In the normal joint there is a balance between proinflammatory and anti-inflammatory events. A disequilibrium between pro- and anti-inflammatory cytokines within the joints of patients with rheumatoid arthritis exists. Both types of cytokines are up-regulated, however the balance is in favor of the proinflammatory cytokines. Some of these cytokines play a prominent role in the pathogenesis of RA. Proinflammatory cytokines such as TNF and IL-1 induce inflammatory mediators like prostaglandins, reactive oxygen species, and nitric oxide. They are also important in the connective tissue breakdown of cartilage, inhibition of matrix synthesis, and within bone via effects on osteoclasts and osteoblasts. Anti-inflammatory mediators such as IL-10, IL-1ra (IL-1 receptor antagonist) and sTNF-R (soluble TNF receptor) also exist and may play pro- and anti-inflammatory roles.
Systemic JIA: Where Are We
Systemic Juvenile IdiopathicArthritis:Where are We?Karen Onel, M.D.Division of Pediatric RheumatologyUniversity of Chicago
A child goes to see thedoctor with a history offever. They have knee painand swelling too!What’s wrong?How can we figure this out?Is this Systemic JIA?
Juvenile Idiopathic Arthritis Most common rheumatic disease of childhood Important cause of disability and blindness Syndrome of diverse etiologies--Idiopathic Criteria – Age less than 16 – Arthritis (vs. arthralgia)-Joint inflammation not just pain – Duration > 6 weeks
Idiopathic We still don’t understand why children get systemic JIA Not likely genetic-rare to have 2 family members involved Some people think it belongs with the autoinflammatory and periodic fever syndromes
Types of JIA Oligoarthritis Extended Oligoarthritis Polyarthritis (either RF+ or -) Psoriatic Arthritis Enthesitis-related Arthritis Systemic Onset
Epidemiology Incidence--10/100,000/year in US Prevalence--100/100,000 children in US Age at onset extremely rare prior to 6 months Peak ages-- – 1-3 years (girls) – 9 years (boys and girls) Lower extremities most often involved
Much more about SystemicJuvenile Idiopathic ArthritisStill’s DiseaseRarest subtype-at most 10%
Lots of things give kids feversand joint pains and jointswelling Infections – Infections in the bone or joint Cancer – Especially cancer that involves the bone marrow Leukemia, lymphoma, neuroblastoma Other rheumatologic illness – Lupus, Dermatomyositis, Vasculitis – Reactive Arthritis – Polyarticular JIA can present with fevers
Systemic Onset JIA-Systemic Arthritis Joints may or may not be involved at the beginning Sex ratio: equal May occur at any age (even adults) Uveitis rare Systemic signs (fever, rash, abnormal labs) may precede the development of arthritis by years (even 10!)
Clinical Features Diagnostic hallmark--high spiking fevers with daily return to normal
Clinical Features Classic rash—usually flat red spots that come and go but can be hives Rash is transient--Koebner’s phenomenon Rash can be very itchy
Clinical Features Joints can be severely involved Often very severe hip involvement Joint and muscle pain may be worse when children have fever
Clinical Features Heart and lungs can be involved Liver and spleen can be involved as well Enlarged lymph nodes are common
Laboratory Evaluation Lab tests show a great deal of systemic stress- ESR, platelet and white blood cells can be very elevated. It would be surprising if they were normal at the beginning Anemia of chronic disease is common and children may not respond to oral iron supplementation.
What about MacrophageActivation Syndrome Acute Hemophagocytic Syndrome – normal, activated macrophages (scavenger white blood cells) eat up red and white blood cells, as well as platelets. – Liver function tests, ferritin and markers of coagulation (blood clotting) are often abnormal – Often early in disease or with flares – Viruses probably play a role, especially EBV which causes mono – Treated with steroids, cyclosporine as well as other medications
How do we make thediagnosis? Above all, JIA is a clinical diagnosis Does the patient have swollen joints not just joint pain? How long has the swollen joint been there? Are they below 16? Do they have any other medical problems? What is the fever pattern Do they have signs of MAS? Did you look for other possibilities?
What about labs? ANA is not useful to make the diagnosis of Systemic JIA but helps to rule out other diseases RF useful for identifying RF+ poly but should be negative here Expect acute phase reactants to be abnormal in active Systemic Arthritis Exclude other causes of joint pain and swellingBUT Systemic JIA is a clinical disease—there is not one lab test that definitively makes the diagnosis
Consensus Treatment PlansDefinition of Systemic JIAPatient should be/have1. Age 6 months to 18 years2. Fever for at least 2 weeks†3. Arthritis in ≥1 joints (6 weeks duration not required)‡4. At least 1 of the following: a. Evanescent erythematous rash b. Generalized lymphadenopathy c. Hepatomegaly or splenomegaly d. Pericarditis, pleuritis, and/or peritonitis
Consensus Treatment Plans- ExclusionsPatient should not have 1. Infection, including concomitant active or recurrentchronic bacterial, fungal, or viral infection at presentation,nor underlying infection that may mimic initial presentationof systemic JIA2. Malignancy From De Witt, et al, A C and R, 64: 1001-1010, 2012
NSAID’s Even in the biologic age, NSAIDs are important. Gastritis is common but ulcers are rare Liquid preparations--ibuprofen, naproxen, meloxicam and indomethacin Others can be dissolved in water or crushed which destroys the enteric coating
Methotrexate We still don’t really know how it works Use of folic acid does not interfere with function like it does for cancer Very slow onset of activity—often 2-3 months Sq form has better absorption but hard to find currently due to drug shortage. Nausea is common but can and should be treated Risk of liver toxicity. Need to follow Liver function tests every 2 months at least
Corticosteroids Continue to play an important role in the treatment of JIA Growth side-effects especially problematic in pediatrics Alternate day steroids generally not effective at controlling inflammation Can be given by mouth, intravenous or in the joint —depends on what you need
Cyclosporine From the transplanters but at lower doses Prevents T cells from becoming activated, decreasing inflammation Mostly useful in the setting of MAS where it plays a critical role
Other DMARDs Thalidomide Hydroxychloroquine Azathioprine Leflunamide Sulfasalazine
TNF Blockade TNF, made by macrophages and T cells is clearly important in the pathogenesis of synovitis and joint destruction Five available agents to interfere with TNF signaling (two are approved for kids with JIA) Response in 70% polyarticular disease within 4 weeks with sustained response—Getting people off is more complicated BUT-doesn’t work for Systemic JIA
Role of IL-1 IL-1 is responsible for bone and cartilage destruction in arthritis IL-1 causes white blood cells to flock to site of infection and to reset the center of the brain responsible for regulating body temperature leading to fever. IL-1 is, therefore, called an endogenous pyrogen IL-1 is also responsible for increased pain associated with fever.
Anikinra (Kineret TM ) Anakinra is a recombinant version of the human Interleukin-1 receptor antagonist (IL- 1Ra) and blocks IL-1 by competitively inhibiting IL-1 binding to the Interleukin-1 type I receptor (IL-1RI) Given once daily as a sq injection Most common side effect is injection site pain
ANAKINRA: CLINICAL USESUsed in RA, but especially useful in: Systemic-Onset Arthritis Gout Cryopyrin-associated periodic syndromes (CAPS): • Muckle-Wells syndrome • Chronic infantile, neurologic, cutaneous and articular syndrome (CINCA) / neonatal-onset multisystem inflammatory disease (NOMID) • Familial cold autoinflammatory syndrome
Anakinra and systemic JIAFrom Nigrovic, et al. A and R 63:545-555, 2011
New Il-1 blockers Rilonocept (ArcalystTM) Canakinumab (IlarisTM) These drugs are currently indicated for the treatment of CAPS but testing in Systemic JIA is ongoing
Role of IL-6 Endothelial cells Mesenchymal cells, Monocytes/ fibroblasts/ macrophages synoviocytes T-cell activation IL-6 Hepatocytes Acute-phase response Maturation of Hepcidin, CRP megakaryocytes ↓ CYP450 B-cells Osteoclast activation Bone resorption Thrombocytosis Auto-antibodies (RF) Hyper-γ-globulinemiaAdapted from 1 Firestein GS. Nature. 2003; 423:356-361.2 Smolen JS, et al. Nat Rev Drug Disc. 2003; 2:473-488. Disc.
Tocilizumab (Actemra TM ) Tocilizumab is a humanized, monoclonal antibody that targets the IL-6 receptor and inhibits IL-6 signaling It is indicated for the treatment of active systemic juvenile idiopathic arthritis in patients 2 years of age and older. It is given intravenously every two weeks Common side effect upper respiratory tract infection, headache, nasopharyngitis and diarrhea. Can cause abnormal liver function tests, decreased white blood cells, allergic reactions, and lipid problems
Actemra and Systemic JIAJIA absence of fever at Week 12 (TENDER TRIAL)
Rituximab (Rituxan TM ) Currently indicated for relapsed or refractory lymphoma and RA Used for many different types of rheumatic diseases Binds to CD20 antigen on normal and malignant pre-B and mature B cells One study showed potential for its use in Systemic JIA
Maybe we just need to knowwhich path to follow… CARRA CONSENSUS TREATMENT PLANS
Stem Cell Transplant When all else fails, autologous stem cell transplantation has been used successfully. Should be done by a center with experience
Prognosis Better each year!!! 70-90% children with JIA have good outcome without serious disability The hardest part is getting children to be medicine free- that time will come! Delay in medical or physical therapy and undertreatment are associated with poor prognosis