25 Rheumatology

25.1 Pediatric approach to rheumatic disease

• Rheumatology is a field of many unknowns, however, it occurs when chronic inflammation affects the MSK system, blood vessels, and other tissues, presenting with periods of exacerbation and remission
• History is essential: constitutional sx, joint/muscle sx (limp, stiffness, regressing milestones, problems walking/with stairs/dressing), pain, rashes, ulcers, chest pain
• Physical exam: focus on eyes, skin, muscle, joints
  • For arthritides see below
• Vaccinations: A few guidelines, but contact Rheumatology for guidance
  • Varicella, live virus/bacteria vaccines: contraindicated in children taking high dose steroids and biologics
  • IVIG: children should wait anywhere from 8-11 months after the last dose for immunizations. PPSV23 and PCV13 should be given to children on immunosuppressants
  • Most importantly, consider the whole picture when arriving at a diagnosis. Presentation, personal/family history, labs must all be taken into account. Autoantibody testing is helpful, however, it is not always diagnostic.

25.2 Inflammatory markers and autoantibodies

Marker	Description
CRP	-Acute phase reactant, produced by liver in response to pathogens/inflammation/tissue damage. -Level rises ~ 4-6 hours after injury/infection, peak at ~24-72 hours, then falls after appropriate treatment -CRP can be normal in SLE, JDM/PM, scleroderma, and Sjorgen’s
ESR	-Acute phase reactant, non-specific marker of inflammation -Rate at which RBCs settle through plasma to form sediment at the bottom of a tube -Slower rise and slower fall compared to CRP -May be elevated due to anemia or hypergammaglobulinemia -May fall quickly in DIC or other conditions that consume or decrease production of fibrinogen
ANA	-Autoantibodies directed against antigens predominantly found in the nucleus -Conditions associated w/ (+) ANA: —Autoimmune: SLE, MCTD, Sjogren’s, Juvenile Ssc, JIA, JDM, autoimmune hepatitis, Graves’, Hashimoto’s —ID: EBV, HIV, TB, SBE —Systemic inflam.: lymphoproliferative disorders, interstitial pulmonary fibrosis, asbestosis -Medications associated w/ (+) ANA and drug-induced lupus (+anti-histone Ab): —Procainamide (90%), Hydralazine (65%), Anti-TNF agents (especially infliximab), INH, Quinidine, Phenytoin, Sulfasalazine, Minocycline, Lithium, chlorpromazine -Titers do not correlate w/ disease severity -Can be found in 10-15% of healthy children, most of whom do not develop autoimmune disease
ANCA	-Ab targeting antigens in cytoplasmic granules of neutrophils; highly sensitive for vasculitides that have predominant pulmonary and renal involvement -Not used on its own for screening patients, as they can be found in non-vasculitides -Cytoplasmic (c-ANCA): antibody to proteinase-3 & positive in about 90% of patients w/ Granulomatosis w/ Polyangiitis (formerly Wegener’s granulomatosis) -Perinuclear (p-ANCA): antibody to myeloperoxidase & associated w/ microscopic polyangiitis, Churg-Strauss, Ulcerative colitis -Titers often do not correlate w/ disease severity
RF	-IgM autoantibody that reacts to Fc portion of IgG antibodies -Present in 2-7% of children w/ JIA -Useful for predicting erosive disease in polyarticular JIA -Higher titers can be seen in Sjogren’s Syndrome, MCTD, GPA -Also seen in infections: Chagas, SBE, Hep C, EBV -Circulating immune complexes may give false positive RF results
dsDNA	-IgG, directed toward ds-DNA -High specificity for SLE -Rising levels associated with flares
SSA/Ro SSB/LA	-Sjogren’s syndrome -Cutaneous lupus -Neonatal lupus/congenital heart block -La less common and usually not found w/o Ro
CCP (ACPA)	-High specificity, low sensitivity for JIA -Adults: 70-80% of RA, predicts erosive disease
Sm (Smith)	-High specificity, 30% of juvenile SLE, 60% of adult SLE -Remains positive when SLE in remission
RNP	->95% MCTD -SLE
Scl-70	-Systemic sclerosis -Assoc. w/ pulmonary fibrosis
Jo-1	-20% of DM/PM -Associated w/ ILD -Mechanic hands -Most frequent Ab in antisynthetase syndrome

25.3 Childhood Vasculitides

*Most Common	Age	Symptoms/Signs	Biopsy/Labs	Treatment
Large Vessel
Takayasu’s arteritis	Females Higher in Asian pop Adol.	Pulseless Disease Blood pressure dif >10 between limbs Bruit over aorta, carotids	Granulomatous inflammation of the aorta elevated ESR/CRP	Steroids Antiplatelet drugs Surgery
Medium Vessel
Polyarteritis nodosa*	Middle childhood	Livedo reticularis, skin nodules, myalgia, HTN, renal involvement	Transmural fibrinoid necrosis Urinalysis: proteinuria/hematuria	Steroids Cyclophosphamide/azathioprine anti-TNF biologics
Kawasaki Disease*	Young children (higher in Asian pop.)	CRASH: Conjunctivitis, Rash, Adenitis, Strawberry tongue, Hand/foot swelling Coronary artery aneurysms	Complete: clinical Incomplete: clinical + labs (see below) Cardiac echo	IVIG Aspirin Steroids
Small Vessel
Microscopic polyangiitis	9-12 yo	HTN, hematuria Hemoptysis Purpura, ulcers	p-ANCA No granulomas Necrotizing glomerulonephritis	Steroids Cyclophos Rituximab
Granulomatosis w/ Polyangiitis (Wegener’s)	Young adults (20s) F>M	Hemoptysis/alveolar hemorrhage Chronic sinusitis, otitis, mastoiditis	c-ANCA Necrotizing granulomas in upper/lower airway, focal segmental necrotizing GN Urinalysis: proteinuria/hematuria CXR: nodules	MTX Steroids RTX/CYC Pheresis (severe)
Eosinophilic granulomatosis w/ polyangiitis (Churg-Strauss)	12yo F>M	Asthma, allergic rhinitis,sinusitis Periph. Neuropathy Cardiomyopathy	p-ANCA Eosinophilia Extravascular necrotizing granulomas	Steroids Cyclophos Mepolizumab
Henoch-Schonlein Purpura (HSP)*	Most common vasculitis in children 3-15yo M>F	Palpable purpura Arthritis/arthralgias Abdominal pain Renal disease (IgA nephro)	IgA mediated Urinalysis Renal/skin biopsy Abd U/S: intussusception	Supportive NSAIDs Hydration Steroids
Behcet disease	Age of onset varies	Aphthous stomatitis Genital ulceration Uveitis, erythema nodosum, purpura, acneiform lesions, pathergy DVT, arterial aneurysm	Associated with HLA-B51 Involves arterial and venous system, occlusive vasculitis Elevated ESR/CRP	Ulcers: sucralfate/GCs/infliximab Uveitis: azathioprine/GCs GCs, DMARDs, Biologics

25.4 Henoch-Schonlein Purpura (IgA vasculitis)

Etiology:

• No clear etiology
• Frequently preceded by upper respiratory infections (esp streptococcus, staphylococcus, and parainfluenza) or immunizations

Pathophysiology:

• Deposition of IgA-containing immune complexes in vessel walls of affected organs and in kidney mesangium activates alternative complement pathway (w/ deposition of C3)
• HSP nephritis and IgA nephropathy are histologically identical

Clinical Manifestations:

• Palpable purpura: symmetric, lower limb predominance
  • Present in all cases, but may not be presenting symptom
• Arthralgias/arthritis: oligoarticular, large lower extremity joints (knees, hips, ankles)
  • Occurs in ¾ of cases
• Abdominal pain: diffuse pain, colicky, worse after meals, often w/ nausea or vomiting
  • Occurs in 2/3 of cases
  • 3-4% of HSP patients develop intussusception
• Renal disease: hematuria is most common, but proteinuria/hypertension may be seen
  • Occurs is 20-50% of cases
  • Usually delayed 1-2 weeks after onset
  • <15% children have long-term kidney damage, <1% develop renal failure

Diagnosis:

• Palpable purpura (w/o thrombocytopenia or coagulopathy), and ≥1 of the following:
  • Abdominal pain
  • Arthritis/arthralgias
  • Biopsy w/ leukocytoclastic vasculitis (skin) or glomerulonephritis w/ IgA deposition (renal)
• Urinalysis (screen for renal involvement), CBC (Plt normal to elevated), IgA level (NOT helpful)
• Abdominal ultrasound if c/f intussusception

Treatment:

• Self-limited, supportive care
• Mild/moderate pain: naproxen
• F/u with PCP for weekly/biweekly urinalysis and BP checks for 1-2months
• Severe pain: steroids reduce sx but do not change clinical course, requires taper (4-8wks)
• Severe renal involvement: proteinuria/hematuria, requires closer follow-up and steroids

25.5 Kawasaki Disease

Epidemiology:

• Acute, self-limited systemic vasculitis of medium-sized arteries in infants/children
• Average age of onset ~ 2 years w/ 80% occurring in those < 4 years old
• Incidence in US: 17-18/100,000, M:F = 1.6:1
• Incidence doubled for Asian Americans, highest incidence in Japan
• Increased rates in winter & spring

Pathophysiology:

• May be related to infectious triggers
• Vasculitis begins as a neutrophilic infiltrate; plasma cells producing IgA in vessel walls

Clinical Manifestations:

• Classical criteria = fever ≥ 5 days w/ ≥ 4/5 classical criteria, w/o alternative diagnosis
  • Conjunctivitis: Bilateral bulbar conjunctival injection (non-exudative & limb sparing)
  • Rash: Polymorphous rash (maculopapular, diffuse erythroderma, or erythema multiforme-like)
  • Adenopathy: Cervical lymphadenopathy (≥1 lymph node, > 1.5 cm in diameter), usually unilateral
  • Serositis: Injected/fissured lips, injected pharynx, or strawberry tongue.
  • Hand/Feet: Erythema of palms/soles, edema of hands/feet (acute), periungual desquamation (convalescent)

25.5.0.1 Complete KD:

• Fever ≥ 5 days and ≥ 4 principal clinical features OR fever ≥ 4 days and 5 clinical features

25.5.0.2 Incomplete (Atypical) KD:

• 2 possible diagnostic criteria:
  • 1. 0 or 1 clinical criteria in a child <6 months old and fever >7 days PLUS positive echo
  • 2. Fever ≥ 4 days + 2-3 clinical criteria + elevated ESR/CRP + ≥ 3 supplemental labs OR positive echo
  • Supplemental labs:
    • Anemia for age
    • ALT > 50 units/L
    • Platelet count > 450,000 after 7th day of fever
    • WBC > 15,000/mm3
    • UA w/ > 10 WBC per hpf (sterile pyuria)
    • Albumin < 3.0 g/dL

Other clinical findings

• Neuro: Irritability, hearing loss, facial nerve palsy
• Cardiac: Coronary artery aneurysms, depressed myocardial function, pericardial effusion, prolonged PR interval.
  • Risk factors for CA aneurysms include: male, <1 y/o, prolonged fever, elevated CRP, low platelets, low albumin levels on diagnosis
• GI: Pain, vomiting/diarrhea, hepatitis, acute acalculous distention of the gallbladder
• MSK: Arthritis, arthralgias (pleocytosis of synovial fluid)
• GU: Urethritis/meatitis, hydrocele

Studies

• Echocardiogram w/i 24 hours (abnormal echo= coronary artery Z score ≥ 2.5)

Treatments

• IVIG (2g/kg) infused over 12 hours→ repeat, if febrile, 36 hours after first infusion.
• Aspirin: medium dose (30-50 mg/kg/d divided QID) until afebrile x 48 hours. Then low dose (3-5 mg/kg/d). (consider starting w/ low dose for age ≤ 6 mo)
• Corticosteroids: trials indicate that steroids may be effective as primary/rescue therapy.
• Repeat echo post-treatment, either before or after discharge, to observe improvement
• Patients w/ severe CA dilation may need long-term anticoagulation therapy
• Under study: infliximab, cyclosporine, other immunomodulatory agents

25.6 Polyarteritis Nodosa

Etiology:

• Focal, segmental, fibrinoid necrosis of walls of medium/small arteries leading to aneurysms
• Rarely caused by loss-of-function mutation in adenosine deaminase 2

Cutaneous PAN:

• Nodular, painful, non-purpuric lesions, +/- livedo reticularis, w/o systemic involvement (as in sPAN)
• Ass. w/ fever, elevated acute phase reactants, myalgia, arthralgia, non-erosive arthritis
• Biopsy: necrotizing non-granulomatous vasculitis
• Labs: ANCA neg, may see + ASO (up to ⅓ of cases are triggered by a strep infection)

Systemic PAN:

• EULAR/PRINTO/PRES Criteria: biopsy for histopathology (necrotizing vasculitis) OR angiography (aneurysms, stenosis, occlusions), AND ≥ 1 of:
  • Skin: livedo reticularis, tender subcutaneous nodules, superficial/deep skin infarctions
  • Rheum: Myalgia or muscle tenderness
  • Cardio: HTN
  • Neuro: Peripheral neuropathy, sensory or motor mononeuritis multiplex
  • Renal: proteinuria, hematuria, RBC casts, GFR <50% normal for age
• Labs: ANCA negative

Laboratory Studies:

• ANCA, ANA, C3/4, CRP, ESR
• Urinalysis, Cr
• Consider other causes: infectious, thrombotic, other autoimmune diseases

Complications:

• Acute: organ failure (cardiac, pulmonary, renal), thrombi, hemorrhage, infection
• Chronic: HTN, ischemic cardiomyopathy, CKD, mesenteric arteritis, hearing loss, orchitis

Treatment:

• Mild (normal renal function, no significant/life-threatening complications): Steroids, may add Azathioprine or MTX
• Moderate to severe (ex: kidney involvement, proteinuria, neuro/cardiac/GI complications): Steroids + Cyclophosphamide, with eventual switch from Cyclophosphamide to Azathioprine or MTX, TNF inhibitors useful as well, especially in cutaneous PAN and DADA2
• Pheresis considered in organ threatening disease
• HTN: ACE Inhibitor

25.7 Connective Tissue Disorders

25.7.1 SLE

Clinical:

• Rash (malar, discoid), photosensitivity, serositis, nephritis, oral/nasal ulcers, seizure, psychosis, arthritis

Lab markers:

• Cytopenias (+)
• anti-RNP (30%)
• +anti-dsDNA (40-60%, assoc w SLE activity and lupus nephritis)
• +anti-Smith (30%, w/ high specificity, remains + in remission)
• +anti-SS-A (Ro, 40%)
• +anti-SS-B (La, 10-15%, more specific than Ro)
• Low C3/C4

25.7.2 Juvenile Polymyositis

Clinical:

• Proximal muscle weakness (symmetric) +/- tenderness
• Makes up 3-6% of childhood idiopathic inflammatory myopathies

Lab markers:

• CK
• Aldolase
• LDH
• AST and ALT (rarely nl unless “burnt out”)
• (+)anti-Jo-1 (20%, a/w ILD, mechanic hands)
• (+)anti-mi2 (5-7%, a/w acute onset, shawl sign, good prognosis)

25.7.3 Juvenile Dermatomyositis

Clinical:

• Proximal muscle weakness (symmetric) +/- tenderness
• Rash (heliotrope on upper eyelids, shawl sign on back, V-sign on chest)
• Nailfold capillary changes (dilation, tortuosity)
• Gottron’s papules or scaly eruption over extensor surfaces such as knuckles (pathognomonic)
• Skin ulcerations - indicate worse prognosis
• Most common idiopathic inflammatory myopathy of childhood (85% of all such myopathies)

Other:

• ILD in 10%, upper esophageal involvement (dysphagia) in 25%; may cause life-threatening aspiration

Lab markers:

• (+)anti-Jo-1 (20%, a/w ILD, mechanic hands)
• (+)anti-Mi2 (5-7%, a/w acute onset, shawl sign, good prognosis)
• (+)anti-MDA5 (ILD, poor prognosis)

25.7.4 Sjogren’s

Clinical:

• Sicca sx (dry mouth/eyes)
• Vasculitis
• Interstitial nephritis
• Neuropathy; 5% lifetime risk of NHL

Lab markers:

• (+)ANA
• (+)anti-SS-A (Ro, 70%)
• (+)anti-SS-B (La, 50-70%, more specific)
• (+)RF

25.7.5 Scleroderma

Clinical:

• Skin tightening & thickening prox to forearms
• Nail fold capillary dilatation & dropout
• ILD & later stages PAH
• GI dysmotility
• Renal crisis (tx w/ ACE-I)

Lab markers:

• (+)anti-Scl 70 (30%)
• (+)anti-centromere (15%)

25.7.6 CREST

Clinical:

• Calcinosis
• Raynaud’s phenomenon
• Esophageal dysmotility
• Sclerodactyly
• Telangiectasias

Lab markers:

• (+)anti-centromere (60%), associated with PAH
• (+)anti-Scl 70 (15%)

25.7.7 Mixed Connective Tissue Disease

Clinical:

• Overlapping features of SLE
• Polymyositis
• Systemic sclerosis
• Raynaud phenomenon
• Swollen fingers
• Arthritis
• Inflam myopathy
• Pleuritic
• Pulm fibrosis, etc.

Lab markers:

• Anti-U1-RNP (Ribonucleoprotein) should be positive

Treatment:

• NSAIDs
• Corticosteroids
• ACE-I
• Supportive measures

25.8 Systemic Lupus Erythematosus

Definition:

• Multiorgan system autoimmune disorder with markedly variable presentations/course

Epidemiology:

• F>M
• Most often after age 8 yo
• Median age of onset for juvenile SLE 12-13 yo
• More common in people of Asian, African, and Hispanic race/ethnicity vs Caucasian

Other presenting symptoms:

• Constitutional: Fever, Weight loss, Anorexia
• Physical exam: Raynaud’s, LAD, HSM, HTN

Neonatal Lupus Erythematosus (NLE):

• 1-2% of Infants born to mothers w/ anti-Ro and/or anti-La antibodies (transplacental)
• Auto-Ab interfere w/ development of cardiac conduction system → permanent AV block
  -Flat/erythematous, annular, photosensitive rash that spontaneously resolves ~6 mo of age (as maternal Abs dissipate)
• No increased risk of autoimmune diseases later in life

SLICC Criteria (Not validated in children/adolescents)	4+ criteria, including 1+ clinical and 1+ immunologic (serial or simultaneously), w/o alternative explanation OR SLE nephritis with +ANA/+dsDNA
Acute cutaneous lupus	Malar rash, bullous, TEN variant, photosensitive rash
Chronic cutaneous lupus	Discoid, hypertrophic/verrucous, panniculitis, mucosal, chilblains, erythema timidus
Non-scarring alopecia	Diffuse thinning or hair fragility with visible broken hairs
Oral/Nasal Ulcers	Palate, buccal, tongue, or nasal
Joint Disease	Synovitis in 2+ joints (swelling/effusion) OR 2+ joint tenderness + >30m AM stiffness
Serositis	Pleurisy or pericardial pain ≥1d, pleural or pericardial effusion, pleural or pericardial rub, pericarditis on TTE
Renal	≥ 500 mg protein/day or RBC casts
Neuro	Seizures, psychosis, mononeuritis multiplex, myelitis, peripheral/cranial neuropathy
Hemolytic anemia	Autoimmune (direct Coombs+), thrombotic MAHA (TTP, HUS)
Leuko/lymphopenia	Leukopenia <4000/mm^3, lymphopenia <1000/mm^3
Thrombocytopenia	<100,000/mm^3, including ITP, TTP
Immuno	ANA (+) , Anti-dsDNA (+) or >twofold reference range on ELISA
Low complement	Low C3, C4, or CH50
Direct Coombs test	Positive in absence of hemolytic anemia
Antiphospholipid	Lupus anticoagulant, RPR (false positive), anticardiolipin Ab, or beta 2-glycoprotein I

Treatment:

• Initial: Hydroxychloroquine (< max 5 mh/kg/d, need regular ophtho evals for visual field testing and color vision) + glucocorticoids (IV or PO depending on severity)
• Mild: No renal/organ involvement→hydroxychloroquine, NSAIDS - arthralgia, Dapsone - derm, MT - arthritis. Can use LD prednisone (<0.35 mg/kg/d), but if needs >3 mo consider second-line agent (ex: MMF)
• Mod: Renal/organ involvement → consider MMF, azathioprine, rituximab, systemic steroids
• Severe: Substantial renal/neuro disease → cyclophosphamide
• Flares:Steroids + MMF, or cyclophosphamide if already on MMF/azathioprine

25.9 Inflammatory Myopathies

	Polymyositis	Dermatomyositis	Inclusion Body Myositis
Path	CD8+ T cells	CD4+ T Cells	Inflam/neurodegen
Clinical	Symmetric proximal muscle weakness (shoulders)	Symmetric proximal muscle weaknessGottron papules, heliotrope (periorbital) rash,“shawl+face ’rash,“mechanics hands”	Distal >> Proximal muscle weakness (Extremely rare in children)
Labs	Increased CK, ANA (+)	Increased CK, ANA (+)	Increased CK, ANA (+)
	Anti-MI-2/MJ	Anti-Jo-1 (Anti-tRNA-synthetase)	Anti-cN1A
	Bx: Endomysial inflam	Bx: Perimysial inflam/atrophy (myopathic), Von Willebrand Factor Ag	Bx: Basophilic rimmed vacuoles, ragged-red fibers
Assoc.	Autoimmune (Crohn’s, Vasculitis, Sarcoidosis, MG)	Lipodystrophy, Calcinosis, ILD, GI bleed Juvenile DM NOT assoc. w/ malignancy like adults	-
Treatment	Steroids (prednisone) followed by long-term immunosuppression (MTX, cyclosporine)	Steroids (prednisone) followed by long-term immunosuppression (MTX, cyclosporine)	Not steroid responsive

25.10 Sjogren Syndrome

Pathophysiology:

• Inflammatory autoimmune disorder of exocrine glands (salivary/lacrimal glands)

Exocrine features:

• Keratoconjunctivitis sicca → dry mouth, salivary hypertrophy, Xerosis of skin
• Xerophthalmia (dry eyes, conjunctivitis, sensation of sand in eyes)
• Xerostomia (dry mouth, dysphagia, enlarged parotid glands, dental caries)

Extraglandular features:

• Arthritis/arthralgias, Raynaud phenomenon, Cutaneous vasculitis, ILD

Lab tests:

• Anti-SSA (Anti-Ro) Abs and Anti-SSB (Anti-La) Abs
• Schirmer Test – objective signs of decreased lacrimation
• Salivary gland biopsy w/ focal lymphocytic sialadenitis

Treatment:

• Dry eyes: Artificial tears, cyclosporine drops
• Dry mouth: Muscarinic agonists – pilocarpine, cevimeline
• Arthritis: Hydroxychloroquine or methotrexate

25.11 Pediatric arthritides: Approach to Joint Disease

Questions to consider:

• Which joint(s) is/are affected?
• For how long? Persistent vs. intermittent?
• Is there morning stiffness?
• Has the distribution changed over time?
• Does anything make joint pain better or worse (e.g. movement or prolonged inactivity)?
• What are associated symptoms (fever, rash, weight loss, etc.)?
• Family history of arthritis or autoimmune disease?
• Any exposures (camping, sexual activity, viral illness, etc.)?

Differential for joint pain

• Trauma/Overuse: LCP, SCFE, patellar tendonitis, patellofemoral syndrome (sports med!)
• Infection:
  • Septic arthritis (red, hot, angry, WBC >50K on joint tap)
  • Lyme Disease (may or may not have seen tick or noticed other Lyme symptoms)
  • Endocarditis (persistent fever and positive cultures)
  • Rheumatic Fever (h/o strep throat)
  • Transient Synovitis (h/o recent URI)
• Inflammatory/Autoimmune:
  • Lupus
  • JIA
  • sJIA

25.12 Juvenile Idiopathic Arthritis

• International League Against Rheumatism (ILAR) → 6 sub-categories+ “undifferentiated” category (not shown)
• Controversy as to whether juvenile and adult inflammatory arthritides should be considered distinct from each other based on genetic and clinical parallels

Definitions:

• JIA: Clinical diagnosis based on having objective signs of arthritis in ≥1 joint for ≥ 6 weeks in a child < 16 after other types of childhood arthritis have been excluded
• Oligoarticular: up to 4 joints affected in first 6 months after diagnosis. Can be “persistent” or “extended,” based on whether stays limited past the 6 month mark
• Polyarticular: affects more than 5 joints in first

Subtype	Age	F: M	% JIA	Pattern	Extra-articular/Notable Features	Treatment
Systemic	1-5	1:1	5-15	Polyarticular (U/L ext, neck, hips)	Recurrent fever and evanescent rash; organ dysfxn; MAS, *note uveitis rare in this population	NSAIDS, MTX, IL-1 inhibitor, IL-6 inhibitor
Oligo	2-4	5:1	30-50	Knee, ankle, wrist, elbow	<5 joints	Uveitis
Poly RF(-)	2-4	8-12	3:1	10-30	Symmetric; small joints (e.g. hands) >5 joints	Uveitis
Poly RF(+)	9-12	3:1	<10	Symmetric; small joints (e.g. hands) >5 joints	Rheumatoid nodules, *note uveitis rare in this population	NSAIDS, MTX, anti-TNF
Psoriatic	2-4	9-11	2:1	5-10	Knees, ankles, tenosynovitis of digits “sausage”	Uveitis, Psoriasis or FmHx, Dactylitis, Nail Changes
Enthesitis-related	9-12	1:3	5-10	Sacroiliac/axial	IBD, HLA-B27 positivity	NSAIDS, steroids, sulfasalazine, anti-TNF

25.13 Systemic JIA (Still’s disease)

• Complex pathogenesis: autoimmune (genetic risk factor in MHC complex) vs. autoinflammatory (F=M, cyclic fevers, response to IL1 inhibitors)
  • Fever and rash may precede chronic arthritis
  • Early disease is mediated by inflammatory cytokines IL-1, IL-6 etc
  • Macrophage activation syndrome is a complication associated with sJIA
  • ILAR classification: Arthritis in ≥1 joint with or preceded by fever for ≥2 weeks that manifests as a daily or “quotidian” in timing for at least 3 days + one or more of the following:
    • Evanescent erythematous rash (i.e. comes and goes, often worse with fever)
    • Lymphadenopathy
    • Hepato/splenomegaly
    • Serositis

Treatment:

• Cytokine inhibitors can attenuate disease progression (ie.anakinra and canakinumab)
• For patients that develop chronic arthritis, co-stimulatory blockade of T-cells has anecdotally provided benefit (e.g. abatacept)

25.14 Macrophage Activation Syndrome (MAS)

• A secondary form of hemophagocytic lymphohistiocytosis (HLH)
• Dysregulation of the immune system with ineffective cytotoxic T and NK cell response leading to cytokine storm and over activation of macrophages
• Can occur with most systemic/rheumatic disorders (ie KD, SLE) OR in the setting of viral illnesses such as EBV
• Incidence is much higher in sJIA (~10-20%)
• PRINTO diagnostic criteria for MAS in SJIA:
  • Fever and serum ferritin > 684ng/mL + any two of the following:
    • Platelet count ≤ 181*109/L
    • AST (>48U/L)
    • Triglycerides > 156mg/dl
    • Fibrinogen ≤ 360 mg/dl

Workup and Treatment

• BCH EBG available → Page 1 = workup (not shown); Page 2 = Treatment (below)
• Multidisciplinary treatment of patient including Rheum and Immunology !MAS

25.15 Fever of Unknown Origin

• Age >3 months
• Parent report of fever measured at >38 C daily for >=7 days
• No source identified during prior workup
• BCH EBG available

Initial Workup:

• Chem 10, LFTs, Ferritin
• IgG level
• LDH, Uric acid
• UA, Urine culture
• Blood culture
• EBV, CMV
• Viral respiratory testing, CXR
• Additional possible testing on individual basis: HIV, PPD/T-spot, Bartonella IgG and IgM, peripheral blood smear, echocardiogram

Consults:

• Infectious Disease
• Rheumatology (if >=1 met):
  • Age <12 months with ESR >=40 mm/hr or CRP >3 mg/kL
  • Ferritin >=500
  • IgG level >=2000 mg/dL
  • Joint symptoms
  • Rash (especially malar, heliotrope, or livedo reticularis)
  • Serositis
  • Inflammatory eye disease
  • 1st degree relative with rheumatologic disease
• GI
  • Poor growth
  • Prominent GI symptoms
  • Anemia
  • Elevated inflammatory markers
• Immunology
  • Recurrent and/or opportunistic infections
  • Failure to thrive
• Oncology
  • Abnormal CBC (cytopenias, blasts)
  • Elevated LDH and/or uric acid

25.16 Autoinflammatory Diseases

Autoimmune vs. Autoinflammatory

• In broad strokes, autoinflammatory conditions are thought to be due to disruptions in innate immunity, whereas autoimmune conditions are due to disruptions in immune tolerance/adaptive immunity
• Autoinflammatory conditions often have mutations in genes related to the inflammatory cascade leading to uncontrolled inflammation with high levels of pro-inflammatory cytokines, fevers + rashes, and a similar incidence in males and females; biologics that block IL-1 and IL-6 can be helpful
• Autoimmune conditions may have auto-antigens and auto-reactive T-cells and B-cells; fever is not a core feature, although may be present; usually F>M; drugs that inhibit T-cells and B-cells are more useful (e.g. calcineurin inhibitors, MTX, rituximab)
• These divisions are not black and white, and most diseases are thought to lie on the spectrum and/or develop in immune pathophysiology over time (see sJIA)

Diagnosis

• Careful H&P (r/o malignancy, infection, cyclic neutropenia) → may confirm w/targeted genetic testing

Categories

• Includes both periodic fever syndromes as well as non-periodic fever syndromes

25.16.1 Periodic Fever Syndromes

	FMF (Familial Mediterranean Fever)	TRAPS (TNF Rec.-associated Periodic Syndrome)	HIDS (Hyper IgD Syndrome a.k.a. Mevalonate kinase deficiency (MDK))	MWS (Muckle Wells Syndrome)	PFAPA (Periodic Fever, Aphthous stomatitis, Pharyngitis, cervical adenitis)
Inherit.	AR	AD	AR	AD	Sporadic
Protein Defect	Pyrin	TNF receptor	Mevalonate kinase	Cryopryrin	Unknown
Ethnicity	Jewish, Turkish, Italian, Arab	Any	Dutch, French	Northern European	Any
Flare Duration	1-3 days	>7-14 days	3-7 days	2-3 days	3-4 days
Interval Between Events	Variable	Variable (days- wks)	Fixed (4-8 wks)	Variable URI trigger	Fixed (2-8 wks)
Age of Onset	School age	School age	Infancy	School age	Early childhood
Clinical	Serositis Peritonitis Renal amyloidosis (if untreated)	Eye stuff (periorbital edema/pain, conjunctivitis) Limb pain Abdominal pain Amyloidosis Rash	LAD Abdominal pain Diarrhea Arthralgias Vomiting Oral Ulcers Developmental Delay (with complete enzyme deficiency)	Sensorineural hearing loss Recurrent hives Amyloidosis	Multiple fever spikes per a day Sore throat Mouth sores Cervical LAD
Treatment	Colchicine IL-1 inhibitor (if resistant to colchicine)	Steroids Etanercept Some evidence for IL-1 inhibitors	NSAIDS/GCs/IL-1 inhibitor during attacks IL-1 blockade or etanercept for maintenance	IL-1 Inhibitor	Steroids Tonsillectomy

25.16.2 Autoinflammatory Disorders without Periodic Fever

• Chronic recurrent multifocal osteomyelitis (CRMO)
  • Multifocal, non-infectious osteomyelitis, diagnosed with whole body MRI
  • Pts may only be symptomatic in one location, making dx difficult
  • Red flags for CRMO (vs. infectious OM) include: clavicular lesions, bilateral/symmetric lesions, concurrent spondylarthritis/IBD/psoriasis/palmoplantar pustulosis, or OM that never had positive cultures and is persistently unresponsive to antibiotics
• Deficiency of the interleukin-1 receptor antagonist (DIRA)
• Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA)
• Juvenile systemic granulomatosis (Blau Syndrome)
• Chronic atypical neutrophilic dermatitis w/ lipodystrophy and elevated temperature (CANDLE)

25.17 Common Rheumatology Medications

Medication	Indication	MOA	Side Effects
Glucocorticoids	JIA, JRA, SLE, vasculitides	Activate the glucocorticoid receptor, decrease chemo/cytokine production, multiple genomic and nongenomic mechanisms	Cushing syndrome, growth suppression, osteoporosis, avascular necrosis, lymphopenia, psychosis, cataracts, myopathy, diabetes IV methylprednisolone: hyper or hypotension, bradycardia, hyperglycemia, acute psychosis
Hydroxychloroquine (Disease modifying antirheumatic drug/DMARD)	JDM, SLE, Sjogren’s	Alters pH of lysosomes, decreasing immune recognition of autoantigens	Retinopathy, N/V, hemolytic anemia in G6PD deficiency
Methotrexate (DMARD)	JIA, RA,JDM, vasculitis, SLE	Dihydrofolate reductase inhibitor, give with folic acid	Hepatotoxicity, Pancytopenias, GI discomfort, Stomatitis
Sulfasalazine (DMARD)	JIA, RA, IBD	Interferes with enzymes that produce leukotrienes, prostaglandins	Maculopapular rash on sun exposed area, Stomatitis, SJS, not given in G6PD def
Leflunomide (DMARD)	JIA, RA, Psor. arthritis	Pyrimidine synthesis inhibitor	Hepatotoxicity, GI upset
Cyclophosphamide	Vasculitis, scleroderma, lupus nephritis	Alkylating agent	Cytopenia, Hemorrhagic cystitis, Pulmonary fibrosis, Skin/bladder cancer (adults)
Azathioprine	DM/PM, SLE, vasculitis	Antimetabolite	GI upset, myelotoxicity
Abatacept, Rituximab, Tocilizumab (Biologics)	JIA, uveitis, RA	Non-TNF inhibitors Abatacept (hIgG1+CTLR4, prevents APCs from activating T-cells) Rituximab (anti-CD20,promotes B cell death) Tocilizumab (anti-IL6)	Infection (TB), infusion reaction, GI upset/perforation
Adalimumab, Etanercept, Infliximab (Biologics)	JIA, RA, Psoriatic arthritis, AS psoriasis, IBD, vasculitis (TA, DADA2)	TNF inhibitors	Infection (TB, fungal), lymphoma, MS
IVIG (biologic)	KD	Prepared from pooled human plasma, neutralize autoantibodies/cytokines/complement	Anaphylactoid reaction, thromboembolism, aseptic meningitis, renal failure, hemolysis, do not give to IgA deficient pts