Advances in Pharmacologic Pain Management of Juvenile Idiopathic Arthritis
Juvenile idiopathic arthritis (JIA), also known as juvenile rheumatoid arthritis, is a heterogeneous group of diseases with joint pain presenting as a clinically significant feature for many of the affected patients. The disease is defined by the International League of Associations for Rheumatology (ILAR) as arthritis of unknown etiology with onset before the age of 16 and persisting for more than 6 weeks.1 One of the most common childhood chronic rheumatic diseases, its worldwide prevalence varies among studies but has been estimated to be 1 per 1,000 children.2
Not unlike rheumatologic diseases in adults, children with JIA are afflicted with other autoimmune diseases at a greater rate than the general population. Specifically, JIA has been shown to be associated with subclinical hypothyroidism, autoimmune thyroiditis, and celiac disease.3 Additionally, patients with JIA are often members of families that have a high degree of autoimmunity.4 A study of a Finnish population found a familial association of JIA with diabetes mellitus type 1, multiple sclerosis, celiac disease, chronic arthritis, rheumatoid arthritis, spondyloarthropathy, and psoriatic arthritis.5
Targeted studies over the last decade have advanced treatments for children suffering from JIA, with a specific focus on controlling pain and inflammation, and achieving inactive disease or remission.6 Just how patients with JIA fare in terms of health-related quality of life (HRQoL) has been recently examined.7 The research found HRQoL to be impaired in approximately half of children with JIA—pain was a significant factor resulting in diminished HRQoL. Therefore, pain management is of central importance in the care of children with JIA. This article reviews the subtypes of JIA and recent advances in pharmacologic pain treatment, with a focus on the 2011 American College of Rheumatology’s (ACR) revised recommendations for the treatment of JIA.2
Subtypes: Clinical Findings
JIA is divided into 5 major subtypes: oligoarticular onset, polyarticular onset, systemic onset, psoriatic arthritis, and enthesitis-related arthritis (Table 1). Variability in the sites of inflammation (other than joints), associated signs and symptoms, and the number of joints affected serve as the basis for differentiation.8 Patients with oligoarticular onset—which accounts for between 50% to 60% of all cases of JIA9—exhibit arthritis of 4 or fewer joints during the first 6 months of illness.1 Children with this subtype most often display arthritis of the knees and ankles, with 50% reporting monoarthritis.9 This subtype occurs more commonly in girls (5:1 female to male ratio); these patients are frequently positive for antinuclear antibodies (60%-90%).6 Approximately 15% to 20% of patients with oligoarticular JIA develop uveitis. Risk factors include the presence of antinuclear antibodies, age less than 6 years at diagnosis, and disease duration of less than 4 years.10,11
Polyarticular onset represents 25% to 40% of JIA cases and is characterized by the involvement of 5 or more joints during the first 6 months of illness. It is further classified as rheumatoid factor (RF) negative or positive, with 10% to 20% of polyarticular JIA reported to be RF positive. Patients typically develop symmetrical arthritis of the small joints of the hands and fingers, with occasional associated complaints of mild fatigue and elevated inflammatory markers.9
Children with systemic onset account for 10% to 20% of JIA cases; clinically, they have intermittent daily spiking fevers, arthritis, and a characteristic salmon-colored macular rash that is evanescent and comes and goes along with the fevers.12 ILAR criteria for diagnosis of systemic arthritis include age less than 16 years and the presence of arthritis in one or more joints with or preceded by fever of at least 2 weeks’ duration. The fever is documented to be daily ("quotidian") for at least 3 days and accompanied by one or more of the following: evanescent (non-fixed) erythematous rash, generalized lymph node enlargement, hepatomegaly and/or splenomegaly, and/or serositis.1 Initial presentations include high, spiking fevers of greater than 39° C that often are associated with significant joint pain. Articular manifestations are most typical in the wrists, knees, and ankles, with any number of involved joints. Arthritic symptoms can progress to include the temporomandibular joint, cervical spine, and hip. The macular, salmon-pink rash with central clearing is regularly found on the limbs and trunk and is most notable when the child is febrile. Characteristic laboratory findings include thrombocytosis, leukocytosis, anemia, and marked elevation in erythrocyte sedimentation rate (ESR) and C-reactive protein.12
Psoriatic arthritis, which makes up 3% to 10% of JIA cases, has a bimodal age distribution during childhood, occurring with peaks in preschool-aged children and again in adolescence. The arthritis may affect any number of joints but is typically oligoarticular and is characteristically episodic. Frequently, there is associated flexor tenosynovitis of the digits, producing what is commonly referred to as "sausage digits." A family history of psoriasis and the presence of nail changes, such as pitting or ridging of the nails, may be additional clues that aid in diagnosis.
Enthesitis-related arthritis refers to a form of JIA associated with inflammation at the sites where tendons or fascia insert into bone. This subtype of JIA, which represents 10% to 25% of cases, occurs most often in boys older than 8 years of age. It is typically oligoarticular and is associated with the human leukocyte antigen B27 in 50% to 70% of patients. This type of arthritis is associated with inflammatory bowel disease as well as juvenile ankylosing spondylitis.8 The large joints of the lower extremities most commonly are affected. Sacroiliitis is more common during childhood among patients with this JIA subtype. Patients are at increased risk of developing spondylitis as they enter their adult years. For those who have associated inflammatory bowel disease, the arthritis may precede the development of bowel symptoms for years.