RHEUMATIC FEVER.

RHEUMATIC FEVER

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.

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 Area Prevalence/1000

RF occurs 1-5wks after streptococcal throat infection avg is 3 wks
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 1,3,5,6,14,12,18,19,24,27,29
Nephritogenic serotypes 12 , 49

structure Capsule hyaluronic acid Cellwall
Outer –fimbria+lipoteichoic acid+M protein Middle-carbohydrate Inner-peptidoglycan layer Cytoplasmic membrane

Autoimmune disease; Antigenic mimicry
Antibodies 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 phagocytosis Crossreactivity- cytoskeleton, tropomyosin and myosin. Group specific polysaccharide wall -> glycoprotein of cardiac valves Antibodies to the streptococcal peptidoglycan complexes have been implicated in rheumatic arthritis Somatic antigens of the cell wall & cell membrane -> myocardial sarcolemma ,vascular initima and skin In 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

Previous RF or RHD ( rheumatoid heart disease)
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%

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

QRS-T changes s/o Myocarditis
Acute phase reactants Raised ESR Elevated CRP ECG Prolonged PR interval Tachycardia AV block QRS-T changes s/o Myocarditis s/o = significant other

Echocardiography Helpful to diagnose silent carditis More sensitive than clinical examination 30% cardiac involvement in patients without clinical carditis

TREATMENT Acute 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. Lac = one hundred thousand

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

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

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 mg BD PO Sulfadiazine <27kg mg OD PO >27kg mg Penicillin/ sulfa allergy Erythromycin mg BD PO

Duration of secondary prophylaxis
Category Duration RF with carditis & residual valvular lifelong RF with carditis yrs or well into but no residual adulthood valvular disease RF without yrs 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, 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 ARTHRITIS Etiology and Pathogenesis
unknown combination of factors environment (infection, trauma, stress) autoimmunity immunogenetic

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) Pathology

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.

ANCILLARY MANIFESTATIONS 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)

Juvenile Idiopathic Arthritis (JIA) Systemic Polyarticular RF+
IMPORTANT ! ILAR Classification Criteria (International League of Associations for Rheumatology) Juvenile Idiopathic Arthritis (JIA) Systemic Polyarticular RF+ Polyarticular RF- Oligoarticular persistent extended Psoriatic arthritis Enthesitis-related arthritis Other arthritis

JUVENILE RHEUMATOID ARTHRITIS Clinical 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 ARTHRITIS Laboratory studies: systemic disease
WBC   , Hgb , platelets  to  , ESR   to    ANA and RF usually negative x-rays : soft tissue swelling

JUVENILE RHEUMATOID ARTHRITIS Clinical 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 ARTHRITIS Laboratory 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 HIGH RISK OF UVEITIS (iridocyclitis)
•Female •< 6 years of age •Pauciarticular •< 2 years duration of arthritis •ANA present

JUVENILE RHEUMATOID ARTHRITIS Clinical 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.

WBC , Hgb , platelets WNL to  ESR  to   ANA may be positive
JUVENILE RHEUMATOID ARTHRITIS Laboratory 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 WNL= with normal limits

JUVENILE RHEUMATOID ARTHRITIS Extra-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 partial degradation 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 ARTHRITIS Treatment
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 steroids sulfasalazine hydroxychloroquine (auranofin) methotrexate (IM gold) (D-penicillamine) etanercept azathioprine cyclophosphamide cyclosporin

Pauci Articular NSAID 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 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 ( 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 Paracoxib Valdecoxib Deracoxib Etodolac Lumiracoxib 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 ENBREL and 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 ENBREL is given once or twice weekly by injection under the skin, REMICADE is 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 ARTHRITIS Treatment: physical measures
heat: analgesia muscle relaxation splinting: provide joint rest maintain functional position correct deformities exercise: passive, active assisted and active range of motion general conditioning rest

understand disease process, treatment and prognosis
JUVENILE RHEUMATOID ARTHRITIS Treatment: 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 ARTHRITIS Poor Prognostic Signs
pauciarticular long duration of active disease conversion to polyarticular disease (30%) chronic uveitis polyarticular 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 case per 100,000 persons. Prevalence rates of 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 rash Naso-oral ulcers Photosensitive rash Discoid rash Arthritis Pleuritis or pericarditis Proteinuria (>500 mg/d) or evidence of nephritis in urinalysis Hemolytic anemia, thrombocytopenia, leukopenia, or lymphopenia Seizure or psychosis Positive ANA finding Positive anti–double-stranded DNA, anti-Smith, or antiphospholipid antibody/lupus anticoagulant The 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.

Arthritis of MCP, PIPs; digital vasculitis; periungual erythema.

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 Rashes are common and varied!

Systemic lupus erythematosus: malar rash, face
This young girl shows the characteristic malar rash seen in all forms of lupus. The rash tends to spare the eyelids and nasolabial

Systemic lupus erythematosus: acute facial rash
An acute malar rash with crusting is demonstrated in this 13-year-old girl with systemic lupus erythematosus. 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 Pleuritis: uni or bilateral pleuritis chest pain, exacerbated by deep inspiration. Pleural effusions usu small volume, can by asx. Pnuemonitis: pulm infiltrates, atelectasis, rales occurs in 10-15% of SLE children. Pulm hemorrhage: chest pain, hemoptysis, pallor, anemia. pHTN resulting from pulm hemorrhage or PE’s from antiphospholipid syn.

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 Pericarditis is the most common cardiac manifestation of SLE, 30% of children with acute dz…may be clinically silent, or represented by chest pain worsened by lying down or deep breathing, relieved by sitting up and leaning forward. Worry of the rare complication of pericardial constriction or tamponade. Myocarditis occurs in 10-15% of SLE children…CHF, cardiomegaly, arrhythmias, narrow pulse pressure, tachycardia in the absence of fever- get EKG. Valvulitis: classic cardiac lesion of SLE is Libman-Sacks endocarditis, is less common in children than in adults. Often subclinical, it is a sterile nodule of fibrinoid necrosis of the collagenous tissue of the valve, MV> AO>PV>TV.

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 50% of SLE pts have some evidence of CNS dz at onset. 40% of SLE pts has onset of CNS dz in first year of dz, or manifestations may appear many yrs later.

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 Depression: very common, hard to tease out from regular adol depression, worries about dz/ side effects/ appearance. Emotional lability, difficulty concentrating and remembering. Organic brain syndrome: disorientation, memory loss and progressive intellectual deterioration- grave prognostic sign. Psychosis: hallucinations, paranoia. Cognitive impairment: failing academically, lower IQ scores. Headache: many causes. Vascular migraine-like headaches are more freq in SLE pts than in controls. Sz: GTC usu. CVA: may occur independently or with venous sinus thrombosis or cerebral vein thrombosis; may be associated with HTN, antiphospholipid-related thrombosis or IVH 2/2 low plts.

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 Vasculitis imaging: hard to look at small vessels

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 K, 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 Leukopenia, esp lymphocytopenia (<1500 cells/ mm3), is a hallmark of acute SLE.

Coagulopathy In SLE Hypocoagulable states: Hypercoagulable 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 Lupus anticoagulant: PTT and PT prolonged, presence of an antibody (antiphospholipid ab) that acts at the junction of the extrinsic and intrinsic pathways (conversion of prothrombin to thrombin by thromboplastin is inhibited). Another antiphospholipid is responsible for the false-positive serologic test for syphilis. TTP: anemia, pupura, fever, changing CNS signs, nephritis, leukocytosis, MAHA, similar to HUS in children.

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 Renal involvement in children is more frequent and of greater severity than in adults. Significant renal disease usually develops within 2 yrs after onset of disease (although we do see it at onset), but occasionally appear many years later. WHO Classification: I:no dz, II: mesangial change, III: focal, segmental glomerulonephritis, IV: diffuse proliferative glomerulonephritis, V: membranous GN, VI: glomerular scerosis. 2004: revised ISN/ RPS classification

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) Acute phase indices of inflammation are increased: ESR, polyclonal hypergammaglobulinemia. CRP is often normal in SLE, increased in SLE c/b infection, serositis, arthritis. Ferritin increased. Factor VIII-related antigen= vWF increased. Low levels IL-1, high IL-6, high TNF-alpha. Can measure specific complements C3, C4, or total CH50 (total complement cascade, both classic or alternative pathways). C3 is depressed less often than the CH50 or C4.

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 Titer specific: low in inactive dz, to high in active dz. Peripheral or homogeneous pattern suggests anti-dsDNA ab. Speckled: Anti-RNP. dsDNA virtually pathognomonic of SLE, rarely associated with other rheumatic diseases. Patients with SSB almost always have SSA, although the converse is not true. Anti Sm ab found more freq in Af Am than in Caucasians. Anti U1 RNA (spliceosome components)= Anti RNP

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

SLE - Treatment 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: chronic dz, characterized by remissions and relapses, assoc with considerable morbidity and mortality. Tx aimed at chronic maintenance meds, meds used to treat acute flares, and meds to prevent long term side effects. Tx itself also assoc with morbidity. General supportive care: sunblock, vaccinations (SLE pts: functional asplenia, give pneumoccocal vaccine), nutrition. NSAIDs: to tx musculoskeletal complaints (ex: naprosyn). Rare side effect of NSAIDs: aseptic meningitis. Antimalarials: hydroxychloroquine- adjunct to tx, rather than a mainstay of treatment. Ophtho exams q6m for retinal toxicity. Steroids: mainstay of treatment. Low dose is defined as 0.5 mg/kg/day in divided doses po.

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 Severe dz examples: severe hemolytic anemia, CNS disease, lupus nephritis, lupus crisis. Pulse dose 30 mg/kg/day IV x 3 days up to 1 g IV q24h. Contraindications to high dose steroids include HTN, uremia, preexisting psychosis. Failure of high dose prednisone to result in substantial improvement in clinical, serologic, and urinary abnormalities within 8 wks should prompt consideration of alternative therapies. Also, start other second line agents if too many steroid side effects (steroids are first line agents). Immunosuppressives (second line): cytoxan, azathrioprine, mtx, cyclosporin a. Azathioprine: help in management of steroid-resistant or steroid-dependent dz without class III, IV nephritis. MTX: experience with MTX in pedsSLE limited and controversial. CSA: controversial. Mycophenolate Mofetil: for lupus nephritis…studies underway.

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: 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

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
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

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 Recurs in 3% Positive family history in 1% but 13% risk of occurrence in twins Overall U.S. in-hospital mortality ≈ 0.17% Kawasaki disease is virtually unheard of in children older than 15 years of age.

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 A number of each of these has been implicated in individual cases or clinical series but typically data are conflicting. A variant strain of Propionibacterium acnes with dust mites playing a role as vectors has been proposed as the causative agent by several investigators but no causative link has been established despite multiple investigations.

Diagnostic Criteria Fever for at least 5 days
At least 4 of the following 5 features: Changes in the extremities Edema, erythema, desquamation 2. Polymorphous exanthem, usually truncal 3. Conjunctival injection 4. Erythema&/or fissuring of lips and oral cavity 5. 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

Immunological/Allergic
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 GI Neurologic Musculoskeletal
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 TESTS
Early Leukocytosis Left shift Mild anemia Thrombocytopenia/ Thrombocytosis Elevated ESR Elevated CRP Hypoalbuminemia Elevated transaminases Sterile pyuria Late Thrombocytosis

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

Suggestive of myocarditis (50%)
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

Younger than 6 months, older than 8 years Males
• 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 ( 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)

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 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 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

RHEUMATIC FEVER.

Similar presentations

Presentation on theme: "RHEUMATIC FEVER."— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

RHEUMATIC FEVER.

Similar presentations

Presentation on theme: "RHEUMATIC FEVER."— Presentation transcript:

Similar presentations

About project

Feedback