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9 Articles in Volume 13, Issue #5
Elvis Presley: Head Trauma, Autoimmunity, Pain, and Early Death
Traumatic Brain Injury: Treatment of Post-traumatic Headaches
Advances in Pharmacologic Pain Management of Juvenile Idiopathic Arthritis
Integrative Treatment Approaches for Juvenile Idiopathic Arthritis
How Changing Hydrocodone Scheduling Will Affect Pain Management
Editor's Memo: Interpreting Indications For Electromagnetic Therapy
Specimen Validity Testing
Can a Buprenorphine Transdermal System (Butrans) Be Used to Treat OUD?
Letters to the Editor: Testosterone, Ultra-high Dose Opioids

Advances in Pharmacologic Pain Management of Juvenile Idiopathic Arthritis

JIA is one of the most common rheumatologic conditions seen in children. Thankfully, there are treatments that can help minimize symptoms and aid in diminishing the potential long-term sequelae of the disease. This article reviews the pharmacological options to control pain and inflammation.

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.

Pain

Pain is a key symptom in JIA, and it can have a significant impact on a child’s life. The chronic pain associated with active inflammatory arthritis can be severe. Studies have shown that 76% of children with the polyarticular subtype of JIA reported pain on greater than 60% of days. These children self-reported daily pain levels ranging from mild to moderate, with 31% recording their pain as severe.13 Clinically significant implications of increased pain levels include decreased levels of participation in school and social activities, increased reports of anxiety, and increased risks of further psychosocial problems.13 Further study of patients with long-standing JIA explores frequency of pain across subsets in 246 adult JIA patients (mean age 35.4 years old), with a mean duration of arthritis of 28.3 years.14 Of these patients, 31.6% were anxious, 5.2% were depressed, and 21.1% had suffered from depression in the past. A reported 7% of patients were pain-free—oligoarticular patients experienced the least pain and systemic arthritis patients reported the greatest.11 Data suggest that a valuable approach to pain management in JIA may involve aggressive treatment with a variety of pharmacologic agents to maintain normal function in school, physical, and social domains.13

Treatment

Non-Steroidal Anti-inflammatory Drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) are the mainstay of treatment and are regularly used as monotherapy in patients with oligoarticular JIA (Table 3).9 Patients classified by the ACR as having "low disease activity, without joint contracture, and without features of poor prognosis" are given NSAID monotherapy for up to 2 months, at which point the addition of supplemental therapy should be considered. Low disease activity in oligoarticular JIA is defined by the ACR as satisfying the following criteria: 1 or fewer active joints, normal ESR or C-reactive protein, a physician global assessment of overall disease activity score of <3 out of 10, and patient/parent global assessment of overall well being score of <2 out of 10.2

Patients with polyarticular JIA with active arthritis classified as having low or moderate disease activity should not be treated with NSAID monotherapy beyond 2 months, irrespective of poor prognostic features. Low disease activity in polyarticular JIA and systemic arthritis with active arthritis (without active systemic features) is defined by the ACR as satisfying all of the following: 4 or fewer active joints, normal ESR or C-reactive protein levels, a physician global assessment of overall disease activity score of <4 out of 10, and a patient/parent global assessment of overall well being score of <2 out of 10. Moderate disease activity is defined as having 1 or more features measuring greater than those describing low disease activity level AND fewer than 3 features of high disease activity.2

The treatment of systemic arthritis is dependent on its two-fold presentation: either active systemic features or active arthritis. If a patient presents with aspects of both active systemic features and active arthritis concurrently, treatment reflects aspects of both guidelines, outlined as follows: NSAID monotherapy for up to 1 month is recommended for low levels of disease activity in patients with systemic arthritis without active systemic features and with active arthritis, irrespective of poor prognostic features. (Low disease activity for this category is defined in the previous paragraph.2) NSAID monotherapy for systemic arthritis with active systemic features and without active arthritis can be divided as follows: patients with active fever and a physician global assessment of overall disease activity score of <7 out of 10 may use NSAID monotherapy for no longer than 1 month. NSAID monotherapy is not advised for patients with active fever and systemic features of high disease activity (eg, significant serositis) that result in a physician global assessment of overall disease activity score ≥7 out of 10.2

While NSAIDs are well tolerated in children, there are few safety studies regarding their use. NSAIDs used for the treatment of JIA include ibuprofen, indomethacin, meloxicam, naproxen, and tolmetin, with liquid formulations available for all but tolmetin. Whereas limited studies differentiate between NSAIDs, factors to consider when choosing a specific NSAID include dosing schedules, availability of liquid formulations, and patient preferences.8,9

Corticosteroids

When NSAIDs fail to control the pain of arthritis in 4 or fewer joints, intra-articular injections of corticosteroids should be considered.15 The injection of corticosteroids has been shown to not only improve symptoms of JIA but also slow the progression of the disease. Pannus formation in the retropatellar knee was shown to have diminished up to 1 year following such an injection.15 Although the response to intra-articular steroids is variable, these injections may induce complete resolution of inflammation for a period of time, thereby eliminating the necessity of taking daily medication. Two formulations of corticosteroids have been approved by the FDA for intra-articular injections: betamethasone and triamcinolone acetonide.16 Furthermore, two different formulations of triamcinolone have been studied in children with inflammatory arthritis: triamcinolone hexacetonide and triamcinolone acetonide.17 The accepted dose in larger joints, such as the knee, is 1 mg/kg of triamcinolone hexacetonide (up to 40 mg maximum) or up to 2 mg/kg of triamcinolone acetonide. Triamcinolone hexacetonide has been shown to be more effective than triamcinolone acetonide; however, it is unclear whether increased doses can alter the efficacy or the duration of effect.16 The duration of clinical response has a wide range, from weeks to more than 1 year; however, the average duration of response is approximately 4 months.

Oral corticosteroids rarely are used due to the risks of adverse effects when they are used in high doses and for prolonged periods of time. Oral corticosteroids may be helpful in alleviating the fevers and other systemic symptoms in those with active systemic onset JIA and also as a bridge treatment while patients are waiting for disease-modifying anti-rheumatic drugs (DMARDs) to become effective.18

Disease-Modifying Anti-Rheumatic Drugs

Although anti-inflammatory agents such as those discussed above classically have been used as first-line therapy for JIA, DMARDs increasingly are being used as first-line monotherapy treatment in patients with poor prognostic features and moderate to high disease activity due to their ability to slow the progression of the disease.18 DMARDs fall into one of two broad categories19: biologic (modified antibodies and receptors) and non-biologic. DMARDs target particular cellular pathways to alter the inflammatory response, although the specific mechanisms of action of some remain unknown (Table 4). While there are many DMARDs used for various rheumatologic conditions, 7 of them are FDA-approved for JIA. Although many other DMARDs may be used off-label for JIA, only those approved specifically for this disease are discussed here.

The most widely used DMARD, methotrexate, has been proven to be safe and effective for all of the subclasses of JIA.2 Methotrexate has been shown to significantly improve the physician and the parent global assessment of disease scores as well as the ESR in oligoarticular JIA,20 especially in the case of "patients with high disease activity and features of poor prognosis."2 Methotrexate also can be used as second-line therapy if NSAIDs or intra-articular corticosteroids are ineffective, even in "patients with moderate disease activity."2 One of the benefits of methotrexate is that it can be dosed once per week and if it is delivered via subcutaneous injection it has increased bioavailability.18 The most common side effect of methotrexate is gastrointestinal upset. Although liver toxicity is a major concern for adults taking methotrexate, this does not seem to be an issue in children, perhaps due to a lower prevalence of pre-existing subclinical liver dysfunction in a pediatric population.8 Pneumonitis, another adverse effect occasionally seen in adults taking methotrexate, is also very rarely seen in children.9 Methotrexate generally is well tolerated at rheumatologic doses, and many of the side effects can be minimized via folate supplementation.18

Abatacept (Orencia) is a modified receptor molecule that blocks the co-stimulatory signal necessary for T-cell activation.21 Abatacept has been shown to be efficacious and safe in children with JIA when previous treatments failed or the patient could not tolerate other DMARDs.22 It was found to be effective in preventing flares without having adverse effects compared with placebo, and to improve both the active joint count and the physician global assessment score.19,23

Another class of DMARDs used to treat JIA is one that inhibits the action of tumor necrosis factor (TNF)-α. Adalimumab (Humira) is a humanized anti-TNF antibody and etanercept (Enbrel) is a soluble TNF receptor.24 Both of these drugs have been shown to be effective after treatment with NSAIDs and/or methotrexate, particularly in decreasing overall disease activity and preventing flares. In fact, etanercept has been shown to have greater activity if given along with methotrexate. This effect is not seen with adalimumab. While these anti-TNF drugs are effective in modulating the symptoms of JIA, they are not without side effects. Common side effects include psoriatic, eczematous, or other cutaneous lesions,25 and mild infections, such as pharyngitis or pneumonia. Reactivation of tuberculosis (TB) is rare but can be a potential significant adverse effect. Nonetheless, it has been shown that with proper monitoring and appropriate prophylaxis for TB, treating children with JIA with anti-TNF drugs is safe with respect to the risk of TB.26

Sulfasalazine is a DMARD with an unknown mechanism of action that has been used for rheumatoid arthritis in adults for several decades. Only recently has sulfasalazine been studied in children suffering from JIA. Sulfasalazine has been shown to be more efficacious than placebo in treating acute symptoms and slowing the progression of disease. Particularly, early treatment with sulfasalazine has been shown to be beneficial in both oligoarticular and polyarticular JIA.27 Additionally, it was noteworthy that sulfasalazine has increased action in children diagnosed with the enthesitis-related subtype of JIA. Sulfasalazine may be associated with anorexia, abdominal pain, and rash. For these reasons, compliance has been an issue, and many patients prefer using other DMARDs with better side effect profiles, such as methotrexate. Research has shown "a clear relation between therapy compliance and a better disease outcome as reflected in joint scores, patients’ scores, and probability of surgical intervention."27

Toclizumab (Actemra) was approved by the FDA for treatment of systemic  and polyarticular JIA. It may be used with methotrexate and other DMARDs. Lastly, canakinumab (Ilaris) was approved for systemic JIA in May 2013.

Adult Toll

Although diagnosed in childhood, the pain and functional impairment associated with this illness often may progress into adulthood and lead to long-term physical disability, as remission without flares is rare without continuous medication.28,29 Aside from acute flare-ups, long-term consequences of the disease process are evident in adult populations living with JIA. For instance, fully grown adults with JIA are shorter in stature compared to the general population. This short stature seems to be correlated with chronic systemic corticosteroid use, which itself is reserved only for severe, refractory disease activity. Thus, it is unclear whether the disease itself or the steroids is the fundamental cause of the short stature of adults with JIA. Additionally, a large percentage of adults with JIA suffer from leg length discrepancy; however, this seems to largely be of an iatrogenic nature, secondary to total hip replacements, which is common given the joint damage suffered by long-standing JIA, especially in those with systemic onset JIA. Also more closely associated with systemic onset JIA, chronic arthritis of the temporomandibular joint leads to jaw dysfunction and impaired ability to widely open one’s mouth. Eye pathology including uveitis, glaucoma, and cataracts are more common in adults living with extended oligoarticular JIA. Finally, the consequences of long-term use of systemic corticosteroids and DMARDs, which can lead to Cushing’s syndrome and immunodeficiencies, among various other side effects, cannot be ignored.30

Another significant concern for adults with longstanding JIA is cardiovascular disease (CVD). While there is a well-studied increased risk for CVD in adults who suffer from rheumatoid arthritis, there is a paucity of research on their counterparts with JIA. Considering the lower level of physical activity in people with JIA and the chronic high level of systemic inflammation in JIA, it is reasonable to be concerned about higher risk for CVD.31 Raab et al studied adult patients who had JIA and found that they had comorbid conditions, which had a significant impact on their perceived health. The more concerning symptoms occurred in those who had systemic onset JIA, which had a higher risk for cardiovascular disease.28

Summary

JIA is one of the most common rheumatologic conditions seen in children. Thankfully, there are treatments that can help minimize symptoms and aid in diminishing the potential long-term sequelae of the disease. Conventional treatment involves anti-inflammatory agents including NSAIDs and intra-articular corticosteroids. More recently, the development of the DMARDs, particularly the biologic agents, has revolutionized the treatment of JIA. A sample of treatment recommendations is given in Figure 1 for the most common cases of JIA. While the use of these drugs has been extremely promising thus far, more research is needed to further elucidate their efficacy compared to placebo and compared to each other, and to determine which agents may be most helpful for each individual subtype of JIA. As treatments continue to be developed, studied, and perfected, the potential for a true cure remains.

Last updated on: April 12, 2017
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