Often we have to look beyond to see what we are supposed to…

Often we have to look beyond to see what we are supposed to…

Pediatric Board Review Course L. Nandini Moorthy, MD MS Pediatric Rheumatology 2009

Case 1: One swollen joint A three year old Caucasian girl presents with two-month history of swollen left knee • No history of fevers • No rash • No weight loss • No other joints are involved • CBC and differential within range • CMP, ESR, CRP, Ig within range • LDH within range • ANA titer 1:320 • RF negative

Juvenile Rheumatoid Arthritis (JRA)Now Juvenile Idiopathic Arthritis (JIA) JIA Definition • Objective arthritis in ≥ 1 joint(s) for ≥ six weeks • Children ≤ 16 years • ≥ 6 mo necessary to examine the clinical features [exception: SoJIA] Clinical recognition of each phenotype is critical Different courses, complications, treatments and prognosis

Oligo-articular onset JIA ~Pauciarticular JIA (PaJIA) • Commonest subtype (› 50%) • 1-5 years of age • Girls > boys • Arthritis in ≤ four joints • Large joints-knees, ankles, elbows • Usually spares hips • Rarely affects wrists, & small joints of hands & feet

PaJIA • Swollen joint (warm, not erythematous) • Limp, or an abnormal gait • Rarely complain of pain. • No constitutional symptoms • Routine lab values -normal • May be ANA +ve

Differential Diagnosis of PaJIA In older children Spondyloarthropathy Leg Calve Perthes disease Osteoid osteoma Slipped capital femoral epiphysis Exclude structural abnormalities Discoid meniscus Hemophilia Other causes of oligoarthritis: Reactive arthritis Lyme arthritis Septic arthritis Trauma Neoplastic disease Dactylitis (< 4 ?psoriatic arthritis)

PaJIA-Course and Complications • Benign course, good prognosis • Recurrences ~ 20% • May progress to extended-oligoarticular arthritis requiring aggressive treatment • Discrepancy in limb lengths • Persistent inflammation • Orthotic/surgical correction • Fixed flexion contractures • PT & OT Usually do well with NSAIDS Intra-articular steroid injections Rarely require systemic steroids or immunosupressives And…

Uveitis • Silent, chronic, anterior uveitis • Mostly ANA positive girls (~ 20%) • Irreversible damage & blindness • Ophthalmologic monitoring

Case 2: Many swollen joints Consider the case of a 6 year old girl who presents with multiple swollen joints, morning stiffness and mild anemia. You must think of Polyarticular JIA.

Extended Oligoarticular JIA~ Polyarticular JIA (PoJIA) • 30% -40% of JIA • Girls > boys • Bimodal peaks: 2-5 years & 10-14 years • Insidious onset, sometimes acute, with progressive involvement of >/=5 joints in the first 6 months • In younger children, onset is usually pauciarticular • AM stiffness and fatigue • May have low-grade fever • Arthritis intermittent or persistent • RF+ve or RF-ve • Small joints of hands & feet • Tenosynovitis of flexor tendon sheaths

PoJIA Atlanto-axial subluxation & C2-C3 fusion Early carpal fusion (more often in JIA) Symmetrically affecting the large joints of knees, elbows, ankles and wrists Hallmark of JIA posterior cervical fusion

PoJIA Labs may be normal or suggest an inflammatory state • Anemia • High ESR • Hypergammaglobulinemia • Leukocytosis • 5-10% RF + • 40-50 % ANA + [Cassidy, 2001] Late-onset PoJIA • Subset of RF+ girls mimics adult RA • Chronic course into adulthood

PoJIA-Differential diagnosis • Infectious causes of polyarthritis • Viral • Septic • Lyme • Other • Serum sickness • Other rheumatic diseases • Inflammatory Bowel Disease (IBD) • Systemic Lupus Erythematosis (SLE) • Dermatomyositis • Sarcoidosis • Scleroderma • Spondyloarthropathies (enthesitis, axial involvement) • Rarer causes • Malignancy • Other immunodeficiences

PoJIA-Course & Complications • Guarded prognosis • Adolescent girls RF+ with late-onset, rapidly progressive erosive arthritis –often have RA like disease as adults • Early involvement of small joints of hands & feet • Persistent inflammation • Subcutaneous nodules • RF + • Destructive hip disease among other joints & eventual disability • Contractures & ankylosis • Short stature (more in children) • Often require joint replacements • Chronic uveitis – 5%[Cassidy, 2001] Usually require aggressive management (immunosupressives/ biologics) May need systemic steroids

Systemic onset JIA (SoJIA) • High spiking quotidian fevers, that returns to normal daily, for at least 2 weeks, with arthritis in one or more joints • Often with chills • Children appear very ill when febrile, but seem drastically improved when afebrile Formerly called Still’s disease ~ 10-20% of JIA diagnoses Affects boys & girls equally Half of them have onset in childhood [Cassidy, 2001]

SoJIA • Salmon-colored evanescent • Erythematous • Macular rash • Trunk and proximal extremities • Non-pruiritic • Migratory • Fleeting nature • Disappears from one area within few hours without any residual mark

SoJIA • Other systemic symptoms • Anorexia, arthralgias, hepatosplenomegaly, lymphadenopathy • Widespread serositis • Arthritis - concomitantly or years after the first presentation • Wrists, knees, ankles, hands, hips, C-spine & TMJ • Lab: Microcytic anemia; Elevation of acute phase reactants; Leukocytosis, thrombocytosis, ESR, CRP, Complements, Ferritin; ANA + in 10% of patients • RF rarely + Differential for FUO Infectious and oncologic etiologies Inflammatory bowel disease SLE Vasculitides such as polyarteritis nodosa [Cassidy, 2001]

SoJIA- Course & Complications • Systemic features may persist for 4-6 months with varying degrees of joint involvement • Prognosis • Complete recovery • Polyarticular pattern • Persistent inflammation &/ or chronic destructive arthritis • Long standing SoJIA • Micrognathia, c-spine fusion and destructive hip disease • Short stature & FTT • Uveitis - rare • Amyloidosis -rare in the US • Macrophage Activation Syndrome • More common in children NSAIDS Steroids Usually require immunosuppressives

Gastrointestinal diseases • IBD • Crohns • UC • ASCA, ANCA • Celiac disease (TTG, Endomysial, Gliadin ab)

Enthesitis-related arthritis Spondyloarthropathy Commonly complain of: • Pain in the back & heel • Morning stiffness Arthritis & /or enthesitis with any 2 of the following: • Sacroiliac joint tenderness, Inflammatory spinal pain or both • Positive family history • Acute anterior uveitis • Arthritis onset in boys > 8 yrs • HLA-B 27 (higher likelihood of developing debilitating ankylosing spondylitis)

Spondyloarthropathy Bamboo spine in Ankylosing spondylitis Acute anterior iritis Treatment: NSAIDS, Sulfasalazine, Anti-TNF agents

QUESTIONWhat screening test will you send a 14 yo male teen withHLA B 27 +ve arthritis?

Consider HLA B 27 associated Aortitis and AR • HLA B27 is a risk factor for endocardial and myocardial damage in patients with B27-JA, even in the presence of only mild articular disease. • Patients with B27-JA should be screened by color-flow Doppler echocardiography for the presence of aortic regurgitation and myocardial inflammation with increased mitral blood flow velocity at atrial contraction due to impaired myocardial relaxation. • Regular monitoring may be required. • These patients might benefit from early pharmacologic intervention by afterload reduction (i.e., with ACE inhibitors). All patients with juvenile arthritis and • Endocarditis prophylaxis should be instituted when necessary.

Psoriatic Arthritis • Arthritis & psoriasis Or arthritis with at least two of the following: • Dactylitis • Nail abnormalities • Family history of psoriasis. • May run a course ~PoJIA & require aggressive treatment • Associated with uveitis

Psoriasis Nail pitting Sausage digits X-ray---Pencil-in-cup appearance

Pathogenesis Cytokine dysequilibrium -- increased IL-1, TNF Increased inflammation, angiogenesis, cartilage degradation and joint destruction EARLY INTERVENTION IS CRITICAL

KEY CONCEPTS- JIA • Characteristics NOT typically associated with the arthritis of JRA------severe pain, inability to weight bear, nocturnal wakening, and hot, erythematous joints. • Uveitis is the often asymptomatic inflammation of the uveal tract, most commonly seen in 20-30% of ANA positive, pauciarticular-JIA girls • Macrophage Activation Syndrome is a complication seen in systemic-JIA, resulting in DIC, encephalopathy, respiratory distress syndrome, renal failure and worsening serositis. Bone marrow biopsy may reveal the presence of histiocytes actively phagocytosing red cells and platelets • Ref: Mead Johnson Board Tutor

Remember!!! If a JRA patient has an autoantibody, it confers a worse prognosis Pauci-JRA + ANA = uveitis risk Poly-JRA + rheumatoid factor (RF) =erosive adult RA (REF: Mead Johnson Board Tutor)

Management • NSAIDS • Disease Modifying Agents (DRUGS) • Joint Replacement • Physical and Occupation therapy • Ophthalmologic monitoring • Social support, education and family counseling

NSAIDS • Naproxen • Nabumetone • Diclofenac • Indomethacin • Ibuprofen, Naprosyn, Celebrex and Tolmentin are approved for children • Used for all types • Usually sufficient for PaJIA, mild spondyloarthropathy & mild cases of other types. • Follow LFTs, UA • Watch for GI, skin and psychiatric symptoms

Disease Modifying Anti-Rheumatic Drugs (DMARD) • Novel Biologics • Etaanercept • Adalimumab • Abatacept • Infliximab • I/articular steroid injection • Steroids • Methotrexate- current gold standard • Sulfasalazine- in enthesitis-related arthritis • Cyclosporine - SoJIA (superior in combination with Mtx) • Hydroxychloroquine • Monitor- LFTs, CBC, UA, BP, neuropathy

NOVEL BIOLOGICS • Etanercept (Enbrel) is a recombinant fusion dimeric protein (sTNFR) • Infliximab (Remicade) -Monoclonal Anti-TNF antibody (murine component) • Combination of Etanercept and Methotrexate • Adalimumab (Humira): Fully humanized TNF alpha Mab with human derived heavy and light chain variable regions and human IgG constant regions. • Anakinra (Kineret): IL-1 Receptor antagonist blocks cellular activation • Abatacept (Orencia) • Adverse events – TB, Fungal, VZV

Not every bird is this easily identifiable… Case 3: 10 year old Caucasian boy presented with new-onset right swollen knee of three days duration. He has been afebrile and without rash. LN Moorthy ‘09

The swollen joint Case 4: 7 year old Caucasian girl presented with left swollen knee. 10 days ago she developed a sore throat. She has been afebrile and without rash. LN Moorthy ‘09

Case 5: 14 year old Hispanic boy had bloody diarrhea a month ago and for the last 2 weeks is complaining of swelling of his left and right wrists, his left ankles, and left and right 3rd and 4th toes. He has been afebrile and without rash.

Now all three children feel generally well except for arthritis

Work-up • All three children have an unremarkable exam except for arthritis • Complete blood count and differential, electrolytes, blood urea nitrogen, creatinine, and urine analysis are within normal limits • Erythrocyte sedimentation rate ranges from 30-40 mm/hour • The X-rays of the respective joints shows only soft tissue swelling • They all started non-steroidal anti-inflammatory drugs

Diagnosis and management • Patient 3 tested positive for Lyme Western Blot IgG; Treated with oral Doxycycline for Lyme disease. • Patient 4 had elevated Antistreptolysin-O titre and anti-strep-DNAse B antibodies and had normal electrocardiogram and echocardiogram; Was started on oral Penicillin treatment and prophylaxis for Post-Streptococcal Reactive Arthritis. • Patient 5 had stool culture positive for Salmonella; Treated with Amoxicillin for Reactive Salmonella Arthritis. All became asymptomatic in three months.

Infection-related arthritis 8-41% of Peds Rheum Clinic patients (UK, US & Canada) Hallmark: Peripheral arthritis, asymmetric arthritis & history preceding infection • Viral: Ebstein Barr Virus, Rubella, Parvovirus, Hepatitis, Mumps, Herpes, HIV, Echovirus • Bacterial: Poststrepococcal arthritis, Rheumatic fever, Gonococcal, Chlamydia, Yersinia, Salmonella, Shigella, Campylobacter, Mycoplasma, Clostridium • Lyme disease • Septic, Tuberculosis, Fungal, Protozoal • Treatment of underlying disease and NSAIDS

Polyarticular disease May be seen in Post--Parvo viral arthritis With Parvol-viral rash, you can also see a reticular rash

Rash, pustule, and bulla With arthritis, and history of sexual encounters- think GC!!!!!

Reactive arthritis • Non-specific arthritis after Reactive arthritis is a sterile arthritis which is preceded by a gastrointestinal or genitourinary infectious with arithrogenic organisms (Chlamydia, Shigella, Salmonella, Yersinia or Campylobacter) • Berlin Diagnostic Criteria • Typical peripheral arthritis PLUS • Evidence of preceding illness • Exclude juvenile idiopathic arthritis and other arthritis of known causes • Usually clinical features characteristic of primary infection • Reiter’s syndrome is a form of reactive arthritis, complicated by uveitis, conjunctivitis, and urethritis or cervicitis Remember Mneumonic: Can’t See. Can’t Pee. Can’t Climb a Tree

IBD associated arthritis Remember HLA B 27 association Jewish predilection Uveitis association

To recap…. HLA B 27 associations • Spondyloarthropathies • Ankylosing Spondylitis • Psoriatic disease • Reactive arthritis (GU/GI-related infections/Reiters) • Acute anterior iritis • IBD • Cardiac (Aortic)

ACUTE RHEUMATIC FEVER • May occur 2-3 weeks post-infection, to as long as 2-3 months after strep pharyngitis (as in Syndenham’s chorea) • Review Jones Criteria • Review prophylaxis • NEED TO KNOW THIS CONDITION IN DETAIL!!!!!!!

Case 6: A teenage Asian girl with 3 month history of malar rash She also presented with: Palatal ulcers Photosensitivity Fatigue Myalgias and arthralgias Mild anemia ANA titre of 1:320

Systemic lupus erythematosus: 1982 classification criteria --4/11 Cytopenias Immunologic disorder (1. Other Lupus serology (anti-Sm, anti-ds-DNA, anticardiolipin antibody, lupus anticoagulant, false positve RPR) Antinuclear antibody Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis (non erosive polyarthritis) Serositis Renal disorder Neurologic disorder Systemic lupus erythematosus: 1982 classification criteria Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271-1277.

Some facts Incidence: 0.36 -0.9 per 100,000 per year Prevalence: <1- 4.5% of patients in pediatric rheumatology Age: Childhood onset occurs in 15-17 %, Rare (but still occurs) below 5 years Sex: More in females (Male:Female ratio 1:4.5) In younger age group, the ratio is almost equal Race: African-American, Hispanic, Asian, Native Higher incidence/severity of renal/CNS lupus in pediatric onset Episodic, Chronic, Fluctuating Autoantibodies

Clinical presentation PRESENTATION - fever, fatigue, weight loss, irritability SKIN • Malar rash-Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds • Discoid rash-Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions • Other types of rash, nail involvement, hair loss (alopecia)

Often we have to look beyond to see what we are supposed to…