Date sent:      	Sat, 12 Oct 2002 

EDITORIAL
Fibromyalgia Syndrome Subgroups

J of Musculoskeletal Pain, Vol. 10(3) 2002, 1-7


There is growing evidence to suggest that there may be subgroups of
fibromyalgia syndrome [FMS] patients (1-9). Several questions are logically
raised by such an assertion:

1. Is there an established basis in human disease for clinical subgroups
within a single diagnosis?

2. How convincing is the evidence that there may be subgroups of FMS patients?

3. Is that impression valid or does this conclusion result from artifacts
derived from studying an outbred population, as all humans, including FMS
patients are?

4. Are the apparent FMS subgroups detected with one form of assessment the
same as the apparent subgroups identified by other methodologies?

5. Would subgrouping help to explain some of the difficulties in defining
the pathogenesis of FMS?

6. Are subgroups identifiable by the presumed underlying etiology of the
FMS [proposed etiologies have included: idiopathic, trauma, febrile
illness, genetically determined, or an associated inflammatory or painful
condition] or would clinical subgrouping more likely be based on a limited
variety of human responses to any kind of insult?

7. Are any of the FMS subgroups genetically determined?

8. Could the recognition of a specific clinical subgroup help to define
more specific, and thus more effective, management?

Hold on now, the reader may be thinking. Some authors don't even believe
that FMS exists, or that it should be acknowledged by having its own name
(10-12), or that it differs importantly from the spectrum of pain in the
general population (13). So why, then, is there a growing momentum to split
FMS into subgroups that would further complicate understanding of this
syndrome, its clinical classification, and its management? It should be
noted that the 1990 report of the American College of Rheumatology [ACR]
FMS research classification criteria study (14) indicated that there were
no defining clinical features in the "secondary" FMS patients that would
clearly distinguishing them from "primary" FMS. Despite that, essentially
all of the current and past FMS clinical trials sponsored by industry or by
government agencies have specified enrollment of only primary FMS patients.
They accomplish that by excluding all subjects with a concomitant rheumatic
disease or with specific organ system abnormalities.

By definition, all patients who meet the 1990 ACR research classification
criteria for FMS (14) have subjective widespread body pain and a lowered
threshold to pressure induced pain, but it is also well recognized that
there can be a number of concomitant clinical manifestations not specified
in the classification criteria. For example, insomnia occurs in about 70
percent of FMS patients (15), depression in about 40 percent (16),
irritable bowel syndrome in about 40 percent (17-20), interstitial cystitis
in about 10 percent (21,22), and hypermobility in about 30 percent (23-26).
How should this heterogeneity of associated manifestations be viewed?
Should clinicians caring for FMS patients and/or investigators studying FMS
be lumpers or splitters?

In response to question number 1 above, it is worthy to consider the
situation with systemic lupus erythematosus [SLE]. The ACR supports the
concept that 11 diagnostic criteria are important to the clinical diagnosis
of SLE but only four of these criteria are required to diagnose SLE in a
given individual (27). Arthritis and antinuclear antibodies are nearly
universal [95+ percent] findings in patients with SLE but it is clear that
there are subgroups of SLE patients whose presentation and clinical course
may differ substantially from other SLE subgroups. The subgroups are
characterized by their patterns of major organ involvement critical to the
prognosis and management of the disorder (28-30). For example, in various
combinations, about 50 percent of SLE patients have renal involvement, 50
percent exhibit lung involvement, cardiac involvement is seen in about 40
percent, neuropsychiatric manifestations are present in about 60 percent,
autoimmune hemolysis occurs in about 5 percent, and about 30 percent have
concomitant FMS. These observations are important since exacerbations of
SLE disease activity tend to breed true, meaning that the pattern of organ
involvement in a given subject tends to be similar with each reactivation
episode. In a given SLE patient, the most useful marker of active disease,
the most useful therapeutic regimen, and the ultimate prognosis are all
dependent upon which "major organ involvement subgroup" has emerged.

In this issue of the Journal, the lead article by Walen and colleagues (5)
begins by reviewing the findings from prior studies in which two or three
distinct clusters [subgroups] of FMS patients have been identified and
studied. Since the prior studies may have suffered from sample size
limitations, the authors conducted extensive evaluations on 600 FMS
patients who were members of a health maintenance organization. Cluster
analysis on the data from those subjects confirmed the previously described
unique clusters of FMS patients that differed from each other with respect
to mood disturbance, pain, physical function, and social support. While
these subgroup differences were statistically definable, all three
subgroups were still much worse than healthy normal controls in the general
population.

Biochemical analysis of fluid samples from patients with FMS has also
identified apparent subgroups. For example, 84 percent of FMS patients had
elevated cerebrospinal fluid levels of substance P, leaving a subgroup of
16 percent whose values were normal by this measure (7). Patients with
"primary" FMS had elevated levels of nerve growth factor not seen in normal
controls, or in FMS patients with concomitant rheumatic diseases
["secondary" FMS], or in rheumatic disease patients not having FMS (4,31).
Similarly, blood samples from a subgroup of about 50 percent of FMS
patients have been found to exhibit an antibody to an environmental polymer
(8), so the antipolymer antibody assay is being proposed as a way to
identify that subgroup which may have an immunoreactive pathogenesis.

Electrophysiological assessment methods, such as combinations of
quantitative electroencephalography [qEEG] and electromyography [sEMG] have
helped to identify distinct FMS subgroups (6,9). Forty patients with FMS,
off their usual FMS medications for five half lives, were stratified into
three subgroups on the basis of their Symptom Checklist-90-Revised
[SCL-90-R] Global Severity Index [GSI] scores (32). The least distressed
subgroup [Subgroup One] exhibited a mean SCL-90-R GSI of 58, while the GSI
for Subgroup Two was 66 and that for Subgroup Three was 77. The subgroups
were then examined by qEEG activity patterns with the subjects resting,
eyes closed. By-subgroup differences in the quantity of the typical qEEG
wave forms were found. Across the GSI-defined subgroups from least to most
distressed, alpha brainwave activity [7.5-13 Hertz] progressively
decreased, while theta activity [3.5-7.5 Hertz] progressively increased.
Beta activity [13-22 Hertz] was low in Subgroup Three, higher in Subgroup
One, and clearly highest in Subgroup Two, while delta activity [0.5-3.5
Hertz] was consistently low across all three subgroups. The addition of
sEMG data in this study demonstrated widely dispersed skeletal muscle
cocontraction in response to a distant volitional stimulus but the
magnitude of this abnormality did not differ among the three GSI-defined
subgroups.

Finally, attempts at diagnostic treatment regimens have disclosed
differences in the responses of FMS patients to ketamine, suggesting that
the N -methyl- D-aspartic receptor [which ketamine inhibits] in the spinal
cord is important to the perceived pain in FMS (2,3,33). Patient volunteers
in one key study (3) were treated [randomized serial cross-over] with brief
intravenous infusions of ketamine, morphine sulfate, lidocaine, or saline
placebo. Of the 18 FMS patients studied, two patients were placebo
responders [responded with improvement to all three agents and the placebo]
and three were nonresponders [no improvement with any of the administered
agents]. The majority [N = 13] responded to one or more of the active
medications but not to placebo. Four patients responded to a single drug
[morphine-one, ketamine- three], six responded to two drugs [lidocaine and
morphine-four, lidocaine and ketamine-two], and three responded to all
three active drugs. Since all of the patients were clinically diagnosed as
having FMS, this study implies substantial heterogeneity in the response of
FMS patients to treatment. It may further help to explain why some patients
fail to respond to a clinician's favorite regimen.

 From the preceding discussion, it seems likely that the composite of FMS
subjects identified by the 1990 ACR criteria for the classification of FMS
(14) are heterogeneous in several important respects. In fact, there are
many additional examples of clinical measures that have disclosed apparent
heterogeneity among FMS patients, but space is limited. So, what then are
the answers to questions 2 through 8 in the list above? Unfortunately, they
must await further research, analysis, and debate. Walen and colleagues (5)
conclude their assessment by saying that: "People with FMS may fall into
distinct subgroups; however, the utility of dividing participants into
these [sub]groups in planning interventions remains unclear." On the other
hand, they also suggest that "the most helpful direction for future
research would involve comparing the effects of interventions designed
especially for each cluster to a 'nontailored' intervention." Finally, It
always comes back to the hopeful prediction that the better we understand
the mechanisms of chronic FMS pain, the more likely we are to find specific
and effective therapies.

Journal readers are also directed to three other original research
contributions in this issue, to three information packed topical columns,
and to two rather glowing book reports. As always, letters to the editor
are welcome.

I. Jon Russell, MD, PhD


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© 2002 by The Haworth Press, Inc. All rights reserved.