Still Disease

6 Interesting Facts of Still Disease

1. Still Disease consists of several subgroups with different clinical characteristics, pathogenesis, and responses to therapy.

2. Systemic JIA (sJIA) symptoms include quotidian fever, rash, and arthritis, which respond best to interleukin (IL)-1 and IL-6 inhibition.

3. Oligoarticular JIA is characterized by young age of onset, female predominance, positive antinuclear antibody (ANA) and chronic anterior uveitis.

4. Polyarticular JIA with a positive rheumatoid factor (RF) resembles adult seropositive rheumatoid arthritis (RA).

5. ANA positivity, female sex, and age <7 years increase the risk of chronic uveitis regardless of the JIA subgroup.

6. Enthesitis-related arthritis (ERA) is characterized by lower extremity enthesitis, male sex, human leukocyte antigen-B27 (HLA-B27), acute anterior uveitis, and sometimes the later development of sacroiliitis.

Still Disease previously referred to as juvenile rheumatoid arthritis (JRA), is a diverse spectrum of chronic arthritides, involving ≥1 joint for ≥6 wk in a patient ≤16 yr of age. Other causes of arthritis must be excluded.

Synonyms

• Juvenile Idiopathic Arthritis
• Juvenile rheumatoid arthritis (JRA)
• Systemic JIA

How common is Still Disease?

1 per 1000 children in the U.S.; more common in children of European ancestry

Physical Findings & Clinical Presentation of Still Disease

Still Disease is subdivided into seven categories based on the International League of Associations for Rheumatology (ILAR) classification criteria. Characteristics of the various categories of JIA are summarized in the below table

• •Systemic onset JIA (sJIA) (4% to 17%)
  • 1.Arthritis in ≥1 joint with or preceded by fever of at least 2-wk duration that is quotidian (once daily) for at least 3 days and associated with at least one of the following: (1) evanescent erythematous rash; (2) generalized lymphadenopathy; (3) hepatomegaly, splenomegaly, or both; and (4) serositis
• •Oligoarticular JIA (27% to 56%)
  • 1.Arthritis in <4 joints in the first 6 mo of disease. There are two subtypes:
    • a.Persistent: ≤4 joints throughout the disease course
    • b.Extended: ≤4 joints during the first 6 mo extending to >4 joints after 6 mo
• •Polyarthritis, rheumatoid factor (RF) negative (11% to 28%)
  • 1.Arthritis in >5 joints during first 6 mo of the disease with negative RF
• •Polyarthritis, RF positive (2% to 7%)
  • 1.Arthritis involves ≥5 joints during first 6 mo of the disease with positive RF on >2 tests run 3 mo apart
  • 2.Anticyclic citrullinated (CCP) antibodies may also be present
  • 3.Most similar to adult rheumatoid arthritis; most likely to progress
• •Psoriatic arthritis (2% to 11%)
  • 1.Psoriasis and arthritis or psoriasis and ≥2 of the following:
    • a.Dactylitis, nail pitting, onycholysis, and psoriasis in a first-degree relative
• •Enthesitis-related arthritis (3% to 11%)
  • 1.Arthritis or enthesitis and ≥2 of the following:
    • a.Sacroiliac tenderness, positive HLA-B27 (human leukocyte antigen B27), male age >6 yr, acute anterior uveitis, or first-degree relative with HLA-B27–associated disease
• •Undifferentiated arthritis (11% to 21%)
  • 1.Fulfills criteria in ≥2 categories above, or none of them

Overview of the Main Features of the Subtypes of Juvenile Idiopathic Arthritis

From Firestein G et al: Kelley’s textbook of rheumatology, ed 9, Philadelphia, 2013, WB Saunders.

ILAR Subtype	Peak Age of Onset (yr)	Female:Male; % of All JIA	Arthritis Pattern	Extraarticular Features	Investigations	Notes on Therapy
Systemic arthritis	2-4	1:1; ∼10% of JIA cases	Polyarticular, often knees, wrists, and ankles; also fingers, neck, and hips	Daily fever; evanescent rash; pericarditis; pleuritis	Anemia; WBC↑︎↑︎; ESR↑︎↑︎; CRP↑︎↑︎; ferritin↑︎ platelets↑︎↑︎ (normal or ↑︎ in MAS)	Less responsive to standard treatment with MTX and anti-TNF agents; consider IL-1Ra in resistant cases
Oligoarthritis	>6	4:1; 50%-60% of JIA (but ethnic variation)	Knees ++; ankles, fingers +	Uveitis in ∼30%	ANA positive in 60%; other tests usually normal; may have mildly ↑︎ ESR/CRP	NSAIDs and intraarticular steroids; occasionally require MTX
Polyarthritis, RF negative	6-7	3:1; 30% of JIA cases	Symmetric or asymmetric; small and large joints; cervical spine; TMJ	Uveitis in ∼10%	ANA positive in 40%; RF negative; ESR ↑︎ or; ↑︎↑︎ CRP↑︎/normal; mild anemia	Standard therapy with MTX and NSAIDs, then if nonresponsive, anti-TNF agents or other biologics
Polyarthritis, RF positive	9-12	9:1; >10% of JIA cases	Aggressive symmetric polyarthritis	Rheumatoid nodules in 10%; low-grade fever	RF positive; ESR ↑︎↑︎; CRP ↑︎/normal; mild anemia	Long-term remission unlikely; early aggressive therapy is warranted
Psoriatic arthritis	7-10	2:1; >10% of JIA cases	Asymmetric arthritis of small- or medium-sized joints	Uveitis in 10%; psoriasis in 50%	ANA positive in 50%; ESR ↑︎; CRP ↑︎/normal; mild anemia	NSAIDs and intraarticular steroids; second-line agents less commonly
Enthesitis-related arthritis	9-12	1:7; 10% of JIA cases	Predominantly lower limb joints affected; sometimes axial skeleton (but less than adult AS)	Acute anterior uveitis; association with reactive arthritis and IBD	80% HLA-B27	NSAIDs and intraarticular steroids; consider sulfasalazine as alternative to MTX

ANA, Antinuclear antibody; AS, ankylosing spondylitis; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; HLA-B27, human leukocyte antigen B27; IBD, inflammatory bowel disease; ILAR, International League of Associations for Rheumatology; IL-1Ra, interleukin-1 receptor antagonist; JIA, juvenile idiopathic arthritis; MAS, macrophage activation syndrome; MTX, methotrexate; NSAID, nonsteroidal antiinflammatory drug; RF, rheumatoid factor; TMJ, temporomandibular joint; TNF, tumor necrosis factor; WBC, white blood cell count.

Characteristics of the Various Categories of Juvenile Idiopathic Arthritis

From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

Category	Age at Onset	Affected Joints	Systemic Features	Major Complications
Oligoarticular persistent	Early childhood	Large joints, asymmetric (knee, ankle, wrist, elbow, temporomandibular, cervical spine)	No	Chronic uveitis Local growth disturbances
Oligoarticular extended	Early childhood	Same as above, but more than four joints involved after the first 6 mo of disease	No	Chronic uveitis Local growth disturbances
Polyarticular RF negative	Throughout childhood	Any, often symmetric, often small joints	Malaise (subfebrile)	Chronic uveitis Local growth disturbances
Polyarticular RF positive	Teenage years	Any, usually symmetric and involving small joints	Malaise (subfebrile)	Local growth disturbances and articular damage
Systemic	Throughout childhood	Any (not necessarily at disease onset)	High fever, rash, polyserositis, marked acute-phase response	Acute: Macrophage activation syndrome Chronic: General growth disturbance, amyloidosis
Psoriatic	Late childhood	Spine, lower extremities, distal interphalangeal joints, dactylitis		Psoriasis Local growth disturbances
Enthesitis related	Late childhood	Spine, sacroiliac, lower extremities, thoracic cage joints	Inflammatory bowel disease	Acute symptomatic uveitis

RF, Rheumatoid factor.

What causes Still Disease?

Genetically susceptible individuals may develop an inappropriate immune response toward a self-antigen after exposure to an environmental trigger.

Variants in HLA, PTPN22, and STAT4 loci may be associated with disease.

Differential Diagnosis of Still Disease

• •Infection: Viral (parvovirus, toxic synovitis) or bacterial (Lyme, osteomyelitis, septic joints)
• •Inflammation: Lupus, serum sickness, inflammatory bowel disease
• •Reactive: Post-streptococcal, rheumatic fever
• •Malignancy: Leukemia, bone tumors

The below table summarizes conditions with arthralgia/arthritis that might be confused with JIA

Differential Diagnosis of Pediatric Arthralgia/Arthritis

From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

Type of Condition	Examples
Infections	Bacterial arthritis and osteomyelitis
Borreliosis (Lyme disease)
Viral and mycoplasmal arthritis
Tuberculosis
Postinfectious conditions	Rheumatic fever
Poststreptococcal arthritis
Postenteritis and other reactive arthritis (Salmonella, Campylobacter, Chlamydia)
Noninflammatory conditions	Hypermobility and Ehlers-Danlos syndrome
Growing pains, trauma, patellofemoral and other overuse syndromes
Osgood-Schlatter disease and other juvenile osteochondroses
Legg-Calvé-Perthes disease
Slipped capital femoral epiphysis
Foreign body synovitis
Other congenital and genetic disorders of supportive tissue
Hematologic disorders	Sickle cell anemia
Hemophilia
von Willebrand disease
Systemic inflammatory disorders	Juvenile systemic lupus erythematosus
Juvenile dermatomyositis
Mixed connective tissue disease
Scleroderma
Vasculitis (e.g., Henoch-Schönlein purpura, Kawasaki disease, Behçet disease)
Autoinflammatory disorders	Cryopyrin-associated periodic syndrome
Familial Mediterranean fever
Other monogenic diseases (e.g., mevalonate kinase deficiency [hyperimmunoglobulinemia D], Blau syndrome, tumor necrosis factor receptor–associated periodic syndrome) Chronic recurrent multifocal osteomyelitis Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA syndrome)
Malignancies	Leukemia
Neuroblastoma
Localized bone tumors
Pain	Complex regional pain syndrome
Pain amplification syndromes and fibromyalgia
Nonspecific musculoskeletal pain
Miscellaneous conditions	Primary immunodeficiencies
Sarcoidosis

How is Still Disease diagnosed?

• •No single diagnostic test. Rule out other causes of arthritis
• •Elevated sedimentation rate and C-reactive protein; high ferritin
• •Mild anemia, leukocytosis
• •Rheumatoid factor
• •Antinuclear antibodies: Elevation associated with ocular complications
• •Pancytopenia, a consumptive coagulopathy, elevated ferritin, and elevated liver enzymes are concerning for macrophage activation syndrome (MAS) in sJIA

Imaging Studies

• •Radiographs show soft tissue swelling and periarticular osteopenia early in the disease
• Joint destruction is less frequent, but bony erosion and cyst formation may be present.

How is Still Disease treated?

Nonpharmacologic Therapy

Collaboration among the patient’s pediatrician, rheumatologist, orthopedist, and physical therapist is essential.

Chronic General Treatment

Patients may require combinations of these therapies.

• •NSAIDs: Should be used in conjunction with other agents
• •DMARDs (disease-modifying antirheumatic drugs): Methotrexate, leflunomide, sulfasalazine
  • 1.Initial therapy with a DMARD is strongly recommended over NSAID monotherapy
  • 2.Required by two thirds of children
  • 3.Axial involvement is less responsive to methotrexate
• •Biologics: Improve morbidity associated with JIA. Individual subtypes show different responses to therapy
  • 1.Tumor necrosis factor antagonists such as etanercept and adalimumab
  • 2.T-cell modulator, abatacept
  • 3.IL-1 (anakinra) and IL-6 antagonists (tocilizumab) useful in sJIA

Meta-analysis of randomized controlled trials did not show statistically significant differences in the efficacy or safety profile of these agents.

• •Chronic systemic corticosteroids should be limited when possible.
• •Major medications and indications for treatment of JIA are summarized in the below table.

Major Medications and Indications for Treatment of Juvenile Idiopathic Arthritis

From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

Medication	Arthritis Subtype	Indication
NSAIDs	All types	Symptomatic: Pain, stiffness, serositis, antiinflammatory in mild cases
Intraarticular corticosteroids	All types, mainly oligoarthritis	Injection of few active joints
Systemic corticosteroids	Systemic, polyarthritis	Fever, serositis, bridging medication, MAS
Methotrexate	All types; less effective for systemic and enthesitis-related axial disease	Disease modifying
Leflunomide	Polyarthritis	Disease modifying
Sulfasalazine	Oligoarthritis, polyarthritis, enthesitis-related peripheral disease	Disease modifying
Cyclosporine	Systemic	MAS
Thalidomide	Systemic	Biologic modifier
Anti-TNF (etanercept infliximab, adalimumab, golimumab, certolizumab)	Polyarthritis, enthesitis-related, uveitis (infliximab, adalimumab), less effective for systemic disease	Biologic modifier
Abatacept	Polyarthritis	Biologic modifier
Anti–IL-1 (anakinra, canakinumab, rilonacept)	Systemic	Biologic modifier, MAS
Anti–IL-6 (tocilizumab)	Systemic, polyarthritis	Biologic modifier
IVIG	Systemic	Steroid sparing, MAS

IL-1, Interleukin-1; IVIG, intravenous immune globulin; MAS, macrophage activation syndrome; NSAID, nonsteroidal antiinflammatory drug; TNF, tumor necrosis factor.

Disposition

• •More than 50% continue to have active disease into adulthood.
• •Patients with persistent oligoarticular disease are most likely to achieve remission, whereas those who are RF positive are least likely to achieve remission.
• •Macrophage activation syndrome is a life-threatening complication of sJIA.
• •Asymmetric joint involvement can lead to growth failure and limb length discrepancies.

Referral

• •Early rheumatology consultation
• •Ophthalmology consultation at diagnosis and at least annually
• •Children ages <7 yr, with + ANA are at the highest risk for ocular inflammation (uveitis) and require screening every 3 to 4 months

Pearls & Considerations

JIA is an autoinflammatory disease with a strong genetic component.

Children with JIA are at risk of permanent joint damage and decreased health-related quality of life.

Normalization of the immune response early in the disease can limit disease progression, and early institution of DMARD therapy is important for optimal outcomes.

Immunomodulators have been shown to improve therapy in refractory disease.

Children with JIA have an increased rate of malignancy compared with the general population.

Seek Additional Information

• Beukelman T., et al.: Risk of malignancy associated with paediatric use of tumour necrosis factor inhibitors. Ann Rheum Dis 2018; 77 (7): pp. 1012-1016.
• De Benedetti F., et al.: Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med 2012; 367: pp. 2385-2395.
• Dick A.D., et al.: Adalimumab plus methotrexate for uveitis in juvenile idiopathic arthritis. N Engl J Med 2017; 376: pp. 1637-1646.
• Giancane G., et al.: Update of the pathogenesis and treatment of juvenile idiopathic arthritis. Curr Opin Rheumatol 2017; 29: pp. 523-529.
• Hersh A.O., Prahalad S.: Genetics of juvenile idiopathic arthritis. Rheum Dis Clin N Am 2017; 43: pp. 435-448.
• Horneff G., et al.: Protocols on classification, monitoring and therapy in children’s rheumatology (PRO-KIND): results of the working group polyarticular juvenile idiopathic arthritis. Pediatric Rheumatology 2017; 15: pp. 78.
• Nigrovic P.A.: Genetics and the classification of arthritis in adults and children. Arthritis Rheumatol 2018; 70 (1): pp. 7-17.
• Ravelli A., et al.: 2016 Classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a European league against rheumatism/American College of Rheumatology/Paediatric Rheumatology international trials organization collaborative initiative. Arth & Rheum 2016; 68 (3): pp. 566-576.
• Ringold S., et al.: 2019 American College of Rheumatology/Arthritis Foundation guideline for the treatment of juvenile idiopathic arthritis: therapeutic approaches for non-systemic polyarthritis, sacroiliitis, and enthesitis. Arthritis Care Res (Hoboken) 2019; 71 (6): pp. 717-734.
• Shoop-Worrall S., et al.: How common is remission in juvenile idiopathic arthritis? A systematic review. Semin Arthritis Rheum 2017; 47: pp. 331-337.