is guarded. Overall 1-5% of children with HSP nephritis progress to endstage renal disease.

Granulomatos is with Polyang i it is

Thiscondition,previouslycalledWegener'sgranulomatosis and characterized by necrotizing granulomatous angiitis affectingtherespiratorytractandkidneys,israreinchildren. Constitutionalsyrr.ptomsarequitecommon.Presenceofanti­ neutrophil cytoplasmic antibodies (ANCAs), especially c­ ANCA,arevirtualiypathognomonic.The diagnostic criteria forchildhoodgranulomatosis with polyangiitisaregiven in Table 21.8. With steroids and cyclophosphamide and occasionally, intravenous immunoglobulin, the longterm outlookisexcellent.

Behc;;et Disease

This is an extremely uncommon vasculitic disorder. The clinical manifestations can be quite variable. These may be classified as:

i.Major. Aphthous stomatitis, genital ulceration, cuta­ neous manifestations and ocular disease

ii.Minor. Gastrointestinal disease, thrombophlebitis, arthritis,familyhistory and neurological involvement.

Behc;et disease is usually characterized by multiple relapses with the ocular and neurological manifestations resulting in significant disability.Widespread thrombosis of the large vessels may be life-threatening.Many patients have the characteristic pathergy test (cutaneous pustular

Table 21.8: Classification criteria for childhood granulomatosis with polyangiitis

Three of the following six features should be present:

i.Abnormal urinalysis

ii.Granulomatous inflammation on biopsy

iii.Nasal sinus inflammation

iv.Subglottic, tracheal or endobronchial stenosis

v.Abnormal chest X-ray or CT scan

vi.Positive c-ANCA staining

reaction following needle pricks) positivity. HLA-BS and B51haplotypeshave been associated with this syndrome. Drug therapy involves use of colchicine and thalidomide. Methotrexate and chlorambucil have also been used.

Suggested Reading

Hari P, Bagga A, Mahajan P, Dinda A. Outcome of lupus nephritis in Indian children. Lupus 2009;18:348-54

Ozen S, Ruperto N, Dillon MJ, Bagga A, Kamorz K, Davin JC, et al. EULAR/PRES endorsed consensus criteria for the classification of childhood vasculitis. Ann Rheum Dis 2006;65:936-41

Ruperto N, Ozen S, Pistorio A, Dolezalova P, Brogan P, Cabral DA, et al. EULAR/PRINTO/PRES criteria for Henoch-Schiinlein purpura, childhood polyarteritis nodosa, Wegener's granulomatosis and childhood Takayasu arteritis: Ankara 2008. Ann Rheum Dis 2010;69:790-7

Singh S, Aulakh R, Bhalla AK, Suri D, Manojkumar R, Narula N, Burns JC. ls Kawasaki disease incidence rising in Chandigarh, North India? Arch Dis Child 2011;96:137-40

Singh S, Bansal A. Twelve years experience of juvenile dermato­ myositis in North India. Rheumatol Int 2006;26:510-5

Singh S, Dayal D, Kumar L, Joshi K.MortaHty patterns in childhood lupus - 10 yr experience in a developing country. Clin Rheum 2002, 21:462-65