Pediatrics Rheumatology

Triggers of the Immune Response

Genetic Predisposition

• Many genetic factors currently being studied

Infection

• Reiter’s syndrome

• Rheumatic fever

• Lyme

• Virus

Toxic

• Adverse drug reaction

• Environmental

• Smoking?

Trauma

• After tissue injury normal inflammation response fails to regulate and cascades

Unknown

• Stress?

Usually have inciting incident that triggers

Manifestations of Inflammation

Synovitis

• Inflammation of the joint synovium

Enthesopathy

• Inflammation at the insertion of a ligament to a bone

Serositis

• Inflammation of serosal lining tissue (pleura, pericardium etc.)

Myositis

• Inflammation of muscle tissue

Vasculitis

• Inflammation of connective tissue/vascular endothelium

Lab Testing Used in Diagnosis of Joint Pain

• Tests are used as an adjunct to diagnosis and to rule out other diseases (ie. infection)

• Negative testing does not always rule out a disease

  • May rely solely on H&P

• Biopsy of tissue may be necessary for accurate diagnosis

  • Ie. Vasculitides such as Wegener’s, scleroderma, sarcoid

Rheumatoid Factor

• Antibodies directed against immunoglobulin G

• Non-specific test

• Often positive in systemic lupus erythematosus (SLE), Henoch-Schonlein pupura (HSP), sarcoid

• Usually NEGATIVE in Juvenile Inflammatory Arthritis (JIA)

Anti-Nuclear Antibody

• Auto-antibodies against nuclear constituents in connective tissue cells

• Non-specific but 60-70% of children with a positive ANA will have or will develop an autoimmune disease

• Often positive in JIA, SLE, dermatomyositis

Complement Protein

• Soluble proteins in the immune system

• Triggers such as allergy and autoimmune disease start the complement cascade, which leads to release of tissue damaging factor

• Complement may be elevated early in an inflammatory disease, along with acute phase reactants

• Decreased levels of C3, C4 and total hemolytic complement C50 are seen in active SLE, SLE nephritis and other vasculidities

Histocompatibility Antigen

• Human Leukocyte Antigen B27

  • Associated with Ankylosing spondylitis, Reiter’s Syndrome, Psoriatic arthritis, Inflammatory Bowel Disease

• Human Leukocyte Antigen DRA

  • Associated with RF positive polyarticular JIA

Acute Phase Reactants

• Various laboratory measurements which become elevated in presence of tissue inflammation

• NON-SPECIFIC for any disease

• Examples

  • Westergren erythrocyte sedimentation rate (ESR)

  • C-reactive protein (CRP)

  • Platelet count

  • Ferritin

  • Total hemolytic complement (CH50)

Other Labs to Consider

• CBC

• Lyme

• LFT’s

• BUN, creatinine

• Hepatitis studies

• Epstein Barr Ab

• Parvovirus B19 Ab

• Thyroid panel

Imaging Studies

• CXR

• Echo

• Joint films

• Bone scans

• MRI

• CT scan

• Ultrasound

Procedures

• PFT’s

• Biopsy

• Arthocentesis

• Pericardiocentesis

JIA General

• Most common rheumatologic disease in children

• Biphasic peak incidence is 2-4 y/o and again at 6-12 y/o

• Systemic onset equal between boys and girls

• Pauciarticular (less than 4 joints affected) and polyarticular (slightly more prevalent in girls)

• Etiology

  • Probably multifactorial

  • Genetic susceptibility

  • External triggers- trauma, infection

Pauciarticular Type 1

• Younger age, peak at 2 yrs

• Female predominant

• Large joints are most commonly affected

  • Knee>ankles>elbows

• Symptoms

  • Chronic uveitis common and may cause photophobia

  • Few to no systemic symptoms

  • Joint swelling is painless: morning stiffness and will be limping

  • Localized growth disturbance may occur if unilateral joint is affected

Pauciarticular Type 2

• Occurs after 8 y/o

• Often a strong family history of back pain, ankylosing spondylitis, IBD, Reiter’s syndrome or psoriasis

• Involves joints of the lower extremity, usually asymmetrically

  • Knee>ankle>1^st MTP

• Symptoms

  • Early indicators include painful enthesopathy of achilles tendon, patellar tendon and plantar fascia

  • Acute uveitis may occur

  • Patients have slowly diminishing motor performance and later in disease have joint swelling

  • Occasional systemic signs

    • Fever, weight loss, anorexia, diffuse arthralgia, myalgia

JIA Lab Studies

Type I

• Rheumatoid factor RARELY present

• ANA positive in >50%

• CBC and ESR usually normal

Type 2

• Rheumatoid factor and ANA usually NEGATIVE

• Children w/o constitutional symptoms have normal labs

• Children with constitutional symptoms may have

  • Elevated ESR

  • Low hemoglobin

  • Positive HLA B27

JIA Other Studies

Imaging

• X-rays initially normal: later may show joint destruction and deformities

• MRI – may show acute synovial inflammation and loss of synovium

Other studies

• May need arthocentesis, echocardiogram and/or synovial biopsy to rule OUT other diseases

Polyarticular JIA

• Most are seronegative for rheumatoid factor

• More common in girls

• Involves small joints of the hands and feet, as well as larger joints

• Systemic manifestations more common

  • Fever anorexia, fatigue

  • Extra-articular symptoms may include a linear salmon pink quickly fading macular rash associated with fever, lymphadenopathy, hepatosplenomegaly

• Imaging may show erosive destruction of joints on x-ray

Seronegative Polyarticular JIA

• RF (-)

• Age usually 10 y/o or younger

• Symptoms

  • 25% have positive ANA and uveitis

  • Less systemic symptoms

  • More favorable outcome

• Lab studies may show

  • Mild anemia

  • Leukocytosis

  • Increased ESR

• Respond better to treatment with NSAIDS

Seropositive Polyarticular JIA

• RF (+) ž

• Peak age is 9-16 y/o

• Symptoms

  • More severe disease with extra-articular symptoms

  • Erosive arthritis

  • Rheumatoid nodules develop over tendons

• Labs ž

  • 50% of pts have positive ANA

  • Other labs include increased ESR, CRP, leukocytosis

• Usually persists into adulthood with course similar to adult onset RA

Systemic JIA

• Least common type

• Affects males and females equally

• Age 16 y/o and younger

• Symptoms

  • Presents with just systemic and no joint pain (joint pain might come later on)

  • Onset associated with high spiking fevers for weeks

  • Irritability, arthralgia, myalgia

  • Polyarticular arthritis not present early, occurs later in the disease

  • Extra-articular manifestations

    • Erythematous macular rash

    • Lymphadenopathy, hepatosplenomegaly

    • Chronic uveitis

    • Pericarditis, pleuritis

  • Rarely fatal except in cases of myocarditis or vascular coagulopathy

• Labs

  • ANA and rheumatic factor are negative

  • Mild anemia of chronic disease

  • Increased WBC with left shift

  • Elevated platelet count

  • Extremely high ESR, CRP

• Diagnostic Criteria

  • High fever for 2 weeks, arthritis in one or more joints for 6 weeks

  • Usually have had intermittent febrile illness may persist for years

JIA Treatment

• Team based approach

• Includes PCP, rheumatology, orthopedics, ophthalmology, nursing, PT/OT

• Behavioral health for patient and family

• Social work for school purposes

• Non-steroidal Anti-Inflammatories

  • Inhibit prostaglandins

  • Need to watch for GI, renal issues

• Steroids

  • Usually given as “pulses” in systemic JIA

  • Also can be given intra-articular

• Immunosuppressants

  • Methotrexate and sulfasalazine

  • Will increase risk of other infection

• Biologics- Immune Modulators

  • TNF blocker/Interleukin 1 antagonist

    • Entanercept, adalimumab, anakinra approved in JIA

    • May increase risk of TB, anaplastic anemia

• IV Ig

SLE General

• Often called the “great pretender” because it can effect almost any system in the body

• 4:1 female to male ratio before puberty

• 8:1 after puberty

• Prevalence higher in Native American, Latin American, Asian, and African Americans

• Peak age is around puberty and again in middle age, rare in children <8 y/o

Causes of SLE

• Innate susceptibility

  • Due to complement levels, hormonal leves, immunoregulatory genes

• Environmental stimuli

  • UV exposure, microbial response, drugs

• Autoimmune proliferation

  • Hyperactive B/T cell activation

  • Defective immune complex clearance

• Autoantibody production

  • Loss of “self tolerance”

Physical Manifestations of SLE

Mucocutaneous

• Classic malar rash (70-80%)

• Photosensitivity rash

• Discoid rash and naso-oral ulcers

• Raynaud’s phenomenon

Systemic

• Fatigue

• Malaise

• Fever

• Anorexia, weight loss

Ocular

• Episcleritis, sicca syndrome

Other

• Hepatosplenomegaly, edema, hypertension

Systemic Involvement in SLE

Renal

• Nephritis, nephrosis, uremia, hypertension

• Be careful with NSAID use

Cardiopulmonary

• Myocarditis, endocarditis, pericarditis, pleuritis, pneumonitis

Hematologic

• Thrombosis secondary to antiphospholipid Ab (cannot be put on OCPs)

• Anemia

Gastrointestinal

• Pancreatitis, mesenteric adenitis, serositis

Neuropsychiatric

• Seizure, stroke, psychosis, peripheral neuropathy, headache, aseptic meningitis, myelitis, depression

SLE Lab Testing

• ANA- positive in almost all patients

• C3,C4, C50 usually low

• Antiphospholipid Ab- associated with thrombosis

• Anti-DS DNA, Anti-Smith Ab

• CBC- leukopenia, thrombocytopenia, hemolytic anemia, reticulocytosis

• Chemistries- evaluate renal function

• Urinalysis- proteinuria, cellular casts

• Increased ESR, CRP

• Anti-histone antibody- if drug-induced lupus suspected

SLE Other Diagnostic Testing

Imaging

• CXR, EKG

• Renal U/S

• High resolution CT to evaluate for pulmonary fibrosis

• MRI of brain if neurologic involvement

Other studies

• Pulmonary function tests

• Renal biopsy

• Tissue or skin biopsy

SLE Treatment

Dependent on manifestations

• NSAIDS

  • Musculoskeletal pain, arthritis

• Hydroxychloroquine

  • Skin and joint involvement

• Oral or IV pulse steroids

  • Wide spread organ system involvement, renal disease

• Cytotoxic agents

  • Cyclophosphamide, azathioprine, mycophenolate

  • Reserved for severe disease not responding to other treatment 

• Biologics

  • Monoclonal antibody- rituximab

Other supportive symptom treatment

• Anticoagulants

  • Patients with positive anti-phospholipid antibody or thromboses

• Anti-hypertensives

  • Patients with renal disease

• Calcium/Vitamin D supplements

  • Patients with arthritis, or on steroids

• Anti-seizure, antidepressants

  • Patients with neurological and psychiatric symptoms

• Dialysis, kidney transplant

Henoch-Schonlein Purpura General

• Most common vasculitis in childhood

• IgA mediated vasculitis

• More common in males

• In ½ to 2/3 of children a viral URI precedes the clinical onset of HSP

• Typically self limiting, but 1/3 of pts have 1 or more recurrences

Causes of HSP

• Autoimmune reaction thought to be triggered by exposure to infection or environment

• Infectious triggers → rhinovirus, adenovirus, EBV, mycoplasma, parvovirus B19, Gp A Strep

• Vaccines

• Drugs

  • PCN’s, quinine based

• Cold exposure

• Insect bites

Complications of HSP

• Acute and chronic glomerulonephritis

• Acute nephrotic syndrome

• Intussusception and ischemic bowel

• Hepatomegaly, hydrops of gallbladder

• Headache, and rarely seizure, paresis, coma

• Pulmonary hemorrhage secondary to vasculitis

Clinical Manifestations of HSP

• Most children present following URI

• Symmetrical purpuric papules and plaques on lower extremities

• GI symptoms follow

  • Nausea, vomiting, abdominal cramping/pain, hematochezia

• >60% have arthralgia and more rarely joint swelling, scalp and scrotal edema

• Headache, irritability

Lab Studies in HSP

• CBC- leukocytosis and thrombocytosis

• Urinalysis- hematuria, +/- proteinuria

• ANA and RF negative

• Serum IgA increased in 50% of pts

• Complement levels often decreased

• BUN/ creatinine elevated with renal involvement

Treatment of HSP

• Most cases self limiting and only require monitoring for GI and renal complications

• Nephropathy is also initially treated conservatively

• Steroids as needed to relieve symptoms

• Immunosuppressants have no role in HSP but may be used if chronic glomerulonephritis develops

Scleroderma General

• Tissue fibrosing disorder- rare in children

• Children develop a localized form, involving skin

  • Morphea- patch like area on trunk or head

  • Linear- extremities

• Progressive systemic sclerosis is the systemic form

  • Involves all systems, especially kidneys, GI tract

• CREST syndrome- milder variant of PSS

  • Calcinosis, Raynaud phenomenon, Esophageal hypo-motility, Sclerodactyly, Telangiectasia

Clinical Symptoms of Localized Scleroderma

• Initially presents as inflamed purplish lesions with raised edges

• Later progresses to hypopigmentation, skin thickening and atrophy

• May involve muscles, ligaments, bone

• Can lead to contractures and limb undergrowth

• Morphea lesions may soften and regress

Clinical Symptoms of Progressive Scleroderma

• Systemic scleroderma

• Raynaud phenomenon is often first sign of disease

• Involvement of digits common, causing flexion contractures

• HTN due to kidney involvement

• Esophageal and intestinal hypo-motility

• Restrictive pulmonary disease, pulmonary hypertension

Lab Testing for Scleroderma

• No specific test, clinical diagnosis

• But ANA, anti-centromere, and anti scl-70 are often positive

Scleroderma Treatment

• Localized and systemic scleroderma are treat with a variety of medications including

• Hydroxychloroquine, corticosteroids, methotrexate and other anti-rheumatic drugs

• Physical therapy often helpful

• Splinting of extremities involved to prevent permanent damage

Juvenile Dermatomyositis General

• Inflammatory disease involving skin and striated muscle tissue

• Affects children <18 y/o

• Diagnosis based on 5 criteria

  • Characteristic skin rash

  • Proximal muscle weakness

  • Elevated muscle enzymes

  • Abnormal electromyography

  • Abnormal muscle biopsy

• Very rare (2-4 per 1,000,000)

• More common in girls

• Typical age presentation 7-8 y/o

Juvenile Dermatomyositis Clinical Manifestation

• Heliotrope facial rash

• Gottren papules on fingers

• Purplish rash in sun-exposed areas

• Telangiectasias in nail folds

• Proximal muscle weakness

• Rarely dysphagia or respiratory muscle compromise

Juvenile Dermatomyositis Diagnostic Testing

• Blood tests not helpful

  • ANA positive in 50%

  • Will see elevated CK

• Electromyography shows decrease proximal muscle function

• Muscle biopsy shows atrophy and inflammatory cell infiltration

Juvenile Dermatomyositis Treatment

• Corticosteroids

• Immunosuppressants

  • Cyclophosphamide, methotrexate, hydroxychloroquine

• IV Ig in steroid resistant patients

• PT/OT

• No cure, some patients go into remission, some progress

Wegener’s Granulomatosis General

• Rare in children, more commonly diagnosed in teens and adults

• Triad of manifestations

  • Necrotizing granulomas of the upper and lower respiratory tract

  • Necrotizing vasculitis of arteries and veins

  • Focal necrotizing glomerulonephritis

• Think lungs and kidneys with significant hemoptysis

Wegener’s Granulomatosis Physical Manifestations

ENT

• Sinusitis, subglottic stenosis, hearing loss

Pulmonary

• Tracheobronchitis, tracheal and bronchial narrowing, pulmonary infiltrates, nodules, hemoptysis

Renal

• Glomerulonephritis with hematuria, proteinuria

Ocular

• Episcleritis, dacryocystitis

General

• Arthralgia, weight loss, non-specific rash

Vascular inflammation and formation of granulomas

Wegener’s Granulomatosis Diagnostic Testing

• Elevated ESR and CRP

• Antineutrophil cytoplasmic antibody

  • Positive in 40-90% of patients with active disease

• CXR/CT- may show nodules or infiltrates

• Biopsy of sinus, bronchi, lung, kidney will show necrotizing granulomas and is diagnostic (very difficult and have to be very specific)

Wegener’s Granulomatosis Treatment

• Corticosteroids

• Immunosuppressants and immune modulators

• Antibiotics for chronic infections

• Surgical treatment of sinus disease and subglottic stenosis