A case of a 14-year-old girl with a 2-year history of peripheral and sacroiliac joint
pain and gastrointestinal symptoms, secondary to enthesitis-related arthritis, is
presented along with the management.
Introduction
Previously considered a chronic condition, enthesitis-related arthritis – a type of
juvenile idiopathic arthritis – may in some cases represent a sensitivity-related
illness and thus respond to antigenic avoidance and remediation of biochemistry. Enthesitis-related
arthritis is a rare but serious cause of childhood disability and chronic pain that
often leads to continuing complications in adult life. Forming a small (1–16%) subset
of children with juvenile idiopathic arthritis,
1,2
enthesitis-related arthritis patients typically experience enthesitis and asymmetrical
hip and lower extremity arthritis.
3–5
Common systemic features include acute iritis
6
and subclinical inflammatory bowel disease (IBD),
7
while symptomatic cardiac myopathies and pulmonary parenchymal disease occur less
commonly.
1,8
Unlike adult-onset spondyloarthropathies, sacroiliitis in enthesitis-related arthritis
tends to present years after disease onset.
8
To meet International League of Associations for Rheumatology (ILAR) classification
for enthesitis-related arthritis, patients must have (1) arthritis and enthesitis;
or (2) arthritis or enthesitis with at least two of the following:
Acute, symptomatic anterior uveitis;
Sacroiliac joint or lumbosacral pain;
Male gender and age over 6 years;
HLA-B27 genotype;
First-degree relative with history of ankylosing spondylitis (AS), enthesitis-related
arthritis, sacroiliitis with IBD, Reiter's syndrome, or acute anterior uveitis.
Exclusion criteria for enthesitis-related arthritis include systemic juvenile idiopathic
arthritis, psoriasis, or two positive findings of IgM rheumatoid factor occurring
three months apart.
9
Genetic factors are particularly significant in enthesitis-related arthritis as 80%
of cases are found to be HLA-B27 positive.
1
Possessing a HLA-B27 genotype confers a 20-fold increase in spondylopathy risk in
Caucasian populations
10
and also increases risk of enthesitis-related arthritis progression to AS.
11
Moreover, HLA-B27 is implicated in cardiac,
12
pulmonary
10
and malignant
13
complications of spondylopathies. While multiple mechanisms have been proposed for
the role of HLA-B27 allotypes in triggering autoimmunity,
10
research is still inconclusive on the exact pathophysiology.
Extensive work has been done on the extent to which genetics influence juvenile idiopathic
arthritis and spondylopathies
14,15
but environmental parameters remain largely unexplored due to the relative rarity
of the condition and the continuing re-classification of juvenile idiopathic arthritis.
Preliminary evidence implicates the absence of breastfeeding, maternal smoking,
16
and infection – particularly streptococcus and Epstein-Barr virus – in the development
of juvenile idiopathic arthritis,
17
but further inquiry is needed. Although children with juvenile idiopathic arthritis
are known to be at risk for malnutrition, nutritional studies have focused on BMI
rather than specific biochemical deficiencies.
18
Management of enthesitis-related arthritis
Non-steroidal anti-inflammatory drugs (NSAIDs) remain the first-line treatment for
enthesitis-related arthritis, while metrotrexate and sulfasalazine are often introduced
in the early stages for better symptom control.
19
AntiTNF-alpha biologics, particularly etanercept,
3
are increasingly used in paediatric autoimmune disease. While generally well-tolerated,
gastrointestinal symptoms including nausea, vomiting and abdominal pain are a significant
adverse effect of all of these options,
3,20
often complicated by inflammation due to disease activity.
21
Beyond gastrointestinal symptoms, each of these medications has significant side-effect
profiles. NSAIDs are also associated with nephrotoxicity, headaches and behavioural
changes, while methotrexate may cause (largely reversible) liver toxicity.
4,22,23
Other reported adverse effects of methotrexate include loss of appetite, alopecia,
malaise, leucopenia,
19,24
and one case each of intestinal sprue
25
and skin toxicity.
26
Sulfasalazine may cause hepatitis, nephritis,
27
and haematologic abnormalities,
28
although these are all uncommon.
29
Meanwhile, antiTNF-alpha agents have been recently correlated to higher incidences
of cancer in adults
30
as well as paediatric malignancy.
31
Although autoimmunity confers an innate predisposition to malignancy, genotoxic effects
from antiTNF-alpha therapy in juvenile idiopathic arthritis have been shown to extend
beyond pre-existing DNA damage.
32
Rarer events include possible increased occurrence of Crohn's disease with etanercept
(although no conclusive link has been established).
33
Finally, steroids are avoided when possible, due to the well-known potential effects
on bone density, mental health, weight and growth.
34,35
Treatment outcomes vary. Although patients with juvenile idiopathic arthritis often
achieve high educational and employment levels,
36
overall quality of life is most dependent on disease subtype, activity and progression.
37
One-third of juvenile idiopathic arthritis patients experience disease continuing
into adulthood with full remission rates ranging from 87% in oligoarthritis to 17–33.4%
in enthesitis-related arthritis.
2,38
Unfortunately, progression to AS occurs in 39–75% of enthesitis-related arthritis
cases
3,39
even with the advent of new therapies. Though evidence on safety and efficacy is mixed,
40–42
what is certain is that the long-term consequences of new immunosuppressive and biologic
therapies in juvenile idiopathic arthritis will not be clear for another generation
and caution must be exercised.
Case report
A 14-year-old girl with a history of enthesitis-related arthritis presented to an
environmental medicine clinic, seeking adjunctive therapy for complications of her
illness. An extensive history, physical exam, environmental assessment
43
and series of laboratory tests
44
were performed.
Sixteen months prior, the previously healthy patient had presented to a family physician
with a one-week history of sudden-onset right knee pain. A joint aspirate was inconclusive
for viral infection and naproxen was prescribed for pain control. Early investigations
showed a positive result for antinuclear antibody and an elevated CRP (result 86.6
mg/L with normal 0–8 mg/L). Results were negative for Streptococcus, Lyme and Bartonella
exposure. Family history included ulcerative colitis in her father, and paternal grandfather,
although neither had sacroiliitis.
Over the next month, symptoms progressed to include stiffness and soreness in her
lower back, bilateral knees and hips, right wrist and right first interphalangeal
joint, at which point rheumatology was consulted and diagnosed enthesitis-related
arthritis, although HLA-B27 testing was not done. Visualizing persistent joint effusions
on ultrasound, the rheumatologist began methotrexate and what would become a five-month
course of prednisone in addition to Naproxen. Sulfasalazine treatment began 14 months
after disease onset, as the patient experienced increasing difficulty swallowing pills.
Although the patient noted some improvement with medications, soreness and stiffness
remained in her back and affected joints. Intra-articular steroid injections were
associated with improved function in her right wrist and thumb, and physiotherapy
and occupational therapy were beneficial, but pain continued to limit her participation
in sports and school activities. Schoolwork was also difficult as she was right-handed.
Significant medication-related nausea and abdominal discomfort were only minimally
lessened with antiemetic medication – ondansetron. However, the patient stated that
compliance with ondansetron was poor as the sight of any pill became associated with
nausea. Moreover, the course of prednisone had resulted in a 20 lb weight gain, about
which the adolescent patient was quite self-conscious. While moderately satisfied
with conventional treatment, the family regularly sought out alternative therapies
such as craniosacral therapy and reflexology; these interventions were felt to be
minimally helpful.
Medical records from the environmental health clinic revealed that physical exam was
unremarkable aside from a high BMI, and exposure history was typical for a North American
teenager. However, biochemical analysis showed severe nutritional abnormalities including
low serum levels of tryptophan, taurine and glutamic acid, and low blood levels of
zinc and copper. Serum levels of sulfate, co-enzyme Q10, alpha-tocopherol, vitamin
A, B-carotene, and 25-hydroxy-vitamin D were also markedly low.
Toxicant analysis revealed elevated arsenic and mercury levels in whole blood, as
well as the presence of two fungal mycotoxins – ochratoxins and tricothecenes in urine
testing – suggesting a history of mold exposure. In light of the prednisone exposure,
bone density analysis was conducted and found low – normal levels in the patient's
hip and spine (total hip z-score –1.2; total spine z-score –0.9).
Given the evidence of toxicant bioaccumulation, it was hypothesized that the mechanism
for development of enthesitis-related arthritis in this case might be related to epigenetic
determinants and sensitivity-related illness
45
– a disease mechanism initially described in the literature by Claudia Miller in a
1996 paper in Toxicology
46
and thought to be mediated primarily through the action of pro-inflammatory cytokines.
45
Accordingly, proposed treatment focused on: (1) removing agents recognized as common
antigenic triggers; (2) restoring nutritional adequacy; and (3) intervening to remove
the bioaccumulated toxicants such as mycotoxins and other toxic elements.
45
This approach has proven worthwhile with other immune-related conditions.
47
Gluten and casein are commonly linked to sensitivity-related illnesses,
48
and were thus eliminated from the patient's diet along with refined sugar, artificial
sweeteners, flavouring agents and corn. Next, initial supplementation focused on vitamin
D, zinc, copper, DHA, strontium, vitamin K2, magnesium and probiotics, due to the
following indications:
Vitamin D deficiencies are linked to autoimmune rheumatic disease in adults,
49
and adequate levels are known to be anti-inflammatory;
50–52
Copper and zinc play significant roles as co-factors in normal immune functioning
53–55
and deficiencies are linked to gut inflammation.
56
Furthermore, copper and zinc deficiencies are associated with rheumatoid arthritis;
57,58
Though evidence for probiotics is not yet conclusive,
59
they may decrease gut inflammation,
60–62
improve arthralgias,
63
and improve gut barrier function.
64
As the combination of steroid treatment and juvenile idiopathic arthritis are known
to predispose patients to a higher lifetime risk of osteoporosis,
65,66
a series of agents were targeted at bone health. Studies support the use of strontium,
magnesium and vitamin D, and to a lesser extent, vitamin K2 and DHA in increasing
osteoblast activity and restoring bone density.
67–73
Zinc and copper are increasingly recognized as important co-factors in preventing
osteoporosis as well.
74,75
Within one month, the patient saw significant improvements in function that allowed
her to decrease, and then completely discontinue the methotrexate, sulfasalazine,
naproxen and ondansetron after six months. At six months, antinuclear antibody testing
was repeated and found to be negative, and CRP levels had returned to normal (result
1.0 mg/L), supporting the clinical picture of inactive disease. Two months after discontinuation,
the patient reported that her functioning and quality of life were ‘just like before’
the onset of enthesitis-related arthritis, and she was fully participating in gym
class without any concerns. She had lost the excess weight, was taking guitar lessons
without further wrist or finger symptoms, and found the diet and lifestyle changes
‘more than worth it’ for the health she was experiencing. At 13 months post intervention,
the patient remains completely well with no recurrence of symptoms. Follow-up will
continue with the environmental health specialist to address the xenobiotics found
on toxic elements and mycotoxin analysis – the suspected factors likely involved in
the initiation of sensitivity-related illness in this patient.
Discussion
By the Wallace criteria, true remission of disease cannot be declared until the patient
has been completely asymptomatic without medication for 12 months with no active arthritis;
no fever, rash, serositis, splenomegaly, or generalized lymphadenopathy attributable
to juvenile idiopathic arthritis; no active uveitis; normal erythrocyte sedimentation
rate (ESR) or CRP and a physician's global assessment of disease activity.
38
As the patient has been asymptomatic for over 12 months, she can be considered to
be in full remission as she meets all criteria.
Nevertheless, to the authors’ knowledge, this is the first reported case of amelioration
of enthesitis-related arthritis symptoms after treatment with dietary changes and
nutritional supplementation. While studies have focused on specific areas of nutritional
deficiency related to juvenile idiopathic arthritis,
17,18,50,76
no treatment strategy has targeted environmental factors as key to enthesitis-related
arthritis and its remission. Still, a growing body of evidence suggests sensitivity-related
illness as a mechanism behind many cases of autoimmune disorders.
45
It is unknown to what degree the specific signs and symptoms in this case are the
direct result of sensitivity-related inflammation or the secondary result of disordered
biology resulting from nutritional deficiency. As maldigestion and malabsorpion are
common problems associated with food intolerance resulting from sensitivity-related
inflammation, nutritional deficiency ensues – which may account for the malnutrition
state in many cases of enthesitis-related arthritis.
In the sensitivity-related illness model, a patient's genetic predisposition towards
illness is compounded by the accumulation of toxicants, including toxic elements
77,78
and mycotoxins.
79,80
Each toxicant may impact immune system functioning, cumulating in sensitivity towards
agents that are typically well-tolerated (such as casein and gluten). In response,
autoantibodies form
45,78
to tissues including that of the joints and the gut,
81
leading to the presenting symptoms. Mycotoxins
80
and medications
59
alike may be determinants in gut inflammation. Inflammation leads to impairment in
absorption of nutrients necessary for healthy immune function and excretion of toxic
substances (Table 1), further worsening symptoms.
45,46,82,83
Table 1
Micronutrient deficiencies identified in the patient
Deficiencies
Significance
Coenzyme Q10
Electron transport chain; ATP production in aerobic respiration
Sulphate
Glutathione production, allowing for heavy metal detoxification through direct conjugation,
free radical neutralization, antioxidant properties
84
Tryptophan
Production of serotonin, melatonin, and endogenous source of niacin
Taurine
Anti-inflammatory properties, antioxidant; blood pressure regulation
85
Glutamic acid
Neurotransmitter
Alpha-tocopherol
Antioxidant;
86
inhibits mast cell and eosinophil proliferation
87
Vitamin A/Beta-carotene
Anti-inflammatory;
88,89
increases Th2 response, decreases Th1
87
Although enthesitis-related arthritis is not usually treated as a sensitivity-related
illness, cases of SLE
90
and of polyarticular juvenile idiopathic arthritis
45
have been reported that are either result from, or are resolved through environmental
manipulation. While more rigorous study is needed to elucidate the pathways behind
the development of enthesitis-related arthritis and to derive consensus conclusions
that can be generalized, individual patients may benefit from an environmental medicine
approach to their disease. Although one case is insufficient to draw firm conclusions
as spontaneous remission is possible, the complete resolution of signs and symptoms
occurring within short order after directed interventions were commenced suggests
that such an approach warrants further investigation in other patients.
Conclusion
In this case report, a patient with a two-year history of enthesitis-related arthritis
experienced a total resolution of symptoms after avoiding certain inciting antigens
and correcting her nutritional deficiencies. Although the conventional approach to
enthesitis-related arthritis manages to control patient symptoms and maintain function,
years of chronic disease and reliance on medications is not ideal if remission is
possible with less toxic measures. Enforcing dietary changes and taking required supplements
to address specific nutritional deficiencies requires a high level of commitment on
the part of patients and their families, but may offer a better quality of life than
the current standard of care. Thus, prior to commencing potentially toxic pharmaceutical
interventions, the authors suggest that it is reasonable to consider a detailed assessment
and remediation of nutritional biochemistry; an eight-week trial of avoidance of common
inciting antigens; and exploration and management of any underlying bio-accumulated
toxicant load resulting from adverse environmental exposures.
DECLARATIONS
Competing interests
None declared
Funding
None
Ethical approval
Written consent to publication has been obtained from the patient or next of kin
Guarantor
SJG
Contributorship
Both authors contributed equally
Acknowledgements
None
Reviewer
Gerry Schwalfenberg