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Clinical Rheumatology
Journal of the International League of
Associations for Rheumatology
ISSN 0770-3198
Volume 33
Number 7
Clin Rheumatol (2014) 33:885-891
DOI 10.1007/s10067-014-2490-9
Fibromyalgia and chronic widespread pain
in autoimmune thyroid disease
Jowairiyya Ahmad & Clement E.Tagoe
1 23
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REVIEW ARTICLE
Fibromyalgia and chronic widespread pain in autoimmune
thyroid disease
Jowairiyya Ahmad &Clement E. Tagoe
Received: 26 November 2013 /Accepted: 5 January 2014 /Published online: 18 January 2014
#Clinical Rheumatology 2014
Abstract Fibromyalgia and chronic widespread pain syn-
dromes are among the commonest diseases seen in rheuma-
tology practice. Despite advances in the management of these
conditions, they remain significant causes of morbidity and
disability. Autoimmune thyroid disease is the most prevalent
autoimmune disorder, affecting about 10 % of the population,
and is a recognized cause of fibromyalgia and chronic wide-
spread pain. Recent reports are shedding light on the mecha-
nisms of pain generation in autoimmune thyroid disease-
associated pain syndromes including the role of inflammatory
mediators, small-fiber polyneuropathy, and central sensitiza-
tion. The gradual elucidation of these pain pathways is
allowing the rational use of pharmacotherapy in the manage-
ment of chronic widespread pain in autoimmune thyroid dis-
ease. This review looks at the current understanding of the
prevalence of pain syndromes in autoimmune thyroid disease,
their likely causes, present appreciation of the pathogenesis of
chronic widespread pain, and how our knowledge can be used
to find lasting and effective treatments for the pain syndromes
associated with autoimmune thyroid disease.
Keywords Autoimmune thyroid disease .Chronic
lymphocytic thyroiditis .Chronic widespread pain .
Fibromyalgia .Hashimoto thyroiditis
Introduction
Fibromyalgia and chronic widespread pain (CWP) syndromes
are among the commonest conditions seen in rheumatology
practice. Fibromyalgia alone constitutes about 10 % of all
outpatient visits while CWP accounts for over 30 % [1,2].
Close study of rheumatology outpatient prevalence data shows
poor patient retention for fibromyalgia patients suggesting a
tendency to migrate among providers of multiple disciplines in
their quest to find ideal treatments. By contrast, patients with
other chronic conditions like rheumatoid arthritis are more
likely to remain in the care of a rheumatologist, perhaps
reflecting more satisfactory outcomes [1]. Fibromyalgia and
CWP collectively carry a significant economic burden and are
associated with tremendous monetary losses to society in direct
healthcare costs and productivity [3,4]. Despite major im-
provements in the treatment of fibromyalgia and CWP, they
remain significant causes of disability and failure to reintegrate
into the workforce with rehabilitation [5].
Autoimmune thyroid disease (AITD) constitutes a spec-
trum of autoimmune disorders with considerable overlap in-
cluding Grave’s disease and Hashimoto thyroiditis, also re-
ferred to as chronic lymphocytic thyroiditis (CLT) [6]. Both
conditions have significant musculoskeletal manifestations.
Though AITD and CLTare often used interchangeably, in this
review, the focus is on the association of CLT in particular
with chronic pain syndromes as seen in clinical practice.
Perhaps 10 % of women and 1 % of men have CLT. These
numbers double in those over 50 years [6]. Our current un-
derstanding of the biology of these conditions provides no
clues for the reasons for such high prevalence rates.
J. Ahmad
Department of Geriatrics, Albert Einstein College
of Medicine, Bronx, NY, USA
e-mail: jahmad@montefiore.org
C. E. Tagoe
Department of Medicine, Albert Einstein College
of Medicine, Bronx, NY, USA
C. E. Tagoe (*)
Division of Rheumatology, Montefiore Medical Center,
111 East 210th Street, Bronx, NY 10467-2490, USA
e-mail: ctagoe@aol.com
C. E. Tagoe
e-mail: ctagoe@montefiore.org
Clin Rheumatol (2014) 33:885–891
DOI 10.1007/s10067-014-2490-9
Author's personal copy
Early CLT seems to involve antigen presenting cell and T
cell infiltration of the thyroid gland perhaps in response to
presentation of autoantigens presumed to include thyroglobu-
lin and thyroid peroxidase. Eventual T cell help of
immunoglobulin-producing B cells results in production of
antibodies to thyroglobulin and thyroid peroxidase in over
90 % of CLT patients [7]. The possible disease-causing roles
of other autoantibodies including thyroid-stimulating hor-
mone (TSH) receptor autoantibodies, antibodies to pendrin,
and antibodies to the thyroidal iodide Na
+
/I
−
symporter are
uncertain [8]. The immunological reaction to the gland is more
proliferative in Grave’s disease, causing the formation of
goiter, and more destructive in CLT but does lead to goiter
formation in some proportion of patients. The characteristic
histological findings in CLT include lymphocytic infiltration
of the thyroid parenchyma, followed by the appearance of
Askanazy cells, cellular destruction, and eventual fibrosis [9].
The majority of persons with CLT remain asymptomatic
throughout their lives. However, in about 20 % of patients,
there is eventual failure of the thyroid gland leading to overt
hypothyroidism, and there are significant numbers who de-
velop a host of rheumatologic, nervous system, psychological,
dermatologic, metabolic, endocrine, and other associations,
some of which are autoimmune in nature. The plethora of
associated findings seems to reflect the complex functions of
the thyroid gland as well as the immunological processes
accompanying thyroid autoimmunity. From the early days of
such reports, chronic pain syndromes and CWP have featured
prominently but not without problems related to classification
and nomenclature. Thus, Carette and Lefrançois were able to
detect pain syndromes in 19 % of a cohort of primary hypo-
thyroid patients, but only 5 % met the then definition of
fibrositis [10]. This review will avoid the intricacies of pain
syndrome nosology and focus on the clinical syndromes of
CWP in CLT as they relate to clinical practice.
Autoimmune thyroiditis and chronic widespread pain
Chronic widespread pain is estimated to affect between 4.1
and 13.5 % of the population and has been shown to have
close association with multiple musculoskeletal disorders
[5,11]. The relationship with AITD in particular has been
known for decades. Becker and colleagues from the Mayo
Clinic described multiple rheumatic associations of
Hashimoto thyroiditis a half-century ago [12]. Secondary
fibrositis was seen in 7.9 % of Hashimoto thyroiditis patients.
Overall, 23.5 % of 119 Hashimoto patients had rheumatic
diagnoses, 18.5 % associated with chronic pain [12].
Golding studied nine hypothyroid patients and tried to make
the distinction between myositis, well recognized as a com-
plication of hypothyroidism at the time, and fibrositis, char-
acterized by muscle, body, and joint pain but not weakness,
which he found to be present in all nine patients in his case
series [13]. Wilke and others also reported their experience of
fibrositis in eight patients with subclinical hypothyroidism
and mild elevations in TSH. Six of the patients improved in
terms of their fibrositis symptoms with thyroid hormone re-
placement [14]. Bland et al. described a similar experience
with hypothyroid patients and supported the hypothesis that
elevations in thyroid-stimulating hormone (TSH) might in-
crease deposition of proteoglycan in musculoskeletal tissues
through stimulation of adenylate cyclase causing pain and
stiffness [15]. This hypothesis led to the belief in the revers-
ibility of the musculoskeletal findings with thyroid hormone
replacement providing they were not inflammatory [16]. More
recent reports challenge the simplicity of that assertion be-
cause treatment of hypothyroidism does not always relieve
pain [17]. Neck and upper thoracic pain has been reported by
several authors including Golding in his review of AITD and
associated rheumatic manifestations [18]. Aarflot and
Bruusgaard noted a significant association between thy-
roid autoimmunity and CWP, speculating that the abnor-
mal regulation of thyrotropin-releasing hormone (TRH)
might modulate abnormal pain perception in autoimmune
thyroid patients [19].
Autoimmune thyroiditis and fibromyalgia
Following the introduction of the American College of
Rheumatology (ACR) classification criteria for fibromyalgia
syndrome (FMS) in 1990, a number of groups were able to
describe the chronic pain manifestations of AITD and CLT in
patients selected for the presence of fibromyalgia [20–23].
These authors found the prevalence of fibromyalgia in AITD
to be in the range of 30 to 40 % [21–23]. Suk and colleagues
presented compelling evidence of an association because they
looked at the question from the point of view of endocrinology
and not rheumatology, thus dispelling any referral bias pecu-
liar to the latter discipline. They found a 19 % prevalence of
thyroid autoimmunity in a cohort of fibromyalgia patients
compared to 7 % of controls, a statistically significant differ-
ence [24]. Ribeiro and Fernando found an association between
fibromyalgia and thyroid autoimmunity with an odds ratio
(OR) of 3.87 among 147 women with fibromyalgia and 74
case-controls. Interestingly, there was also an association of
fibromyalgia with depression with an OR of 3.94 in their
univariate analysis, but no association between depression
and AITD. In their final adjusted logistic regression model,
the association between fibromyalgia and AITD strengthened
to an OR of 4.52 [25]. These data compare with a background
prevalence of fibromyalgia of about 2.4 % in women and
1.8 % in men in one study using the 2010 preliminary diag-
nostic criteria for fibromyalgia from the ACR [26]. Estimates
using the 1990 criteria are twice as high [2]. Of course, the
886 Clin Rheumatol (2014) 33:885–891
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symptom complex associated with hypothyroidism tends to
overlap with that of fibromyalgia and includes complaints of
insomnia, weight gain and subjective swelling, chronic fa-
tigue, headaches, irritable bowel syndrome, mood disorders,
and arthralgias. Furthermore, symptoms can wax and wane in
both conditions making differentiation and diagnosis a chal-
lenge. However, as mentioned previously, treatment of the
underlying endocrine disorder seldom completely relieves
patients of their chronic pain suggesting that AITD itself
contributes to the pathogenesis of the pain syndromes [17].
Thyroid autoimmunity can extend beyond the thyroid
alone and overlap with other autoimmune conditions [6].
This autoimmune context was observed by Soy and col-
leagues who noted that fibromyalgia was the most common
rheumatologic presentation, seen in 31 % of 65 AITD patients
[27]. Another study looked at a similar population of AITD
patients but excluded all those with known connective tissue
disease and still found a prevalence of FMS of 59 % [28].
Autoimmune thyroiditis and spinal pain
There is an association of widespread pain with spinal pain
that makes the distinction between fibromyalgia pain and
secondarily generalized spinal degenerative disc disease-
associated pain difficult. Spinal pain was noted in several
of the earlier reports and has been mentioned by more recent
reports as well [12,15,28]. Indeed, the study by Tagoe et al.
found spinal degenerative disc disease in 45 % of their
cohort of 46 AITD patients with no well-defined connective
tissue disease [28]. The etiology of spinal and paraspinal
pain is likely multifactorial and might indeed include fibro-
myalgia pain; CWP centering around the neck, shoulders,
and upper thoracic region; and secondarily generalized spi-
nal arthritis pain.
Autoimmune thyroiditis and chronic widespread pain
associated with connective tissue diseases
Because of the complex overlap of AITD with more general-
ized autoimmunity, it can be difficult to separate chronic pain
pertaining to AITD per se from other overlapping autoim-
mune phenomena [6]. The association with other connective
tissue diseases was examined by one group, who showed that
51 % of Hashimoto thyroiditis patients had an association
with a well-defined systemic autoimmune disease including
mixed connective tissue disease (MCTD), Sjogren’s syn-
drome (SS), systemic lupus erythematosus (SLE), rheumatoid
arthritis (RA), systemic sclerosis (SSc), and polymyositis/
dermatomyositis [29]. Other authors have reported similar
findings, and it is well known that the genetics of AITD are
closely interlinked with those of other autoimmune diseases
[30,31]. Lazurova et al. found a prevalence of AITD of 24 %
in both SLE and RA compared to 8 % in their control popu-
lation [32]. The prevalence of persistent fibromyalgia in SLE
and RA has been estimated in one review article to be about 40
and 17.1 %, respectively [33]. These numbers are consider-
ably higher in acute active disease and suggest that there are
multiple causes of widespread pain and fibromyalgia in well-
defined connective tissue diseases. The active inflammatory
state most likely contributes significantly to widespread pain
in established systemic autoimmune disease. Given the con-
siderable overlap between these conditions and AITD, it is
possible that mechanisms of chronic pain generation peculiar
to AITD contribute to the generation of widespread pain in
connective tissue diseases when the two coincide. The fact
that patients with no established well-defined connective tis-
sue disease experience severe fibromyalgia and CWP even in
the absence of clinically demonstrable active inflammation
suggests separate and perhaps non-inflammatory mechanisms
for AITD-induced widespread generalized pain [28].
Pathogenesis of pain syndromes in autoimmune
thyroiditis
Small-f iber polyneuropathy
The causes of chronic pain in hypothyroid and AITD patients
are poorly understood. There are few studies exploring the
etiology of pain in thyroid diseases. Small-fiber
polyneuropathy, which mainly affects the small myelinated
(Aδ) and unmyelinated (C) fibers, is well described as a
feature of several conditions including diabetes and connec-
tive tissue diseases like SLE and SS. It has also been demon-
strated in and suggested as a cause of fibromyalgia. Although
this is an attractive hypothesis explaining the total body pain
of fibromyalgia, some authors have observed significant dif-
ferences between the chronic pain of fibromyalgia and the
peripheral neuropathic pain of diabetes mediated by small-
fiber neuropathy suggesting that the mechanisms of pain
production are distinct [34]. However, it is quite reasonable
to assume that small-fiber polyneuropathy is one of many
compounding pathologies responsible for generalized pain in
fibromyalgia. Oaklander and colleagues identified 27 patients
with fibromyalgia and 30 matched controls using the 2010
ACR diagnostic criteria [35]. They assessed distal leg
neurodiagnostic skin biopsies plus autonomic function testing
(AFT) and found that 41 % of skin biopsies from subjects with
fibromyalgia compared to 3 % of biopsies from normal con-
trol subjects were diagnostic for small-fiber polyneuropathy.
There was some attempt at elucidating the causes of fibromy-
algia in that study. The 13 subjects with fibromyalgia and
positive small-fiber polyneuropathy on biopsy had normal
hemoglobin A
1C
<6.0 mg/dL making diabetes an unlikely
Clin Rheumatol (2014) 33:885–891 887
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cause. Furthermore, none of the 13 had abnormal serum
chemistries, blood counts, thyroid function, folate levels, tri-
glycerides, C-reactive protein, and serum angiotensin-
converting enzyme or positive tests for Lyme disease, SLE,
SS, or celiac disease. However, thyroid autoantibodies or
evidence of AITD were not ascertained. Given the high prev-
alence of fibromyalgia in AITD, such information would be
extremely useful in future studies in discerning the cause of
AITD-related widespread pain. Direct evidence of small-fiber
polyneuropathy in hypothyroid patients is provided by a num-
ber of publications including those by Ørstavik and colleagues
[36]. They looked at 38 hypothyroid patients and 38 normal
controls and found statistically significant differences for var-
ious measures of small-fiber polyneuropathy. Some serologi-
cal testing was done, which showed that eight patients had
positive ANAs. Twenty-one of the 38 patients had serological
evidence of AITD, and all patients were adequately treated for
their hypothyroidism. The authors therefore suggest a possible
mechanism of pain and small-fiber injury independent of the
endocrine defect and possibly involving immunological cross-
reactivity with some component of nervous tissue.
Immunological cross-reactivity
Cross-reactivity of autoantibodies in AITD with components
of the nervous system has not been systematically examined
as a cause of generalized pain. It is not clear whether there is
an association between either the anti-thyroid peroxidase an-
tibody or the anti-thyroglobulin antibody with CWP.
Although early studies suggest a lack of correlation, more
detailed work is clearly needed [28]. Certainly, thyroglobulin,
which is subject to extensive post-translational modification
including iodination and glycosylation, and is one of the
largest autoantigens in man, is known to share sequence
homology with several proteins [37]. Thyroglobulin shares
close sequence homology at its C-terminal end with acetyl-
cholinesterase [38,39]. This similarity has generated interest
in a possible association of antithyroglobulin antibodies with
Grave’s ophthalmopathy [40]. Much less interest has been
directed towards the possibility of such cross-reactivity being
involved in the generation of pain through peripheral mecha-
nisms or perhaps through the involvement of the cholinergic
interneurons that mediate central sensitization.
Central sensitization
Central sensitization clearly has a role in fibromyalgia, and
given the overlap of fibromyalgia with AITD could help to
explain the generation of pain in AITD patients [41]. Glial
cells are increasingly known to play a role in the generation of
central sensitization through the secretion of cytokines,
chemokines, nitric oxide, prostaglandins, reactive oxygen
species, and excitatory amino acids [42]. Glial cells are
involved in the cell surface activation of TNF-α-converting
enzyme (TACE), crucial for the activation of TNF-α[43].
Together, the molecules produced by glial cells enhance and
prolong spinal cord hyperexcitability [44]. This is particularly
relevant since the function of glial cells is directly regulated by
thyroid hormones and their metabolites [45].
Another possible mechanism of pain generation could in-
volve immunological involvement indirectly of ion channels
or more directly through cross-reactivity with such channels.
To date, no such acquired “channelopathy”has been described
in AITD although sodium channel mutations have been im-
plicated in fibromyalgia. It remains to be seen if there is any
more pervasive association between such inherited traits and
an acquired condition like AITD [46]. The access of the
central nervous system to circulating autoantibodies has al-
ways been a sticking point in such immunologically mediated
theories because of the blood–brain barrier, which normally
prevents such access. One would therefore have to explain
how in those patients with fibromyalgia the blood–brain bar-
rier is breeched. Obviously, not all patients with AITD expe-
rience generalized pain. Therefore, a breakdown in the blood–
brain barrier would be an attractive hypothesis to explain why
a subset of patients experience widespread pain. More than
likely, there is interplay between a number of peripheral and
central nervous system mechanisms leading to generalized
pain in AITD patients.
Spinal pain
Our own finding of the prominence of spinal degenerative
disc disease in AITD suggests that secondarily generalized
widespread pain could be very prominent as a cause of sec-
ondary fibromyalgia and other forms of CWP in that syn-
drome [28]. The involvement of the immune system and in
particular leukocytes in the generation of pain following inju-
ry to the nucleus pulposus has been known for some time[47].
Whether there is an exaggerated response to the otherwise
normal processes of spinal degeneration or a targeted and de
novo assault on the intervertebral bodies by an activated
immune system in AITD is unknown. Again, this is an area
calling for more research and clearly begs the question of
whether immunological cross-reactivity with matrix compo-
nents of the vertebral discs is at play in AITD.
Inflammation
The role of inflammation and inflammatory cytokines in
generating chronic pain syndromes is very well established
[48,49]. Several cytokines including interleukin-1β(IL-1β),
interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis
factor-α(TNF-α) are associated with causing hyperalgesia
[49]. There are numerous other inflammatory byproducts that
mediate pain and contribute to chronic pain syndromes
888 Clin Rheumatol (2014) 33:885–891
Author's personal copy
including bradykinin, prostaglandins, growth factors, nitric
oxide, and substance P. However, these molecules can be
expected to operate only in the subset of patients who are
inflammatory as part of their AITD or have an overlap syn-
drome expressing more generalized autoimmunity [50]. The
clinical implication is that maximal treatment of any underly-
ing inflammatory condition would improve fibromyalgia and
widespread pain that are caused or augmented by inflamma-
tion [51,52]. Any residual pain could therefore be expected to
be from non-inflammatory causes including the immunolog-
ical cross-reactivity speculated on above.
Implications of mechanisms of widespread AITD pain
for therapy
Because of the high prevalence of CLT and its direct associ-
ation with CWP, serologic testing for CLT should probably be
an integral part of any rheumatologic work up for chronic
generalized pain or FMS. Understanding the various causes of
pain is central to defining rational therapy for the chronic
debilitating widespread pain suffered by CLT patients. The
role of autoantibodies and immunologically derived pain
needs clarification. The use of B cell depletion with the anti-
CD20 agent rituximab has not been shown to improve the
thyroid function of AITD or hypothyroid patients with other
autoimmune diseases like rheumatoid arthritis [53]. However,
serial measurements of antithyroid antibody levels would
have to be made to demonstrate consistent reduction of im-
munoglobulin levels with rituximab since long-lived plasma
cells are not affected by that agent. Such treatments would
likely not work if long-lived plasma cells contribute signifi-
cantly to the pathologic antithyroid autoantibodies. Although
one group has suggested improvement in thyroid autoanti-
bodies levels and thyroid function in rheumatoid arthritis
patients treated with adalimumab, an anti-TNF inhibitor, the
improvements over the course of the 6-month study were
modest and did not reduce the need for standard therapies
AITD
+
CWP or FMS
Associated connective
tissue disease
No associated
connective tissue
disease
Treat underlying
connective tissue
disease
Normal inflammatory
parameters
Elevated inflammatory
parameters
Treat CWP or FMS Treat CWP or FMS
+ DMARDs e.g.
hydroxychloroquine to
normalize elevated
acute phase reactants
Treat CWP or FMS Treat CWP or FMS
+ Escalated
management of
underlying connective
tissue disease using
stepped approach
Normal inflammatory
parameters
Elevated inflammatory
parameters
Fig. 1 Treatment algorithm for
chronic widespread pain (CWP)
and fibromyalgia syndrome
(FMS) in AITD
Clin Rheumatol (2014) 33:885–891 889
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for thyroid insufficiency [54]. The majority of these patients
were also on methotrexate and oral corticosteroids under
supervised care, and it is not clear if improved medications
adherence under those conditions could have improved the
measured indices. There was no comment on the presence of
chronic pain in the patients. Indeed by contrast, Atzeni and
colleagues did not find any influence on thyroid autoimmunity
by adalimumab in their clinical experience [55].
Current evidence suggests that it is important to separate
the presence of inflammatory from non-inflammatory causes
in the management of AITD patients with CWP. Purely in-
flammatory pain responds well to traditional anti-
inflammatory and immunomodulatory treatments. Patients
rapidly improve once serum acute phase reactants and other
indicators of inflammation return to normal and cytokine,
chemokine, and other inflammatory mediator levels decline.
However, there is clearly a subset of patients in whom non-
inflammatory pain-generating mechanisms are prominent
[51]. Understanding the role of AITD in these pain syndromes
helps to identify such patients and prevent their excessive
exposure to escalating regimens of potentially toxic immuno-
suppressive medication. In such patients, the focus should
rapidly shift to the treatment of chronic pain using traditional
pain and fibromyalgia medications along with non-
pharmacologic interventions. Clearly, identifying causes like
severe spinal degenerative disc disease with secondarily gen-
eralized pain can allow specific targeting of interventions
designed to curb spinally generated pain including spinal
epidural corticosteroid injections and neurotropic medications
like gabapentin and pregabalin. It is unclear at this point if
thyroidectomy might alleviate some or all of the symptoms of
chronic pain in AITD that are autoantibody mediated.
Although thyroid autoantibody levels fall after thyroid remov-
al in the majority of patients requiring thyroidectomy, it is
unknown if clones of antibody producing cells persist in some
similar to what is seen in chronic hepatitis C infection after
viral eradication where persistence of B cell clones leads to
continued production of autoimmune phenomena including
cryoglobulin generation. This is an area which clearly requires
more investigation. A rational therapeutic approach to the
patient with AITD-associated CWP or fibromyalgia based
on current evidence is summarized in Fig. 1.
Conclusion
We have presented a succinct review of the CWP syndromes
associated with AITD, in particular, its CLT manifestation. We
have examined the possible mechanisms of pain generation and
their implications for therapy. An emphasis on separating in-
flammatory from non-inflammatory etiologies is central to ra-
tional management of this patient population. That distinction
allows a combination of pharmacologic and non-pharmacologic
measures to be used as part of our armamentarium for non-
inflammatory causes of pain. We acknowledge the scarcity of
knowledge in this field and agree that a clearer understanding of
the causes of pain in AITD would hold promise and hope for
millions of women and men who at present have their misery
compounded by a lack of knowledge of the mechanisms under-
lying their pain. Most patients with AITD-associated pain feel
bewildered, lost, misunderstood, and frequently neglected be-
cause many physicians still do not make the association between
AITD and chronic pain. Because the pain of CWP and fibro-
myalgia associated with AITD like the apparition of Banquo to
Macbeth, is perceived by the sufferer alone, it exacts a heavy
physical toll but perhaps just as much an enormous psycholog-
ical burden. It is our fervent hope that these pain syndromes
should get the full attention they deserve and that further re-
search into AITD as the commonest autoimmune syndrome
with significant morbidity and enormous economic costs would
greatly improve the lives of what now constitutes a silent
multitude of suffers.
Disclosures None.
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