Overview

Juvenile idiopathic arthritis, formerly known as juvenile rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis (RA) is a symmetric, inflammatory polyarthritis and chronic, progressive, autoimmune disorder. Presentation occurs most commonly in middle-aged women with joint swelling, pain, and morning stiffness (often in the hands). Rheumatoid Arthritis, is the most common chronic rheumatological disease in the pediatric population. While there are multiple subgroups with distinct pathogeneses, the key feature is arthritis. 

Definition

Juvenile idiopathic arthritis is a term used to describe a group of inflammatory conditions of the joints affecting children younger than 16 and lasting 6 weeks or longer.

Classification

Classification according to symptomatology (as per the International League of Associations for Rheumatology):

• Oligoarticular JIA: 
  • Arthritis in fewer than 5 joints
  • Further subdivided in:
    • Persistent oligoarthritis: patients with 1–4 affected joints who do not develop arthritis in 5 or more joints during the first 6 months of disease
    • Extended oligoarthritis: patients with 1–4 affected joints who develop arthritis in more than 4 joints after the first 6 months of disease
• Polyarticular JIA: 
  • Arthritis in ≥ 5 joints
  • Further subdivided in:
    • Rheumatoid factor (RF)–positive polyarthritis
    • RF-negative polyarthritis
• Systemic JIA (previously called Still’s disease):
  • Arthritis in 1 or multiple joints 
  • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever ≥ 2 weeks that happens daily for at least 3 days
  • 1 or more of the following: 
    • Evanescent, erythematous rash
    • Hepatomegaly 
    • Splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly
    • Lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy (LAD)
    • Serositis
• Psoriatic JIA:
  • Present with arthritis and psoriasis Psoriasis Psoriasis is a common T-cell-mediated inflammatory skin condition. The etiology is unknown, but is thought to be due to genetic inheritance and environmental triggers. There are 4 major subtypes, with the most common form being chronic plaque psoriasis. Psoriasis
  • May present with arthritis alone and 1 of the following:
    • Psoriasis in a 1st-degree relative
    • Dactylitis
    • Fingernail abnormalities
• Enthesitis arthritis (also called pediatric spondyloarthropathy):
  • Present with arthritis and enthesitis ( inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of the entheses, the sites where tendons or ligaments insert into the bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones)
  • May present with only either arthritis or enthesitis and 2 of the following criteria:
    • Tenderness of the sacroiliac (SI) joint or lumbosacral pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain due to inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation
    • Positive HLA-B27
    • 1st-degree relative with acute anterior uveitis Uveitis Uveitis is the inflammation of the uvea, the pigmented middle layer of the eye, which comprises the iris, ciliary body, and choroid. The condition is categorized based on the site of disease; anterior uveitis is the most common. Diseases of the Uvea, ankylosing spondylitis Ankylosing spondylitis Ankylosing spondylitis (also known as Bechterew's disease or Marie-Strümpell disease) is a seronegative spondyloarthropathy characterized by chronic and indolent inflammation of the axial skeleton. Severe disease can lead to fusion and rigidity of the spine. Ankylosing Spondylitis, inflammatory bowel disease (IBD) with sacroiliitis, or reactive arthritis Reactive arthritis Reactive arthritis is a seronegative autoimmune spondyloarthropathy that occurs in response to a previous gastrointestinal (GI) or genitourinary (GU) infection. The disease manifests as asymmetric oligoarthritis (particularly of large joints in the lower extremities), enthesopathy, dactylitis, and/or sacroiliitis. Reactive Arthritis
    • Acute anterior uveitis Uveitis Uveitis is the inflammation of the uvea, the pigmented middle layer of the eye, which comprises the iris, ciliary body, and choroid. The condition is categorized based on the site of disease; anterior uveitis is the most common. Diseases of the Uvea
    • Onset of arthritis in boys > 6 years old
• Undifferentiated JIA:
  • Patients meeting criteria for more than 1 category
  • Patients not meeting full criteria for another category

Epidemiology

• Most common rheumatic disease in children
  • Overall incidence in the US and Canada: 0.041–0.061 per 1,000 children
  • Frequencies of different subtypes: 
    • Oligoarthritis: 50%–60% 
    • RF-negative polyarthritis: 11%–28% 
    • RF-positive polyarthritis: 2%–7% 
    • Systemic arthritis: 10%–20%
    • Psoriatic arthritis: 2%–15% 
    • Enthesitis-related arthritis: 1%–7% 
• Prevalence varies secondary to disease and patient variables: 
  • Gender:
    • Mostly predominant in girls (girl-to-boy ratio = 2:1–3:1)
    • Systemic JIA girl-to-boy ratio = 1:1
    • Enthesitis-related arthritis is predominant in boys.
  • Geographical location:
    • RF-negative polyarthritis is more common in North America.
    • Oligoarthritis is more common in southern Europe.
    • Systemic arthritis and enthesitis-related arthritis are more common in Southeast Asia.
  • Age (note: by definition, onset must be before 16 years of age):
    • 1–3 years of age: peak incidence of JIA (predominantly girls) 
    • 8–10 years of age: 2nd peak (smaller, and more boys with oligoarticular JIA)
    • Mean age of onset for both systemic and polyarticular disease: approximately 6 years old 
    • Mean age of onset for oligoarticular disease: 4 years in girls and 10 years in boys 

Etiology and Pathophysiology

Etiology

While genetic susceptibility plays a role in JIA, the exact etiology and pathogenesis of the disease is incompletely understood. Juvenile idiopathic arthritis is believed to be caused by an interplay between environmental exposures and genetic predisposition.

Environmental component:

• Possible risk factors:
  • Antibiotic use 
  • C-section birth
  • Exposure to pathogens (e.g., parvovirus B19 Parvovirus B19 Primate erythroparvovirus 1 (generally referred to as parvovirus B19, B19 virus, or sometimes erythrovirus B19) ranks among the smallest DNA viruses. Parvovirus B19 is of the family Parvoviridae and genus Erythrovirus. In immunocompetent humans, parvovirus B19 classically results in erythema infectiosum (5th disease) or "slapped cheek syndrome." Parvovirus B19, EBV, enteric bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview, Chlamydophila pneumoniae, and Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus)
• Possible protective factors:
  • Breastfeeding Breastfeeding Breastfeeding is often the primary source of nutrition for the newborn. During pregnancy, hormonal stimulation causes the number and size of mammary glands in the breast to significantly increase. After delivery, prolactin stimulates milk production, while oxytocin stimulates milk expulsion through the lactiferous ducts, where it is sucked out through the nipple by the infant. Breastfeeding 
  • Household siblings 

Genetic component:

• Monozygotic twins have a 25%–40% concordance rate of developing the disease.
• Patterns of inheritance are not Mendelian or single gene (having an affected sibling does not significantly increase risk).
• Specific HLA alleles as well as non-HLA genes may be associated with specific JIA subtypes.
• The more HLA-DR risk alleles a patient has, the more likely they are to develop JIA and the earlier they develop it.

Pathophysiology

• Pathogenesis varies related to the subtype:
  • Autoimmune or autoinflammatory disease
  • Imbalance between the overactivation (both innate and adaptive) and regulation of the immune system
• Synovium is the primary target of the inflammatory response:
  • Immune system cells are activated and secrete proinflammatory cells, such as tumor necrosis factor Tumor necrosis factor Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) ( TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF))–alpha, IL-6 cells, and IL-1 cells.
  • T- lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes and B- lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes are involved in the development of the inflammatory state of the joint.
  • The synovium proliferates and becomes inflamed, increasing blood flow to the joint, which leads to edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema and swelling of the joint:
    • Increased amount of synovial fluid
    • Decreased viscosity of synovial fluid
  • Persistent synovitis ultimately causes joint destruction.
  • Eventually, bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones, tendon, and ligament destruction is also produced.

Management

The primary goal in the management of JIA is to limit the extent of joint damage and restrict the loss of function. Juvenile idiopathic arthritis is a chronic disease, and inducing remission with the least amount of toxicity is essential.

Overall management

• Pharmacological therapy:
  • NSAIDS
  • Disease-modifying antirheumatic drugs Disease-modifying antirheumatic drugs Disease-modifying antirheumatic drugs are antiinflammatory medications used to manage rheumatoid arthritis. The medications slow, but do not cure, the progression of the disease. The medications are classified as either synthetic or biologic agents and each has unique mechanisms of action and side effects. Disease-modifying Antirheumatic Drugs (DMARDs)
  • Biologic agents
  • Intra-articular and oral steroids
• Nutrition: addressing bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones health and anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview ( iron deficiency anemia Iron Deficiency Anemia Iron deficiency anemia is the most common type of anemia worldwide. This form of anemia is caused by insufficient iron due to a decreased supply, an increased loss, or an increased demand. Iron deficiency anemia is seen across all ages, sexes, and socioeconomic strata; however, children, women of childbearing age, and patients from lower socioeconomic strata are at higher risk. Iron Deficiency Anemia (IDA)) with diet 
• PT and occupational therapy:
  • Joint protection and optimizing function
  • Consider orthoses to protect the joint.
• Psychosocial: family, school issues
• Medical therapy/medications for JIA are best guided by a pediatric rheumatologist.

Oligoarticular JIA

• Low disease activity: NSAIDs and/or intra-articular steroid therapy as indicated
• High disease activity:
  • NSAIDS, intra-articular steroid therapy, and escalate to DMARDs (MTX initially)
  • Folic acid (with MTX therapy)
• TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) inhibitors used if not responding after 3 months

Polyarticular JIA

• DMARD DMARD Disease-modifying antirheumatic drugs are antiinflammatory medications used to manage rheumatoid arthritis. The medications slow, but do not cure, the progression of the disease. The medications are classified as either synthetic or biologic agents and each has unique mechanisms of action and side effects. Disease-modifying Antirheumatic Drugs is recommended at the time of diagnosis (rare for NSAIDS alone to control the inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation).
• MTX is the initial DMARD DMARD Disease-modifying antirheumatic drugs are antiinflammatory medications used to manage rheumatoid arthritis. The medications slow, but do not cure, the progression of the disease. The medications are classified as either synthetic or biologic agents and each has unique mechanisms of action and side effects. Disease-modifying Antirheumatic Drugs choice: folic acid (with MTX therapy).
• Corticosteroids for moderate or high disease activity:
  • Oral initially
  • Injected into joint if resistant to therapy after 3 months
• Consider biologics ( TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF)-alpha initial choice)

Systemic JIA

• Mild disease (or during initial workup): NSAIDS as an initial trial 
• More severe disease and evidence of systemic manifestations:
  • Glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids and NSAIDS
  • DMARDS or biological agents are both used by pediatric rheumatologists.

Psoriatic JIA

• NSAIDS initially
• Intra-articular glucocorticoids
• DMARDS as indicated (MTX is the most frequently used)
• Biologics as indicated

Remission

American College of Rheumatology criteria for complete remission:

• No inflammatory joint pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
• No fatigue
• No synovitis
• No morning stiffness
• Normal ESR and CRP levels

Differential Diagnosis

• Gonococcal arthritis: an infection due to Neisseria gonorrhoeae. Disseminated disease can present similar to JIA with an acute, inflammatory, asymmetric arthritis with urethritis. Diagnosis is based on the clinical history, synovial fluid analysis, and culture results. Management includes antibiotics. 
• Reactive arthritis: a seronegative, autoimmune spondyloarthropathy that is often precipitated by a GI or genitourinary infection. Patients present with an asymmetric oligoarthritis, enthesopathy, dactylitis, and/or sacroiliitis. The diagnosis is clinical, and a negative synovial Gram stain and culture will help rule out septic arthritis Septic arthritis Septic arthritis is an infection of the joint due to direct inoculation, contiguous extension, or hematogenous spread of infectious organisms into the joint space. This process causes an acute, inflammatory, monoarticular arthritis. Septic Arthritis. Management includes NSAIDs, DMARDS, and treatment of an active infection.
• Osteoarthritis Osteoarthritis Osteoarthritis (OA) is the most common form of arthritis, and is due to cartilage destruction and changes of the subchondral bone. The risk of developing this disorder increases with age, obesity, and repetitive joint use or trauma. Patients develop gradual joint pain, stiffness lasting < 30 minutes, and decreased range of motion. Osteoarthritis (OA): an arthritis due to cartilage Cartilage Cartilage is a type of connective tissue derived from embryonic mesenchyme that is responsible for structural support, resilience, and the smoothness of physical actions. Perichondrium (connective tissue membrane surrounding cartilage) compensates for the absence of vasculature in cartilage by providing nutrition and support. Cartilage destruction and changes of the subchondral bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones. Patients develop gradual joint pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, stiffness lasting < 30 minutes, and decreased range of motion (ROM). Physical exam may reveal crepitus with joint motion and osteophyte formation. The diagnosis is clinical. Synovial fluid will be noninflammatory, which differentiates OA from septic arthritis Septic arthritis Septic arthritis is an infection of the joint due to direct inoculation, contiguous extension, or hematogenous spread of infectious organisms into the joint space. This process causes an acute, inflammatory, monoarticular arthritis. Septic Arthritis. Management includes analgesics, glucocorticoid intra-articular injections, and surgery for advanced disease. 
• Osteomyelitis Osteomyelitis Osteomyelitis is an infection of the bone that results from the spread of microorganisms from the blood (hematogenous), nearby infected tissue, or open wounds (non-hematogenous). Infections are most commonly caused by Staphylococcus aureus. Osteomyelitis: an infection of the bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones, most commonly caused by Staphylococcus Staphylococcus Staphylococcus is a medically important genera of Gram-positive, aerobic cocci. These bacteria form clusters resembling grapes on culture plates. Staphylococci are ubiquitous for humans, and many strains compose the normal skin flora. Staphylococcus aureus. Patients present with pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, redness, and swelling of the affected site and may have associated symptoms such as fever and chills. Laboratory values will demonstrate elevated WBC, CRP, and ESR in most cases. The most sensitive and specific imaging modality to diagnose osteomyelitis is MRI. Management requires long-term antibiotics and potential surgical debridement.
• Lyme disease Lyme disease Lyme disease is a tick-borne infection caused by the gram-negative spirochete Borrelia burgdorferi. Lyme disease is transmitted by the black-legged Ixodes tick (known as a deer tick), which is only found in specific geographic regions. Patient presentation can vary depending on the stage of the disease and may include a characteristic erythema migrans rash. Lyme Disease: a tick-borne infection caused by the Gram-negative spirochete Spirochete Treponema is a gram-negative, microaerophilic spirochete. Owing to its very thin structure, it is not easily seen on Gram stain, but can be visualized using dark-field microscopy. This spirochete contains endoflagella, which allow for a characteristic corkscrew movement. Treponema Borrelia Borrelia Borrelia are gram-negative microaerophilic spirochetes. Owing to their small size, they are not easily seen on Gram stain but can be visualized using dark-field microscopy, Giemsa, or Wright stain. Spirochetes are motile and move in a characteristic spinning fashion due to axial filaments in the periplasmic space. Borrelia burgdorferi. Patients with late disease may develop a migratory polyarthritis, particularly in large joints. An erythema migrans rash as well as neurologic, cardiac, and ocular manifestations may also be present. Synovial fluid analysis and serologic testing can confirm a Lyme infection and will differentiate the disease from septic arthritis Septic arthritis Septic arthritis is an infection of the joint due to direct inoculation, contiguous extension, or hematogenous spread of infectious organisms into the joint space. This process causes an acute, inflammatory, monoarticular arthritis. Septic Arthritis. Antibiotic therapy is used for treatment.