Recent Advances In The Management Of Juvenile Idiopathic Arthritis

Recent Advances
In The Management Of
Juvenile Idiopathic Arthritis
Dr C Naveen Kumar,
1st Year PG,
Department of Pediatrics
Dr Naveen Kumar Cheri
S.V. Medical College, Tirupati

Introduction
• The term “rheumatological disorders” refers to diseases that
affect the major connective tissues of the body (e.g. skin,
bone, blood vessels, cartilage and basement membrane).
• Juvenile Idiopathic Arthritis (JIA) is the most common
pediatric rheumatologic disease. It is associated with
significant long term morbidity.
• It was previously called as, Juvenile Rheumatoid Arthritis
(by ACR – American College of Rheumatology) or Juvenile
Chronic Arthritis (by ELAR – European League Against
Rheumatism).

Definition
International League of Associations for Rheumatology
(ILAR) proposed uniform definition and classification criteria
for JIA.
• Arthritis in ≥ 1 joints
(Swelling OR effusion OR the presence of 2 or more of the
following signs: limitation of range of motion, pain or
tenderness on motion, increased heat.)
• Age of onset – before 16 years
• Duration ≥ 6 weeks
• Exclusion of other forms of juvenile arthritis

Sub categories
1. Systemic-onset JIA
2. Oligoarticular JIA (Persistent & Extended forms)
3. Polyarthritis (Rheumatoid Factor-negative)
4. Polyarthritis (Rheumatoid Factor-positive)
5. Psoriatic arthritis
6. Enthesitis-related arthritis
7. Undifferentiated arthritis

Category Definition Exclusions
Systemic-onset
JIA
Arthritis in ≥1 joints with, or
preceded by, fever of at least 2 wk
in duration that is documented to
be daily (“quotidian”) for at least 3
days and accompanied by ≥1 of the
following:
1. Evanescent (nonfixed)
erythematous rash.
2. Generalized lymph node
enlargement.
3. Hepatomegaly or splenomegaly
or both.
4. Serositis.
a)Psoriasis or a history of psoriasis in the patient or a
1st-degree relative.
b)Arthritis in an HLA-B27–positive boy beginning
after the 6th birthday.
c)Ankylosing spondylitis, enthesitis-related arthritis,
sacroiliitis with inflammatory bowel disease, Reiter
syndrome, or acute anterior uveitis, or a history of
one of these disorders in a 1st-degree relative.
d)Presence of Ig-M RF on at least 2 occasions at least
3 months apart.
Oligoarticular
JIA
Arthritis affecting 1-4 joints during
the 1st 6 mo of disease. Two
subcategories are recognized:
1. Persistent oligoarthritis -
affecting ≤4 joints throughout the
disease course.
2. Extended oligoarthritis -
affecting >4 joints after the 1st 6
mo of disease
a, b, c, d (above)
plus
e) Presence of systemic JIA in the patient.

Category Definition Exclusions
Polyarthritis
(RF-negative)
Arthritis affecting ≥5 joints during the 1st 6 months of
disease; a test for RF is negative.
a, b, c, d, e
Polyarthritis
(RF-positive)
Arthritis affecting ≥5 joints during the 1st 6 months of
disease; ≥2 tests for RF at least 3 months apart
during the 1st 6 months of disease are positive.
a, b, c ,e
Psoriatic arthritis
Arthritis and psoriasis, or arthritis and at least 2 of the following:
1. Dactylitis.
2. Nail pitting and onycholysis.
3. Psoriasis in a 1st-degree relative.
b, c, d, e
Enthesitis-related
arthritis
Arthritis and enthesitis, or arthritis or enthesitis with at least 2 of the
following:
1. Presence of or a history of sacroiliac joint tenderness or
inflammatory lumbosacral pain or both.
2. Presence of HLA-B27 antigen.
3. Onset of arthritis in a male > 6 yr old.
4. Acute (symptomatic) anterior uveitis.
5. History of ankylosing spondylitis, enthesitis-related arthritis,
sacroiliitis with IBD , Reiter syndrome, or acute anterior uveitis in a
1st-degree relative.
Undifferentiated
arthritis
Arthritis that fulfills criteria in no category or
that fits in ≥2 of the above categories.

Glossary of terms used in ILAR
classification of JIA
• Arthritis: Swelling within a joint, or limitation in the range of joint movement with
joint pain or tenderness, which persists for at least 6 weeks.
• Nail pitting: A minimum of 2 pits on one or more nails at any time.
• Onycholysis: Detatchment of nail from nail bed.
• Quotidian fever: Daily recurrent fever that rises to 39°C or above once a day and
returns to 37°C or below between fever peaks.
• Serositis: Pericarditis, pleuritis, and/or peritonitis.
• Enthesitis: Tenderness at the insertion of a tendon, ligament, joint capsule, or
fascia to bone.
• Spondyloarthropathy: Inflammation of entheses and joints of the lumbosacral spine.
• Serositis: Pericarditis, pleuritis, or peritonitis, or some combination of the three.
• Dactylitis: Swelling of ≥1 digits, usually in an asymmetric distribution, that extends
beyond the joint margin.
• Inflammatory lumbosacral pain: Lumbosacral pain at rest with morning stiffness
that improves on movement.

Etiology & Pathogenesis
Immunogenetic susceptibility
HLA I, HLA II alleles
Non HLA candidate loci
TNF-α, MIF, IL-6, IL-1α encoding gene polymorphisms
External trigger
Bacterial and viral infections
(Parvo virus B19, Rubella, EBV)
Bacterial or mycobacterial Heat Shock Proteins
Abnormal reproductive hormone levels
Joint trauma
ABNORMAL IMMUNE
RESPONSE

ABNORMAL IMMUNE RESPONSE
Humoral
B-Cell activation
• Complement consumption
• Immune complex formation
• Auto antibodies (ANA etc.)
• Elevated serum Ig
Cell mediated
TNF-α, IL-6, IL-1 are
pro-inflammatory cytokines
Favour TH1 response over TH2
• Enhanced adhesion molecules expression in synovium results in T cell recruitment
into synovium. >> Dense infiltrates, inflammatory synovitis; villous hyperplasia,
hypertrophy, hyperemia & edema; vascular endothelial hyperplasia and pannus
formation.
• Activation of metalloproteinase enzymes which lead to damage of synovium and
adjacent tissues.

Pathogenesis
• All forms of JIA other than sJIA, are disorders of adaptive
immunity – autoimmune disorders. Lymphocytes (TH1 cells)
play major role in the pathogenesis.
• JIA (Systemic onset JIA) is a disorder of innate immunity –
an auto inflammatory disorder. Neutrophils, monocytes &
macrophages play a major role in the pathogenesis.
• Balance between pro inflammatory cytokines (TNF-α, IL-1,
IL-6, IL-8) and anti-inflammatory cytokines (IL-4, IL-10, IL-
1 receptor antagonists) determines the degree of joint damage
(severity of arthritis).

Clinical manifestations
• Involved joints are often swollen, warm to touch, and painful on
movement or palpation with reduced range of motion but usually
are not erythematous.
• Morning stiffness with a limp or gelling after inactivity.
• Easy fatigability and poor sleep quality may be associated.
• Arthritis in large joints, especially knees, initially accelerates linear
growth, causing the affected limb to be longer and resulting in a
discrepancy in limb lengths.
• Continued inflammation stimulates rapid and premature closure of
the growth plate, resulting in shortened bones.

Clinical manifestations - SoJIA
• SoJIA characterized by arthritis, fever, and prominent visceral
involvement, including hepatosplenomegaly, lymphadenopathy,
and serositis (pericarditis).
• Quotidian fever. The fever is often present in the evening.
• Characteristic faint, erythematous, macular rash.
The evanescent salmon-colored lesions are linear or circular and are
most commonly distributed over the trunk and proximal extremities.
Nonpruritic and migratory with lesions lasting <1 hr.
Koebner phenomenon often present.
Heat, such as from a warm bath, also evokes rash.
• Arthritis is classically polyarticular, may be very destructive, and
includes hip, cervical spine, and TMJ.

Clinical manifestations –
Oligoarthritis
• Oligoarthritis large joints of the lower extremities, such as the
knees and ankles . Often only a single joint is involved.
• Involvement of the hip almost never occurs and if present
suggests a spondyloarthropathy or nonrheumatologic cause.
• The presence of a positive antinuclear antibody (ANA) test result
confers increased risk for asymptomatic anterior uveitis, requiring
periodic slit-lamp examination.

Clinical manifestations –
Polyarthritis
• RF positive polyarticular disease resembles the characteristic
symmetric presentation of adult rheumatoid arthritis.
• Rheumatoid nodules on the extensor surfaces of the elbows and
over the Achilles tendons are associated with a more severe course
and almost exclusively occur in RF-positive individuals.
• Chronic Temporomandibular joint (TMJ) disease results in
micrognathia.
• Cervical spine involvement, manifesting as decreased neck
extension, occurs with a risk of atlantoaxial subluxation and
neurologic sequelae.
• Hip disease may be subtle, with findings of decreased or painful
range of motion on exam.

Subtype Peak
age of
onset
Female
:Male
ratio
Arthritis pattern Extraarticular features
Systemic
onset
2-4 Yrs 1:1 Poly articular, often affecting knees, wrists
and ankles; also fingers, neck and hips
Daily fever; evanescent rash;
pericarditis; pleuritis
Oligoarthritis <6 Yrs 4:1 Knees ++; ankles, fingers + Uveitis in 30% of cases
Polyarthritis
RF negative
RF positive
6-7 Yrs
9-12 Yrs
3:1
9:1
Symmetric or asymmetric; small and large
joints; cervical spine; TMJ involvement
Aggressive symmetric polyarthritis
Uveitis in 10% cases
Rheumatoid nodules in 10%,
low grade fever
Psoriatic
arthritis
7-10 Yrs 2:1 Asymmetric arthritis of small or medium
sized joints
Uveitis in 10%, Psoriasis in
50%
Enthesitis
related
arthritis
9-12 Yrs 1:7 Predominantly lower limb joints affected;
sometimes axial skeleton (but less than in
adult, ankylosing spondylitis)
Acute anterior uveitis;
association with reactive
arthritis and IBD

Laboratory findings & investigations
• Elevated WBC and platelet counts and a microcytic anemia
(anemia of chronic disease).
Low WBC count, low platelet count >> suspect MAS (Macrophage
Activation Syndrome)
• Eevated ESR and C-reactive protein (CRP)
• Elevated ANA titers are present in 40-85% of children with
oligoarticular or polyarticular JIA but are rare with SoJIA. It is
associated with increased risk of chronic uveitis in JIA.
• 5-10% of patients with polyarticular JIA are seropositive for RF.
• Anti–cyclic citrullinated peptide (CCP) antibody, like RF, is a
marker of more aggressive disease.
• HLA-B27 is positive in enthesitis related form.

Laboratory findings & investigations
MRI is more sensitive than radiography to early changes most sensitive
radiologic indicator of disease activity. It can depict synovial hypertrophy,
define soft tissue swelling, and demonstrate excellent detail of the status of
articular cartilage and overall joint integrity.
Early radiographic changes of
arthritis include
• Soft tissue swelling
• Periarticular osteoporosis and
• Periosteal new-bone apposition
around affected joints .
Continued active disease may lead
to
• Subchondral erosions
• Loss of cartilage
• Varying degrees of bony
destruction and,
• Fusion.

MANAGEMENT

Management
• Children with JIA are best managed in a specialist multidisciplinary set
up.
Management may include one or all of the following areas:
• Pharmacologic management
• Psychosocial factors, including counseling for patients and parents
• School performance, such as academic counseling, school-life
adjustments, and physical education adjustments
• Nutrition, particularly to address anemia and generalized osteoporosis
etc.
• Physical therapy, to relieve pain and to address range of motion, muscle
strengthening, activities of daily living, and conditioning exercises
• Occupational therapy, including joint protection, a program to relieve
pain, range of motion, and attention to activities of daily living

Pharmacologic management
Primary goals of medical therapy are:
• To eliminate active disease
• To normalize joint function
• To preserve normal growth
• To prevent long-term joint damage
Children with JIA need individualized treatment plans, and
management is tailored according to
• Disease subtype
• Severity
• Presence of poor prognostic indicators, and
• Response to medications.

Commonly used drugs in the present
day treatment of JIA
NSAIDs Steroids
Disease Modifying
Anti-rheumatologic
Drugs (DMARD)
Biologicals
• Ibuprofen
• Naproxen
• Indomethacin
• Meloxicam
• Intra articular
triamcinolone
hexacetonide
• Oral prednisolone
• Topical ocular
preparations
• Intravenous
methyl
prednisolone
• Methotrexate
• Sulfasalazine
• Leflunomide
• Cyclosporine
• Adalimumab
• Etanercept
• Infliximab
• Abatacept
• Toclizumab
• Rituximab
• Anakinra
• Canakinumab
• Rilonacept
• Toclizumab

Non steroidal anti-inflammatory drugs
(NSAIDs)
• NSAIDs have been the mainstay of treatment for inflammatory arthritis for
decades because of their analgesic and anti-inflammatory properties.
• But the approach today is to introduce disease modifying agents DMARDs
early in the course of the disease.
• NSAIDs control the symptoms but don’t alter the natural history of the
disease.
• In general, NSAIDs should only be considered as monotherapy for initial
therapy in low disease activity. If control is not achieved in 1 to 2 months,
additional therapy should be considered.
• NSAIDs are frequently used for symptom control as an adjunctive therapy to
more definitive therapies.
• One of the main actions of NSAIDs is the inhibition of cyclooxygenase
(COX) with resultant decrease in the production of prostaglandins resulting in
analgesia.

NSAIDs side effects:
• Bleeding - inhibition of platelet function
• Gastrointestinal (GI) toxicity
• Pseudoporphyria - Naproxen
• Headache, mood change, and decreased school performance
• Liver toxicity
• Renal toxicity
ACR Recommendations for monitoring of NSAIDs in JIA patients:
What to monitor?
Complete blood cell count, liver enzymes, serum creatinine
When to monitor?
• Prior to or soon after initiation of routine use
• Repeat twice yearly for chronic daily use
• Repeat once yearly for routine use (3-4 days per week)

Corticosteroids - Mechanism of action
In physiologic or low-dose,
Bind to cytosolic receptors >> translocate as a complex to the
nucleus >> the complex binds to DNA >> induces mRNA
transcription of some genes encoding for anti-inflammatory
proteins and decreases the transcription of genes encoding pro-
inflammatory proteins.
As the dose increases,
Very rapid, non-receptor mediated events occur, causing
apoptosis (programmed cell death) of lymphocytes and other
inflammatory cells.

Intra articular corticosteroids
• The use of intra-articular Triamcinolone hexacetonide (THA), 1 mg/kg
in large joints such as the knee and 0.5 mg/kg in smaller joints such as the
ankle, has been found to be superior to Triamcinalone acetonide.
• Early treatment is associated with better outcome.
• Intra articular steroids are expected to result in clinical improvement of
arthritis for at least 4 months.
• Difficult-to-reach joints such as the hip, sacroiliac (SI) joint,
temporomandibular joint (TMJ), and subtalar joint may be injected using
ultrasound or fluoroscopy.
• The use of IASs for active arthritis has been recommended by the ACR
guidelines regardless of concurrent therapy, JIA subtype, disease
activity, prognostic features, or joint contracture.
• If the duration of clinical improvement is shorter than 4 months, systemic
treatment (e.g.,MTX) may be indicated.

Systemic corticosteroids
ACR recommendations for JIA treatment were unable to make
any recommendations for systemic corticosteroid use, except
• In systemic juvenile idiopathic arthritis (sJIA) for severe
systemic features and
• In polyarticular JIA, in order to bridge constitutional features
of pain and fatigue while waiting for DMARDs or biologic
therapies to reach their therapeutic effect. (Bridge therapy)
Toxicity: obesity, short stature, hypertension, osteoporosis,
cataracts, mood changes, diabetes mellitus, avascular necrosis,
and susceptibility to infection.

Methotrexate
• Methotrxate is the most commonly used DMARD in JIA.
• Starting MTX early will lead to a better response.
• Mechanism of action: Inhibits Dihydro folate reductase
(DHFR).
• Maximum dose of 0.6 mg/kg once weekly (equivalent to 15
mg/m2/week, maximal 25 mg/week) of parenteral MTX.
• Daily folate supplementation at 1 mg/day.

Methotrexate
• Side effects: Nausea, vomiting, oral ulcerations, hepatitis,
blood dyscrasias and immunosuppression.
ACR Recommendations for monitoring of Methotrexate in JIA
patients:
What to monitor?
When to monitor?
• Prior to initiation
• 1 month after initiation
• 1–2 months after increase in dose
• Every 3–4 months if prior results normal and dose stable

Sulfasalazine
• Mechanism of action: Sulfasalazine and its metabolites are weak
inhibitors of cyclooxygenase (both COX-1 and COX-2).
Sulfasalazine inhibits folate metabolizing enzymes such as DHFR.
• Sulfasalazine is efficacious particularly in Enthesitis-Related
Arthritis.
• It is contraindicated for use in Systemic Arthritis, at least during
the acute phase of the disease, because of good evidence of
increased toxicity in this situation
• Adverse effects: GI upset, allergic reaction, pancytopenia, renal
and hepatic toxicity.

TNF – alpha inhibitors
• Act by inhibiting pro inflammatory cytokine TNF-α
• Adalimumab, Etanercept, Infliximab
• Adverse effects: Serious infections, demyelinating processes, optic
neuritis, injection site reactions or infusion reactions, development
of autoimmune conditions and reactivation of tuberculosis.
ACR Recommendations for monitoring of TNF-α inhibitors in JIA
patients:
• Prior to initiation and then at every 3–6 months
Tuberculosis screening
• Prior to initiation and then, once yearly

Other biologicals
Abatacept (CTLA4-Ig) T cell co-stimulatory inhibitor
Canakinumab Human monoclonal antibody targeted at interleukin-1 β
Rilonacept Interleukin-1 inhibitor
Anakinra Interleukin-1 receptor antagonist
Toclizumab Humanized monoclonal antibody against the IL-6 receptor
Rituximab Chimeric monoclonal antibody against CD-20
Adverse effects: Immunosuppression, malignancy.

2013 ACR recommendations for pharmacotherapy of
Juvenile Idiopathic Arthritis
ACR treatment subgroups The ACR issued recommendations for the treatment of
JIA on the basis of the following 5 treatment groups:
1. History of arthritis in 4 or fewer joints
2. History of arthritis in 5 or more joints
3. Active sacroiliac arthritis
4. Systemic arthritis with active systemic features and without active arthritis.
5. Systemic arthritis with active arthritis and without active systemic features.
Within each treatment group, choice of therapy is guided by
• Severity of disease activity (Number of joints with active arthritis, inflammatory
marker levels ESR & CRP, fever, physician/parent/patient global assessment
scales etc.)
• Presence or absence of features indicating a poor prognosis (defined
separately for each group)

This group includes patients with the ILAR categories of persistent
oligoarthritis, as well as patients with psoriatic arthritis, enthesitis-related
arthritis, and undifferentiated arthritis who have developed active arthritis
in only four or fewer joints total throughout the history of their disease
course.
Features of poor prognosis:
• Arthritis of the hip or cervical spine
• Arthritis of the ankle or wrist AND marked or prolonged inflammatory
marker elevation
• Radiographic damage (erosions or joint space narrowing by radiograph)
In this treatment group, escalation of therapy typically proceeds from
NSAIDs TO intra-articular glucocorticoid injections TO
methotrexate/sulfasalazine TO TNF-α inhibitors.

• NSAIDs alone may be adequate for patients with involvement of a single joint
and other indications of low disease activity (eg, normal inflammatory marker
levels); response should be evident within 2 months. For other patients, NSAIDs
may be used as adjunctive treatment, as needed.
• Intra-articular injections of triamcinolone can be used for any joint involved with
active arthritis.
• Methotrexate can given to patients who fail to show adequate response to
NSAIDs and/or joint injections. It is recommended as initial treatment for patients
in this treatment group who have high disease activity and features indicating
poor prognosis.
• In patients with enthesitis-related JIA, sulfasalazine rather than methotrexate is
recommended for patients who have an inadequate response to joint injection or
an adequate trial of NSAIDs.
• Patients in this treatment group who fail to respond adequately to joint injections
and to 3-6 months of methotrexate/sulfasalazine are candidates for Anti TNF-α
treatment.

This group includes patients with the ILAR categories of extended
oligoarthritis, RF negative polyarthritis, RF positive polyarthritis, as
well as patients with psoriatic arthritis, enthesitis-related arthritis,
and undifferentiated arthritis who have developed active arthritis in
five or more joints total throughout the history of their disease.
Patients in this group need not currently have five or more active
joints.
• Arthritis of the hip or cervical spine
• Positive rheumatoid factor OR anti-cyclic citrullinated peptide
(anti CCP) antibodies
• Radiographic damage (erosions or joint space narrowing by
radiograph)

• After 1 month of NSAID treatment in patients with low disease activity, or 1-2
months in those with moderate disease activity but without poor prognostic
features it is appropriate to escalate to methotrexate, plus adjunctive NSAIDs and
joint injection as needed.
• In patients with moderate disease activity and poor prognostic features, as well as
in patients with high disease activity, treatment may start with methotrexate.
Leflunomide may be used as an alternative to methotrexate.
• Interleukin (IL)-6 inhibitor Tocilizumab can be used for the treatment of
polyarticular JIA in children 2 years of age and older with active disease, either
alone or in combination with Methotrexate.
• Escalation to a TNF-α inhibitor follows if 3-6 months of methotrexate or
leflunomide provides inadequate control.
• If there is inadequate response after 3-4 months of TNF-α inhibitor treatment can
be switched to a different TNF-α inhibitor or to Abatacept.
• If these agents prove inadequate, patients may be started on Rituximab (especially
useful in RF positive polyarthritis)

3. Active Sacroiliac Arthritis
• This group includes patients from any of the ILAR JIA category
with clinical and imaging evidence of active sacroiliac arthritis.
• Radiographic damage of any joint (erosions or joint space
narrowing by radiograph).
• Use of a TNF-α inhibitor is recommended more readily for patients
in this group.
• A TNF-α inhibitor may be started after failure of an adequate trial
of NSAIDs or after 3-6 months of methotrexate or sulfasalazine
proves inadequate.

4. Systemic arthritis with active systemic
features and without active arthritis
• This group includes all patients who fulfill the ILAR criteria
for systemic arthritis and who have active fever of systemic
JIA with or without other systemic features, but without
active arthritis.
• 6 month duration of significant active systemic disease,
defined by: fever, elevated inflammatory markers, or
requirement for treatment with systemic glucocorticoids

4. Systemic arthritis with active systemic
features and without active arthritis
• A 2-week trials of NSAIDs may be used in patients who have
fever and less severe disease, and have had significant active
systemic disease for less than 6 months; after that, patients
should be started on systemic glucocorticoids, with adjunct
NSAIDs as needed.
• Patients with high systemic disease activity (eg, significant
serositis) may be started on steroids as a first step.
• Patients who sustain or develop active fever while on
systemic steroid therapy can be started on Anakinra.
• Toclizumab abd Canakinumab are also approved for use in
children with systemic JIA.

5. Systemic arthritis with active arthritis
(and without active systemic features)
• This category includes all patients who fulfill the ILAR
criteria for systemic arthritis AND who have active arthritis,
but without active systemic features.
• Arthritis of the hip
• Radiographic damage (erosions or joint space narrowing by
radiograph)

5. Systemic arthritis with active arthritis
(and without active systemic features)
• NSAID therapy, with intra-articular joint injections as
needed, may be adequate for patients with low disease
activity who do not have hip involvement or radiographic
signs of joint damage.
• Methotrexate can be added for patients with any degree of
disease severity who continue to have active arthritis.
• After 3 months of Methotrexate therapy, the next step in
escalation is to Anakinra or a TNF-α inhibitor.
• Patients who show inadequate response to TNF-α inhibitor
treatment can be started on Abatacept.

Macrophage activation
syndrome (MAS)
• It is a rare but potentially fatal
complication of SoJIA, that can
occur at anytime during the
disease course.
• Also referred to as secondary
hemophagocytic syndrome or
hemophagocytic
lymphohistiocytosis (HLH).
• The erythrocyte sedimentation
rate (ESR) falls because of
hypofibrinogenemia and hepatic
dysfunction, a feature useful in
distinguishing MAS from a flare
of systemic disease.
CLINICAL FEATURES
• Profound anemia
• Thrombocytopenia or
leukopenia
• High, spiking fevers
• Lymphadenopathy
• Hepatosplenomegaly
• Purpura
• Mucosal bleeding
• Elevated fibrin split
product
• Prolonged PT, aPTT

PRELIMINARY DIAGNOSTIC GUIDELINES FOR MACROPHAGE
ACTIVATION SYSTEM (MAS)
LABORATORY CRITERIA
1. Decreased platelet count (≤262 × 109/L).
2. Elevations of aspartate aminotransferase (>59 U/L).
3. Decreased white blood cell count (≤4.0 × 109/L).
4. Hypofibrinogenemia (≤2.5 g/L).
CLINICAL CRITERIA
1. Central nervous system dysfunction (irritability, disorientation, lethargy, headache,
seizures, coma).
2. Hemorrhages (purpura, easy bruising, mucosal bleeding).
3. Hepatomegaly (edge of liver ≥3 cm below the costal arch).
HISTOPATHOLOGIC CRITERION
• Evidence of macrophage hemophagocytosis in the bone marrow aspirate
The diagnosis of MAS requires the presence of any 2 or more laboratory criteria or of any 2 or 3 or
more clinical and/or laboratory criteria. A bone marrow aspirate for the demonstration of
hemophagocytosis may be required only in doubtful cases.
MAS often responds to cyclosporin A, and some case reports have detailed a
response toAnakinra. Treatment of MAS is a medical emergency.

Nonpharmacologic Therapy – Exercise
• Exercise preserves joint range of motion and muscular strength, and it
protects joint integrity by providing better shock absorption.
• Types of exercises: Muscle-strengthening program, range-of motion activity,
stretching of deformities, and endurance and recreational exercises.
• Hydrotherapy is a good form of exercise that helps achieve the
aforementioned objectives.
• Leg-length discrepancy can result from neovascularization of growth plates
of an affected knee. Treatment consists of a shoe lift on the contralateral
side.

Surgical Treatment
Synovectomy It may be used in children in whom a single joint
or just a few joints are involved and who have very active,
proliferative synovitis.
Osteotomy and arthrodesis are salvage procedures for patients
whose JIA is associated with severe joint destruction or deformity.
Arthrodesis is superior to arthroplasty for children who have
rheumatic disease in the wrist and fingers and in the ankle.
Total hip and knee replacements provide excellent relief of pain
and restore function in a functionally disabled child with
debilitating disease. Joint replacement is usually delayed until
bone growth has completed, as indicated by epiphyseal closure.

Treatment of Uveitis
• Uveitis is often asymptomatic.
• Patients are typically young girls who have positive levels of
ANA.
• Treatment with topical corticosteroid medication and with
mydriatic agents (to prevent closed-angle glaucoma) often can
prevent progression of disease to development of calcium
deposition in the lens and posterior synechiae.
• Methotrexate or cyclosporine, may help control chronic uveitis.
Infliximab can be effective in some patients who are resistant to
immunosuppressive agents.

Diet and Activity
• Because active JIA has been associated with decreased
osteoblastic activity and a risk of osteopenia, encourage the
inclusion of at least 3 servings of calcium-rich foods each day.
Consider supplementation when poor calcium intake persists.
• Encourage patients to be as active as possible. Bed rest is not a
part of the treatment. In fact, the more active the patient, the
better the long-term prognosis.

PROGNOSIS
• Children with persistent oligoarticular disease fare well, with a majority
achieving disease remission. Those in whom more extensive disease
develops have a poorer prognosis.
• The child with polyarticular JIA often has a more prolonged course of
active joint inflammation and requires early and aggressive therapy.
Predictors of severe and persistent disease include
• Young age at onset
• RF seropositivity or rheumatoid nodules
• The presence of anti-CCP antibodies
• Large numbers of affected joints
• Disease involving the hip and hand and wrist
• Fever lasting >3 months
• Increased inflammatory markers for >6 months

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