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Recent Advances
In The Management Of
Juvenile Idiopathic Arthritis
Dr C Naveen Kumar,
1st Year PG,
Department of Pediatric...
Introduction
• The term “rheumatological disorders” refers to diseases that
affect the major connective tissues of the bod...
Definition
International League of Associations for Rheumatology
(ILAR) proposed uniform definition and classification cri...
Sub categories
1. Systemic-onset JIA
2. Oligoarticular JIA (Persistent & Extended forms)
3. Polyarthritis (Rheumatoid Fact...
Category Definition Exclusions
Systemic-onset
JIA
Arthritis in ≥1 joints with, or
preceded by, fever of at least 2 wk
in d...
Category Definition Exclusions
Polyarthritis
(RF-negative)
Arthritis affecting ≥5 joints during the 1st 6 months of
diseas...
Glossary of terms used in ILAR
classification of JIA
• Arthritis: Swelling within a joint, or limitation in the range of j...
Etiology & Pathogenesis
Immunogenetic susceptibility
HLA I, HLA II alleles
Non HLA candidate loci
TNF-α, MIF, IL-6, IL-1α ...
ABNORMAL IMMUNE RESPONSE
Humoral
B-Cell activation
• Complement consumption
• Immune complex formation
• Auto antibodies (...
Pathogenesis
• All forms of JIA other than sJIA, are disorders of adaptive
immunity – autoimmune disorders. Lymphocytes (T...
Clinical manifestations
• Involved joints are often swollen, warm to touch, and painful on
movement or palpation with redu...
Clinical manifestations - SoJIA
• SoJIA characterized by arthritis, fever, and prominent visceral
involvement, including h...
Clinical manifestations –
Oligoarthritis
• Oligoarthritis large joints of the lower extremities, such as the
knees and ank...
Clinical manifestations –
Polyarthritis
• RF positive polyarticular disease resembles the characteristic
symmetric present...
Subtype Peak
age of
onset
Female
:Male
ratio
Arthritis pattern Extraarticular features
Systemic
onset
2-4 Yrs 1:1 Poly art...
Laboratory findings & investigations
• Elevated WBC and platelet counts and a microcytic anemia
(anemia of chronic disease...
Laboratory findings & investigations
MRI is more sensitive than radiography to early changes most sensitive
radiologic ind...
MANAGEMENT
Dr Naveen Kumar Cheri
S.V. Medical College, Tirupati
Management
• Children with JIA are best managed in a specialist multidisciplinary set
up.
Management may include one or al...
Pharmacologic management
Primary goals of medical therapy are:
• To eliminate active disease
• To normalize joint function...
Commonly used drugs in the present
day treatment of JIA
NSAIDs Steroids
Disease Modifying
Anti-rheumatologic
Drugs (DMARD)...
Non steroidal anti-inflammatory drugs
(NSAIDs)
• NSAIDs have been the mainstay of treatment for inflammatory arthritis for...
NSAIDs side effects:
• Bleeding - inhibition of platelet function
• Gastrointestinal (GI) toxicity
• Pseudoporphyria - Nap...
Corticosteroids - Mechanism of action
In physiologic or low-dose,
Bind to cytosolic receptors >> translocate as a complex ...
Intra articular corticosteroids
• The use of intra-articular Triamcinolone hexacetonide (THA), 1 mg/kg
in large joints suc...
Systemic corticosteroids
ACR recommendations for JIA treatment were unable to make
any recommendations for systemic cortic...
Methotrexate
• Methotrxate is the most commonly used DMARD in JIA.
• Starting MTX early will lead to a better response.
• ...
Methotrexate
• Side effects: Nausea, vomiting, oral ulcerations, hepatitis,
blood dyscrasias and immunosuppression.
ACR Re...
Sulfasalazine
• Mechanism of action: Sulfasalazine and its metabolites are weak
inhibitors of cyclooxygenase (both COX-1 a...
TNF – alpha inhibitors
• Act by inhibiting pro inflammatory cytokine TNF-α
• Adalimumab, Etanercept, Infliximab
• Adverse ...
Other biologicals
Abatacept (CTLA4-Ig) T cell co-stimulatory inhibitor
Canakinumab Human monoclonal antibody targeted at i...
2013 ACR recommendations for pharmacotherapy of
Juvenile Idiopathic Arthritis
ACR treatment subgroups The ACR issued recom...
1. History of arthritis in 4 or fewer joints
This group includes patients with the ILAR categories of persistent
oligoarth...
1. History of arthritis in 4 or fewer joints
• NSAIDs alone may be adequate for patients with involvement of a single join...
Dr Naveen Kumar Cheri
S.V. Medical College, Tirupati
2. History of arthritis in 5 or more joints
This group includes patients with the ILAR categories of extended
oligoarthrit...
2. History of arthritis in 5 or more joints
• After 1 month of NSAID treatment in patients with low disease activity, or 1...
Dr Naveen Kumar Cheri
S.V. Medical College, Tirupati
3. Active Sacroiliac Arthritis
• This group includes patients from any of the ILAR JIA category
with clinical and imaging ...
4. Systemic arthritis with active systemic
features and without active arthritis
• This group includes all patients who fu...
4. Systemic arthritis with active systemic
features and without active arthritis
• A 2-week trials of NSAIDs may be used i...
Dr Naveen Kumar Cheri
S.V. Medical College, Tirupati
5. Systemic arthritis with active arthritis
(and without active systemic features)
• This category includes all patients w...
5. Systemic arthritis with active arthritis
(and without active systemic features)
• NSAID therapy, with intra-articular j...
Dr Naveen Kumar Cheri
S.V. Medical College, Tirupati
Macrophage activation
syndrome (MAS)
• It is a rare but potentially fatal
complication of SoJIA, that can
occur at anytime...
PRELIMINARY DIAGNOSTIC GUIDELINES FOR MACROPHAGE
ACTIVATION SYSTEM (MAS)
LABORATORY CRITERIA
1. Decreased platelet count (...
Nonpharmacologic Therapy – Exercise
• Exercise preserves joint range of motion and muscular strength, and it
protects join...
Surgical Treatment
Synovectomy It may be used in children in whom a single joint
or just a few joints are involved and who...
Treatment of Uveitis
• Uveitis is often asymptomatic.
• Patients are typically young girls who have positive levels of
ANA...
Diet and Activity
• Because active JIA has been associated with decreased
osteoblastic activity and a risk of osteopenia, ...
PROGNOSIS
• Children with persistent oligoarticular disease fare well, with a majority
achieving disease remission. Those ...
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Recent Advances In The Management Of Juvenile Idiopathic Arthritis

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The term “rheumatologicaldisorders” 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).

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Recent Advances In The Management Of Juvenile Idiopathic Arthritis

  1. 1. 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
  2. 2. 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). Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  3. 3. 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 Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  4. 4. 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 Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  5. 5. 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. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  6. 6. 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. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  7. 7. 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. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  8. 8. 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 Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  9. 9. 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
  10. 10. 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). Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  11. 11. 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. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  12. 12. 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. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  13. 13. 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. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  14. 14. 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. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  15. 15. 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 Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  16. 16. 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. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  17. 17. 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. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  18. 18. MANAGEMENT Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  19. 19. 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 Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  20. 20. 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. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  21. 21. 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 Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  22. 22. 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. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  23. 23. 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) Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  24. 24. 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. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  25. 25. 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. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  26. 26. 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. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  27. 27. 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. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  28. 28. Methotrexate • Side effects: Nausea, vomiting, oral ulcerations, hepatitis, blood dyscrasias and immunosuppression. ACR Recommendations for monitoring of Methotrexate in JIA patients: What to monitor? Complete blood cell count, liver enzymes, serum creatinine 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 Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  29. 29. 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. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  30. 30. 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: Complete blood cell count, liver enzymes, serum creatinine • Prior to initiation and then at every 3–6 months Tuberculosis screening • Prior to initiation and then, once yearly Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  31. 31. 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. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  32. 32. 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) Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  33. 33. 1. History of arthritis in 4 or fewer joints 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. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  34. 34. 1. History of arthritis in 4 or fewer joints • 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 S.V. Medical College, Tirupati
  35. 35. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  36. 36. 2. History of arthritis in 5 or more joints 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. Features of poor prognosis: • 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) Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  37. 37. 2. History of arthritis in 5 or more joints • 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 S.V. Medical College, Tirupati
  38. 38. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  39. 39. 3. Active Sacroiliac Arthritis • This group includes patients from any of the ILAR JIA category with clinical and imaging evidence of active sacroiliac arthritis. Features of poor prognosis: • 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. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  40. 40. 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. Features of poor prognosis: • 6 month duration of significant active systemic disease, defined by: fever, elevated inflammatory markers, or requirement for treatment with systemic glucocorticoids Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  41. 41. 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. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  42. 42. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  43. 43. 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. Features of poor prognosis: • Arthritis of the hip • Radiographic damage (erosions or joint space narrowing by radiograph) Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  44. 44. 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. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  45. 45. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  46. 46. 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 Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  47. 47. 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. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  48. 48. 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. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  49. 49. 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. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  50. 50. 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. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  51. 51. 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. Dr Naveen Kumar Cheri S.V. Medical College, Tirupati
  52. 52. 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 Dr Naveen Kumar Cheri S.V. Medical College, Tirupati

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