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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

Integrative Treatment Approaches for Juvenile Idiopathic Arthritis

Parents of children with JIA often turn to complementary and alternative approaches to handle their child’s disease. Family values and resources play a critical role in determining which integrative therapies to recommend first. Therefore, forming a collaborative partnership with patients and their families is essential for avoiding “treatment fatigue” and improving overall success.

Juvenile idiopathic arthritis (JIA), also known as juvenile rheumatoid arthritis, is a nonspecific type of arthritis appearing before the age of 16 years and lasting at least 6 weeks.1,2 JIA is the most common chronic arthritis in children.2 Two peaks of onset have been described at 2 to 4 and 6 to 12 years of age,4 most often in Caucasian and female patients.5 In 2011, the American College of Rheumatology (ACR) updated their recommendations for pharmaceutical management of patients with JIA to include the following treatments alone or in combination: non-steroidal anti-inflammatory drugs (NSAIDs), intra-articular glucocorticoid injections, methotrexate (MTX), sulfasalazine, tumor necrosis factor alpha (TNF-α) inhibitors (ie, etanercept [Enbrel] and adalimumab [Humira]), leflunomide, abatacept (Orencia), anakinra (Kineret), and systemic glucocorticoids.2

Because of concerns of adverse events, the ACR recommends that NSAID and MTX safety monitoring consist of baseline serum creatinine levels, urinalysis, complete blood count, and liver function testing with repeat lab measurements over time. TNF-α inhibitors also require yearly tuberculosis screening. Hepatitis B and C screening are recommended prior to MTX and TNF-α administration if the patient has risk factors for infection.2 Data on combining these pharmaceuticals and natural health products (NHPs) are sparse, so if the clinician decides to use some natural products with the above medications, the lab studies can help with safety monitoring of novel combinations.

Benefits/Risks of Pharmaceutical Therapy

Since most JIA patients will be on prescription medications to aleviate painful symptoms, it is important to understand the benefits and risks of treatments. In a double-blind placebo-controlled trial of early aggressive therapy, 85 patients with JIA were randomly assigned to two groups: 42 patients received a combination of MTX 0.5 mg/kg/week (maximum 40 mg) subcutaneously, etanercept 0.8 mg/kg/week (maximum 50 mg), and prednisolone 0.5 mg/kg/day (maximum 60 mg) tapered to 0 by 17 weeks; and 43 patients received MTX 0.5 mg/kg/week, etanercept-placebo, and prednisolone-placebo.

Results from the study found that a cohort of 85 JIA patients achieved clinically inactive disease status in 32% of patients by 6 months and in 66% by 12 months. Patients who were treated earlier during the course of the disease in both arms experienced a higher rate of JIA remission with these treatments. Despite the success of these treatments, both arms of the study reported severe to less severe adverse events, including significant transaminase elevations, peritonsillar abscess, worsened pre-existing herpes infection, pneumonia, psychotic episodes during steroid taper, and septic hip joints.6 Concerns regarding malignancy and infection are also important to consider for patients taking a biologic agent.7-10

Prognosis

Fifty percent or more of patients with JIA have the risk of ongoing arthritis as adults, which necessitates long-term support for those patients.11,12 Despite MTX use in 66% and NSAID use in 88% of the children surveyed with polyarticular arthritis, many still experienced pain and reduced function, resulting in missed school and social activities. Higher levels of anxiety correlated with higher pain and function complaints, so adequate pain control should include mind–body approaches at promoting a sense of calm.13

Integrative Rheumatology In JIA

The use of NHPs and complementary and alternative medicine (CAM) is common in JIA. Parental fear of medication side effects, pain relief, a desire to improve their child’s well being, longer disease duration and multiple illnesses in the child, parental CAM use, and parental perception of whether medications are helping or not have all been found to drive pediatric CAM use in JIA.14-17 To follow is a discussion of alternative therapies for JIA.

Clinicians have few guidelines on the judicious, safe, and effective use of NHPs and CAM modalities for improving JIA symptoms, with or without standard-of-care medications and exercise prescriptions. Clinical outcomes in JIA patients who used CAM and NHP therapies showed that outcomes were no better compared to non-users. However, CAM users were more adherent to conventional therapy compared to non-users.18-20

The most commonly used CAM therapies include dietary modification, NHPs, chiropractic care, relaxation techniques, homeopathy, prayer, massage, meditation, acupuncture, and naturopathy.15-17,21-23 This article will discuss the practical aspects of recommending a select group of these CAM therapies for the clinician managing the young patient with JIA. The following discussion provides a good sample of evidence-based recommendations, but does not include all possible therapies due to space constraints.

Anti-inflammatory Diet, Intestinal Permeability, and Autoimmune Disease

Increased intestinal permeability (IP) has been implicated in several autoimmune and inflammatory conditions like rheumatoid arthritis, ankylosing spondylitis, multiple sclerosis, celiac disease, type 1 diabetes, asthma, and inflammatory bowel disease.24,25 Mielants et al studied ileum biopsies of JIA patients and found a majority with histologic gut inflammation.26,27 Bacteria, antigenic fragments, and primed immune cells may migrate to joints from distant sites that originated in the "leaky gut," subsequently promoting synovitis.28 More research is needed to firmly establish this relationship. Based on ongoing research on IP and its role in autoimmune disease, there is potential in mitigating diseases like JIA with therapies that can reduce gut permeability.

Testing for Intestinal Hyperpermeability

The lactulose/mannitol test may help diagnose IP.29 Another possible non-invasive test for gut inflammation is the fecal calprotectin test, although more study is needed to validate its use.30-32 The lactulose/mannitol and fecal calprotectin tests are available commercially, and are often bundled with other tests aimed at identifying parasites, candida, and pathogenic bacteria as causes of gut dysfunction. Testing for IP may be skipped unless the patient requests the tests or the clinician needs test data for better compliance with recommendations.

The Elimination Diet

Certain food substances have been identified as negatively affecting the health of the small intestinal mucosa, whose functions include nutrient absorption, barrier function, metabolism, detoxification, immune modulation, and production of many biologically active compounds.33 Some food substances have been implicated in the production of advanced glycation end products (AGEs) and glycated lipids (ALEs). The production of AGEs and ALEs form free radicals that can exacerbate IP through inflammation. Certain foods higher in AGEs and ALEs include fructose, casein (dairy), gluten (wheat, barley, rye), tea, coffee, diet soda, roasted peanuts, and soybean products.34

Elimination diets have been studied for autoimmune diseases like Crohn’s disease, rheumatoid arthritis, and immunoglobulin E–mediated diseases like eosinophilic esophagitis. A vegan diet was studied in adult rheumatoid arthritis patients, showing that the respondents who adhered to the diet for 1 year had improvement in their symptoms compared to the control group. But, neither group achieved improvement on x-rays of the hands and feet after the intervention.35 A small study of adults with rheumatoid arthritis showed symptom improvement with a 2-week exclusive elemental diet composed of commercially prepared amino acids, vitamins, minerals, and medium/long chain triglycerides.36

Recommendations for the very restrictive elemental or vegan diet are likely unrealistic and stressful burdens to uphold for most families unless the child and parent are motivated to remain compliant with these diets. Instead, there may be value to an empiric trial of a 6-food elimination diet (namely, cow’s milk, soy, wheat, egg, peanut/tree nuts, and seafood)37,38 for 4 to 6 weeks. Important nutrients like calcium and omega-3 fatty acids (fish oil is allowed) are supplemented during the elimination.

Elimination of refined sugar and nightshade vegetables may also be helpful in the dietary trial for patients with JIA. Nightshade vegetables include potatoes, tomatoes, peppers, and eggplant. Reintroduction of the child’s most frequently eaten food is then added back one at a time, over a period of 3 to 4 days following the elimination diet. This challenge phase may elucidate specific food triggers if JIA or other symptoms worsen. Parents and the child should document symptoms in a journal to note their progress and identify trigger foods during reintroduction. Trigger foods would need to be avoided long term for best results.

Elimination diets run the risk of inducing stress in the parent and child, particularly if the child’s favorite foods consist of trigger foods. For parents and children who are reluctant to change the diet, the author recommends saving the elimination diet trial for a time after the patient consistently has taken recommended NHPs, mind–body therapies, massage, exercise, or acupuncture for several months to prevent treatment fatigue.

An excellent educational review was written by David R. Seaman on an anti-inflammatory diet for patients with pain, and can serve as a guideline for dietary prescribing.39

NHPs to Aid IP and JIA

Turmeric

Curcumin is the yellow pigment found in the spice turmeric. Curcumin has antioxidant, anti-inflammatory, antibacterial, antifungal, antiviral, pro-apoptotic, and antiproliferative effects. TNF-α inhibition activity has been noted with curcumin, which may have a valuable role in reducing inflammation and intestinal permeability found in autoimmune diseases, including JIA.40 Curcumin combined with piperine (black pepper extract) may have enhanced bioavailability versus curcumin alone, which is poorly bioavailable. Safety studies have demonstrated doses as high as 15 g per day for 3 months were safe with no toxicity reported in adult subjects.40 Few pediatric dosing studies have been performed, and in a small trial, a 2-g dose of curcumin twice daily was well tolerated by 11- to 18-year-old children with inflammatory bowel disease.4 The average adult daily intake of turmeric in India is 2 to 2.5 g, which is equivalent to 60 to 100 mg of curcumin.42

Glutamine

The most abundant amino acid in the body, glutamine, has several beneficial effects on gut epithelium through antioxidant, anti-inflammatory, and intestinal cell protective mechanisms. This generally well-tolerated compound has been shown to reduce IP in ischemia/reperfusion injury,43 critically ill patients,44 malnourished children,45 and low birth weight children with allergies.46 Glutamine dose varies in studies of children with several chronic diseases, trauma, burns, and cancer from 0.25 g/kg/day to 0.7 g/kg/day for infants and children.47 An average dose of 0.5 g/kg/day may be reasonable for children. More research is needed to determine clearer guidelines on safety and efficacy of glutamine use in children.

Probiotics

Probiotics are bacterial strains known to have beneficial effects on intestinal mucosa and gut immunity. They may also have a role in reducing IP with respect to autoimmune disease.48,49 Evidence for using probiotics in rheumatologic disease is currently sparse, with little guidance on optimal strains or dosing in adult or pediatric rheumatology. A general rule of thumb based on data from the 2011 Johnston Cochrane analysis of probiotics for antibiotic-associated pediatric diarrhea is to prescribe 5 billion colony-forming units (CFU) or more per day.50 The best blend of strains is unclear, but Lactobacillus rhamnosus and Saccharomyces boulardii were the most commonly studied strains in the meta-analysis, and the dose range went as high as 40 billion CFU per day with few adverse effects in healthy individuals.50 Some studies looked at Lactobacillus and Bifidobacterium species to improve symptoms, with mixed results seen in pediatric arthritis.51,52 While generally well tolerated and safe in healthy individuals, probiotics should be avoided in patients with severe pancreatitis, immunosuppression, or the critically ill due to concerns about harm.53,54

Calcium and Vitamin D Supplementation

Calcium intake of 1,000 mg per day for 4 to 8 year olds and 1,300 mg per day for 9 to 18 year olds through food and supplementation is important for children with JIA to promote bone growth and density. Patients with JIA are at risk for osteoporosis given their exposure to systemic steroids and the reduction of physical activity during pain flares.55-57

Vitamin D

At present, no clear evidence exists to support a link between vitamin D levels and JIA.58 25-hydroxy vitamin D testing can identify children with vitamin D deficiency and, if identified, should be treated with supplemented vitamin D2 or D3, vitamin D rich food like fish and eggs (unless the patient is allergic to these foods), and judicious exposure to sunlight. Vitamin D’s role in bone mineralization and immune modulating effects are especially important for a growing child. A daily vitamin D2 or D3 dose of 2,000 international units is likely safe,59 although guidance on specific dosing and length of treatment is unclear. The "optimal" 25-hydroxy vitamin D level is also a matter of controversy, but normal levels are defined as greater than 50 nmol/L (or 20 ng/mL). 25-hydroxy vitamin D levels less than 25 nmol/L (or 10 ng/mL) are considered a severe deficiency.60 Clinicians should definitely aim for vitamin D 25-hydroxy levels higher than 20 ng/mL, and strive for levels in the 40 to 50 ng/mL range.

Traditional Chinese Medicine

Acupuncture

IP, or "leaky gut," is considered a complex and difficult-to-treat entity in traditional Chinese medicine (TCM). This entity would be referred to as a "knotty" disease, which includes conditions like allergies, autoimmune disease, and intestinal dysbiosis. In the TCM paradigm, "knotty diseases" come from complex imbalances of qi, or "life force," which may include spleen qi vacuity, damp heat, liver qi stagnation, and other conditions beyond the scope of this article.61

Acupuncture, herbs, movement, and nutrition comprise the main treatments used in TCM. Acupuncture has been studied the most, with very low side effects documented in children and adults. The most common side effect of pediatric acupuncture is puncture site redness. Although significant side effects can occur, like organ puncture, this is extremely rare.62 The 2005 Casimiro Cochrane review showed inconclusive evidence of acupuncture’s effects on rheumatoid arthritis,63but other meta-analyses noted statistically significant improvement in neck,64 back,65 and shoulder66 pain with acupuncture versus sham controls.67 Based on acupuncture’s excellent safety profile, the therapeutic relationship between practitioner and patient, and current evidence from related conditions, acupuncture is a useful treatment to advise to patients with JIA if the family can afford the treatments. Treatments are typically once weekly, and the author suggests a baseline of 10 treatments before assessing efficacy and continuation of the therapy.

Massage

Daily massage for 15 minutes by a parent for 30 days showed decreased levels of anxiety, serum cortisol, pain, and morning stiffness in juvenile rheumatoid arthritis patients compared to progressive muscle relaxation. Massage consisted of two phases in a sequence typically followed by massage therapists. For the first phase, the child was placed in a supine position, and oil was applied to allow smooth, continuous stroking movements of the face, stomach, legs, feet, and arms. The child is then placed in a prone position, and the parent gently massages the back, shoulders, neck, and feet.68

Exercise

Exercising 3 times per week for 12 weeks with free weights, core exercises, and jumping rope can improve leg strength, bone health, and mental health without increasing pain scores in JIA patients.69 Prescribing exercise and activity in a fun, positive way (ie, walking the dog twice daily) may be more effective than prescribing it as "physical therapy," which implies a sick role.70 Regular physical activity may also help regulate sleep patterns, anxiety, and promote an overall sense of well being, all of which are important for reducing chronic pain from JIA.

Sleep

Chronic pain and sleep problems may feed upon one another. The need for restorative sleep is critical to managing pain, quelling anxiety, and improving health. Good sleep hygiene is imperative and includes avoidance of late-day caffeine, large meals just before bedtime, television, video games, Internet chats and surfing, and other mentally stimulating activities at bedtime that interfere with falling and staying asleep.71,72

Mind–Body Approaches

Cognitive behavioral therapy helps patients recognize negative or incorrect thoughts and teaches one to respond to difficult situations like pain in a more effective way. Some of the tools used to deal with mental and physical challenges include progressive muscle relaxation, guided imagery, and meditative breathing, which may reduce pain intensity and improve function for patients with JIA.73,74

Putting it All Together: Avoiding "CAM Treatment Fatigue"

It is important to balance integrative therapy recommendations with the individual’s level of interest, motivation, resources, and school/family support to maximize successful compliance and to observe changes or side effects from treatments. Trying too many recommendations at the same time often overwhelms and frustrates parents and children, so a stepwise approach with initial assessments over a 2- to 3-month span of time may be appropriate with more frequent visits or phone calls if necessary (Figure 1). Open communication with the patient’s rheumatologist and primary care physician regarding the care plan is also essential.

Individualized Treatment Plans

Patient values and resources play a critical role in determining which integrative therapies to recommend first, since many therapies are an out-of-pocket expense. For instance, some patients are more interested in exploring acupuncture before changing their diet. Other patients may be motivated to take vitamins and herbs before employing mind–body therapies. Other patients can only afford to try breathing and meditation with some diet changes. Given the myriad potential treatment options, forming a collaborative partnership with patients and their families is a beneficial therapy in and of itself.

Last updated on: July 1, 2016
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