Preface

I began my career in rheumatology in 1971. As an intern, I took over the rheumatology clinic on Wednesday mornings for indigent patients staffed by an intelligent, recently graduated rheu‐ matologist. He knew all the latest about rheumatic diseases. In hindsight, it was not much.

In those days, we had an anemic treatment arsenal for most rheumatic diseases, including rheumatoid arthritis (RA) that, in fact, barely worked. Antimalarials, parenteral gold, corti‐ costeroids, d-penicillamine, and the relatively new prostaglandin inhibitors such as ibupro‐ fen were included among them [1]. The science of RA was also relatively primitive [2]. We knew that RA was an inflammatory disease, but immunology was in its infancy and consist‐ ed chiefly of T cells, B cells, serum complement, and a few circulating inflammatory pro‐ teins, one of which was associated with malignancy and caused wasting called cachectin, later named tumor necrosis factor-alpha.

Even more so for fibromyalgia syndrome (FMS), it was then known as fibrositis. Although a great many etiopathologic hypotheses existed, a "functional condition" was largely consid‐ ered; that is, function was subjectively impaired, but no pathophysiologic abnormalities were evident [3]. Most local practitioners considered it as imaginary, prescribed "a sedative" or an opiate, and sent the patient away without follow-up [4].

Today, we have made fantastic strides in both understanding the pathophysiology and treating RA. We have identified various biochemical players in what we now know to be an extensive, redundant inflammatory cascade and blocked their activity. Remission or near-re‐ mission is now an achievable outcome [5].

Alternatively, although we understand some of the factors that play an etiopathologic role in FMS such as depression, anxiety, helplessness, disordered sleep, and poor physical condi‐ tioning, the biochemistry underlying and connecting these factors remains mysterious [6]. And unfortunately, even when we therapeutically manipulate a few mechanistic factors that we do understand such as serotonin or norepinephrine, the response is very limited [7].

Back in the early 1970s, most RA experts were opposed to the use of antineoplastic drugs or a combination of agents to improve inflammation in rheumatoid arthritis [8]. From my per‐ spective, a rheumatology fellow who was being taught by Art Schebrel to use methotrexate and other cytotoxic agents in 1974 to treat various rheumatic diseases, I learned through contemporary literature, as well as angry calls and letters that the rheumatology community viewed this kind of treatment metaphorically as "A bull looking for a china shop." Antici‐ pated unacceptably, high toxicity was the major issue [9]. Fortunately, those dire prophecies failed to materialize.

In retrospect, maybe the rheumatology community should have been a little more intellectu‐ ally curious about new therapies for RA and novel etiopathogenic hypotheses. They also should have allowed themselves to be more skeptical about the results of contemporary treatment, the very modest outcomes associated with prevailing therapies, and the flawed etiopathogenic hypotheses. Had attitudes been a little more opened-minded, the treatment outcomes of RA and its science might have progressed more rapidly.

mary symptoms, and curiosity is about the phenotypic alterations by comorbid FMS. What does such a modification do to diagnostic criteria and measures of disease activity? As it turns out, when FMS is comorbid, the validity of outcome measures in the primary disease is modified, and diagnostic phenotypic changes are considerable. This is particularly true of indices that consist of subjective, patient-only-report measures. The resulting diagnostic and

The science and treatment of FMS, when compared to that of RA, have much catching up to

Rheumatology Department, Orthopedic and Rheumatology Institute (retired)

[1] Schmid FR, Tesar JT, Rosen JS, et al. Rheumatoid arthritis. Postgraduate Medi‐

[2] Abruzzo JL. Rheumatoid arthritis: reflections on etiology and pathogenesis. Ar‐

[3] Glyn JH. Rheumatic pains: some concepts and hypotheses. Proceedings of the

[4] Kraft GH, Johnson EW, Laban MM. The fibrositis syndrome. Archives of Physical

[5] Ruderman EM. Treating to target in rheumatoid arthritis – challenges and oppor‐

[6] Gracely RH, Schweinhardt P. Key mechanisms mediating fibromyalgia. Clinical

[7] Hauser W, Bernardy K, Uceyler N, Sommer C. Treatment of fibromyalgia syn‐ drome with antidepressants. A meta-analysis. JAMA. 2009;**301**:198-209. [8] Goldman JA, Hess EV. Treatment of rheumatoid arthritis-1970. Bulletin on the

[9] Black RL, O'Brien WM, VanScot El, et al. Methotrexate therapy in psoriatic arthri‐

chives of Physical Medicine and Rehabilitation. 1971;**52**:30-38.

tunities. Bulletin Hospital for Joint Diseases. 2013;**71**:214-217.

and Experimental Rheumatology. 2015;**33**(Suppl. 88):S2-S6.

tis: double blind study on 21 patients. JAMA. 1964;**189**:743-747.

Royal Society of Medicine. 1971;**64**:22-28.

Rheumatic Diseases. 1970;**21**:609-612.

Medicine and Rehabilitation. 1968;**49**:155-162.

**William S. Wilke MD,** Senior Staff Physician

Preface IX

Cleveland Clinic, Cleveland, OH, USA

do. This little book about unusual FMS topics is a step in the right direction.

treatment considerations are discussed.

cine. 1971;**50**:143-149.

**References**

Our understanding of FMS pathogenesis and treatment remains relatively rudimentary compared to that of RA. So, it is in our and our patients' best interest to adopt those atti‐ tudes that were largely missing in understanding RA in 1970. We must remain open-mind‐ ed manifested as curiosity a skepticism if the science of FMS and its treatment for FMS and its science is to progress. To that end, this book is useful.

Skepticism is the prominent intellectual attitude adopted in the first chapter. Because FMS is classified among autoimmune diseases and because most of the signs and symptoms includ‐ ing pain and fatigue are due to inflammatory autoimmune mechanisms, it might follow that the signs and symptoms of FMS are also due to inflammation. While it is true that inflamma‐ tory cytokines have been reported to be elevated in FMS in a few studies, the serologic concen‐ trations in FMS are trivial compared to levels in active RA. It has also been shown that treatment with agents that nonspecifically lower serum cytokine concentrations do not im‐ prove signs and/or symptoms in FMS. Finally, primary depression, sleep disturbance, and other core FMS symptoms have been reported to be associated with similar low-level cytokine elevation that has been suggesting multifactorial etiology for any cytokine elevation in FMS.

In the second chapter, which is an exercise in curiosity, the authors present plausible hy‐ potheses and provide preliminary data to show that oxidative stress plays at least a partial role in FMS etiopathogenesis.Dysfunction of both the endocrine and autonomic nervous sys‐ tems is common in FMS, the etiology of which can be CNS damage from oxidation by free radicals. They invoke mitochondrial dysfunction as a primary explanation for this damage and show that antioxidants such as CoQ10 improve signs and symptoms associated with this damage. A curious attitude concludes that this concept begs further elucidation.

Chapter 3 should appeal to the skeptics. Western theories of treatment development are often reductionist, that is, discover the occult biological mechanisms underlying signs and symp‐ toms, modify them, and expect reciprocal change. The skeptic might ask, "Why make it so difficult?" For instance, helplessness worsens the pain of FMS. Education reduces helpless‐ ness. Simple. Sleep is disrupted in FMS. Sleep hygiene is taught. Simple. The third chapter examines the studies that have shown empirical benefit from these practical interventions.

The fourth chapter appeals primarily to intellectual curiosity. The biological effects of sub‐ stances that are "natural" can be mild-to-profound, beneficial, or not so much. Consider, for example, acetylsalicylic acid, on the positive side, and arsenic as an alternative. The authors provide well-referenced discussions of various natural products, efficacy trials, and clear de‐ scriptions of the beneficial effects and toxicities. They also address the mechanisms of action in the context of presumed FMS pathophysiology. We should expect that as these natural products are refined, just as digitalis leaf yielded a safer and more effective digoxin, new FMS medicines should emerge.

The last chapter invokes both skepticism and curiosity; skepticism is about the validity of outcome measures for some autoimmune diseases, in which pain and fatigue are the pri‐ mary symptoms, and curiosity is about the phenotypic alterations by comorbid FMS. What does such a modification do to diagnostic criteria and measures of disease activity? As it turns out, when FMS is comorbid, the validity of outcome measures in the primary disease is modified, and diagnostic phenotypic changes are considerable. This is particularly true of indices that consist of subjective, patient-only-report measures. The resulting diagnostic and treatment considerations are discussed.

The science and treatment of FMS, when compared to that of RA, have much catching up to do. This little book about unusual FMS topics is a step in the right direction.

#### **William S. Wilke MD,**

Senior Staff Physician Rheumatology Department, Orthopedic and Rheumatology Institute (retired) Cleveland Clinic, Cleveland, OH, USA

#### **References**

In retrospect, maybe the rheumatology community should have been a little more intellectu‐ ally curious about new therapies for RA and novel etiopathogenic hypotheses. They also should have allowed themselves to be more skeptical about the results of contemporary treatment, the very modest outcomes associated with prevailing therapies, and the flawed etiopathogenic hypotheses. Had attitudes been a little more opened-minded, the treatment

Our understanding of FMS pathogenesis and treatment remains relatively rudimentary compared to that of RA. So, it is in our and our patients' best interest to adopt those atti‐ tudes that were largely missing in understanding RA in 1970. We must remain open-mind‐ ed manifested as curiosity a skepticism if the science of FMS and its treatment for FMS and

Skepticism is the prominent intellectual attitude adopted in the first chapter. Because FMS is classified among autoimmune diseases and because most of the signs and symptoms includ‐ ing pain and fatigue are due to inflammatory autoimmune mechanisms, it might follow that the signs and symptoms of FMS are also due to inflammation. While it is true that inflamma‐ tory cytokines have been reported to be elevated in FMS in a few studies, the serologic concen‐ trations in FMS are trivial compared to levels in active RA. It has also been shown that treatment with agents that nonspecifically lower serum cytokine concentrations do not im‐ prove signs and/or symptoms in FMS. Finally, primary depression, sleep disturbance, and other core FMS symptoms have been reported to be associated with similar low-level cytokine elevation that has been suggesting multifactorial etiology for any cytokine elevation in FMS. In the second chapter, which is an exercise in curiosity, the authors present plausible hy‐ potheses and provide preliminary data to show that oxidative stress plays at least a partial role in FMS etiopathogenesis.Dysfunction of both the endocrine and autonomic nervous sys‐ tems is common in FMS, the etiology of which can be CNS damage from oxidation by free radicals. They invoke mitochondrial dysfunction as a primary explanation for this damage and show that antioxidants such as CoQ10 improve signs and symptoms associated with

this damage. A curious attitude concludes that this concept begs further elucidation.

Chapter 3 should appeal to the skeptics. Western theories of treatment development are often reductionist, that is, discover the occult biological mechanisms underlying signs and symp‐ toms, modify them, and expect reciprocal change. The skeptic might ask, "Why make it so difficult?" For instance, helplessness worsens the pain of FMS. Education reduces helpless‐ ness. Simple. Sleep is disrupted in FMS. Sleep hygiene is taught. Simple. The third chapter examines the studies that have shown empirical benefit from these practical interventions. The fourth chapter appeals primarily to intellectual curiosity. The biological effects of sub‐ stances that are "natural" can be mild-to-profound, beneficial, or not so much. Consider, for example, acetylsalicylic acid, on the positive side, and arsenic as an alternative. The authors provide well-referenced discussions of various natural products, efficacy trials, and clear de‐ scriptions of the beneficial effects and toxicities. They also address the mechanisms of action in the context of presumed FMS pathophysiology. We should expect that as these natural products are refined, just as digitalis leaf yielded a safer and more effective digoxin, new

The last chapter invokes both skepticism and curiosity; skepticism is about the validity of outcome measures for some autoimmune diseases, in which pain and fatigue are the pri‐

outcomes of RA and its science might have progressed more rapidly.

its science is to progress. To that end, this book is useful.

VIII Preface

FMS medicines should emerge.


**Chapter 1**

**Provisional chapter**

**Introductory Chapter: A Challenge to the Concept that**

Among the chapters in this monograph are those that examine the treatment of fibromyalgia syndrome (FMS) using nonpharmacologic natural products and other relatively novel agents [1–3]. Although the modes of therapy described are diverse, a role for disordered immune mechanisms is implicit in each of the three chapters. These include reference to sulfur springs considered to inhibit interleukin-2 and interferon-gamma [1], introductory explanations of FMS pathogenesis that invokes inflammatory dysfunction [2], and mention of inflammatory cytokine production associated with autonomic nervous system dysfunction-stimulated microglial and astrocyte cell activation [3]. The discussion in the fourth chapter about the impact of FMS on the evaluation of inflammatory diseases assumes the opposite that clini-

**Introductory Chapter: A Challenge to the Concept that** 

DOI: 10.5772/intechopen.72936

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

In some contemporary reviews of FMS pathogenesis, inflammation is referenced in passing, as it is in these three chapters [9]. Whether this is done for "completeness," after all, FMS is

Face validity favoring a major pathogenic role for cytokine-mediated inflammation in FMS has been addressed in the past. Although initial reports of intermuscular fibrous tissue inflammation by Stockman led Gowers to name the condition "fibrositis," [5, 6], contemporary light and magnetic resonance imaging histological reports showed no evidence for peripheral muscle inflammation [7, 8]. These data should have closed the book on inflammation as a promi-

nent etiopathogenic mechanism in FMS. Then along came inflammatory mediators.

**Inflammation Plays a Prominent Pathogenic Role in**

**Inflammation Plays a Prominent Pathogenic Role in** 

**Fibromyalgia**

**Fibromyalgia**

William S. Wilke

**1. Introduction**

William S. Wilke

Additional information is available at the end of the chapter

cally significant inflammation is not a feature of FMS [4].

**2. Case (should have been previously) closed**

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.72936

**Provisional chapter**

## **Introductory Chapter: A Challenge to the Concept that Inflammation Plays a Prominent Pathogenic Role in Fibromyalgia Inflammation Plays a Prominent Pathogenic Role in Fibromyalgia**

**Introductory Chapter: A Challenge to the Concept that** 

DOI: 10.5772/intechopen.72936

William S. Wilke Additional information is available at the end of the chapter

William S. Wilke

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.72936
