Rheumatologic Diseases

Megan A. Cooper

Andrew J. White

Pediatric rheumatology is a broad field that deals with disorders of the joints, connective tissues, muscles, and vasculature as well as autoimmune and autoinflammatory disorders.

APPROACH TO THE CHILD WITH JOINT PAIN AND/OR SWELLING

Joint pain is a common complaint in children.
It is generally transient, secondary to trauma and/or increased activity.

Etiology and Differential Diagnosis

It is important to determine if the pain is secondary to joint, muscular, ligament, or bone or if it is referred pain.
Joint pain (arthralgia) should be distinguished from arthritis, which has objective physical examination findings of effusion, warmth, and/or erythema.
Joint pain may be because of various conditions depending on the number and kind of joints involved.
- Single joint (monoarticular):
  - Infectious: septic joint, osteomyelitis, Lyme arthritis, or gonococcal infection
  - Fracture
  - Hemarthrosis (primarily seen in sickle cell disease)
  - Malignancy: primary bone tumor or leukemia
  - Inflammatory: juvenile idiopathic arthritis (JIA) or other inflammatory arthritis (e.g., spondyloarthropathy, sarcoidosis)
- Multiple joints (polyarticular)
  - Inflammatory: JIA, Henoch-Schönlein purpura (HSP), systemic lupus erythematosus (SLE), serum sickness-like reaction, sarcoidosis, inflammatory bowel disease (IBD)-associated arthritis, or Kawasaki disease
  - Malignancy: leukemia
  - Infectious: Lyme arthritis or Neisseria gonorrhoeae
  - Reactive arthritis: Salmonella, Shigella, Yersinia, Campylobacter, or Chlamydia
  - Rheumatic fever
  - Rickets
- Hip involvement (rare as the sole presentation of an inflammatory arthritis in children)
  - Avascular necrosis: Legg-Calve-Perthes disease, sickle cell disease, or chronic steroid use
  - Slipped capital femoral epiphysis (SCFE)
  - Transient synovitis (formerly known as toxic synovitis)
  - Septic joint
  - Lyme arthritis

Laboratory Studies

Initial Evaluation

Blood cultures: any time there is fever and new-onset joint pain
Complete blood count (CBC):
- Elevated white blood cells (WBCs): infection, inflammatory arthritis, malignancies
- Cytopenias: SLE, malignancy
- Microcytic anemia: IBD, systemic JIA
- Thrombocytosis: systemic JIA
Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP): elevated in infectious and inflammatory conditions; these are both nonspecific but can be useful for tracking established disease activity
Renal function panel: SLE, vasculitis (e.g., HSP, ANCA-associated vasculitis, Goodpasture syndrome)
Antinuclear antibody (ANA): if there is clinical concern for SLE or with established diagnosis of JIA to stratify risk of uveitis (see JIA section)

Joint Fluid Analysis (Table 23-1)

For isolated effusions with fever, joint aspiration is necessary to exclude a septic joint and should be done quickly and before initiation of antibiotics if the patient is stable.
Do not consider a rheumatologic etiology or initiate steroids in a child with fever and joint effusion before conducting a thorough investigation for a septic joint or osteomyelitis.

Imaging

Plain film radiographs of involved joints may show evidence of trauma, arthritis, and bony abnormalities.
In cases where there is a history of trauma, concern for septic joint and/or osteomyelitis, or the diagnosis of arthritis is uncertain, a magnetic resonance imaging scan with and without contrast can be useful.

Treatment

A patient who presents with joint pain and fever should be presumed to have a septic joint or osteomyelitis until proven otherwise.
A potentially septic joint or osteomyelitis is an emergency that requires prompt recognition, involvement of orthopedic surgery, radiologic imaging, and initiation of intravenous (IV) antibiotics once blood and synovial fluid (if appropriate) cultures are obtained.
Drugs frequently used in rheumatology are described in Table 23-2.

TABLE 23-1 Properties of Synovial Joint Fluid

	Normal	Reactive arthritis	Inflammatory (e.g., JIA)	Infectious
Color	Variable	Yellow	Yellow	Variable
Clarity	Clear	Clear to cloudy	Clear to cloudy	Cloudy, turbid
White blood cell count (per mm³)	<200	5,000-10,000	5,000->100,000	>50,000
% Neutrophils	<25%	>50%	>50%	>75%
Culture	Negative	Negative	Negative	Positive
JIA, juvenile idiopathic arthritis.

TABLE 23-2 Common Drugs Used in Rheumatology^*

Drug	Mechanism/actions	Dosage	Major side effects
NSAIDs
Naproxen Ibuprofen Aspirin	Anti-inflammatory Cyclooxygenase enzyme inhibition	20 mg/kg/day PO div. q12h 10 mg/kg/dose PO q6h 75-90 mg/kg/day PO div. q.i.d	Easy bleeding and bruising Gastrointestinal: gastritis, bleeding Reye syndrome (aspirin) Nephrotoxicity
Corticosteroids
Triamcinolone hexacetonide (IA)	Anti-inflammatory	Varies, 10-40 mg per joint	Skin atrophy at site of injection; very rarely infection
Prednisone (PO) Methylprednisolone (IV)	Anti-inflammatory Immunosuppressive (T cell)	Varies, 0.5-2 mg/kg/day PO Pulse dose: 30 mg/kg/day IV, maximum 1 g/day	Cushing syndrome, growth delay, osteoporosis, avascular necrosis
Immunosuppressives
Methotrexate	Inhibits purine synthesis	5 – 15 mg/m² once weekly PO or SC	Hepatotoxicity Cytopenias
Cytotoxic Agents
Cyclophosphamide	Alkylating agent Causes lymphopenia	Varies, pulse therapy monthly is 500-1,000 mg/m² IV	Cystitis Increased risk of infection Risk of infertility with high total dose
Cyclosporine	Thought to inhibit T-cell activation	Not standardized	Nephrotoxicity
Biologic Agents			Hepatotoxicity
Rituximab	Anti-CD20 mAb (anti-B cell)	Pediatric dosing not standardized, given as an IV infusion	Infusion reactions Increased risk of infection including reactivation of JC virus
Intravenous immune globulin	Pooled human immunoglobulin	Up to 2 g/kg IV	Infusion reactions Aseptic meningitis
Anakinra	Soluble IL-1Ra (inhibits IL-1)	Pediatric dosing not standardized, SC daily	Local injection site reactions
Anti-TNF-α Agents			For all Anti-TNF-α agents:
Etanercept (Enbrel) Infliximab (Remicade) Adalimumab (Humira)	Soluble TNF-α receptor Anti-TNF-α chimeric mAb Humanized anti-TNF-α mAb	0.4 mg/kg SC twice weekly 3-10 mg/kg IV q 4-8 weeks SC; dosing in pediatrics not standardized	Infusion/injection site reactions Reactivation of tuberculosis Possible increased risk of malignancy
^*These medications are each used in a variety of rheumatologic diseases; many are investigational, and all should be given in consultation with a pediatric rheumatologist.
NSAID, nonsteroidal anti-inflammatory drug; IA, intra-articular; PO, by mouth; IV, intravenous; TNF, tumor necrosis factor; SC, subcutaneous.

JUVENILE IDIOPATHIC ARTHRITIS

JIA is a chronic inflammatory arthritis characterized, but its exact etiology is unknown.
This disease may be classified into three main subsets: oligoarticular, polyarticular, and systemic (Table 23-3). Other types of JIA also include psoriatic arthritis, enthesitis-related arthritis (including juvenile ankylosing spondylitis), and undifferentiated arthritis.

Diagnosis

JIA is a diagnosis of exclusion (see Table 23-3).
Diagnosis requires arthritis in one or more joint for at least 6 weeks, age of onset <16 years, and exclusion of other causes of joint inflammation.
Laboratory values are of little use in diagnosis but can help to exclude other diagnoses, and are for prognosis (e.g., increased risk of uveitis with a positive ANA), for further classification of established chronic arthritis (e.g., rheumatoid factor and HLA-B27), and for tracking disease activity (ESR, CRP, and CBC).

Treatment

Pharmacologic therapy
- Anti-inflammatory agents
  - Nonsteroidal anti-inflammatory drugs (NSAIDs): naproxen 20 mg/kg/day divided q12h or ibuprofen 40 mg/kg/day divided q6h. Patients should take this on a scheduled basis for initial therapy.
  - Intra-articular corticosteroids: first-line therapy for patients with oligoarticular arthritis in joints amenable to intra-articular injection. Many patients will experience 6+ months of remission following a joint injection. Triamcinolone hexacetonide is a long-lasting formulation preferred for intra-articular injection of children.
  - Systemic corticosteroids: used for flares unresponsive to other therapies or severe systemic manifestations; can be given orally or intravenously. Systemic corticosteroids are generally not used as a first-line therapy anymore due to the early use of biologic medications.
- Disease-modifying antirheumatic drugs (DMARDs)
  - Methotrexate and leflunomide: need to monitor liver function and blood counts
  - Antitumor necrosis factor-α agents (biologic agents): etanercept, infliximab, adalimumab
  - Other biologic medications: IL-1 inhibitors (anakinra, rilonacept, canakinumab), IL-6 receptor antibody (tocilizumab), CTLA4-Ig (abatacept)
- See Table 23-2 for dosages and further information for select medications.
Special considerations for therapy of systemic JIA
- Initial treatment often is instituted during hospitalization until systemic symptoms are under control.
- NSAIDs may help to control pain and swelling, but are not used alone.
- Initial treatment often consists of steroids and methotrexate with a biologic medication.
- Early use of biologic agents, especially inhibitors of the IL-1 or IL-6 pathways, may be beneficial in some patients after evaluation by a pediatric rheumatologist.
Other monitoring/therapies
- Ophthalmology examinations for uveitis are necessary every 3-6 months for oligoarticular and polyarticular JIA and yearly for systemic JIA. Children <6 years old with a positive ANA and oligoarticular disease are at highest risk for eye disease.
- Physical therapy, occupational therapy, and psychological support can be important for long-term outcome. However, with improving therapies, fewer physical disabilities related to JIA now occur.