Collagen Vascular Disease

in Children

Roy Maynard, M.D.

September 22, 2011

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Objectives

• Define collagen vascular disease.

• Identify 3 collagen vascular diseases

that affect children.

• Understand the role new biological

modifying agents have on treating

collagen vascular disease.

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Definition

• A diverse group of multi-system inflammatory disorders, affecting primarily collagen in the skin and joints. Autoantibody formation and other autoimmune dysfunction suggest a complex immune basis in the pathogenesis of the disease process which remains largely idiopathic

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Classification

• Vasculitis

• Arthritides

• Connective tissue disease

• Infectious diseases

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Collagen Vascular Disease

• Systemic Lupus Erythematous

• Dermatomyositis

• Scleroderma

• Juvenile Idiopathic Arthritis

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Epidemiology

• 150-200 children/million

• 0.015 to 0.02% of children

• Female preponderance

• Fairly uncommon disease in children

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Pathogenesis

• Molecular mimicry: Infectious agents alter the surface markers of ones own cells leading to them being recognized as foreign by your immune system.

• Autoimmunity: Idiopathic alterations in the basic immune system leading to the recognition of cells and tissues as foreign and subsequently attack as foreign.

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Treatment

• Glucocorticsteroids

• Immunosuppressives

• Immunomodulators

• Anti-inflammatory

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Systemic Lupus Erythematosus

• Diagnosis

– Malar rash

– Discoid rash

– Photosensitivity

– Oral ulcers

– Arthritis

– Serositis (pleural or pericardial)

– Renal (proteinuria)

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Systemic Lupus Erythematosus

Malar rash

http://www.emedicinehealth.com/script/main/art.asp?articlekey=107976 Accessed on 9/19/11

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Systemic Lupus Erythematosus

• Epidemiology

– 0.36 to 0.4 children/100,000

– Girls/boys (4:2 to 7:1)

– Rare diagnosis before age 5

– Peaks young adulthood

– 15-20% of adults started disease in childhood

– Age 12 to 14 years when disease diagnosed

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Systemic Lupus Erythematosus

• Diagnosis

– Neurologic (seizures or psychosis)

– Hematologic

• Hemolytic anemia

• Leukopenia

• Lymphopenia

• Thrombocytopenia

– Immunologic disorder

• Positive LE prep

• Anti-dsDNA antibody

• Anti-Smith antibody

• False positive syphilis test

• Antinuclear antibody, C3 and C4

– Other organs

• Kidneys, lungs, cardiac

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Systemic Lupus Erythematosus

• Prognosis

– In 1950, only 30% survived 5 years

– Now 5-year survival > 90%

– Pediatric SLE has a worse prognosis than adult SLE

– Risk factors for poor outcome include kidney disease, frequent flares, infections, neuropsychiatric manifestations

– Lower physical and psychosocial than healthy children

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Systemic Lupus Erythematosus

• Treatment

– Hydroxychloroquine

– Azathioprine

– Glucocorticoids

– NSAID

– Chemotherapeutic agents • Methotrexate, Cyclophosphamide

– IVIG

– Biologicals - rituximab

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Dermatomyositis

• Autoimmune disease

• Primarily affects skin and muscle

• Incidence: under age 16, affects 3,000-5,000 children in U.S. 3 new cases per year/million people

• Average age of onset is 7 (ages 5 – 10)

• Found worldwide, more prevalent in North America

• May be more common in African-Americans

• Adult version presents age 50

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Dermatomyositis

• Etiology idiopathic

• Combination of genetics and infection

• May be partially inherited (genetic

predisposition to acquire the disease)

• Not contagious

• More common in females than males

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Dermatomyositis

• Signs and symptoms:

– Fever

– Fatigue

– Skin rash

– Muscle weakness

– Pain

– Lung disease

– Joint contractures

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Dermatomyositis

Heliotrope rash

http://www.pediatricsconsultantlive.com/pedsquiz/content/article/1803329/1691415 Accessed on 9/20/11

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Dermatomyositis

• Diagnosis:

– Clinical diagnosis

– Increased CPK, aldolase, SGOT

– MRI of involved muscles

– Muscle biopsy

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Dermatomyositis

http://www.learningradiology.com/caseofweek/caseoftheweekpix2006/cow207lg.jpg Accessed on 9/20/11

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Dermatomyositis

http://www.nlm.nih.gov/medlineplus/ency/imagepages/1866.htm Accessed on 9/20/11

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Dermatomyositis

• Treatment:

– Prednisone

– Methotrexate

– Hydroxychloroquine

– Cyclosporine

– IVIG

– Mycophenolate

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Dermatomyositis

• Prognosis:

– Most children go into remission within 2 years

– Pulmonary involvement heralds poor prognosis

– Increased risk for malignancy

– Joint contractures are a long term complication

– Some do not respond well to medications

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Scleroderma

• Autoimmune disease

• Normal tissues replaced with dense, thick scar tissue

• Skin most common site

• Kidneys, heart, lung, GI tract

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Scleroderma

• 5,000 – 7,000 children in U.S.

• Only 1.5% develop disease before age 10

• 7% develop disease between age 10 to 19

• 2/3 are female

• Immune system triggers other cells to produce excessive collagen

• Idiopathic

• Not contagious

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Pediatric Scleroderma

• Two types:

– Localized scleroderma

• Skin (linear and morphea)

– Systemic scleroderma

• multiple organs

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Pediatric Scleroderma

• Localized Scleroderma:

– Most common form in children

– Usually skin only, occasionally underlying muscle

– Linear type appears as a band usually on

extremities, may limit motion when crosses a joint

– Morphea type - patches, waxy skin with an ivory or

white color

– Both appear white with purple borders

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Scleroderma

• Signs and symptoms:

– Loss of stretch in skin

– Discoloration of skin

– Thinning of the skin

– Contractures of fingers

– Joint inflammation

– Raynaud’s phenomenon

– Ulcers on fingertips

– Dysphagia and other GI tract problems

– Fatigue, muscle weakness

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Scleroderma

http://www.skinpatientalliance.ca/en/skin-conditions-diseases/connective-tissue-disorders Accessed on 9/20/11

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Scleroderma

• Diagnosis:

– Clinical diagnosis

– Skin biopsy

– Autoimmune blood testing

– Swallow study

– Lung testing

– Cardiac echo

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Linear Scleroderma

http://bjo.bmj.com/content/91/10/1311/F1.large.jpg Accessed on 9/20/11

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Scleroderma

• Treatment:

– Prednisone

– Methotrexate

– NSAID

– Environmental

– Physical therapy

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Scleroderma

• Prognosis:

– Chronic and slowly progressive

– Months to years

– Localized vs. systemic

– May stabilize without progression for years

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Juvenile Idiopathic Arthritis

• Clinical manifestations: – Fever

– Rash

– Serositis

– Joint involvement pain, swelling, stiffness, limping

– Growth delay/weight loss

– Psoriasis

– Uveitis, eye pain, vision disturbances

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Juvenile Idiopathic Arthritis

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idiopathic-arthritis/&docid=L5cA1hDwO1EF4M&w=200&h=114&ei=gwN5TvKEJ8Watwey0cT2Dw&zoom=1&biw=1440&bih=730&ia

ct=rc&dur=225&page=1&tbnh=91&tbnw=160&start=0&ndsp=20&ved=1t:429,r:12,s:0&tx=89&ty=61)

Accessed on 9/19/11

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Juvenile Idiopathic Arthritis

• Diagnosis: – >6 weeks of arthritis

– Less than 16 years of age

– Unknown cause R/O Lyme’s, infection, Kawasaki’s Disease, immunodeficiency

• Epidemiology: – Most common childhood chronic rheumatic

disease

– Incidence: 2-20 cases/100,000

– Prevalence: 16-150/100,000

– 0.07–4.01 per 1,000 children worldwide

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Juvenile Idiopathic Arthritis

(ROY—CLARIFY WEBSITE REFERENCE FROM ORIGINAL SLIDE #38)

Accessed on 9/19/11

http://trialx.com/curetalk/wp-content/blogs.dir/7/files/2011/05/diseases/Juvenile_Idiopathic_Arthritis-1.jpg Accessed on 9/20/11

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Juvenile Idiopathic Arthritis

Drug Des Devel Ther. 2011; 5:61-70

• Systemic 5-10

• Oligoarthritis 40-50 – Persistent 25-35 – Extended 15-20

• Polyarthritis 30-40 – Rheumatoid factor neg 25-35 – Rheumatoid factor pos 5

• Psoriatic arthritis 5-10

• Other 15-20

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Juvenile Idiopathic Arthritis

IMAGE 1: http://images.rheumatology.org/image_dir/album75693/md_99-06-0019.tif.jpg

IMAGE 2: http://www.google.com/imgres?imgurl=http://www.ajronline.org/content/vol185/issue2/images/large/00_04_1385_07a.jpeg&imgrefurl=http://www.ajronline.org/cgi/content-nw/full/185/2/522/FIG17&usg=__M1LQ2tyC2JT86hM8wz41fj-SGpk=&h=1800&w=1037&sz=257&hl=en&start=23&zoom=1&tbnid=aRD8JZwu9_P_6M:&tbnh=150&tbnw=86&ei=e-pfTqadMYi3twf8v6imCw&prev=/search%3Fq%3Djuvenile%2Bidiopathic%2Barthritis%26start%3D21%26hl%3Den%26sa%3DN%26rls%3Dcom.microsoft:en-us%26rlz%3D1I7ADRA_en%26tbm%3Disch%26prmd%3Divnsb&itbs=1)

Accessed on 9/20/11

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Juvenile Idiopathic Arthritis

• Pathogenesis:

– Multifactorial autoimmune

– Environmental and genetic factors

– Polygenomic

– European ancestry may be a risk factor

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Juvenile Idiopathic Arthritis

• Treatment:

– Non-steroidal

– Steroids

– Disease-modifying anti-rheumatic drugs

• Methotrexate blocks folate interaction so decreased DNA, RNA, proteins

• Sulfasalazine blocks production of proinflammatory prostaglandins

• Leflunamide blocks pyrimidine production, anti-proliferative

– Biological Modifying agents

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Juvenile Idiopathic Arthritis

• Biological Modifying agents:

– Etanercept (Enbrel) synthetic protein binds to TNF alpha, prevents TNF from binding to cells

– Infliximab (Remicade) monoclonal antibody to TNF

– Adalimumab (Humira) human monoclonal antibody against TNF

– Abatacept (Orencia) fusion protein blocks stimulation of T cells

– Anakinra (Kineret) interleukin-1 receptor antagonist

– Tocilizumab (Actemra) monoclonal antibody against interleukin-6

– Rituximab (Rituxan) monoclonal antibody against CD20 positive B cells

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Juvenile Idiopathic Arthritis

• Prognosis:

– Goal is clinical remission

– Definition of remission: No active

arthritis, fever, rash, serositis,

lymphadenitis, uveitis, normal CRP and

sed rate, no disease activity for 6 months

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Long-Term Complications

• Functional limitation

• Osteopenia

• Nutritional deficiencies

• Chronic pain

• Psychological distress

• Infection

• Delayed puberty

• Cancer?

• Death

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Conclusion

• Collagen vascular diseases are rare in children

• More common in females than males

• Not contagious

• Etiology largely unknown but genetics and environment may play a role

• New biologic agents may improve the outcome for these patients

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Q&A

Thank you for attending!

QUESTIONS?