Arthritides

Juvenile idiopathic arthritis (JIA) and reactive arthritis are the most common causes of noninfectious inflammatory joint swelling in children. Diagnosis of both conditions is primarily based on clinical features and exam findings, but laboratory studies and imaging can provide additional diagnostic support. JIA is a chronic inflammatory arthritis without a known inciting trigger, whereas reactive arthritis is a self-limited arthritis with a preceding infectious trigger. This section covers the following arthritides:

• Juvenile Idiopathic Arthritis

• Reactive Arthritis

Juvenile Idiopathic Arthritis

JIA is the umbrella term for chronic, noninfectious, synovial inflammation in children, and it is the most common chronic childhood rheumatologic disease (incidence, 1-100 cases per 100,000 children). JIA is defined as the onset of arthritis with unknown etiology before the age of 16 years with symptoms lasting at least 6 weeks. The etiology of JIA is thought to be multifactorial and involve the interaction of genetic factors, immune mechanisms, and environmental exposures.

Classification

JIA is comprised of several disease subtypes. The 2001 International League of Associations for Rheumatology (ILAR) classification criteria for JIA include the following seven specific subtypes:

• oligoarthritis

• polyarthritis (rheumatoid factor [RF] negative)

• polyarthritis (RF positive)

• enthesitis-related arthritis (ERA)

• psoriatic arthritis (PsA)

• undifferentiated arthritis

• systemic JIA (sJIA)

Pathophysiology

The underlying pathophysiology of JIA also differs from one type of onset to another as follows:

• Autoantibodies are common in oligoarthritis (antinuclear antibodies [ANA]) and RF-positive polyarthritis (IgM rheumatoid factor, anticitrullinated peptide antibodies [anti-CCP antibodies])

• Autoantibodies are not common in enthesitis-related arthritis (ERA), but ERA is associated with misfolding of the protein coded for by the genetic marker HLA-B27 (the strongest HLA association)

• Multiple other specific HLA alleles are linked to specific JIA disease subtypes

• In all categories of JIA, products of activated T cells and macrophages are involved in pathogenesis of synovitis

• Systemic arthritis is characterized neither by the presence of autoantibodies nor a strong genetic predisposition and is considered an autoinflammatory disease

  • It is important to note that sJIA is a distinct entity, different in pathophysiology and clinical symptoms from the other subtypes of JIA. However, it is still included in the ILAR classification schema due to presence of chronic inflammatory arthritis.

Clinical Manifestations

An affected joint is defined as one with swelling or a combination of pain on motion and limitation of motion. Previously affected joints may have only limitation of motion. Affected joints may be warm, although this is not always apparent. A joint is considered affected only if there is an abnormal physical examination, not by imaging alone. The American College of Rheumatology (ACR) image library includes images of the clinical manifestations of JIA mentioned below.

General:

• limp, joint swelling with morning stiffness, pain with inactivity

• painless swelling (in 25% of children)

• systemic symptoms of significant fatigue, weight loss, and anorexia only with severe polyarticular disease, systemic JIA, and/or associated conditions such as inflammatory bowel disease or celiac disease; should prompt suspicion for malignancy if present in other subtypes of JIA

Musculoskeletal exam findings:

• swelling/effusion

• limited range of motion

• warmth

  • joint erythema is not common and should raise concern for septic arthritis or reactive arthritis, including acute rheumatic fever

• contracture, limb-length discrepancies, and wasting of musculature proximal to affected joint are associated with chronic untreated arthritis and can help differentiate between acute and chronic arthritis

• micrognathia, trismus, or jaw deviation should raise concern for arthritis of temporomandibular joint

Anterior uveitis:

• inflammation of the iris and ciliary bodies of the eye

• most common in ANA-positive young females

• asymptomatic in oligo- and polyarthritis

• more commonly symptomatic (and often unilateral) in enthesitis-related arthritis and psoriatic arthritis

• not associated with systemic JIA

• pupil irregularities, synechiae, band keratopathy on exam; may lead to visual loss, cataract, glaucoma

Macrophage activation syndrome (MAS)/secondary hemophagocytic lymphohistiocytosis (HLH): a potentially life-threatening complication associated with systemic JIA (but not other subtypes of JIA)

• symptoms: may include unremitting fever, hepatosplenomegaly, lymphadenopathy, coagulopathy with bruising and mucosal bleeding, liver dysfunction, respiratory distress, encephalopathy, and renal involvement progressing to multisystem organ failure

• laboratory test results typical of MAS:

  • profound hyperferritinemia

  • fall in leukocyte count, (leukopenia), hemoglobin (anemia), and platelets (thrombocytopenia)

  • elevated liver enzymes

  • rising CRP with paradoxically low ESR due to hypofibrinogenemia

  • elevated D-dimer level

  • elevated lactate dehydrogenase (LDH) level

  • prolonged prothrombin time (PT) and partial thromboplastin time (PTT)

  • hypertriglyceridemia

  • elevated soluble interleukin (IL)-2 receptor

  • evidence of macrophage hemophagocytosis on bone-marrow biopsy (low sensitivity)

• Complications associated with JIA diagnosis:

  • higher incidence of septic arthritis in patients with JIA

  • risk of pseudoporphyria with nonsteroidal anti-inflammatory drug (NSAID) use

  • steroid toxicity, leading to growth impairment, decreased bone-mineral density, avascular necrosis, obesity, glaucoma

Diagnosis

The diagnosis of JIA is primarily based on clinical presentation and exam and requires exclusion of other known conditions. Diagnostic criteria for the various subtypes are provided in the table above.

Laboratory evaluation: No laboratory test can specifically confirm the diagnosis of chronic arthritis. However, laboratory studies can be used to provide evidence of inflammation, support the clinical diagnosis, monitor for toxicity of therapy, and better understand the pathogenesis of the disease.

• erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)

  • most often normal with exception of systemic JIA, severe oligo- or polyarthritis, active sacroiliitis, or overlapping IBD

• complete blood count (CBC)

  • platelets may be elevated

  • normal or low platelets in the setting of systemic inflammation should raise concern for malignancy or MAS in patients with sJIA

• antinuclear antibody (ANA)

  • positive ANA associated with increased risk of developing uveitis

  • not useful for diagnostic purposes

• rheumatoid factor

  • positive in minority of patients with polyarthritis

  • useful for prognostic purposes only (predictive of more-severe and protracted disease course)

• anti-cyclic citrullinated peptide (anti-CCP) antibodies

  • most common in RF-positive polyarthritis

  • predictive of more-severe disease course

• HLA-B27

  • positive in 60%-80% of patients with ERA

  • not diagnostic without other disease features (present in 8% of general population)

• joint fluid aspirate

  • obtained either during diagnostic workup if the diagnosis of JIA is uncertain or during a therapeutic intra-articular glucocorticoid injection

  • leukocyte count usually 2000-50,000 per mm3 (or higher); neutrophil predominance

Imaging:

• radiographs not routinely obtained at baseline but may show joint erosions

• ultrasonography to confirm joint effusion and/or assess for synovial proliferation

• MRI in atypical presentations to confirm inflammatory synovitis and/or rule out other etiologies of articular symptoms (malignancy, osteochondral defects, pigmented villonodular synovitis [PVNS])

Treatment

Oligoarthritis (includes psoriatic arthritis and ERA with oligoarticular course without axial involvement):

• First-line: intra-articular glucocorticoid injections

• Second-line: methotrexate (oral or subcutaneous) if no response to intra-articular glucocorticoid injections or if manifestations are severe

• Third-line: addition of tumor necrosis factor (TNF)-alpha inhibitors (e.g., etanercept, adalimumab, infliximab) if methotrexate is not effective after 12 weeks of therapy

• NSAIDs (e.g., naproxen) for symptomatic relief, but not appropriate as monotherapy to treat arthritis

Polyarthritis (includes psoriatic arthritis and ERA with polyarticular course without axial involvement):

• First-line: initiation of methotrexate (oral or subcutaneous) +/- intra-articular glucocorticoids of most symptomatic joints; systemic glucocorticoids may be used as a short-term bridge for patients with significant pain or functional impairment

• Second-line: addition of TNF-alpha inhibitors (e.g., etanercept, adalimumab, infliximab)

  • New data suggest that the early addition of TNF-alpha inhibitors as dual therapy with methotrexate (i.e., at the initiation of systemic therapy) or as first-line monotherapy portends better disease control and earlier remission for patients with polyarthritis

• Third-line: CTLA-4 Ig (abatacept), IL-6 receptor antagonist (tocilizumab), B-cell depletion (rituximab), tofactinib (Janus kinase inhibitor)

• *Note: Rheumatoid factor and/or anticitrullinated-antibody positive are associated with poor prognosis and often necessitate aggressive therapy.

Enthesitis-related arthritis or psoriatic arthritis with axial involvement (axial involvement refers to sacroiliitis or arthritis of the spine):

• First-line: TNF-alpha inhibitors (etanercept, adalimumab, infliximab) in combination with methotrexate; methotrexate NOT effective for axial disease

• Second-line: secukinumab (IL-17 inhibitor), ustekinumab (IL-23/IL-12 inhibitor), tofacitinib

Systemic JIA:

• First-line: Nonsteroidal anti-inflammatory drugs (NSAIDs; indomethacin, naproxen) for mild disease without MAS features; most patients will require escalation of therapy due to persistent systemic features (fever, rash, elevated inflammatory markers) or arthritis

• Second-line: IL-1 inhibitors (anakinra or canakinumab) or IL-6 receptor inhibitor (tocilizumab) with or without systemic glucocorticoids depending on disease severity

• Third-line: cyclosporine (particularly with refractory MAS), tacrolimus, tofactinib or ruxolitinib (janus kinase inhibitors)

• Cyclophosphamide: for interstitial lung disease, reserved for refractory and life-threatening cases

Uveitis:

• Screening:

  • slit-lamp exam to diagnose asymptomatic uveitis

  • screening every 3-6 months initially, depending on age at onset and ANA status; every 12 months is adequate in systemic JIA (mostly for monitoring of toxicity in a patient on glucocorticoids)

• Treatment:

  • First-line: topical steroid drops, but low threshold to initiate methotrexate if difficulty weaning after a few weeks

  • Second-line: biologic therapy with either infliximab or adalimumab

Dietary/nutrition:

• ensure adequate calcium, vitamin D

Physical therapy and occupational therapy:

• helpful in patients with joint contractures and/or muscle atrophy from untreated arthritis

• goal is to maintain and improve joint function and motion

Immunizations:

• avoid live vaccines (varicella, measles-mumps-rubella [MMR], intranasal influenza) for individuals on high-dose systemic glucocorticoids or immunosuppressants

• administer inactivated influenza vaccine annually

• additional pneumococcal vaccination with both PCV13 in combination with PPSV23, or PCV20 alone, in patients on immunosuppressive medications

• encourage COVID-19 vaccination (including current CDC guidance on extra dose of initial series and booster dose, depending on age and immunocompromised status)

Reactive Arthritis

Reactive arthritis is a self-limited, predominantly lower-extremity, asymmetric arthritis with demonstration of a preceding infection (most commonly enteric or genitourinary) with arthritogenic pathogens. The estimated prevalence is 4%-9% in the United States, Canada, and the United Kingdom. It is more common in boys with a peak age of 6-8 years, but age and sex distribution vary by causative organism. Common preceding infections include Yersinia, Salmonella, Shigella, Campylobacter, and Chlamydia. HLA-B27 is strongly associated with reactive arthritis, although the role in the pathogenesis is unclear. There is probable CD8+ T-cell cross-reactivity with bacterial epitopes.

Clinical Manifestations

General:

• vary by inciting organism:

  • abdominal pain and diarrhea for enteric pathogens

  • dysuria, frequency, and a urethral or vaginal discharge for genitourinary pathogens (e.g., Chlamydia)

• HLA-B27-positive patients:

  • often have recurrent episodes, more joints involved, more-severe symptoms, and the triad of arthritis, conjunctivitis, and urethritis

  • may later evolve into ERA or juvenile ankylosing spondylitis

• systemic symptoms (fever, weight loss, and fatigue)

  • often occur during disease activity

Musculoskeletal involvement:

• oligoarthritis and enthesitis are more common than polyarthritis

• painful, often with overlying erythema

• usually affects knees and ankles but sometimes small joints of the hands and feet

• axial inflammation can result in spinal and sacroiliac pain and stiffness

• follows enteric infection within 7-30 days

Mucocutaneous and ocular involvement:

• painless, shallow ulcers of the oral mucosa and palate are common

• urethritis and cervicitis rare but can occur with chlamydial infection

• erythema nodosum (triggered by Yersinia)

• circinate balanitis

• keratoderma blennorrhagicum

• conjunctivitis in two-thirds of patients; anterior uveitis also reported

• mucocutaneous involvement parallels activity in peripheral joints

Diagnosis

Diagnosis of reactive arthritis is primarily based on clinical presentation, physical exam, and ruling out other etiologies that require alternative management (e.g., septic arthritis or acute rheumatic fever). Official diagnosis requires documentation of preceding infection (with stool or urethral culture), but this is rare in practice.

Laboratory evaluation:

• ESR and CRP: usually elevated

• CBC: anemia in severe disease, thrombocytosis, leukocytosis; may see marrow suppression in the setting of a viral or post-viral arthritis

• urinalysis: may show sterile pyuria, should also prompt testing for Chlamydia

• synovial fluid: to rule out septic arthritis; leukocyte count usually ~20,000 per mm³ (see table above) with neutrophil predominance

Imaging:

• ultrasound: useful to evaluate for hip effusions or if physical exam is equivocal

• MRI: not usually necessary if other signs present to support diagnosis; may show marrow edema, synovitis +/- tenosynovitis

Treatment

• primarily supportive with NSAIDs (indomethacin is particularly effective), as course is usually self-limited

• glucocorticoids for severe, widespread disease

• intra-articular glucocorticoid injection for rapid relief in the case of monoarthritis

• antibiotics not clearly efficacious, except perhaps in patients with Chlamydia-associated reactive arthritis

• systemic immunosuppression rarely used for more refractory cases

  • Sulfasalazine is particularly useful for HLA-B27-positive patients with refractory or recurrent course

  • Methotrexate is often the short-term treatment of choice