**Meet the editor**

Dr. William S Wilke received a Bachelor of Science degree from the University of Notre Dame and a Doctor of Medicine degree from the Medical College of Wisconsin. His medical internship and residency were completed at Akron City Hospital. Afterward, he finished rheumatology training and remained at the Cleveland Clinic foundation for 37 years, retiring in April, 2011. Through-

out the span of his career, Dr. Wilke was Chairman of the Medical Grand Rounds Committee and the Pharmacy and Therapeutics Committee. He was also head of Subspecialty Clinics from 1981-1995. Since 1990, he has been Associate Editor of the Cleveland Clinic Journal of Medicine. Outside activities included annual "Meet the Professor" meetings at the American College of Rheumatology from 1991-1993, and participation as a member of the United States Pharmacopeia General Committee from 1995-2000. Dr. Wilke is the author of 121 various publications, editor of Methotrexate Therapy in Rheumatic Disease: Marcel Dekker Inc, 1989, and authored The Cleveland Clinic Guide to Fibromyalgia: Kaplan Publishing, 2010.

## Contents

#### **Preface XI**

#### **Part 1 Pathogenesis of Fibromyalgia 1**

	- **Part 2 Definition and Diagnosis of Fibromyalgia 99**
	- **Part 3 Treatment of Fibromyalgia 167**

## Preface

I try, not always successfully, to read most of each week's edition of *The Economist.* In the October 15th-21st science section a report Transporter of Delight, discusses new information about the genetic underpinning of happiness, and confirmed some of my biases about the biopsychosocial nature of fibromyalgia. The story reported that Jan-Emanuel De Neve and colleagues performed a rigorous case control study involving 1,939 adolescents (De Neve J-E et al, 2011). Genetic information was collected and correlated with a validated satisfaction questionnaire. They controlled for other important potentially causative factors including education, economic status, religiosity, and many others, and discovered a gene that regulates happiness, the same gene that is found in people with fibromyalgia. The magazine story is the genesis for this polemic.

#### **A little background**

Human DNA is composed of approximately 21,000 genes, distinct regions arranged in 23 pairs - one each from the mother and father. The two components of each separate gene have subtle differences of amino acid distribution, which affect their function. These slightly different functional variants of the same gene are called alleles. The gene of interest is called 5-HTTLPR and modulates serotonin concentrations in the nervous system. This gene consists of a short and long allele, based on the number of amino acid residues in their structures - the long one produces more serotonin transporter proteins, which produce more serotonin than the shorter allele.

The researchers found that individuals with long alleles and those with higher serotonin concentrations in the nervous system were statistically more likely to be very satisfied with their life, compared to individuals with short alleles (p=0.012).

Serotonin is a chemical, which is released by neurons and governs the magnitude of neural activity. Low serotonin concentrations in the central nervous system is causally linked to affective disorders (Thieme K et al, 2004; Abeles AM et al, 2007). This same alteration of the serotonergic system is a crucial factor underlying the severity and pathogenesis of FMS (Russell IJ et al 1992; Stahl SM et al, 2009).

Familial aggregation occurs in fibromyalgia. For example, among 533 first degree relatives of 78 fibromyalgia patients compared to 272 first degree relatives of 40

#### X Preface

rheumatoid arthritis patients, the odds ratio for having fibromyalgia was 8.5 in fibromyalgia relatives versus the rheumatoid arthritis relatives (Arnold LM et al, 2004). Others have demonstrated an increased frequency of the short allele of the serotonin transporter gene 5-HTTLPR in fibromyalgia (Offenbacher M et al, 1999). In the general population, the short allele confers vulnerability to a spectrum of illnesses including anxiety disorder, depression, and bipolar disorder (Lucki I, 1998). Furthermore, increased amygdala activation to environmental stresses such as facial expression, proven by functional magnetic resonance imaging (Hariri AR et al, 2006), and other methods (Munafo MR et al, 2008) has been linked to this same allele. The amygdala is responsible for negative interpretation of environmental stimuli; increased activation equals higher "fear factor".

#### **Next piece, temperament**

In 1993, C. Robert Cloninger postulated that temperament, which can be best understood as automatic emotional responses to situations in society by an individual, might be primarily due to inheritance (Cloninger CR et al, 1993). He constructed a model of four descriptive personality dimensions, which included novelty seeking, harm avoidance, reward dependency and persistence. People with harm avoidance were described as having "... pessimistic worry in anticipation of future problems, ...fear of uncertainty, shyness of strangers and rapid fatigability." Those with novelty seeking were curious, disorganized, quick-tempered and impulsive. Reward dependence traits include sensitivity and a need for societal contact. Not surprisingly, people with the persistence trait were described as industrious and hard working. He suggested that all of our personalities are a mixture of these traits, and in some individuals, one or another trait dominates.

He further predicted that each of these traits was due to different genes which were intimately related to brain chemistry metabolism. Harm avoidance was related to serotonin pathways, novelty seeking to dopamine pathways, and the last two to norepinephrine pathways. Research since 1992 has shown that these relationships are a bit more complicated, but the general concept is largely confirmed. Of significance, a recent publication has shown a higher frequency of both the short 5-HTTLPR allele and harm avoidance temperament trait in patients with fibromyalgia compared to controls (Cohan H et al, 2002).

#### **The genetic plus side**

At this point, I have associated unhappiness, 5-HTTPR short allele, harm avoidance due to amygdala activation, low central nervous system serotonin with fibromyalgia. This relationship makes sense. In the medical and in psychology and economic literature, people with harm avoidance are prone to increased situational fear responses, depression, and low self direction, as well as fibromyalgia (Celikel FC et al, 2009; Glazer Y et al, 2010). However, they are also more likely to be creative, more spiritual, more likely to participate in the arts (Bachner-Melman R et al, 2005), and perform better academically (Calapoglu M et al, 2011). In my own clinic, patients with FMS tell me that they always lock their doors, have insurance, pay their bills on time, wear their seat belts and vote regularly. They are good, careful people, people with high harm avoidance. The long allele is not associated with harm avoidance-they are happy, but not necessarily very careful people. They take chances.

Our first attempts at literature were epic poems that celebrated heroes. These were people like Beowulf, who went off into the dark woods to slay the monster Grendel, and Odysseus, who sailed off beyond the sight of land to great adventure. Why were these people celebrated? Because they came back. Most people who entered the great woods alone or sailed beyond the sight of land never returned. Who were these people? Certainly not the ones with high harm avoidance traits. The harm avoidance people stayed home and procreated. This was a good trait. They were a bit afraid, but they weren't stupid. They planned ahead, put up stocks and were ready for winter. They brought order and law to society. What's more, in times of societal stress, they slept lightly and gave the first alarms. With their enhanced central sensitivity, they were the first to hear the enemy, to perceive signs of the attacker in the woods, to smell the hunting animal's approach. It mattered little to the genes how these harm avoiders felt during times of stress. All that was important was getting through the danger safely. Anyway, most of those ancient stressful events resolved quickly and were short-lived. For most of our history, having these genes was predominantly a good thing.

#### **Societal prospective**

X Preface

rheumatoid arthritis patients, the odds ratio for having fibromyalgia was 8.5 in fibromyalgia relatives versus the rheumatoid arthritis relatives (Arnold LM et al, 2004). Others have demonstrated an increased frequency of the short allele of the serotonin transporter gene 5-HTTLPR in fibromyalgia (Offenbacher M et al, 1999). In the general population, the short allele confers vulnerability to a spectrum of illnesses including anxiety disorder, depression, and bipolar disorder (Lucki I, 1998). Furthermore, increased amygdala activation to environmental stresses such as facial expression, proven by functional magnetic resonance imaging (Hariri AR et al, 2006), and other methods (Munafo MR et al, 2008) has been linked to this same allele. The amygdala is responsible for negative interpretation of environmental stimuli;

In 1993, C. Robert Cloninger postulated that temperament, which can be best understood as automatic emotional responses to situations in society by an individual, might be primarily due to inheritance (Cloninger CR et al, 1993). He constructed a model of four descriptive personality dimensions, which included novelty seeking, harm avoidance, reward dependency and persistence. People with harm avoidance were described as having "... pessimistic worry in anticipation of future problems, ...fear of uncertainty, shyness of strangers and rapid fatigability." Those with novelty seeking were curious, disorganized, quick-tempered and impulsive. Reward dependence traits include sensitivity and a need for societal contact. Not surprisingly, people with the persistence trait were described as industrious and hard working. He suggested that all of our personalities are a mixture of these traits, and in some

He further predicted that each of these traits was due to different genes which were intimately related to brain chemistry metabolism. Harm avoidance was related to serotonin pathways, novelty seeking to dopamine pathways, and the last two to norepinephrine pathways. Research since 1992 has shown that these relationships are a bit more complicated, but the general concept is largely confirmed. Of significance, a recent publication has shown a higher frequency of both the short 5-HTTLPR allele and harm avoidance temperament trait in patients with fibromyalgia compared to

At this point, I have associated unhappiness, 5-HTTPR short allele, harm avoidance due to amygdala activation, low central nervous system serotonin with fibromyalgia. This relationship makes sense. In the medical and in psychology and economic literature, people with harm avoidance are prone to increased situational fear responses, depression, and low self direction, as well as fibromyalgia (Celikel FC et al, 2009; Glazer Y et al, 2010). However, they are also more likely to be creative, more spiritual, more likely to participate in the arts (Bachner-Melman R et al, 2005), and

increased activation equals higher "fear factor".

individuals, one or another trait dominates.

controls (Cohan H et al, 2002).

**The genetic plus side** 

**Next piece, temperament** 

If we consider the evolution of our species during the last 100,000 years, we live in very special, very different times. We no longer respect diurnal variation, the dictates of the sun and moon. We have efficient artificial lighting. We're shift workers with little respect for sleep. Unprecedented sensory input from radio, television, PCs, iPods, Blackberries, cell phones, and beepers allow no down time and facilitates "multitasking" as never before. We're told by advertisers that we need more and more of these things so that we can watch Reality Shows which demean contestants as a substitute for entertainment, tune in to news shows which compete under the mantra, "If it bleeds, it leads", and experience the negative radio and television sound bites for politicians who will protect us from the terrorists who, incidentally, are everywhere (Hassett AL et al, 2002). We, especially in the United States, are stressed and in trouble.

Expenditures for health care per capita in the United Kingdom are less than half the monies spent in the United States (\$2164 versus \$5274 ), but people in the United States are relatively less healthy according to Banks and colleagues (Banks J et al, 2006). They analyzed self-reported illness profiles completed by approximately 10,000 US residents and approximately 5,500 UK residents all middle-aged or older, and discovered that the usual risk factors for diabetes, atherosclerotic heart and vascular disease, which include *traditional* definitions of lower socioeconomic status, obesity, tobacco, and alcohol use, did not fully explain these differences. From the same study, we also learned that C- reactive protein (CRP), which is also associated with the risk of

#### XII Preface

heart and vascular disease (Ridker PM et al, 2002), was 20 percent higher in US residents, and also not explained by those previously mentioned traditional disease risk factors. They concluded that there must be some other important risk factor(s).

In Banks' discussion, we are reminded that psycho-social factors (also known as stress) play a major role in conferring poorer health for people in lower socio-economic stratas of society. Lower social status has been shown to increase the risk of the Metabolic Syndrome (Wannamethee SG et al, 2007), which is at the root of diabetes and cardiovascular disease. In addition, the serum level of CRP rises as socioeconomic status falls (Steptoe A et al, 2003). Banks points out that we are progressively losing our middle class in the US (Banks J et al, 2006). This places more and more of us, if not in the *traditional* lower class, but still at accelerating "socio-economic risk". Therefore, increasing stress, an important cause of FMS, and which increases as social status declines, also mediates elevation of CRP, which is at the very least a surrogate measure of declining overall health.

One valid interpretation of Banks' important report is that people who live in the US experience greater stress than do people who live in the UK, hence the higher CRP, and that stress makes people in the US less healthy than their UK counterparts - US residents, therefore, live in a stressful and not very healthy society. The concept that origins of most diseases are at least in part due to social inequities and mood/affective disorders is still novel for most physicians, but hardly a new or unique interpretation (Syme SL et al, 1976; Moussavi S et al 2007). Moreover, certain illness profiles might preferentially manifest in the genetically susceptible.

Genes determine magnitude of response to stress, susceptibility to depression, and are a major determinant of who manifests fibromyalgia and who doesn't (Martinez-Lavin M et al, 2007; Caspi A et al, 2003).

As we already know, genetic background dictates susceptibility to depression, and the short allele contributes (Munafo MR et al, 2006)). When distress begets depression, it gradually reduces health scores (Moussavi S et al, 2007), accelerates atherosclerosis (Faramawi MF et al, 2007), and by shortening telomeres, may contribute to premature cellular senescence (Simon NM et al, 2006). Stress also raises markers of inflammation and is an important player in the pathogenesis of FMS (Chandola T et al, 2006; Abales AM et al, 2007).

An analysis by Wolfe and co-workers might help us to understand this better (Wolfe F et al, 2006). In Wolfe's "Survey Criteria", used to diagnose fibromyalgia, if numerical values are given to two symptoms, pain and fatigue, and the values added, a numerical Symptom Intensity Scale is produced. When this scale was applied to 25,417 patients in his data base, regardless of the presence or absence of fibromyalgia, higher scores on the scale were associated with more severe medical illnesses of all kinds, greater mortality, and more socioeconomic disadvantage. So, having cardinal symptoms of stress, pain, and fatigue, often a surrogate for depression, is clearly associated with poor health. Furthermore, this study allows us to generalize the concept to the entire population, a population in which as we are told by economists, the middle class is shrinking. We're all getting increasingly stressed, our moods worsened, and some of us manifest this situation as the symptoms of pain and fatigue. Add a new study, which shows that negative mood mediates sleep abnormalities in people with chronic pain, and the conceptual illness fibromyalgia is complete (O'Brien EM et al, 2010).

#### **Canaries**

XII Preface

measure of declining overall health.

M et al, 2007; Caspi A et al, 2003).

AM et al, 2007).

preferentially manifest in the genetically susceptible.

heart and vascular disease (Ridker PM et al, 2002), was 20 percent higher in US residents, and also not explained by those previously mentioned traditional disease risk factors. They concluded that there must be some other important risk factor(s).

In Banks' discussion, we are reminded that psycho-social factors (also known as stress) play a major role in conferring poorer health for people in lower socio-economic stratas of society. Lower social status has been shown to increase the risk of the Metabolic Syndrome (Wannamethee SG et al, 2007), which is at the root of diabetes and cardiovascular disease. In addition, the serum level of CRP rises as socioeconomic status falls (Steptoe A et al, 2003). Banks points out that we are progressively losing our middle class in the US (Banks J et al, 2006). This places more and more of us, if not in the *traditional* lower class, but still at accelerating "socio-economic risk". Therefore, increasing stress, an important cause of FMS, and which increases as social status declines, also mediates elevation of CRP, which is at the very least a surrogate

One valid interpretation of Banks' important report is that people who live in the US experience greater stress than do people who live in the UK, hence the higher CRP, and that stress makes people in the US less healthy than their UK counterparts - US residents, therefore, live in a stressful and not very healthy society. The concept that origins of most diseases are at least in part due to social inequities and mood/affective disorders is still novel for most physicians, but hardly a new or unique interpretation (Syme SL et al, 1976; Moussavi S et al 2007). Moreover, certain illness profiles might

Genes determine magnitude of response to stress, susceptibility to depression, and are a major determinant of who manifests fibromyalgia and who doesn't (Martinez-Lavin

As we already know, genetic background dictates susceptibility to depression, and the short allele contributes (Munafo MR et al, 2006)). When distress begets depression, it gradually reduces health scores (Moussavi S et al, 2007), accelerates atherosclerosis (Faramawi MF et al, 2007), and by shortening telomeres, may contribute to premature cellular senescence (Simon NM et al, 2006). Stress also raises markers of inflammation and is an important player in the pathogenesis of FMS (Chandola T et al, 2006; Abales

An analysis by Wolfe and co-workers might help us to understand this better (Wolfe F et al, 2006). In Wolfe's "Survey Criteria", used to diagnose fibromyalgia, if numerical values are given to two symptoms, pain and fatigue, and the values added, a numerical Symptom Intensity Scale is produced. When this scale was applied to 25,417 patients in his data base, regardless of the presence or absence of fibromyalgia, higher scores on the scale were associated with more severe medical illnesses of all kinds, greater mortality, and more socioeconomic disadvantage. So, having cardinal symptoms of stress, pain, and fatigue, often a surrogate for depression, is clearly associated with poor health. Who are the first people, the early warning system, who notice this toxic environmental state of affairs? The harm avoiders of course, and with their sensitive serotonin genes, they experience it viscerally, with symptoms. People with fibromyalgia, genetically determined neurologic central sensitivity, have real physiologic symptoms, which constitute illness by definition when they seek medical care. The pathogenesis of their symptoms is multifactorial and includes chronic distress/stress from living in a society that would have been described as a dystopia in 1950's science fiction literature.

Genes interacting with society; no wonder it's so hard to treat fibromyalgia. These sensitive, relatively unhappy people whose fear nerves fire at lower thresholds, are the canaries in our society's coal mine. Canaries first. Eventually, we are all at risk.

#### **Back to the book**

This discussion is a polemic, a persuasion and a hypothesis about how the various pieces fit and interact in the puzzle that is fibromyalgia, and reduced to the most fundamental, happiness and society. Since we're ultimately dealing with science, it is one approximation of "the truth". This book provides further pieces to the puzzle. We'll keep trying to get it right.

#### **Dr. William S. Wilke, M.D.**

Department of Rheumatic and Immunologic Diseases, A50 Cleveland Clinic, Orthopedic and Rheumatologic Institute, Cleveland, Ohio, USA

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