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Childhood L. Nandini Moorthy, MD MS Associate Professor of Pediatrics, Div. of  Rochester Epidemiology Program Project , RWJMS‐Rutgers, New database, an incidence of 13.9 cases of Brunswick, NJ juvenile rheumatoid arthritis (JRA) per 100,000 per year was reported  Incidence rate estimates ranging from 0.008‐0.226 per 1000 children, and prevalence from 0.07‐4.01 per 1000 children  83,000 ED visits per year!

 A 2007 CDC study; Sacks JJ, Helmick CG, Luo YH, Ilowite NT, Bowyer S. Prevalence of and annual ambulatory health care visits for pediatric arthritis and other rheumatologic conditions in the United States in 2001–2004. Arthritis Care Res 2007;57(8):1439–1445.

Nandini 2015

Genetics of JIA Complex genetic trait ‐ multiple genes interact to result in a specific phenotype. 1. Asthma Monozygotic twin concordance rates ‐25% and 40% 2. Congenital heart disease Prevalence of JIA among siblings of probands ‐ 15‐ to 30‐fold 3. Cerebral palsy greater than that of the general population 4. Diabetes HLA‐DR accounts for only about 17% of the genetic burden 5. Epilepsy of JIA, which suggests that other variants within and outside 6. Childhood arthritis the MHC play a role in susceptibility

More children have arthritis than those with muscular dystrophy, cystic fibrosis and sickle cell combined.

Histopathology PATHOGENESIS Hyperplastic Synovium Disequilibrium of Cytokines Pannus

Arthroscopic view

Nodular Tendonitis

Pro-inflammatory Anti-inflammatory

Feldmann M, et al. Cell. 1996;85:307‐310.

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Key Actions Attributed to Cytokines

 Objective arthritis in ≥ 1 joint(s) for ≥ six IL‐6 weeks  Children ≤ 16 years  ≥ 6 mo necessary to examine the clinical features [exception: SoJIA]

IL‐6

Recognition of each phenotype early is critical! IL‐6 Poor growth, anemia Different courses, complications, treatments and prognosis… IL‐1 : , bone & cartilage destruction

1. Oligoarthritis (50% of cases)‐ persistent and extended  2 year old Caucasian girl comes in limping to your office 2. Polyarthritis (30‐40% of cases) ‐RF‐ve and RF+  She has a swollen knee  Mother noticed it a couple of weeks ago while 3. Systemic arthritis (10‐15% of cases) giving her a bath‐ she initially thought her girl was chubby 4. Psoriatic arthritis (usually –ve RF)  Mother recalls she has been limping in the mornings for a few months and has asked to 5. Enthesis‐related arthritis be picked up (ILAR classification)

Reviewed in TJAL, Classification of juvenile arthritis UpToDate, March 2015

 Commonest subtype (›50%) • Swollen joint (warm, not red)  1‐5 years of age, peaks at 2‐3 yrs of age • Limp or an abnormal gait  Girls > boys • Rarely complain of pain  Walks funny in the mornings but then is alright • No constitutional symptoms  Arthritis in ≤ four joints • Routine lab values ‐normal  Commonly affects large joints (knees, • Frequently ANA +ve ankles, elbows) • to dsDNA, Ro, La, Sm,  Usually spares hips  Rarely affects small joints of hands & feet RNP, and RF should be absent

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Two groups:  Dactylitis (more typical of psoriatic arthritis)  Persistent oligoarthritis ‐with 1‐4 joints affected during the 1st 6 months  Children >9 yrs with arthritis involving the hips or knees and of disease enthesopathic symptoms (spondyloarthropathy) st  Extended oligoarthritis ‐1‐4 joints affected during the 1 6 months of  Neoplastic disease (ALL, neuroblastoma) disease who subsequently experience involvement of >4 joints.  Infectious/post‐infectious/reactive Descriptors:  If hip involved, consider:  Age at onset . Toxic synovitis  Pattern of joint involvement (large versus small joints, both large and . Legg Calve Perthes disease small joints with upper or lower limb predominance, and symmetric or . Osteoid osteoma asymmetric disease).  Presence of ANA . Neoplasm  Occurrence of uveitis . Spondyloarthropathy Reviewed in TJAL, Oligoarticular JIA UpToDate, March 2015 . SCFE

 Benign course and prognosis‐ many resolve within 6 mo  NSAIDs approved for use in children with JIA: st st  About 50% remit completely; Recurrences ~ 20% (1 year or 1 5 years) . Naproxen  May progress to . Tolmetin . Persistent oligoarthritis . Meloxicam . Extended‐oligoarticular arthritis . . Chronic destructive arthritis Celecoxib  Risk factors in the 1st 6 mo that identify higher risk . Ibuprofen of progression to extended polyarthritis,  Intra‐articular steroid injection (Remission more than 6 mo in form/erosions, persistent synovitis and disability: 82% of injections, Padeh et al) . >4 joints . Complications‐ infection, subcutaneous atrophy . Symmetric disease  Methotrexate . Ankle or wrist involvement  Biologic agents‐ Etanercept, Adalimumab . Laboratory evidence of inflammation

Reviewed in TJAL, Oligoarticular JIA UpToDate, March 2015 Reviewed in TJAL, Oligoarticular JIA UpToDate, March 2015

Silent, chronic, anterior uveitis  Permanent visual damage >15% of  1/3‐1/2 will have the following affected patients despite therapy. complications: –Mostly ANA positive girls (~ 20%)  Systemic agents: . cataracts – Irreversible damage & blindness ▪ glucocorticoids . synechiae –Ophthalmologic monitoring (AAP schedule) ▪ methotrexate . glaucoma –+ve ANAs and <6 yrs at diagnosis ‐at the greatest risk of developing ▪ cyclosporine . band keratopathy uveitis ▪ mycophenolate . macular ▪ adalimumab . legal blindness ▪ Infliximab . male gender ‐ risk factor for a more ▪ rituximab poorer outcome

Band keratopathy and synechiae

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 Affected limb longer  11 to 36% with persistent oligoarticular JIA  <1 cm are probably not clinically significant  >1 cm‐associated with increased strain on the shorter leg, and  perhaps accelerated degeneration of the contralateral hip. Growth retardation was more likely in children who required treatment with disease modifying rheumatic drugs  Appropriate lift in the opposite shoe (DMARDs) than those who were treated with intra‐articular  Orthopedic consultation before skeletal maturity glucocorticoid injections alone  Stapling‐surgically close the distal tibial epiphysis in the leg which is longer and allow catch‐up growth on the opposite side.  Risk factors:  Knee is most commonly involved‐ since two‐thirds of . younger age at onset longitudinal growth occurs around this joint . elevated ESR  Joint injection with glucocorticoids early in the course of oligoarticular JIA may prevent leg length discrepancies. Reviewed in TJAL, Oligoarticular JIA UpToDate, March 2015

2. The girl who is tired, and cannot button her shirt

 Risk generally small in patients with JIA •12 year old AA girl has been very tired for the last several months  An increased risk in those with extended •She walks like grandma in the morning oligoarticular disease •Has difficulty getting ready in class •Fingers look puffy •Teacher says she gets tired while tired while writing

 20% ‐20% of JIA  Begins similarly to oligoarticular disease with 1‐2 joints affected  Girls > boys  Spreads to involve ≥5 joints during the 1st 6 mo after onset.  2‐5 years & 10‐14 years  Often intercurrent infection precipitates a dramatic increase in symptoms  Progressive involvement of >/=5  Rapid onset of polyarthritis –likely reactive arthritis joints in the first 6 months  Relentlessly progressive with relapses with an increasing number of involved joints  AM stiffness and fatigue  Symmetrical involvement with the knees, wrists, and ankles most frequently affected  see fig  May have low‐grade  Dactylitis followed by progression to polyarticular Fingers & toes exhibit both peri‐ disease over several months  Do not appear systemically ill articular & soft‐tissue swelling  Uveitis –ANA positive are at greater risk Ruddy: Kelley's Textbook of Rheumatology, 6th ed  Tenosynovitis of flexor tendon Rare to see children <10 years of age with a +ve RF Reviewed in TJAL, Polyarticular juvenile idiopathic arthritis: Clinical manifestations and  Arthritis intermittent or persistent sheaths diagnosis UpToDate, March 2015

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PoJIA‐ hand X‐ray •Soft‐tissue swelling ‐3rd MCP •Joint space is narrowed  Rapid onset of inflammation in multiple joints •Extensive periosteal new bone formation  Often many small joints of the hands and feet within 2‐3months of the 3rd metacarpal  Pain in the small joints  Commonly affected ‐ fingers, wrists, elbows, the cervical spine, hips, knees, and ankles  +ve RF group: . female . severe disease . may be HLA‐DR4‐+ve and/anti‐CCP ab +ve,  Most children RF‐ve: Early carpal fusion . Rare to have +ve CCP ab (more often in JIA) Reviewed in TJAL, Polyarticular juvenile idiopathic arthritis: Clinical manifestations and diagnosis UpToDate, March 2015 Hallmark of JIA posterior cervical fusion

PoJIA‐Differential diagnosis

Infectious Other rheumatic diseases  Arthritis in >4 joints during the 1st 6 mo . Viral (parvo?) . Psoriatic arthritis  Labs may be nl or suggest an inflammatory state: . Septic . Spondyloarthropathie . Elevated ESR (≥40 mm/hr) . Lyme . IBD . Anemia (Hgb≤11 g/dL) . Other . Celiac disease • Serum sickness . SLE . Hypergammaglobulinemia • Rarer causes . Dermatomyositis . +ve ANA (40‐50%) –younger . Malignancy . Sarcoidosis . 5‐10% RF + . Immunodeficiencies . Scleroderma . Leukocytosis . Vasculitis

 Flexion contractures  OCULAR ‐ Uveitis (14%)  Difficulty with ambulation . More likely in ANA +ve and RF –ve and < 6 yrs old  Bony erosions and joint destruction  Vertebral compression fractures  Severe disability requiring total joint replacement  VISCERAL‐ Internal organ involvement is rare  . TMJ involvement Ruddy: Kelley's Textbook of Rheumatology, 6th ed Chronic anemia  Osteopenia . Malaise,  Weakness . Systemic complications that may occur in adult RA such as  Short stature vasculitis and pneumonitis, are uncommon in children with polyarthritis

Reviewed in TJAL, Polyarticular juvenile idiopathic arthritis: Clinical manifestations and diagnosis Reviewed in TJAL, Polyarticular juvenile idiopathic arthritis: UpToDate, March 2015 Early carpal fusion (more often in JIA) Clinical manifestations and diagnosis, UpToDate, March 2015

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 Low likelihood of developing spontaneous remission (over 50% may have active disease after years despite meds) Aggressive therapy  RF +ve ‐ probably represent the early onset of adult type disease NSAIDS . At risk for progressive arthritis and the STEROIDS complications associated with adult‐onset RA DMARDS . May have CCP, seen in adults w/ severe RA (Methotrexate, . Studies of early aggressive therapy in adults leflunamide) with RA confirm better responses and improved joint preservation BIOLOGICS PoJIA‐ hand X‐ray . Earlier damage Soft‐tissue swelling ‐3rd MCP Joint space is narrowed Extensive periosteal new bone formation of the 3rd metacarpal

Is Bigger Better?

Ibuprofen  Toxicity  Ineffective for axial disease  Folic acid addition  Genotyping (677TT genotype is associated with elevated risk of methotrexate (MTX) toxicity (Tukovaj 2010 J Rheum) Etanercept  Higher levels of the phagocyte activation marker myeloid‐ related proteins 8 and 14 heterocomplex (MRP8/14) were at greater risk of relapse after discontinuation of methotrexate (Froell et al 2010 JAMA)  Risk of malignancy and nodulosis (Muzaffer et al, Padeh et al)

Courtesy: Dr. Prahalad S, Emory Univ.

Etanercept (Enbrel) –soluble Trial of aggressive therapy in PoJIA, receptor for TNF Etanercept consists of the Wallace et al, Arthritis and 2012 extracellular ligand‐binding Recombinant Fusion Dimeric Protein sTNFR portion of the human TNF receptor linked to the Fc •Multicenter prospective RCT in 85 children with portion of human IgG1. The Fc PoJIA Human p75 component of etanercept TNF receptor contains the Ch2 domain, the •Arm 1: Etanercept+ MTX+prednisone Ch3 domain and hinge region, but not the Ch1 domain of •Arm 2: MTX S S S S Hinge region IgG1. •By 6 mo clinically inactive disease was achieved SS in 40% of patients from arm 1 and 23% of IgG1 Fc

S patients from arm 2 (p=0.088) S •After 12 mo, clinical remission was achieved in 9

TNF pts in arm one and 3 patients in arm 2 (p=0.053) Etanercept (Enbrel) TNFR TNF

Target cell

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Infliximab (Remicade)

Activated macrophage

TNFR

Target cell

•Binds and inactivates TNF alpha •Given as IV infusion at weeks 0, 2, and 6 and then every 8 weeks thereafter. • Usually given with Methotrexate

Aggressive combination drug therapy in very early polyarticular JIA ‐TynjäläP et al 2011 ADALIMUMAB •54‐week multicenteropen‐label clinical trial •60 DMARD‐naive patients were randomly assigned into 3 treatment arms: • Recombinant humanized Fully humanized TNF alpha Mab with – infliximab plus methotrexate (TNF) human derived heavy and light chain – methotrexate alone (MTX) (100%) anti TNF variable regions and human IgG constant regions (Tynjala 2008, Vazquez 2006, – methotrexate, sulphasalazine and hydroxychloroquine (COMBO) •Given by subcutaneous •Mean age : 9.6±0.4 years; duration of JIA 1.9±0.2 months Foeldvari 2007, Lovell 2004). •Number of active joints 18±1. injection every other •ACR Pedi 75 was achieved in: week. – 100% (19/19) of patients receiving TNF –65% (13/20) on COMBO (95% CI 44% to 86%) • Pediatric trial in JIA –50% (10/20) on methotrexate (95% CI 28% to 72%) p<0.0001 patients (Lovell et all • 13 receiving TNF (68%; 95% CI 47% to 89%) achieved inactive disease •8(40%; 95% CI 22% to 63%) on COMBO 2008 NEJM) suggest a •5 (25%; 95% CI 6% to 44%) on methotrexate did (p=0.002) favorable response. • Patients on TNF spent a mean 26 weeks (95% CI 18 to 34) with inactive disease, longer than did those receiving COMBO or methotrexate

Anti TNF agents‐ adverse events

• Generally effective  A soluble fusion protein •Safe and well tolerated –Injection site reactions, URI symptoms  Extracellular domain of human CTLA4, linked to a modified Fc portion (hinge CH2 and CH3 domains) of human IgG1 • When on one of these agents, infections should be treated early

•Serious infections (Glucocorticoid likely risk factor –Bukelman etal)  Targets T‐cell activation by disrupting CD28 costimulation pathway –Tuberculosis – Opportunistic infections (e.g. histoplasmosis, listeriosis,  Inhibition of immune responses by coccidiodomycosis, PCP) CTLA4‐Ig molecules can result in downregulation of both naive and –Non‐opportunistic infections memory T‐cell proliferation initiated by: • Demyelinating events . dendritic cells • Autoantibodies . cytokine production • ?Malignancies (MTX‐ a risk?; rate of malignancy higher in JIA . inhibition of humoral immune response compared to general population, Bukelman et al)  Trial by Ruperto et al (Lancet 2008) 41 showed efficacy

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Tocilizumab (Actemra)

• A humanized anti‐human interleukin‐6 (IL‐6) receptor  Chimeric structure monoclonal antibody  Binding regions from original murine anti‐ human CD20 • Binds to membrane‐bound and soluble IL‐6 receptor,  Consists of variable regions of Ig heavy and light chains, are fused to human IgG1 heavy‐ inhibiting IL‐6 inflammatory signals. chain and human kappa light‐chain constant regions. • A phase 3 randomized trial of tocilizumab demonstrated  Fc portion from human IgG1 was selected for effectiveness in children with polyarticular JIA >2 years of age its ability to fix complement and activate who had inadequate response to Methotexate over 6 mo antibody (Brunner et al 2014)

• FDA approved for JIA

Other Disease Modifying Drugs

• Leflunomide  Chronic synovitis, flexion contractures, weakness, and difficulty with •Not superior to MTX (Silverman et al) ambulation ‐physical therapy, joint replacement •Hepatic toxicity  TMJ‐ injections, systemic , surgical correction • Sulfasalazine (van Rossum 2007) • Does not prevent erosive disease  Uveitis (5%) ‐topical corticosteroids, systemic medications • SJS, Counts, LFTs  Osteoporosis and growth retardation — Growth hormone therapy (Rooney et al, Bechtold etal, Simon et al, Saha et al) have shown some • Systemic glucocorticooids improvement in bone mineral content and accelerated linear growth. • Low‐dose glucocorticoids (<0.25 mg/kg/d prednisone/equivalent) . Associated w/increased deformities and scoliosis • low dose corticosteroids beneficial with DMARDs in adult RA (Svensson et al) . Alendronate (Bianchi et al, Thornton et al) may be useful in • Intra‐articular glucocorticoids osteoporosis

• Cyclosporine, Azathioprine  Counseling, School issues • ? JAK inhibitor? Reviewed by TJAL Polyarticular JIA: Management , UptoDate, Lit review current through March 2015

3. The boy whose shoes do not fit •13 year old boy with foot pain and said that his 10‐19% of all pts classified as JIA (Demirkaray et al, Solau‐Gervais et al, Yimaz et shoes never fit. al, Saurenmann et al) •Dad says that he limps during and after soccer Arthritis and enthesitis (jn 75%), or arthritis and 2 or more of the following: •Dad says that he walks like grandpa and is  Sacroiliac joint tenderness  Inflammatory spinal pain stretching in the mornings. He is usually feels  Human‐leukocyte antigen (HLA)‐B27. better in school  +ve family history of anterior uveitis w/ pain, spondyloarthropathy, or IBD •You see that he has  Anterior uveitis associated with pain, redness, or photophobia swollen achilles and The descriptors for this group include:  Age at onset. a swollen foot  Pattern of large or small joint involvement.  Presence of axial involvement, symmetry, and progression to polyarthritis

TJAL, UpToDate, March 2015

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SPONDYLOARTHROPATHY

Spondyloarthropathies •8‐12 yrs, males •Lower extremity •Axial pain, SI involvement and stiffness AS •Frequency is about 13% Reactive • Recurrent sprains and strains arthritis • Recurrent hip pains • Heel pain, plantar fasciitis, tarsal swelling •Onset‐ oligoarticular, asymmetric Acute anterior iritis Undifferentiated • Dactylitis spondyloarthropathy •HLAB27 +ve (90% AS, 60% spondyloarthropathies) Psoriatic •ESR IBD Arthritis •GI, Skin, Uveitis associated • Differential diagnosis‐IBD, injuries, mechanical disorders (LCP, SCFE) arthritis (Taurog et al, Cabral et al, Jacobs et al)

Prognosis

 NSAIDs ‐Indomethacin, diclofenac, piroxicam, and tolmetin •Presence or absence of the allele HLA‐B27 (Taurog  Those with systemic manifestations, such as fatigue or anemia, who do not respond to typical NSAIDs within 3‐6 months may improve with sulfasalazine et al) (Huang et al)  Patients w/ HLA‐B27‐ve spondyloarthropathies rarely require treatment with immunosuppressive agents •Other risk factors for development of sacroiliitis  Aggressive therapy with anti‐TNF agents for peripheral arthritis or enthesitis include(Pagnini et al, Stoll et al, Flato et al): unresponsive to treatment or who develop sacroiliitis  Persistent peripheral synovitis –higher numbers of active joints and entheses at  DMARD (methotrexate or leflunomide)(van der Horst‐Bruinsma IE) disease onset  Anti‐TNF agents may also prevent disease progression  Thus, anti‐TNF agents are preferred in children with persistent peripheral –hip arthritis synovitis and/or axial arthritis. –and elevated ESR (Rowchoudhry et al, Haibel et al, Henrickson et al, Tse Et al, Sieper et al, Sulpice et al, Otten et al)

4. The little girl with a swollen toe

•Mother said that she played in the beach 5 months ago, and that day she noticed that the 4th  Long term follow up required as many with sacroiliitis will develop AS toe was a little red and puffy within 10 years (Genseler et al) • Sometimes it gets less puffy •If mother accidentally presses the toe, she cries  10 of 58 patients had evidence of sacroiliitis after an average of f 5 •Mother brought her to your office but does not years (Jacobs et al). think she should get any medications. It is only a toe…

Bamboo spine in Ankylosing spondylitis

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7% of all JIA Includes two groups:  Wide variation in presentation  Children with arthritis and psoriasis. . mild enthesitis to polyarthritis and axial involvement  Children with arthritis and a positive family history of psoriasis in a first‐degree relative, plus dactylitis or appropriate fingernail abnormalities (eg, pitting or . 1 or more joint onycholysis)  Psoriasis may not be evident initially Descriptors include:  Psoriasis occurs in 0.5 to 1% of all children, rising to 2‐3% in  Age at onset adulthood (Ferrandiz et al, Gelfand et al, Kurd etal)  preschool similar to Oligo JIA (mostly girls, +ve ANA )  Dactylitis (sausage digits), wrist . Middle‐late childhood similar to adult‐onset PsA (M:F ~1:1)  Arthritis mutilans ▪ Tend to develop enthesitis, spinal or SI disease  Constitutional symptoms  Disease course (pauci/polyarthritis)  Presence of ANA and uveitis

(Reivewed in UpToDate, P Nigrovic, Psoriatic juvenile idiopathic arthritis: Pathogenesis, clinical manifestations, and diagnosis, TJAL, UpToDate, March 2015 Lit review current date March 2015)

 Extinguish synovitis in order to avoid damage to cartilage and bone. Peripheral  Critical for the growing skeleton, where injury to growth plates and arthritis growth centers can cause permanent derangement of bone shape and length (Simon et al, Ansel et al)

 Absence of pain and lack of functional impairment are imperfect guides to successful therapy, since children may adapt remarkably well to Cutaneous Psoriatic Spondylitis ongoing arthritis (McGhee et al) Disease JIA  >80% treated with MTX

 >50% receive anti‐TNFs

 NSAIDS, Intra‐articular glucocorticoids, Uveitis DMARDS, Abatacept

Pencil‐in‐cup appearance

 Clinical remission (on ) in the majority of patients in both older and younger subgroups (Stoll et al) • Still’s disease •~ 10‐20% of JIA  Among patients with psJIA followed for at least 5 years, persistently diagnoses active disease in 70% percent and physical activity limitations in 1/3 (Roberton et al) • Affects boys & girls equally  Patients with psJIA followed for at least 15 years demonstrated worse •Half of them have onset functional outcomes than patients with oligo‐ or polyarticular JIA, and 33 in childhood percent still required DMARD therapy (Flato et al) •High spiking quotidian at least 2 weeks,  Poor outcomes and long‐term disability were seen principally in patients with arthritis in one or who experienced a long delay in diagnosis or in whom effective therapy more joints  This form is now widely thought to be an was not instituted •Often with chills autoinflammatory condition unrelated to other forms of childhood arthritis and requiring different therapy

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Often appear very ill when febrile, but seem drastically improved when afebrile

• Salmon‐colored evanescent

• Erythematous

• Macular rash

• Trunk and proximal extremities

• Non‐pruiritic

• Migratory

• Fleeting nature

• Elicit Koebner’s phenomena

Rash of sJIA mimics parvoviral and other SJIA infectious processes •Systemic symptoms – Anorexia, arthralgias, hepatosplenomegaly, lymphadenopathy – Serositis • Arthritis occurs concomitantly or later – Wrists, knees, ankles, hands, hips, C‐spine & TMJ •Labs –Elevation of acute phase reactants –Microcytic anemia –ANA +ve 10% of patients –RF rarely +ve

Differential for FUO

•Infectious and oncologic etiologies  Systemic features may persist for 4‐6 months with varying degrees of • Inflammatory bowel disease joint involvement •SLE  Monophasic/polyphasic/persistent • Vasculitides such as polyarteritis nodosa  Systemic and/or polyarthritis •Other auto‐inflammatory diseases  Can lead to persistent inflammation &/ or chronic destructive arthritis  Micrognathia, c‐spine fusion and destructive hip disease

 Short stature & FTT  Uveitis ‐ rare  Amyloidosis ‐rare in the US  Macrophage Activation Syndrome

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SoJIA‐outcome Amyloidosis

•24 patients <19 years with biopsy‐proven amyloidosis •47 patients with SOJIA with atleast 2 years of disease –5‐year survival rate of the series to be 88% (95% CI 75% to 100%) •43% patients exhibited damage –10‐year survival to be 75% (54% to 92%) –38% with articular –10/24 died during a mean follow‐up of 15.4 years –19% with extraarticular damage –Chief cause of death was related to JIA in 9 patients. –Patients treated with corticosteroids alone after the diagnosis of •The chief determinants of damage were cervical spine amyloidosis had a higher mortality than those taking disease modifying arthritis and corticosteroid usage in the first 6 months of the antirheumatic drugs (p = 0.001). disease course. –Of the 14 patients who were alive, 12 had normal renal function (3 of them • Damage scores correlated with number of joints with limited had undergone renal transplantation), one had renal insufficiency, and one motion, and functional disability {Russo, 2008}. had proteinuria. {Immonen, 2008}

HPI 5. 8 y/o girl with fevers • Appears systemically ill

Normal • Arthralgia LABS HD 1HD 2 8 y/o female presented at the time of her initial diagnosis Range with a 13 day history of fevers, polyarthritis and rash and • Generalized myalgia WBC 15.7 16.5 4‐10 Hb 10.9 10.0 11.5‐15.5 lymphadenopathy • Rash ESR 94 96 0‐20 • Hepatosplenomegaly CRP 20.7 20.7 0.0‐0.7 AST 41 34 12‐45 • Lymphadenopathy ALT 80 57 3‐40 • Muscle tenderness to FERRITIN ‐‐‐ 1,545 20‐175 palpation TRIGLYCERIDES ‐‐‐ 128 35‐114 • Serositis 125‐220 LDH ‐‐‐ 419

D‐dimer ‐‐‐ 1,716 0‐243

The next day after her Treatment and course appointment… •Was treated with: Lab Tests Lab tests Results Lab Normal Performed Solumedrol x 3D, Results Range WBC 8.8 Tociluzimab x 1D, At Clinic •She had persistent Hb 12.2 Anakinra x 1D WBC 16.4 4‐10 high fevers which ESR 16 Hb 12 11.5‐15.5 lasted for 3 days (tmax 104.2°F) ESR 25 0‐20 AST 468 •At her follow up visit at . Fatigue Rheumatology clinic (in CRP 3.9 0.0‐0.7 ALT 542 . Diffuse Headache 2 weeks after AST 23 12‐45 FERRITIN 10,880 . Redness over face, treatment), she ALT 15 3‐40 TRIGLYCERIDES 183 remained afebrile and palms FERRITIN 1447 20‐175 asymptomatic LDH 25,062 D‐dimer 0.8 0‐243 D‐dimer 468

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Macrophage activating syndrome Defect in NK Cells

•Incidence 6.7%‐‐13%

•MAS in active SJIA and SJIA in remission

• Mortality rate ranges between 8–22%

• Genetic associations: Mutated perforin gene (PRF1); Polymorphism of both MUNC13‐4; Interferon regulatory factor 5 (IRF5) genes

(Gurion R, Lehman T and Moorthy LN, 2012 Journal of Inflammation 2012; reviewed in Kelly et al, Curr Op Rheum 2007)

Macrophage hemophagocytosis in the bone marrow Increased CD163 staining of the bone marrow

MAS Management Macrophage activating syndrome Triggers –Steroids ABNORMAL •Most commonly – Anakinra SoJIA – Cyclosporin A • Decreased NK cell •EBV or other viral function –IVIG • Abnl perforin expression etiologies –Etoposide • Medications – Supportive care (Anakinra, NSAIDS) – Trigger avoidance • Malignancy NORMAL

Production of IL‐1b by activated SJIA PBMCs (Pascual et al) ANAKINRA (a) temperature; (b) active joint count; (c) WBC; (d) Hgb;(e) platelets; (f) ESR in 9 SJIA patients. (Pascual et al)

Anakinra: IL‐1 Receptor antagonist blocks cellular activation (Lovell 2005)

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The Role of medications in JIA Pathology

MTX, X Steroids X Abatacept  NSAIDS 2008 Lancet) Prostaglandins etc  Systemic steroids  Thalidomide (TJAL 2007) COXX NSAIDS Etanercept  Anti‐IL1  Biologics Arachidonic acid Infliximab X . Anakinra  Cyclosporine Adalimumab X Anakinra . Canakinumab (Ruperto et  Methotrexate X al, Beneditti 2012 NEJM)  Bone marrow . NEJM 2012) transplantation (Brinkman et al) Anti‐IL6 . Rilonacept MRA

 Anti‐IL6 Courtesy: Dr. Prahalad S, Emory Univ. . Tocilizumab (Yokota et al

Remission and disability in JIA

 1/5th with disability (Solari)

 Growth failure most common extra‐articular manifestation (Sarma)

 The chief determinants of poor functional ability were younger age at disease onset and a greater restricted joint count (Magnimanzoni)

 Motor performance and functional ability (van der Net 2008)

 Physical activity (Lelieveld et al)

 HRQOL (Oliveira, 2007)

 Mental health (Mullick)

 Pain, coping, podiatry, GI From Prahalad S, Current Medical Literature 2006

. CBC w/ diff w/ platelets . IgA, IgG, IgM . CMP . TSH . UA . Anti‐TTG IgA . ESR . Varicella IgG . CRP . TB testing . ANA‐ IFA . CXR . RF  Guided by clinical . Anti CCP antibody presentation, past medical . HLA B 27 history and family history . ASLO . Lyme WB . Ferritin, LDH, Ddimers

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Control of Disease Progression Should Start Early to Young girl with stiff knee Limit Joint Damage Limp in morning; gone by noon Think of JIA Disease onset Oligo JA End Stage Early Established No more than four joints first One third may extend.

Radiographic damage Critical Window of Poly JIA Opportunity Progressive erosive joint disease Five joints in first six months K Impairment of growth & development Few teens have RF E Chronic eye disease Y Psychosocial issues Naproxen used first S Methotrexate may be next T Advocate early aggressive therapy O Steroids in few joints N Ophthalmologic monitoring E Medication monitoring Three agents block this S PT, OT, nutrition & counseling Haikus by Dr. Prahalad S, Tumor necrosis factor Emory Univ. Enbrel is one such

For my garden is the garden of children Cometh naught there but golden hours, For the children are its joy and its sunshine, And they are its heaven sent flowers. Sir Gregory Frederick Still

May 2015 is arthritis awareness month!!!

LNM2015

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