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 CheriS.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. Dr Naveen Kumar Cheri

S.V. Medical College, Tirupati

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 TOmethotrexate/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. Dr Naveen Kumar Cheri



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




• 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)Dr Naveen Kumar Cheri


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



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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