Acute rheumatic fever is a non-infectious delayed

complication of streptococcal sore throat due to Group A Beta hemolytic streptococcus

(GABHS)

HISTORY Historical evidence is clouded probably

because of multisystemic disease RF is relatively recent Crowded and poor working conditions

fostered by Industrial revolution contributed to spread of RF

World War II was associated with ravaging epidemics

EPIDEMIOLOGY

Incidence of rheumatic fever and RHD ( rheumatic heart disease) has decreased in the United States and other industrialized countries during the past 80 years. Prevalence of RHD in the United States is now less than 0.05 per 1000 population

Worldwide, an estimated 5-30 million children and young adults have chronic RHD, and 90,000 patients die from this disease each year.

Incidence

The incidence of RF in Developing countries is 27-100/1 mil /yr

In developed countries is <5/ 1mil/yr

(G.S.Sainani Japi 2006)

Area Prevalence/1000

US 0.3 Japan 0.3 India 2.2 Africa 5.7 South America 1.3

Pathogenesis

RF occurs 1-5wks after streptococcal throat

infection avg is 3 wks

Streptococci- GABHS ( group A beta haemolitic streptococcus)

Gram positive cocci occuring in chains Capsulated with fimbria

STREPTOCOCCI

Streptococci pyogenes Beta Haemolytic-Complete haemolysis

on blood agar Lancefield groups 19 –according to

carbohydrate antigen ( A to U except I,J)

Surface M protein -80 serotypes T,R proteins.

GABHS Rheumatogenic serotypes

1,3,5,6,14,12,18,19,24,27,29Nephritogenic serotypes 12 , 49

structure

Capsule hyaluronic acid Cellwall Outer –

fimbria+lipoteichoic acid+M protein

Middle-carbohydrate Inner-peptidoglycan

layer Cytoplasmic

membrane

Autoimmune disease; Antigenic mimicryAntibodies against these antigens result

in a hyperactive immune response

M protein helical protein-constant ,variable and highly variable region; M protein of GABHS virulence factor -> ability to resist phagocytosisCrossreactivity- cytoskeleton, tropomyosin and myosin.Group specific polysaccharide wall -> glycoprotein of cardiac valvesAntibodies to the streptococcal peptidoglycan complexes have been implicated in rheumatic arthritisSomatic antigens of the cell wall & cell membrane -> myocardial sarcolemma ,vascular initima and skinIn Sydenham chorea, antibodies directed against the cell membrane cross react with tissues in the caudate nucleus of the brain

TOXINS

Streptolysin (Hemolysin) O and S Erythrogenic toxin Streptokinase DNAase NADase Hyaluronidase Proteinase

STREPTOCOCCI Throat, skin, URTI ( upper respiratory

tract infections) Isolated from 10-50% throat culture of

healthy school children

PATHOLOGY

RF is a multisystem connective tissue disease

Inflammatory lesions in the heart, joints & subcutaneous tissue

Microscopy Aschoff granuloma is the pathological

hallmark of RF. It consists of central fibrinoid necrosis surrounded by histiocytes (Anitschkow cells) with a typical “owl-eye” nucleus.

Aschoff nodule and Anitschkow cell

Gross appearance Valves appear dull & thickened

Verucous vegetations on the atrial surface of the mitral valve, chords, ventricular surface of aortic valve with edema or hemorrhage in the leaflet tissue

Vegetations are composed of fibrin

MITRAL VALVE ENDOCARDITIS

Characteristics of Juvenile Rheumatic Mitral Stenosis

Fusion of cusps

severe Subvalvular fusion

Fixed fibrotic valve, no calcification

Mobile cusps with commissural fusion

Associated mild Mitral Regurgitation

Early & Severe pulmonary hypertension

Positive diagnosis of rheumatic fever

Sir T .Duckett Jones 1944

Modified in 1956,1965,1984 and 1992

JONES CRITERIA 1992

MAJOR MANIFESTATIONS

Carditis Polyarthritis Chorea Erythema marginatum Subcutaneous nodules

MINOR MANIFESTATIONS

Previous RF or RHD ( rheumatoid heart disease)

Clinical findings Athralgia Fever

Lab findings Raised ESR Elevated C-reactive protein Prolonged PR interval

Supporting evidence of antecedent GABHS

infection

Positive throat culture or Rapid streptococcal antigen test

Elevated or rising streptococcal antibody titer

Diagnosis of Rheumatic Fever

Two major manifestations OR One major & Two minor manifestations

if supported by evidence of preceding GABHS infection indicate a high probability of Acute RF

Sensitivity 77%, Specificity 97%

Jones Criteria (Revised) for Guidance in theDiagnosis of Rheumatic Fever*

Major Manifestation MinorManifestations

Supporting Evidence of Streptococal Infection

Clinical LaboratoryCarditisPolyarthritis

ChoreaErythema Marginatum

Subcutaneous Nodules

Previousrheumaticfever orrheumaticheart diseaseArthralgiaFever

Acute phasereactants:Erythrocytesedimentationrate, C-reactiveprotein,leukocytosis Prolonged P-R interval

Increased Titer of Anti-Streptococcal Antibodies ASO (anti-streptolysin O),othersPositive Throat Culture for Group A StreptococcusRecent Scarlet Fever

*The presence of two major criteria, or of one major and two minor criteria,indicates a high probability of acute rheumatic fever, if supported by evidence ofGroup A streptococcal nfection.

Recommendations of the American Heart Association

Carditis Seen in 42% of patients with acute RF 80% of patients who develop carditis

within the first 2 wks of onset of RF Rheumatic carditis is a pancarditis

affecting the endocardium, myocardium & pericardium to various degrees

Predominant effect is scarring of the heart valves

Endocarditis

Most commonly effects mitral & aortic valves

Mitral valve disease 70-75% pts of RHD Mitral + Aortic valve disease 20-25% Isolated Aortic valve disease 5-8% Isolated Aortic stenosis is rare 3-4% (Kinare S G AIAMS 1972)

Isolated tricuspid & Pulmonary valve is never involved

Tricuspid valve along with Mitral & Aortic valve is involved in 11.8% of RHD patients

Rheumatic Pulmonary valve is very rare , if present it is quadrivalve

POLYARTHRITIS

Incidence > 2/3 rd of patients Asymmetric, migratory involving

large joints- knees, ankles, elbows & wrists

Axial joints are rarely involved Swelling, redness ,hot, severe pain,

limitation of joint movements are the main symptoms

Physical findings disproptionate to symptoms

Joints are involved at various intervals lasts for 4-5 days

Arthritis resolves by 3 to 4 wks without any permanent damage

Joint aspirate >10000 WBCs/cu.mm

Dramatic response to aspirin –improves within 48hrs

Differential diagnosis

Post streptococcal reactive arthritis Septic arthritis Gonococcal arthritis Juvenile rheumatoid arthritis Tuberculosis arthritis Hepatitis B Henoch-Scholein purpura Serum sickness

CHOREA (St.Vitus dance)

It is a series of jerky, nonrepeatative, involuntary movements involving the face & extremities with emotional lability.

Movements disappear during sleep Due rheumatic inflammation of basal

ganglia & caudate nucleus Late manifestation after several weeks

(3mths or longer) after RF

SKIN MANIFESTATIONS

Subcutaneous nodules(1 to 21%) Late manifestation of RF Indicate presence of underlying carditis Firm, painless, moveable 0.5 to 3cm in size On bony prominence, extensor tendons

(elbows, knees , wrists, ankles), vertebral spinous process,suboccipital region,medial border of scapulae

Appear in crops, disappear in 8 to 12wks

SUBCUTANEOUS NODULES

Erythema Marginatum Early or late manifestation Incidence 10-15 % Indicate presence of underlying carditis On trunk & proximal extremities Serpigenious erythrematous

macular/papular nonpuritic rash Rash extends outwards with central

clearing No residual scarring May appear or disappear in mins-hrs

Erythema Marginatum

Laboratory Diagnosis

Throat Culture Positive in only 11% cases of ARF

Streptococcal Antibody Tests ASLO Titer Slide agglutination test Elevated in 80% patients with ARF Reach a maximum level 2-3wks after

infection, plateau for 3-6mths & disappear in the next 6-12mths

Adults /preschool children < 85 todd units

School age = 170 todd units Titers alter with age, geographical area ASO titer >250 Todd units in adults

>333 Todd units in children is used for diagnosis,

AntiDNAse B/Antihyaluronidase test

Done when ASO is nondiagnostic Levels remain elevated for several

mths Less affected by antibiotics and

steriods. DNA ase 6-12 mths Titre > 300 IU/dl

normal values Anti DNase B titer 1:60 unit in preschool,

1:480 units in –  school children & 1:340 in adults)

Antihyaluronidase > 200 IU/dl

Streptozyme test – 5 antigens Rapid slide agglutination test

Acute phase reactants Raised ESR Elevated CRP

ECG Prolonged PR interval Tachycardia AV block QRS-T changes s/o Myocarditis

Echocardiography

Helpful to diagnose silent carditis More sensitive than clinical

examination 30% cardiac involvement in patients

without clinical carditis

TREATMENTAcute Rheumatic fever Inj. Benzathine Penicillin 12 lac units

i.m single dose OR Erythromycin 40mg/kg/day in 2-4

divided doses for 10 days Aspirin 100mg/kg/day in 4-5 divided

doses for 3-4 wks, dose is gradually tapered depending upon ESR & CRP levels.

Treatment of Rheumatic Carditis Without Failure Same as ARF If no response to aspirin ,start

Corticosteroids With Failure/severe carditis Prednisone 1-2mg/kg/day for

minimum of 2 wks & then tapered for next 2 wks

Aspirin is started during the tapering course of Corticosteroids and is continued for 4 wks or until there is sufficient clinical &laboratory evidence of reduced rheumatic activity

Aspirin for minimum 12 wks It is given to reduce the rebound

activity after stopping of steroids. 5% of patients of ARF continue to have

rheumatic activity for >6mths

SEVERE CASES

Anti failure therapy

SURGICAL THERAPY Mitral valve repair Mitral valve replacement

Prevention of RF PRIMODIAL PREVENTION Involves measures to prevent the

occurrence of a GABHS sore throat Clean & Healthy environment. Mass chemoprophylaxis can work in

some high risk situations Vaccines are in experimental phase Not feasible in all situations

Primary prophylaxis Benzathine penicillin G <27kg 0.6 MU IM Once >27kg 1.2 MU PenicillinV Children 250 mg bd/tid PO 10days Adults 500 mg bd/tid Penicillin allergy Erythromycin 250mg qid PO 10days Azithromycin 500mg PO 1 day 250mg OD 4 days Others – nafcillin, ampicillin, amoxycillin, clindamycin, cephalexin

SECONDARY PREVENTION

Involves prevention of streptococcal sore throat in patients with previous episodes of RF & thereby prevent recurrent cardiac damage

RF is a recurrent disease Recurrence per infection 40-60% Permanent cardiac damage

increases with Recurrences

Secondary prophylaxis

Benzathine penicillin G 1.2 MU IM Penicillin V 250mg BD PO Sulfadiazine <27kg 500mg OD PO >27kg 1000mg Penicillin/ sulfa allergy Erythromycin 250mg BD PO

Duration of secondary prophylaxis

Category Duration RF with carditis & residual valvular lifelong RF with carditis 10yrs or well

into but no residual adulthood valvular disease

RF without 5yrs or until age 21

carditis

Juvenile Rheumatoid Arthritis

Juvenile Rheumatoid Arthritis is an inflammatory arthritis in which

joints, usually including those of the hands and feet, are inflamed, resulting in swelling, pain, and often destruction of joints.

Juvenile rheumatoid arthritis is now called by several different names : juvenile chronic arthritis (JCA) or juvenile idiopathic arthritis (JIA). No matter which of these names you use , JRA is not a single disease.;

EPIDEMIOLOGY 1. Juvenile arthritis (JRA) most frequent

connective tissue disease of childhood 2. Incidence Mayo Clinic, 1966, 13.9 cases per

100,000. 3. Prevalence a. Mayo Clinic Survey, 113.4 cases per 100,000 children. b. English schoolchildren, Bywaters,

65 cases per 100,000.

AGE OF ONSET

Onset usually after 6 months of age

The highest frequency occurs at 1 to 3 years of age. Largely children with pauciarticular arthritis

Another peak occurs at 9 years of age. This peak has an equal contribution between

boys and girls and is a much broader peak.

JUVENILE RHEUMATOID ARTHRITISEtiology and Pathogenesis

unknown combination of factors

environment (infection, trauma, stress)

autoimmunity immunogenetic

Pathology

Synovium Synovium becomes

hyperplastic and locally invasive at the synovial interface with cartilage and bone.

• The destructive tongue of tissue is called pannus and is responsible for marginal erosions observed on X-rays.

• The pannus is comprised primarily of invasive lining cellsmetalloproteinases)

CRITERIA FOR THE CLASSIFICATION OF JA

1. Age of onset < 16 years.

2. Arthritis in one or more joints defined as swelling or effusion, or presence of two or more of the following signs: limitation of range of motion, tenderness, or pain on motion, and increased heat.

3. Duration of disease ≥ 6 weeks.

4. Exclusion of other forms of juvenile arthritis.

ANCILLARYMANIFESTATIONS OF JA 1. Morning Stiffness 2. Rheumatoid rash 3. Intermittent fever 4. Pericarditis 5. Chronic uveitis 6. Cervical spondylitis 7. Rheumatoid nodules 8. Tenosynovitis 9. Antinuclear antibodies 10. Rheumatoid factors

CLASSIFICATION OF THE

TYPES OF ONSET OF JA 1. Polyarticular arthritis (5 or more joints) a. Rheumatoid factor negative b. Rheumatoid factor positive

2. Pauciarticular arthritis (4 or fewer joints)

a. Early childhood onset b. Late onset

3. Systemic disease (arthritis with intermittent fever)

IMPORTANT !

ILAR Classification Criteria(International League of

Associations for Rheumatology)

Juvenile Idiopathic Arthritis (JIA)SystemicPolyarticular RF+Polyarticular RF-Oligoarticular

persistentextended

Psoriatic arthritisEnthesitis-related arthritisOther arthritis

JUVENILE RHEUMATOID ARTHRITISClinical features: systemic disease 10-20% of patients with JRA prominent systemic symptoms:

fever, rash, lymphadenopathy, hepatosplenomegaly, pericarditis, pleuritis

arthritis may be absent for months to years

uveitis uncommon

In systemic disease (Still's disease), inflammation occurs at sites other than the joints (which also may be affected)

high fever and rash that frequently appear before joint pain and swelling. The fever comes and goes, usually for at least 2 weeks. The temperature is usually highest in the afternoon or evening (often 103° F [39° C] or higher) and then returns rapidly to normal.

A child -tired and irritable. The rash is made up of flat, pink-colored or salmon-colored patches—on the trunk and the upper part of the legs or arms. It appears for hours at a time (often in the evening with the fever) and does not always appear in the same spot.

The liver, spleen, and lymph nodes may enlarge. Sometimes -pericarditis,pleuritis causing chest pain.

JUVENILE RHEUMATOID ARTHRITISLaboratory studies: systemic disease

WBC , Hgb , platelets to , ESR to ANA and RF usually negative x-rays : soft tissue swelling

JUVENILE RHEUMATOID ARTHRITISClinical features: pauciarticular disease

40-60% of patients with JRA insidious onset morning irritability/stiffness subtle systemic symptoms: usually

absent large joints (rarely hip),

asymmetric involvement uveitis 20% subtypes

In pauciarticular juvenile idiopathic arthritis, four or fewer joints, usually those of the leg (and often the jaw), are affected by pain and swelling. The knee is the most common joint affected. The hip and shoulder are usually spared. Occasionally, a single toe, a finger, or a wrist becomes stiff and swollen.

JUVENILE RHEUMATOID ARTHRITISLaboratory Studies: Pauciarticular Disease

CBC: normal ESR: usually normal ANA: frequently positive RF: usually negative synovial fluid: class II

(inflammatory) x-ray findings: soft tissue swelling,

periarticular osteoporosis, growth disturbance, loss of joint space

Inflammation of the iris in the eye (iridocyclitis) can develop with any type of juvenile idiopathic arthritis, but most often iridocyclitis develops with pauciarticular juvenile idiopathic arthritis or polyarthritis. Iridocyclitis in juvenile idiopathic arthritis is asymptomatic (there is no pain or redness), but it can lead to permanent loss of vision if untreated.

FACTORS DETERMINING HIGHRISK OF UVEITIS (iridocyclitis) •Female •< 6 years of age •Pauciarticular •< 2 years duration

of arthritis •ANA present

JUVENILE RHEUMATOID ARTHRITISClinical features: polyarticular disease 30-40% of patients with JRA morning irritability/stiffness more

prominent systemic symptoms: mild to moderate large and small joints including cervical

spine, symmetric involvement uveitis 5% subtypes

polyarthritis

five or more (sometimes as many as 20 to 40) joints are affected. The inflammation usually affects the same joint on both sides of the body—for example, both knees or both hips. The jaw, neck joints, and wrists may be affected.

Inflammation may develop in the tendons and connective tissues around joints (tenosynovitis), causing pain, swelling, and warmth.

Rarely, generally in adolescents, small lumps (rheumatoid nodules) may form over the elbows, fingers, or toes

joints may be stiff when the child awakens. joints often become swollen and warm,

joints may become painful, but the pain may be milder than expected from the amount of swelling. Pain may become worse when the joint is moved. A child may be reluctant to walk or may limp. Joint pain persists for years if untreated.

any type of juvenile idiopathic arthritis can interfere with physical growth. Joint deformities may develop if untreated. When juvenile idiopathic arthritis interferes with growth of the jaw, a small chin (micrognathia) can result.

long-standing (chronic) joint inflammation can eventually cause deformities or permanent damage of the affected joint.

JUVENILE RHEUMATOID ARTHRITISLaboratory features: polyarticular disease

WBC , Hgb , platelets WNL to ESR to ANA may be positive RF may be positive Synovial fluid: class II

(inflammatory) X-ray findings: soft tissue swelling,

periarticular osteoporosis, joint space narrowing, erosions

JUVENILE RHEUMATOID ARTHRITISExtra-articular Manifestations

generalized or local growth disturbances

delayed puberty pericarditis, myocarditis, rarely

endocarditis plural effusion, rarely pneumonitis, pulmonary fibrosis hepatitis hematuria

Laboratory test for juvenile idiopathic arthritis.

The erythrocyte sedimentation rate is usually very high in the systemic form, less so in the polyarticular form, and usually normal in the pauciarticular form.

Rheumatoid factor and antinuclear antibodies, which are present in some people with rheumatoid arthritis and related diseases (for example, autoimmune diseases, such as lupus, polymyositis, or scleroderma).

Some children with juvenile idiopathic arthritis do not have rheumatoid factor or antinuclear antibodies in their blood. An adolescent with polyarticular juvenile arthritis and a positive test result for rheumatoid factor has a form of arthritis that is very similar to rheumatoid arthritis in adults.

Children with juvenile idiopathic arthritis who have antinuclear antibodies in their blood are at a higher risk of developing iridocyclitis. X-ray studies eventually may show characteristic changes in the bones or joints.

Children must be examined several times a year by an ophthalmologist for iridocyclitis regardless of whether symptoms are present. If the children have systemic juvenile idiopathic arthritis, then an annual eye exam suffices.

Synovial Fluid Analysis in JA

•Cloudy•Poor mucin clot, due to partialdegradation of hyaluronic acid •Leukocyte count > 2,000/cmm(2,000-50,000)> 50% neutrophils

1. Pauciarticular JA and Polyarticular (Factor negative)

– a. DR 8 (DRB1*0801) – b. DR 5 (DRB1*1101 and *1104) – c. DR 6 (DRB1*1301) – d. DP w2.1 (DPB1*0201)

2. Polyarticular Erosive Disease

– a. DQA1*0101 – b. DRB1*0101 – c. DPw3

3. Polyarthritis RF+ a. DR 4, Dw4 (DRB1*0401) b. DR4, Dw14 (DRB1*0404)

JUVENILE RHEUMATOID ARTHRITISTreatment

supportive not curative involves multidisciplinary team approach goals:

to suppress articular and/or systemic inflammation with as little risk as possible

to maintain function/prevent disabilities to foster normal psychological and social

development

heterogenity of disease mandates individualization

Medications in the Treatment of JRA

NSAID

intra-articular steroidssulfasalazine

hydroxychloroquine(auranofin)

methotrexate

(IM gold)(D-penicillamine)

etanercept azathioprine

cyclophosphamidecyclosporin

Pauci Articular NSAID

2-4 weeks

No response

Change NSAID (2-4 weeks)

No response Methotrexate

no response

Intra Articular Steroid

Poly Articular NSAID (2-4 weeks)

no response

Change NSAID (2-4 weeks)

no response 2 Methotrexate (10-15 mg/m/ week

Steroid ( Bridge therapy) Newer

drugs

Systemic Onset

Less severe disease

NSAIDs for 2 weeks. No response

Change NSAIDs( 2 weeks)

Oral steroids and taper

slowly

Life threatening/ severe features

Acute onset flare

Pulse steroid

MP( 30 mg/kg/day) x 3 days.

Oral steroid

Typically, nonsteroidal anti-inflammatory drugs (NSAIDs) are used, but children with severe systemic disease may require given by mouth or intravenously.

When corticosteroids ( 1.5 -2 mg/kg) are necessary, the lowest possible dose is used to decrease the chance of long-term complications such as slowed growth, osteoporosis, and osteonecrosis (death of bone tissue). If just a few joints are inflamed, doctors may inject corticosteroids directly into the joint.

NSAIDs Salicyclic acids ( aspirin ) Phenylacetic acid ( diclofenac) Carbo- and Heterocyclic Acid: *Etodolac Indomethacin, Sulindac, Tolmetic,

Ketorolac Propionic acids: Flurbiprofen,

Ketoprofen, Oxaprozin, *Ibuprofen, Naproxen, Fenoprofen

Fenamic acids: **Mefanamic Pyrazolones : *Phenylbutazone Oxicams : piroxicam, metoxicam Nabumetone

COX-2-selective inhibitors (Coxibs) Meloxicam Nimesulide *Celecoxib Rofecoxib Meloxicam Nimesulide Paracoxib Valdecoxib Deracoxib Etodolac Lumiracoxib Valdecoxib Deracoxib Etoricoxib

Sometimes, stronger drugs, such as methotrexate are used for pauciarticular juvenile idiopathic arthritis and are usually needed to treat polyarticular and systemic juvenile idiopathic arthritis. Side effects include bone marrow depression and liver toxicity, so children taking these drugs require regular blood tests.

Etanercept Some Trade Names ENBRELand infliximab Some Trade Names REMICADE drugs that block tumor necrosis factor (a protein involved in inflammation), are effective and have improved the outcome for children with juvenile idiopathic arthritis significantly. Systemic juvenile arthritis is often treated with anakinra, a drug that blocks the inflammatory protein interleukin 1.

Iridocyclitis is treated with corticosteroid eye drops or ointments, which suppress inflammation. If this treatment is not enough, methotrexate

Used in Treatment of JRA • Methotrexate • Arava (leflunomide) • Anti-malarial drugs – chloroquine – OH-chloroquine (Plaquenil) • Immunosuppressive drugs – cyclophosphamide – azathiaprine – Chlorambucil – Cyclosporin A • Gold salts oral or injectable • D-penicillamine Role of TNF- α in JA

Etanercept ENBREL infliximab REMICADE and adalimumab are TNF inhibitors and can be dramatically effective for people who do not respond sufficiently to methotrexate ENBRELis given once or twice weekly by injection under the skin, REMICADEis given by vein every 8 weeks after loading doses.

Adalimumab is injected under the skin once every 1 or 2 weeks. TNF is part of the body's immune system, so inhibition of TNF can impair the body's ability to fight infections. These drugs should be avoided in people who have active infections. Etanercept Some Trade Names ENBREL

infliximab Some Trade Names REMICADE, and adalimumab can be used with methotrexate .

IL-1 Receptor Antagonist(Anakinra, Kineret)

• Patients with RA were given IL-1ra sq daily

in varying doses ranging from 30mg to 115 mg/dose.

• By 24 weeks after onset, significant reductions in radiologic progression

were noted (using hand radiographs). • IL1ra was felt to be safe, and

effective.

Newer Therapies • Anti-T cell therapy – Abatacept (Monoclonal antibodies to CTLA4Ig (Cytotoxic T-

Lymphocyte Antigen 4) • Anti B cell therapy – Rituximab (antibodies directed

against CD20) • Therapy directed against innate immunity

– Leukotrienes and other inflammatory mediators • Antigen-specific immunosuppression

– Induction of tolerance – Analog peptide therapy

Along with drugs to reduce joint inflammation, a treatment plan for rheumatoid arthritis should include nondrug therapies, such as exercise, physical or occupational therapy, and sometimes surgical treatment. Inflamed joints should be gently stretched so they do not freeze in one position. As the inflammation subsides, regular, active exercises can help, although a person should not exercise to the point of excessive tiredness (fatigue; exercise in water may be easier.

JUVENILE RHEUMATOID ARTHRITISTreatment: physical measures

heat: analgesiamuscle relaxation

splinting: provide joint restmaintain functional positioncorrect deformities

exercise: passive, active assisted andactive range of motiongeneral conditioning

rest

JUVENILE RHEUMATOID ARTHRITISTreatment: education and supportive counseling

understand disease process, treatment and prognosis

understand roles in care as normal possible:

discipline/family life school peer relationships

counseling

JUVENILE RHEUMATOID ARTHRITISPoor Prognostic Signs

pauciarticular long duration of active disease conversion to polyarticular disease (30%) chronic uveitis

polyarticular long duration of active disease articular erosions RF positivity/rheumatoid nodules

systemic conversion to polyarticular disease (25-50%)

Pediatric Systemic Lupus Erythematosus

Systemic lupus erythematosus (disseminated lupus erythematosus, lupus) is a chronic inflammatory connective tissue disorder that can involve joints, kidneys, mucous membranes, blood, heart, lungs, CNS and blood vessel walls.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting multiple organ systems with protean manifestations.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by antinuclear antibody (ANA) production with widespread immune dysregulation, often resulting in multiorgan system inflammation. 15% of all lupus cases have onset in childhood

 Incidence rates among children younger than age 15 years have been reported to be 0.5-0.6 case per 100,000 persons. Prevalence rates of 4-250 cases per 100,000 persons 

ETIOPATHOGENY

The American Rheumatism Association (ARA) criteria were called “criteria for classification” as they were not meant to be exclusive or restrictive. The ACR’s ( American College of Rheumathology) diagnostic criteria for SLE include the following:Malar rashNaso-oral ulcersPhotosensitive rashDiscoid rashArthritisPleuritis or pericarditisProteinuria (>500 mg/d) or evidence of nephritis in urinalysisHemolytic anemia, thrombocytopenia, leukopenia, or lymphopeniaSeizure or psychosisPositive ANA findingPositive anti–double-stranded DNA, anti-Smith, or antiphospholipid antibody/lupus anticoagulantThe Systemic Lupus International Collaborative Clinics recently published a modification of the ACR criteria. Lupus patients meet 4 criteria with at least one clinical and one immunologic criterion or with biopsy-proven nephritis in association with positive ANA and anti-dsDNA

Symptoms

may develop gradually over months or years with episodes of fever, feeling unwell, or any of the symptoms discussed below alternating with periods when symptoms are absent or minimal.

Joint Problems: Joint symptoms, ranging from intermittent joint pains (arthralgias) to sudden inflammation of multiple joints (acute polyarthritis), occur in about 90% of people and may exist for years before other symptoms appear. In long-standing disease, marked joint deformity may occur (Jaccoud's arthropathy) but is rare. However, joint inflammation is generally intermittent and usually does not damage the joints.

Mucocutaneous Manifestations Frequency: 76%

Malar rash - butterfly-like redness Discoid lupus Vasculitis (purpura, petechiae) Raynaud’s phenomenon Nail involvement Alopecia Periungual erythema/ Livedo reticularis Photosensitivity Oral/ nasal ulcers

Acute malar rash

Pulmonary Findings In SLE

Incidence: 5-67% May be subclinical (abnormal PFTs) Pleuritis Pleural effusion Pneumonitis Pulmonary hemorrhage Pulmonary hypertension Restrictive lung disease & diffusion

defects most commonly observed abnormalities on PFTs

Cardiovascular Findings In SLE

Pericarditis Myocarditis Sterile valvular vegetations (rarely

clinically significant except for risk of bacterial endocarditis)

Arrhythmias Cor pulmonale Vasculitis (small vessels) Atherosclerosis/ Coronary Heart disease Dyslipoproteinemias

Lymph Node and Spleen

Wide-spread enlargement of the lymph nodes is common, particularly among children, young adults, and blacks of all ages.

Enlargement of the spleen (splenomegaly) occurs in about 10% of people. People may experience nausea, diarrhea, and vague abdominal discomfort

Neuropsychiatric Manifestations Of SLE

Frequency: 20-40% Difficult to diagnose and treat Second to nephritis as most common

cause of morbidity & mortality Can occur at any time; even at

presentation Standard lab examinations have not been

helpful in diagnosing or managing CNS sxs Imaging modalities are not specific enough

SLE patients have imaging abnormalities but are clinically normal

Neuropsychiatric Manifestations Of SLE

COMMON: Depression, organic brain syndrome, functional psychosis, headaches, seizures, cognitive impairment, dementia, coma

OCCASIONAL: Cerebral vascular accidents (thrombosis or vasculitis), aseptic meningitis, peripheral neuropathy, cranial nerve palsies

RARE: Paralysis, transverse myelopathy,chorea

Diagnosis Of CNS Lupus

CNS: CSF analysis shows pleocytosis; CT, MRI, MRA all may be normal or nonspecific

Autoantibodies (anti-neuronal, anti-cardiolipin, anti-ribosomal P) are not helpful

Vasculitis: CT, MRI, MRA may or may not be positive → conventional angiography

CVA (cerebrovascular accident ): CT, MRI often positive

Spectamine (PET) scans positive in mild, acute, or old disease

Neurocognitive testing Electroencephalography for seizures

Hematologic Findings In SLE

Leukopenia, especially lymphopenia Anemia

mild to moderate, common, due to chronic disease and mild hemolysis

severe, uncommon (5%), due to immune mediated hemolysis (Coombs +)

Thrombocytopenia mild 100-150K, common due to immune mediated

damage severe <20K, uncommon (5-10%),

immune mediated damage Bone marrow suppression/arrest--very rare,

due to antibodies against precursors

Coagulopathy In SLE

Hypocoagulable states: Anti-platelet antibodies--decreased numbers of

platelets or decreased function (increased bleeding time)

Other platelet dysfunction and thrombocytopenia Anti-clotting factor antibodies

Hypercoagulable states: Antiphospholipid Antibody Syndrome (APS): more

later Protein C and S deficiencies

Thrombotic thrombocytopenic purpura

GI INVOLVEMENT IN SLE

Mild LFT elevation--not significant clinically--BUT NEED TO EXCLUDE AUTOIMMUNE HEPATITIS

Colitis Mesenteric vasculitis Protein-losing enteropathy Pancreatitis Exudative ascites

Renal Findings In SLE

Most common cause of morbidity & mortality Glomerulonephritis – at least 75% Microscopic or gross hematuria Proteinuria, including nephrotic syndrome Hypertension Decreased GFR Renal failure (up to 30-50% of children prior

to 1980) Renal biopsy predictive of potential for renal

damage ISN/ RPS classification with NIH activity and

chronicity indices

Histological Classifications • WHO classification: – I normal – II Mesangiopathic – III Focal and segmental

proliferation – IV Diffuse proliferative – V Membranous – VI Advanced sclerosing

Laboratory Findings

Cytopenias (anemia, thrombocytopenia, leukopenia)

Elevated ESR, CRP, Immunoglobulins Hypoalbuminemia Proteinuria; RBCs, casts in urine Decreased creatinine clearance Low complement levels (C3/ C4) Autoantibodies (ANA, APL

(Antiphospholipid antibody), Coombs, anti-platelet Ab, rheumotoid factor, etc.)

(Immune complexes)

LABORATORY antinuclear antibodies. if antinuclear antibodies are detected,

antibodies to double-stranded DNA, other autoimmune antibodies (autoantibodies,

anti-smith antibodies. antibodies to phospholipids, can help

identify people at risk of recurrent blood clots.

blood tests can also indicate anemia, a low white blood cell count, or a low platelet count.

Antinuclear Antibodies (ANA) Sensitive but not specific, 95-98% pts positive Against nuclear components of the cell Titer specific- up to 10% of population have +ANA w/o

disease; also see with infections, medications, malignancy

Subtypes: dsDNA (Double-stranded (ds, native) DNA : high

specificity for lupus (over 80%) ENA (extractable nuclear antigen) = RNP/ Smith

ribonucleoprotein/Smith; RNP assoc w/ MCTD (Mixed connective-tissue disease), Smith specific for SLE

Ro/ La (SS-a/ SS-b): neonatal lupus, Sjogren’s Histone: drug induced lupus

Anti-C1q – Increase in anti-C1q correlates with proliferative GN • Others: Complement levels, ESR,

Hgb, renal function

MILD DISEASE: Rashes, arthralgias, leukopenia, anemia, arthritis, fever, fatigue Treatment: NSAIDs, low dose corticosteroids

(<60 mg/day), antimalarials (hydroxychloroquine), low dose methotrexate

MODERATE DISEASE: Mild disease + mild organ system involvement such as: mild pericarditis, pneumonitis, hemolytic anemia, thrombocytopenia, mild renal disease, mild CNS disease

SLE - Treatment

MODERATE DISEASE (cont.): Treatment: Prednisone 1-2 mg/kg/day,

NSAIDS, Antimalarials, Low dose methotrexate, Azathioprine, MMF

SEVERE DISEASE: Severe, life-threatening organ system involvement Treatment: High dose corticosteroids (2-3

mg/kg/day or pulse), Immunosuppressives (IV pulse Cyclophosphamide), Plasmapheresis, Anticoagulation where appropriate

SLE - Treatment

• Serositis is usually treated with a short course of low-dose steroids and a NSAID. If the serositis recurs when the steroids are discontinued, a steroid-sparing agent such as azathioprine or methotrexate is typically added to the treatment regimen. Hydroxychloroquine is beneficial in treating arthritis in SLE but may require several months before the maximal benefit is seen. Central nervous system (CNS) inflammation in childhood lupus requires aggressive therapy, often requiring high-dose steroids and cyclophosphamide

• Cytopenia in SLE usually responds to low- to moderate-dose corticosteroids; however, occasionally a child will present with acute hemolytic crisis that may require pulse intravenous (IV) corticosteroids to gain rapid control of the hemolytic process. The presence of antiphospholipid antibodies requires attention. The primary treatment in these patients is anticoagulation as antiphospholipid antibody levels are resistant to immunosuppressive or cytotoxic agents.

• The treatment of lupus nephritis varies depending on the renal lesion present.

• In mesangial disease, low-dose steroids are usually adequate. • Treatment of focal proliferative glomerulonephritis : moderate doses of

corticosteroids plus azathioprine. • The treatment of diffuse proliferative glomerulonephritis is in

transition. The current treatment of this serious renal lesion is sequential therapy designed to induce and then maintain disease remission with the goal of improving the rate of remission and at the same time minimizing the long-term toxicity of the treatment.

• The most common approach is to induce remission with monthly IV cyclophosphamide +high-dose corticosteroids (IV pulses followed by high-dose daily oral glucocorticoids) for 3 to 6 months, followed by a less-toxic treatment regimen to maintain remission.

• Maintenance therapy typically consists of either less-frequent (quarterly) IV cyclophosphamide or, more commonly, discontinuing cyclophosphamide and replacing it with either azathioprine or mycophenolate mofetil.

• Using this approach, renal outcomes have improved in diffuse proliferative glomerulonephritis (GN). Yet, despite the improvement in the treatment, many children with diffuse proliferative glomerulonephritis (DPGN) go on to end-stage renal disease (ESRD).

• Membranous lupus nephritis continues to be difficult to treat. This type of lesion is less responsive to immunosuppressive therapy and a substantial proportion of individuals with membranous disease develop nephrotic syndrome and ESRD. Despite the poor response to treatment, those individuals with membranous disease who develop nephrotic syndrome are treated with IV pulse cyclophosphamide and glucocorticoids

Management of Pediatric Systemic Lupus Erythematosus• General Use high-SPF sunscreen throughout the year.

• Encourage good sleep and nutritional patterns. • Address psychological aspects of

disease/treatment. • Prescribe calcium and vitamin D supplements

(especially if on corticosteroids). • Immunize against pneumococcus. • Treat with anticoagulant if evidence of

antiphospholipid antibody is present (agent depends on if the child has had a clot or not).

• Perform annual ophthalmologic evaluations (especially if on hydroxychloroquine).

• Treat dyslipoproteinemia when present. • Maintain good blood pressure control in those with

hypertension

• Noncytotoxic Nonsteroidal anti-inflammatory medications: – Prescribe for constitutional symptoms (arthralgia,

fatigue, malaise). – Avoid ibuprofen (associated with aseptic

meningitis in SLE).

• Use hydroxychloroquine (<6.5 mg/kg/day, not to exceed 400 mg/day) for: – Arthritis. – Cutaneous disease.

• Low-dose methotrexate may be useful with mild disease and when arthritis is a prominent feature.

• Glucocorticoids Use topical steroids for cutaneous disease.

• Use low-dose oral (< 0.5 mg/kg/day) for: – Arthritis. – Serositis. – Mild cytopenia.

• Use moderate-dose oral (0.5 to 1 mg/kg/day) for mild nephritis (mesangial, focal proliferative, membranous).

• Use high-dose oral (1 to 2 mg/kg/day) for: – Diffuse proliferative lupus nephritis and membranous

disease with nephrotic syndrome. – CNS disease. – Acute hemolytic anemia.

• Use pulse intravenous for: – Severe, life-threatening or organ-threatening

disease. – Severe, hematologic abnormalities. – Catastrophic antiphospholipid syndrome.

• Cytotoxic Azathioprine can be used as a steroid-sparing drug for: – Arthritis. – Serositis. – Following induction therapy with cyclophosphamide to

maintain remission. • Mycophenolate mofetil can be used as a steroid-sparing

drug, especially if patient does not tolerate azathioprine, for: – Following induction therapy with cyclophosphamide to

maintain remission. – Induction therapy in nephritis for patients who do not

want the toxicity associated with cyclophosphamide. • Cyclophosphamide is used for:

– Major renal involvement, particularly diffuse proliferative glomerulonephritis.

– CNS lupus. – Catastrophic antiphospholipid syndrome. – Other Use plasmapheresis for catastrophic

antiphospholipid syndrome. – Use IVIG for refractory thrombocytopenia. – Experimental Therapies* Anti-CD20 B-cell depletion

therapy. – Autologous stem cell transplantation. – CTLA4Ig.

SPECIAL CONSIDERATIONS IN CHILDREN AND ADOLESCENTS

Life-long burden of renal failure and (multiple) renal transplant(s)

Steroid toxicity Immunosuppressive toxicity Infection risk different in children:

CMV, EBV Bacterial infections, esp. strep Fungal infections

Developmental age and psychosocial issues

Henoch-Schönlein purpura (HSP) is an immunoglobulin (Ig) A-mediated small-vessel vasculitis that predominantly affects children but also is seen in adults. HSP is a subset of necrotizing vasculitis characterized by fibrinoid destruction of blood vessels and leukocytoclasis.

Henoch-Schönlein purpura, an uncommon disease, affects mainly young children, but it can affect older children and adults.

The disease is believed to result from an autoimmune reaction

Clinical manifestations primarily include palpable purpura, arthralgia or arthritis, abdominal pain, gastrointestinal (GI) bleeding, and nephritis. The most serious long-term complication from HSP is progressive renal failure, which occurs in 1-2% of patients.

Small bluish purple spots on their feet, legs, arms, and buttocks. Over several days, the purpura may become raised and hard; crops of new purpura may break out for several weeks after the first one appears.

Swollen, achy joints are common, usually accompanied by fever.

Bleeding in the digestive tract may cause abdominal cramps and pain.

Blood in the urine (hematuria) may develop.

Most children recover completely within a month, but symptoms may recur several times

The diagnosis is based on the symptoms. Sometimes a sample of affected skin is removed and examined under a microscope (biopsy) to confirm the diagnosis.

Treatment

A drug that may be causing an allergic reaction is discontinued immediately.

Corticosteroids (for example, prednisone ) may help relieve swelling, joint pain, and abdominal pain, but they do not prevent or reverse kidney damage. Drugs that reduce the activity of the immune system (immunosuppressive drugs), including azathioprine or cyclophosphamide, are sometimes used if kidney damage develops, but it is not known if they are helpful.

KAWASAKI DISEASE

Vasculitis of unknown etiology Multisystem involvement and

inflammation of small and medium sized arteries with aneurysm formation

More common among children of Asian decent

Usually children <5 years; peak 2-3 years

Kawasaki Disease

Mucocutaneous lymph node syndrome Disease of children Fever, conjuctivitis, red dry lips, erythema

of oral mucosa, polymorphous truncal rash, desquamation of the fingers and toes, cervical lymphadenopathy

Oral cavity erythema and cervical adenopathy are presenting symptoms

Cardiac abnormalities cause 1-2% mortality rate

KAWASAKI DISEASE

In children < 3 months of age Usually see atypical course leading to rapid and

severe coronary artery damage (CAD) ECHO mandatory if considered in this age

group; diagnosis very difficult Age is independent risk factor for CAD CAD develops in 5% of timely treated

patients Incomplete/atypical definition

Fever, at least 2 of the clinical criteria for KD, and laboratory data showing systemic inflammation; 2D echos should be performed

KAWASAKI DISEASE

Prolonged fever is hallmark of the disease Lymphadenopathy is least common

finding (seen in 75% of cases compared with 90% for other signs)

Coronary lesions are usually not present until 10 days; therefore decision to treat made prior to knowledge of cardiac outcome

Other useful signs Extreme irritability Inflammation of BCG scar

KAWASAKI DISEASE – CLINICAL PRESENTATION

Acute phase (1-2 weeks) Sudden onset of high fever followed by

conjunctival erythema, mucosal changes, cervical adenopathy, swelling of hands and feet

Irritability Abdominal pain, hydrops of gall bladder Arthritis Carditis – tachycardia, CHF, giant

coronary artery aneurysms

KAWASAKI DISEASE – CLINICAL PRESENTATION

Subacute phase Lasts up to 4th week Resolution of fever and other symptoms Desquamation of fingers and toes Elevation of platelet count Coronary artery aneurysms

Convalescent phase Disappearance of clinical symptoms 6-8 weeks after initial symptoms

CLINICAL DIAGNOSIS

Kawasaki Disease

A self-limited vasculitis of unknown etiology that predominantly affects children younger than 5 years. It is now the most common cause of acquired heart disease in children in the United States and Japan

Idiopathic multisystem disease characterized by vasculitis of small & medium blood vessels, including coronary arteries

Epidemiology

Median age of affected children = 2.3 years

80% of cases in children < 4 yrs, Males:females = 1.5-1.7:1 Recurs in 3% Positive family history in 1% but 13%

risk of occurrence in twins Overall U.S. in-hospital mortality ≈

0.17%

Etiology

Age-restricted susceptible population Seasonal variation Well-defined epidemics Acute self-limited illness similar to known

infections Bacterial, retroviral, superantigenic bacterial

toxin Immunologic response triggered by one of

several microbial agents

Diagnostic Criteria

• Fever for at least 5 days • At least 4 of the following 5 features:

1. Changes in the extremities Edema, erythema, desquamation

2. Polymorphous exanthem, usually truncal3. Conjunctival injection4. Erythema&/or fissuring of lips and oral

cavity5. Cervical lymphadenopathy

• Illness not explained by other known disease process

DIFFERENTIAL DG

Infectious Measles & Group A beta-

hemolytic strep can closely resemble KD

Bacterial: severe staph infections w/toxin release

Viral: adenovirus, enterovirus, EBV, roseola

• Infectious– Spirocheteal: Lyme disease, Leptospirosis– Parasitic: Toxoplasmosis– Rickettsial: Rocky Mountain spotted fever,

Typhus• Immunological/Allergic

– JRA (systemic onset)– Atypical ARF– Hypersensitivity reactions– Stevens-Johnson syndrome

• Toxins– Mercury

PHASES OF DISEASE

Acute (1-2 weeks from onset) Febrile, irritable, toxic appearing Oral changes, rash, edema/erythema of

feet Subacute (2-8 weeks from onset)

Desquamation, may have persistent arthritis or arthralgias

Gradual improvement even without treatment

Convalescent (Months to years later)

ANGULAR CHELITIS

STRAWBERRY TONGUE

CONJUNCTIVAL HYPEREMIA

ERYTHEMATOUS MACULAR ERUPTION - KAWASAKI SYNDROME

DESQUAMATION OF THE SKIN

• Respiratory– Rhinorrhea, cough, pulmonary infiltrate

• GI– Diarrhea, vomiting, abdominal pain,

hydrops of the gallbladder, jaundice• Neurologic

– Irritability, aseptic meningitis, facial palsy, hearing loss

• Musculoskeletal– Myositis, arthralgia, arthritis

Kawasaki Disease: Lab TESTSEarly

LeukocytosisLeft shiftMild anemiaThrombocytopenia/ ThrombocytosisElevated ESRElevated CRPHypoalbuminemiaElevated transaminasesSterile pyuria

LateThrombocytosisElevated CRP

Cardiovascular Manifestations of Acute Kawasaki Disease EKG changes

Arrhythmias Abnormal Q waves Prolonged PR and/or QT intervals Low voltage ST-T–wave changes.

CXR–cardiomegaly

None Suggestive of myocarditis (50%)

Tachycardia, murmur, gallop rhythms Disproportionate to degree of fever &

anemia Suggestive of pericarditis

Present in 25% although symptoms are rare

Distant heart tones, pericardial friction rub, tamponade

Echocardiography

Myocarditis with dysfunction Pericarditis with an effusion Valvar insufficiency Coronary arterial changes

Coronary Arterial Changes 15% to 25 % of untreated

patients develop coronary artery changes

3-7% if treated in first 10 days of fever with IVIG

Most commonly proximal, can be distal Left main > LAD > Right

• Patients most likely to develop aneurysms Younger than 6 months, older than 8

years Males Fevers persist for greater than 14 days Persistently elevated ESR Thrombocytosis Pts who manifest s/s of cardiac

involvement

Cardiovascular Sequelae

0.3-2% mortality rate due to cardiac disease 10% from early myocarditis

Aneurysms may thrombose, cause MI/death

MI is principal cause of death in KD 32% mortality Most often in the first year Majority while at rest/sleeping About 1/3 asymptomatic

• IVIG: 2g/kg as one-time dose– Beneficial effect 1st reported by

Japanese– Mechanism of action is unclear

• Aspirin– High dose (80-100 mg/kg/day) until

afebrile x 48 hrs &/or decrease in acute phase reactants

– Decrease to low dose (3-5 mg/kg/day) for 6-8 weeks or until platelet levels normalize

Juvenile dermatomyositis (JDM) is an inflammatory disease of the muscle (myositis), skin and blood vessels that affects about 3 in 1 million children each year

idiopathic inflammatory myopathy

PATHOGENESIS

• pathogenetic mechanisms involved in the myopathy

• recent studies reveal abnormal levels of nitric

oxide, elevation of circulating tumor necrosis factor (TNF) receptors, elevated soluble CD40 expression, and increased expression of major histocompatibility complex class I and interleukin 1a within the muscle.

• the pathogenesis of the cutaneous disease is poorly understood.

CLINICS

• violet‐colored or dusky red rash, most commonly on the face, eyelids, and areas around the nails, knuckles, elbows, knees, chest and back. The rash, which can be patchy with bluish‐purple discolorations, is often the first sign of dermatomyositis

• skin rashes that range from mild redness to severe ulcers

Gottron’s papules are found over bony prominences, particularly the metacarpophalangeal joints, the proximal

interphalangeal joints, and/or the distal interphalangeal joints

They may also be found overlying the elbows, knees, and/or feet. Photosensitivity

• weakness in the large muscles around the neck,

shoulders and hips.• difficulty in climbing stairs, getting into cars,

getting up from a chair or off the floor, or brushing hair.

• symptoms range from minimal muscle weakness, including falling when running and having to turn over to out of bed, to not being able to swallow and changes in the voice ; dysphagia or dysphonia generally signifies a rapidly progressive course and may be associated with poor prognosis.

• fatigue, fever and weight loss• hardened deposits of calcium under the skin • stomach ulcers and intestinal tears • lung problems • occur in children ages 5 ‐10 and adults ages 40‐50.

Women are affected about twice as often as men.

Dermatomyositis is a multisystem disorder . Arthralgias and/or arthritis The usual picture is one of

generalized arthralgias accompanied by morning stiffness.

The small joints of the hands, wrists, and ankles may be involved with symmetrical non-deforming arthritisthat is non-erosive.

• Esophageal disease as manifested by dysphagia is estimated to be present in 15% to 50% of patients with inflammatory myopathy. The dysphagia can be of 2 types: proximal dysphagia or distal dysphagia

• Pulmonary disease occurs in DM and PM in approximately 15% to 65% of patients.40-43 Interstitial pneumonitis is a primary process observed in DM

• Calcinosis of the skin or muscle may occur in up to 40% of children or adolescents with DM.

• Calcinosis cutis is manifested by firm, yellow, or fleshcolored nodules, often over bony prominences. Occasionally these nodules can extrude through the surface of the skin, in which case secondary infection may occur.

• Calcification of the muscles is often asymptomatic and

• may be seen only on radiologic examination. In severe

forms, the calcinosis can cause loss of function, and, rarely bone formation is possible.

The reported frequency of malignancy

in DM has varied from 6% to 60% Increased association of ovarian

cancer, but also noted increases in lung, pancreatic, stomach, colorectal cancer, and non-Hodgkin’s lymphoma.

Laboratory manifestations of dermatomyositis • 1. Muscle enzyme elevation (CPK, serum aldolase, LDH,

ALT, AST, carbonic anhydrase isoenzyme II) • 2. Autoantibodies • i. ANA levels elevated in 60 to 80% of patients with

classic dermatomyositis • ii. Anti-Jo-1 most common antisynthetase found; 20% of

patients with dermatomyositis may have positive result • iii. Anti-EJ may be more associated with typical skin

lesions • iv. SRP occurring in 5% patients • v. Mi-2 antibodies (a nuclear protein complex):

occurring in 15 to 20% of patients with classic dermatomyositis, associated with a more treatment-responsive form, shawl sign and prominent cuticular changes

• vi. Anti-PM-Scl antibodies associated

• vii. Anti-Ku antibodies associated with overlap of scleroderma or SLE with dermatomyositis.

• 3. ESR • It is elevated in approximately 50% patients (does not correlate well with

disease activity). • 4. Rheumatoid factor • It is seen in 20% patients, mostly in those with overlap syndrome. • 5. von Willebrand factor • It is reported to correlate with juvenile dermatomyositis. • 6. EMG • There is myopathic pattern, 10% are false-negative. • 7. Magnetic resonance imaging • It is useful for assessing the presence of an inflammatory myopathy in patients

without weakness. It is also useful in differentiating steroid myopathy from continued inflammation and may serve as a guide in selecting a muscle biopsy site.2,3,4,5,6

Anti–Jo-1 antibody (and the 6 other antisynthetase autoantibodies) is predictive of pulmonary involvement and is much more common in patients with PM than in those with DM. Anti–Mi-2 occurs in roughly 25% to 30% of patients with DM

The anti–155-kd antibody may also be associated with juvenile DM and might predict a chronic course. Anti-Ro (SS-A) antibody may occur rarely. When other antibodies such as PM-SCL or U1-RNP are present, an overlap syndrome is suggested

POSITIVE DIAGNOSIS

(1)progressive proximal symmetrical weakness,

(2) elevated muscles enzymes, (3) an abnormal electromyogram, (4) an abnormal muscle biopsy (5) presence of compatible

cutaneous disease. DM differed from PM only by the

presence of cutaneous disease

THERAPY

• Different systemic medications used in dermatomyositis

• Oral corticosteroids 0.5 to 1.5 mg/kg daily until serum CK normalizes, then slowly taper over 12 months Consider adjunctive therapy if no improvement in objective muscle strength after three months of therapy

• Methotrexate Oral: 7.5 to 10 mg/week, increased by 2.5 mg/week to total of 25 mg/week

• Intravenous: 10 mg/week, increased by 2.5 mg/week to total of 0.5 to 0.8 mg/kg First-line adjuvant therapy in patients unresponsive to steroids

• Azathioprine 2 - 3 mg/kg/day tapered to 1 mg/kg/day once steroid is tapered to 15 mg/day Screen patients for thiopurine methyltransferase deficiency before therapy

•

• Cyclophosphamide Oral: 1 -3 mg/kg/day Intravenous: 2 -4 mg/kg/day, in conjunction with prednisone In refractory cases only

• Hydroxychloroquine 200 mg twice daily in adults; 2-5 mg/kg/day in children

• Intravenous immunoglobulin 2 g per kg in divided doses once per month for 3 months

Diet Physical therapy Skin protection Speech therapy

• Fludarabine • It prevents the development and growth of

malignant cells. • Tacrolimus • This transplant rejection drug may work to inhibit

immune system. • Monoclonal antibodies • These are man-made antibodies designed to target

and destroy specific types of cells. • Prognosis • The disease may spontaneously remit in 20% of

patients. 5% of patients have fulminant progressive course with eventual death. Many patients require long-term therapy.2,3

• 40