Clin Rheumatol DOI 10.1007/s10067-014-2488-3
BRIEF REPORT
Dermatologic manifestations of fibromyalgia Valerie Laniosz & David A. Wetter & Desiree A. Godar
Received: 23 July 2013 / Revised: 24 December 2013 / Accepted: 5 January 2014 # Clinical Rheumatology 2014
Abstract The aim of this study was to determine the common dermatologic diagnoses and skin-related symptoms in a cohort of patients with fibromyalgia seen in a tertiary referral center. A retrospective chart review was performed of all patients with a fibromyalgia diagnosis from January 1 to December 31, 2008, whose diagnosis was confirmed in the Fibromyalgia and Chronic Fatigue Clinic at Mayo Clinic in Rochester, Minnesota. Charts were reviewed for dermatologic conditions and cutaneous symptoms. Demographic and clinical data were collected to assess the frequency of skin-related issues in patients with fibromyalgia. Of 2,233 patients screened, 845 patients met the inclusion criteria of having a confirmed diagnosis of fibromyalgia. Among these fibromyalgia patients, various dermatologic conditions and cutaneous problems were identified, including hyperhidrosis in 270 (32.0 %), burning sensation of the skin or mucous membranes in 29 (3.4 %), and various unusual cutaneous sensations in 14 (1.7 %). Pruritus without identified cause was noted by 28 patients (3.3 %), with another 16 patients (1.9 %) reporting neurotic excoriations, prurigo nodules, or lichen simplex chronicus. Some form of dermatitis other than neurodermatitis was found in 77 patients (9.1 %). Patients with fibromyalgia may have skin-related symptoms associated with their fibromyalgia. No single dermatologic diagnosis appears to be overrepresented in this population, with the exception of a subjective increase in sweating. Keywords Cutaneous dysesthesia . Dermatology . Fibromyalgia . Hyperhidrosis
V. Laniosz : D. A. Wetter (*) : D. A. Godar Department of Dermatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA e-mail: [email protected]
Introduction Fibromyalgia is not classically thought to be a disease with related cutaneous findings. However, several studies have showed objective differences in the skin of patients with fibromyalgia compared to persons without the disorder. In particular, investigators have demonstrated that patients with fibromyalgia, when compared to control participants, have increased numbers of mast cells and increased mast cell degranulation in the skin [1]; increased inflammatory cytokines in the skin [2]; altered collagen metabolism, with collagen deposition around peripheral nerves [3]; cutaneous microcirculatory abnormalities [4, 5]; autonomic nervous system dysfunction [6–10]; and increased levels of cutaneous opioid receptors [11]. Given these skin alterations, we hypothesized that patients with fibromyalgia had an increased burden of dermatologic disease. Our aim in the present study was to assess for the dermatologic conditions and cutaneous reports of patients with a diagnosis of fibromyalgia confirmed in a tertiary referral center.
Materials and methods The charts of patients who had received the code for a diagnosis of fibromyalgia between January 1 and December 31, 2008 were collected and reviewed so that only patients with a confirmed fibromyalgia diagnosis in the Fibromyalgia and Chronic Fatigue Clinic at Mayo Clinic in Rochester, Minnesota were included in the study. The fibromyalgia diagnosis was confirmed according to the American College of Rheumatology criteria for the diagnosis of fibromyalgia from 1990 to 2010 or from modification to the criteria in 2011. Approval for the study was obtained from the Mayo Clinic Institutional Review Board before initiation of chart review. Patients who had denied research authorization were excluded from the study. Charts were reviewed for basic demographic
Clin Rheumatol
information, including age and sex, along with confirmation of the diagnosis of fibromyalgia, dermatologic diagnoses in the Department of Dermatology and primary care notes, and patient reports of cutaneous problems in the Fibromyalgia and Chronic Fatigue Clinic notes.
Results In 2008, a total of 2,233 patients seen at Mayo Clinic were identified as having fibromyalgia. Among them, 897 patients were seen in the Fibromyalgia and Chronic Fatigue Clinic, with confirmation of the diagnosis of fibromyalgia in 845 patients. The average age of these 845 patients was 48.9 years, with female preponderance of 90.6 % (Table 1). Thirty-two discrete categories of dermatologic diagnoses or cutaneous reports were identified. The only skin-related item of the standard systems review questionnaire at the Fibromyalgia and Chronic Fatigue Clinic was increased sweating, which was reported in nearly a third of the patients with fibromyalgia (32.0 %) (Table 2). Although patients had tender points and many also noted a burning sensation, the burning was related specifically to the skin or oral cavity for 3.4 % of patients. One other patient had a diagnosis of erythromelalgia. In addition to the sensation of cutaneous and mucosal burning, 1.7 % of patients related cutaneous pain or other unusual sensations of the skin. These unusual symptoms from different patients were varied and included such descriptions as the sensation of a “sliver” in the skin with light touch, a feeling that the “nerves are on the outside of the skin,” a feeling that a light touch was like a “slap,” a perception of “boils under the skin,” and an oral discomfort likened to “eating Pop Rocks.” In the dermatologic diagnosis category of pruritus, 3.3 % of patients specifically noted itching, with clinical diagnoses of neurotic excoriations, prurigo nodules, and lichen simplex chronicus in another 1.9 % of patients. Regarding other neurodermatoses, three patients were identified as having acne excoriée and one patient received a diagnosis of trichotillomania.
Table 1 Average, median, and mode of age and sex distribution of 845 patients with fibromyalgia Characteristic
Value
Age, mean, years Age, median (range), years Age, mode, years
48.9 49 (17–84) 51
Sex, no. (%) Female Male
766 (90.7) 79 (9.3)
Most of these conditions or concerns could be grouped. However, ten patients were identified as having “rash, other” (Table 2). Throughout the study period, these patients continued to have only descriptive terminology for their rash, such as “plaque-like rashes on arms and legs with sun exposure,” “facial rash,” “transient migratory rash,” or “pruritic rash not otherwise specified.” In the absence of histopathologic correlation by the patient’s clinician, these patients were not assigned to a more specific category.
Discussion We sought to determine the common dermatologic conditions and cutaneous concerns that would be found in a cohort of Table 2 Number and percentage of patients with fibromyalgia who had various dermatologic diseases and symptoms, listed in order of frequency Condition
Patients affected, no. (%)
Increased sweating Dermatitis excluding neurodermatitis Pruritus Raynaud phenomenon Psoriasis Acne, other Rosacea Burning skin sensation Cutaneous pain/odd sensations Folliculitis Urticarial Burning/painful mouth/tongue Hair loss/telogen effluvium Rash, other Neurodermatitis/excoriations Oral ulcers Cutaneous lupus
270 (32.0) 77 (9.1) 28 (3.3) 22 (2.6) 19 (2.2) 18 (2.1) 18 (2.1) 17 (2.0) 14 (1.7) 14 (1.7) 13 (1.5) 12 (1.4) 12 (1.4) 10 (1.2) 8 (0.9) 7 (0.8) 6 (0.7)
Prurigo nodules Lichen simplex chronicus Lichen planus Vasculitis Acne excoriée Lichen sclerosus Hidradenitis suppurativa Livedo reticularis Systemic sclerosis (limited) Morphea Dermatitis herpetiformis Darier disease Trichotillomania Calcinosis cutis Erythromelalgia
4 (0.5) 4 (0.5) 4 (0.5) 3 (0.4) 3 (0.4) 2 (0.2) 2 (0.2) 2 (0.2) 1 (0.1) 1 (0.1) 1 (0.1) 1 (0.1) 1 (0.1) 1 (0.1) 1 (0.1)
Clin Rheumatol
patients with a fibromyalgia diagnosis who were seen at a tertiary referral center. We hypothesized—on the basis of the literature showing increased levels of mast cells, inflammatory cytokines, opioid receptors, dysfunctional mitochondria, and both structural and functional changes in the skin of fibromyalgia patients—that skin-related concerns, particularly dysesthesias and pruritus, would be overrepresented in this patient population. Findings in the basic science literature In 1 study, skin biopsies of 63 patients with fibromyalgia were compared with 49 age-matched controls. Interestingly, patients with fibromyalgia showed a statistically significant increase in mast cell number compared with the controls (mean per high-power field, 5–14 mast cells vs. 0 or 1 mast cell) [1]. Another study comparing skin biopsy specimens showed not only greater mean mast cell numbers in patients with fibromyalgia, but also increased mast cell degranulation and immunoglobulin G deposits intradermally, which, the authors hypothesized, were suggestive of neurogenic inflammation in fibromyalgia patients [12]. Reverse transcriptase polymerase chain reaction was used to analyze several inflammatory cytokines in skin biopsy specimens from 53 patients with fibromyalgia and showed increases in interleukin 1β, interleukin-6, and tumor necrosis factor-α in approximately a third of test participants. Decreased coenzyme Q10, increased oxidative stress, and dysfunctional mitochondria also have been observed in the skin of patients with fibromyalgia, in addition to increased reactive oxygen species in the blood [13, 14]. Investigators have suggested that structural differences in skin may underlie the pathogenesis of fibromyalgia. A difference in collagen metabolism, with subsequent collagen deposition around peripheral nerves, has been hypothesized to lead to the reduction of pain tolerance in fibromyalgia patients [3]. A blinded electron microscopic analysis of skin biopsies of 13 patients with fibromyalgia compared with 5 matched controls showed ballooning of the unmyelinated Schwann cells in 9 of the 13 test participants—a finding that was not seen in any control biopsy specimen and was correlated to peripheral localization of axons within the unmyelinated Schwann cell sheaths [15]. Evidence has showed reduction in microcirculation and temperature in the skin overlying tender points in fibromyalgia, as well as decreased capillary density in the skin [4, 5]. Autonomic nervous system dysfunction also has been implicated in the pathogenesis of fibromyalgia [6–10]. From electroneuromyography, abnormalities in the sympathetic nervous system have been shown in the skin of patients with fibromyalgia [6]. Finally, when the levels of μ, κ, and δ opioid receptors in the skin of 25 patients with fibromyalgia were compared with controls, κ, and δ opioid receptor levels were an impressive 59.0- and 21.1-fold higher, respectively, than in
controls [11]. Table 3 summarizes data regarding differences in skin biopsy findings of patients who have fibromyalgia compared with patients who do not have the disorder. Findings in previous clinical literature To our knowledge, only one study looked specifically at skin disease in persons with fibromyalgia. This cross-sectional study included 66 fibromyalgia patients and 79 healthy controls who were seen on the same day by a sole dermatologist and identified an increased incidence of xerosis and neurotic excoriations in the patients with fibromyalgia [16]. An earlier study investigating clinical signs in fibromyalgia identified several cutaneous findings, including dermatographism, reticulated hyperpigmentation, hyperalgesia due to pressure, reactive hyperemia of the skin, and Raynaud phenomena [17]. Although no other studies have looked retrospectively at skin disease in patients with fibromyalgia, some studies have analyzed fibromyalgia incidence in both psoriasis and lupus erythematosus. Of 1,269 patients with a new diagnosis of psoriasis over a 3-year study period, 105 (8.3 %) were found to have concomitant fibromyalgia, with more female patients who had both diagnoses than male patients (93 women vs. 12 men) [18]. In a multicenter study of 60 patients with lupus erythematosus, 10 patients were found to have fibromyalgia, with an overrepresentation of systemic lupus erythematosus compared with other types of lupus [19]. Fibromyalgia has been shown to be increased in patients with lupus and psoriasis; yet, we did not observe an increase in these diseases in our cohort of patients with fibromyalgia. It is conceivable that the fibromyalgia symptoms may have been secondary to the lupus symptoms in a portion of these patients. Dermatologic diagnoses and symptoms In the present study, 845 patients with a confirmed diagnosis of fibromyalgia had 32 distinct dermatologic conditions or cutaneous symptoms. The most striking skin-related finding in this cohort was increased sweating, which in most patients was a subjective report noted on the intake form from their visit to the Fibromyalgia and Chronic Fatigue Clinic, rather than a clinical diagnosis of hyperhidrosis confirmed through thermoregulatory testing. Several reasons may explain the number of patients who noted increased sweating. First, the symptomology may be out of proportion to true disease. Second, an objective increase in sweating may occur in patients with fibromyalgia, given the evidence of dysautonomia having a role in fibromyalgia pathogenesis. Regardless, an interesting hypothesis is that a greater number of skin-related symptoms would be elicited from patients with fibromyalgia if these symptoms were listed on a questionnaire given to the patients.
Clin Rheumatol Table 3 Skin biopsy findings of patients with fibromyalgia compared with controls in the literature, listed in order of publication date Authors, year
Fibromyalgia patients, no. Controls, no. Findings in skin biopsy specimens
Beritze et al., 2010 [1] Cordero et al., 2010 [13] Kim et al., 2008 [15] Salemi et al., 2007 [11] Salemi et al., 2003 [2] Jeschonneck et al., 2000 [4] Enestrom et al., 1997 [12]
63 2 13 25 53 20 25
49 2 5 10 10 20 22
Increased mast cells CoQ10 deficiency, mitochondrial dysfunction, increased oxidative stress Peripheral localization of axons within unmyelinated Schwann cell sheaths Increased δ and κ opioid receptor expression Increased interleukin-1β, interleukin-6, and tumor necrosis factor α Vasoconstriction and decreased temperature within tender points Increased mast cell degranulation and intradermal IgG deposits
CoQ10 coenzyme Q10, IgG immunoglobulin G
Many additional skin diseases were identified in the study group of fibromyalgia patients, including dermatitis (n=77), psoriasis (n=19), and acne or rosacea (n=36). It is arguable whether these diagnoses were related in any way to the underlying pathophysiologic factors of fibromyalgia or were a result of the demographic characteristics of the sample population. Consistent with the prior cross-sectional study of skin findings in patients with fibromyalgia [16], we identified a number of patients with neurodermatitis, in addition to several other psychogenic dermatologic diseases, such as trichotillomania and acne excoriée. Neurodermatoses were not the predominant finding in our retrospective review, yet it is interesting to hypothesize whether similar findings could have been identified in our cohort on skin examination. No other additional overrepresentation of any one entity was apparent. However, we identified 44 patients when the sensation of burning and pain of the skin and oral cavity were combined with erythromelalgia. An additional 28 patients were identified who noted pruritus in the absence of an identified cause, with another 16 having a diagnosis of prurigo nodules, lichen simplex chronicus, excoriations, or neurodermatitis. Thus, in a sampling of fibromyalgia patients, one in ten might have cutaneous or mucosal symptoms without an identifiable cause. Although true dermatologic disease can and does exist in patients with a fibromyalgia diagnosis, the present study highlights that, after ruling out skin disease, the cutaneous symptoms of this cohort may be a result of the fibromyalgia itself. Fibromyalgia as the cause of skin and mucosal symptoms should be a diagnosis of exclusion. In some cases, it may be the only plausible explanation. Study limitations and future research The present study was a retrospective chart review, which limits our extraction of cutaneous findings and problems to what information is available in the chart. Additionally, while in some cases, the diagnosis of fibromyalgia may have preceded the evaluation by dermatology, in others it followed. It
is difficult to speculate whether this may have influenced the dermatologist’s assessment of the underlying cause for the cutaneous symptoms, although this is certainly a possibility. The previously published prospective controlled study looking at skin findings in patients with fibromyalgia showed increased dryness of the skin and excoriations, which indicates that differences were seen even in a blinded setting [16]. Furthermore, the study was limited to patients seen in the Fibromyalgia and Chronic Fatigue Clinic for confirmation of a fibromyalgia diagnosis, which may select for more severe cases of fibromyalgia. We acknowledge also that, because of the demographic characteristics of the patients reviewed (i.e., predominantly perimenopausal women), some of the categories of dermatologic diseases and cutaneous problems may have been a result of selection bias. Despite this potential, the present study highlights the relations between fibromyalgia and the skin and opens up many new avenues for research. Another limitation of this study is the lack of age and gendermatched controls with which to compare these various dermatologic diseases and skin-related symptoms. The authors acknowledge that some of the cutaneous findings in the fibromyalgia population may at least in part be represented in a control group and would be an interesting future study. For future study, one of the most exciting avenues involves looking at whether traditional treatments for fibromyalgia, such as antidepressants, analgesics, and antiepileptic agents, may have an effect on cutaneous problems in patients with fibromyalgia. This information would be particularly helpful for patients with cutaneous symptoms in the absence of an identifiable dermatologic diagnosis. In addition, although this study gives a good overview of skin disease in a cohort of patients with fibromyalgia, an age- and sex-matched comparison would be useful. Finally, an interesting exploration would be to investigate how many other patients with fibromyalgia identify cutaneous symptoms when this history is elicited from the patients.
Disclosures None.
Clin Rheumatol
References 1. Beritze N, Arguelles M, Carcaba V, Fernandez F, Janciauskiene S, Oikonomopoulou K, Serres F, Fernandez-Bustillo E, Hollenberg M (2010) Abnormal overexpression of mastocytes in skin biopsies of fibromyalgia patients. Clin Rheumatol 29(12):10p. doi:10.1007/ s10067-010-1474-7 2. Salemi S, Rethage J, Wollina U, Michel BA, Gay RE, Gay S, Sprott H (2003) Detection of interleukin 1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha in skin of patients with fibromyalgia. J Rheumatol 30(1):146–150 3. Sprott H, Muller A, Heine H (1998) Collagen cross-links in fibromyalgia syndrome. Z Rheumatol 57(Suppl 2):52–55 4. Jeschonneck M, Grohmann G, Hein G, Sprott H (2000) Abnormal microcirculation and temperature in skin above tender points in patients with fibromyalgia. Rheumatology (Oxford) 39(8):917–921 5. Morf S, Amann-Vesti B, Forster A, Franzeck UK, Koppensteiner R, Uebelhart D, Sprott H (2005) Microcirculation abnormalities in patients with fibromyalgia—measured by capillary microscopy and laser fluxmetry. Arthritis Res Ther 7(2):R209–R216. doi:10.1186/ar1459 6. Cakir T, Evcik D, Dundar U, Yigit I, Kavuncu V (2011) Evaluation of sympathetic skin response and F wave in fibromyalgia syndrome patients. Turkish Journal of Rheumatology (Turkish League Against Rheumatism//Turkiye Romatizma Arastirma ve Savas Dernegi) 26(1):6p. doi:10.5606/tjr.2011.006 7. Unlu E, Hamamcioglu K, Odabasi Z, Cakci A, Vural O (2006) Dysautonomia in fibromyalgia syndrome: sympathetic skin responses and RR interval analysis. Rheumatol Int 26(5):5p. doi:10. 1007/s00296-005-0007-1 8. Ulas U, Gurcay E, Tuncay R, Berber S, Cakci A, Odabasi Z (2006) Genital sympathetic skin responses in fibromyalgia syndrome. Rheumatol Int 26(11):6p. doi:10.1007/s00296-006-0131-6 9. Yildiz M, Koklukaya E (2012) The correlation of laboratory tests and sympathetic skin response parameters by using artificial neural
networks in fibromyalgia patients. J Med Syst 36(3):8p. doi:10. 1007/s10916-010-9643-4 10. Yoldas T, Yigiter R, Kaya A, Ardicoglu O (2006) R-R interval variation and sympathetic skin response in fibromyalgia. Arch Med Res 37(5):5p. doi:10.1016/j.arcmed.2005.11.008 11. Salemi S, Aeschlimann A, Wollina U, Gay RE, Michel BA, Gay S, Sprott H (2007) Upregulation of delta-opioid receptors and kappaopioid receptors in the skin of fibromyalgia patients. Arthritis Rheum 56(7):2464–2466. doi:10.1002/art.22735 12. Enestrom S, Bengtsson A, Frodin T (1997) Dermal IgG deposits and increase of mast cells in patients with fibromyalgia—relevant findings or epiphenomena? Scand J Rheumatol 26(4):308–313 13. Cordero MD, Moreno-Fernandez AM, Carmona-Lopez MI, Sanchez-Alcazar JA, Rodriguez AF, Navas P, de Miguel M (2010) Mitochondrial dysfunction in skin biopsies and blood mononuclear cells from two cases of fibromyalgia patients. Clin Biochem 43(13– 14):1174–1176. doi:10.1016/j.clinbiochem.2010.06.013 14. Cordero MD, Diaz-Parrado E, Carrion AM, Alfonsi S, SanchezAlcazar JA, Bullon P, Battino M, de Miguel M (2013) Is inflammation a mitochondrial dysfunction-dependent event in fibromyalgia? Antioxid Redox Signal 18(7):800–807. doi:10.1089/ars.2012.4892 15. Kim DH, Oh D-H, Clauw DJ (2008) Characteristic electron microscopic findings in the skin of patients with fibromyalgia–preliminary study. Clin Rheumatol 27(2):5p. doi:10.1007/s10067-007-0739-2 16. Yalcinkaya EY (2009) Skin problems in fibromyalgia. Nobel Medicus Journal 5(2):3p 17. Granges G, Littlejohn GO (1993) A comparative study of clinical signs in fibromyalgia/fibrositis syndrome, healthy, and exercising subjects. J Rheumatol 20(2):344–351 18. Thune PO (2005) The prevalence of fibromyalgia among patients with psoriasis. Acta Derm Venereol 85(1):33–37. doi:10.1080/ 00015550410001044 19. Grafe A, Wollina U, Tebbe B, Sprott H, Uhlemann C, Hein G (1999) Fibromyalgia in lupus erythematosus. Acta Derm Venereol 79(1):62– 64
BRIEF REPORT
Dermatologic manifestations of fibromyalgia Valerie Laniosz & David A. Wetter & Desiree A. Godar
Received: 23 July 2013 / Revised: 24 December 2013 / Accepted: 5 January 2014 # Clinical Rheumatology 2014
Abstract The aim of this study was to determine the common dermatologic diagnoses and skin-related symptoms in a cohort of patients with fibromyalgia seen in a tertiary referral center. A retrospective chart review was performed of all patients with a fibromyalgia diagnosis from January 1 to December 31, 2008, whose diagnosis was confirmed in the Fibromyalgia and Chronic Fatigue Clinic at Mayo Clinic in Rochester, Minnesota. Charts were reviewed for dermatologic conditions and cutaneous symptoms. Demographic and clinical data were collected to assess the frequency of skin-related issues in patients with fibromyalgia. Of 2,233 patients screened, 845 patients met the inclusion criteria of having a confirmed diagnosis of fibromyalgia. Among these fibromyalgia patients, various dermatologic conditions and cutaneous problems were identified, including hyperhidrosis in 270 (32.0 %), burning sensation of the skin or mucous membranes in 29 (3.4 %), and various unusual cutaneous sensations in 14 (1.7 %). Pruritus without identified cause was noted by 28 patients (3.3 %), with another 16 patients (1.9 %) reporting neurotic excoriations, prurigo nodules, or lichen simplex chronicus. Some form of dermatitis other than neurodermatitis was found in 77 patients (9.1 %). Patients with fibromyalgia may have skin-related symptoms associated with their fibromyalgia. No single dermatologic diagnosis appears to be overrepresented in this population, with the exception of a subjective increase in sweating. Keywords Cutaneous dysesthesia . Dermatology . Fibromyalgia . Hyperhidrosis
V. Laniosz : D. A. Wetter (*) : D. A. Godar Department of Dermatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA e-mail: [email protected]
Introduction Fibromyalgia is not classically thought to be a disease with related cutaneous findings. However, several studies have showed objective differences in the skin of patients with fibromyalgia compared to persons without the disorder. In particular, investigators have demonstrated that patients with fibromyalgia, when compared to control participants, have increased numbers of mast cells and increased mast cell degranulation in the skin [1]; increased inflammatory cytokines in the skin [2]; altered collagen metabolism, with collagen deposition around peripheral nerves [3]; cutaneous microcirculatory abnormalities [4, 5]; autonomic nervous system dysfunction [6–10]; and increased levels of cutaneous opioid receptors [11]. Given these skin alterations, we hypothesized that patients with fibromyalgia had an increased burden of dermatologic disease. Our aim in the present study was to assess for the dermatologic conditions and cutaneous reports of patients with a diagnosis of fibromyalgia confirmed in a tertiary referral center.
Materials and methods The charts of patients who had received the code for a diagnosis of fibromyalgia between January 1 and December 31, 2008 were collected and reviewed so that only patients with a confirmed fibromyalgia diagnosis in the Fibromyalgia and Chronic Fatigue Clinic at Mayo Clinic in Rochester, Minnesota were included in the study. The fibromyalgia diagnosis was confirmed according to the American College of Rheumatology criteria for the diagnosis of fibromyalgia from 1990 to 2010 or from modification to the criteria in 2011. Approval for the study was obtained from the Mayo Clinic Institutional Review Board before initiation of chart review. Patients who had denied research authorization were excluded from the study. Charts were reviewed for basic demographic
Clin Rheumatol
information, including age and sex, along with confirmation of the diagnosis of fibromyalgia, dermatologic diagnoses in the Department of Dermatology and primary care notes, and patient reports of cutaneous problems in the Fibromyalgia and Chronic Fatigue Clinic notes.
Results In 2008, a total of 2,233 patients seen at Mayo Clinic were identified as having fibromyalgia. Among them, 897 patients were seen in the Fibromyalgia and Chronic Fatigue Clinic, with confirmation of the diagnosis of fibromyalgia in 845 patients. The average age of these 845 patients was 48.9 years, with female preponderance of 90.6 % (Table 1). Thirty-two discrete categories of dermatologic diagnoses or cutaneous reports were identified. The only skin-related item of the standard systems review questionnaire at the Fibromyalgia and Chronic Fatigue Clinic was increased sweating, which was reported in nearly a third of the patients with fibromyalgia (32.0 %) (Table 2). Although patients had tender points and many also noted a burning sensation, the burning was related specifically to the skin or oral cavity for 3.4 % of patients. One other patient had a diagnosis of erythromelalgia. In addition to the sensation of cutaneous and mucosal burning, 1.7 % of patients related cutaneous pain or other unusual sensations of the skin. These unusual symptoms from different patients were varied and included such descriptions as the sensation of a “sliver” in the skin with light touch, a feeling that the “nerves are on the outside of the skin,” a feeling that a light touch was like a “slap,” a perception of “boils under the skin,” and an oral discomfort likened to “eating Pop Rocks.” In the dermatologic diagnosis category of pruritus, 3.3 % of patients specifically noted itching, with clinical diagnoses of neurotic excoriations, prurigo nodules, and lichen simplex chronicus in another 1.9 % of patients. Regarding other neurodermatoses, three patients were identified as having acne excoriée and one patient received a diagnosis of trichotillomania.
Table 1 Average, median, and mode of age and sex distribution of 845 patients with fibromyalgia Characteristic
Value
Age, mean, years Age, median (range), years Age, mode, years
48.9 49 (17–84) 51
Sex, no. (%) Female Male
766 (90.7) 79 (9.3)
Most of these conditions or concerns could be grouped. However, ten patients were identified as having “rash, other” (Table 2). Throughout the study period, these patients continued to have only descriptive terminology for their rash, such as “plaque-like rashes on arms and legs with sun exposure,” “facial rash,” “transient migratory rash,” or “pruritic rash not otherwise specified.” In the absence of histopathologic correlation by the patient’s clinician, these patients were not assigned to a more specific category.
Discussion We sought to determine the common dermatologic conditions and cutaneous concerns that would be found in a cohort of Table 2 Number and percentage of patients with fibromyalgia who had various dermatologic diseases and symptoms, listed in order of frequency Condition
Patients affected, no. (%)
Increased sweating Dermatitis excluding neurodermatitis Pruritus Raynaud phenomenon Psoriasis Acne, other Rosacea Burning skin sensation Cutaneous pain/odd sensations Folliculitis Urticarial Burning/painful mouth/tongue Hair loss/telogen effluvium Rash, other Neurodermatitis/excoriations Oral ulcers Cutaneous lupus
270 (32.0) 77 (9.1) 28 (3.3) 22 (2.6) 19 (2.2) 18 (2.1) 18 (2.1) 17 (2.0) 14 (1.7) 14 (1.7) 13 (1.5) 12 (1.4) 12 (1.4) 10 (1.2) 8 (0.9) 7 (0.8) 6 (0.7)
Prurigo nodules Lichen simplex chronicus Lichen planus Vasculitis Acne excoriée Lichen sclerosus Hidradenitis suppurativa Livedo reticularis Systemic sclerosis (limited) Morphea Dermatitis herpetiformis Darier disease Trichotillomania Calcinosis cutis Erythromelalgia
4 (0.5) 4 (0.5) 4 (0.5) 3 (0.4) 3 (0.4) 2 (0.2) 2 (0.2) 2 (0.2) 1 (0.1) 1 (0.1) 1 (0.1) 1 (0.1) 1 (0.1) 1 (0.1) 1 (0.1)
Clin Rheumatol
patients with a fibromyalgia diagnosis who were seen at a tertiary referral center. We hypothesized—on the basis of the literature showing increased levels of mast cells, inflammatory cytokines, opioid receptors, dysfunctional mitochondria, and both structural and functional changes in the skin of fibromyalgia patients—that skin-related concerns, particularly dysesthesias and pruritus, would be overrepresented in this patient population. Findings in the basic science literature In 1 study, skin biopsies of 63 patients with fibromyalgia were compared with 49 age-matched controls. Interestingly, patients with fibromyalgia showed a statistically significant increase in mast cell number compared with the controls (mean per high-power field, 5–14 mast cells vs. 0 or 1 mast cell) [1]. Another study comparing skin biopsy specimens showed not only greater mean mast cell numbers in patients with fibromyalgia, but also increased mast cell degranulation and immunoglobulin G deposits intradermally, which, the authors hypothesized, were suggestive of neurogenic inflammation in fibromyalgia patients [12]. Reverse transcriptase polymerase chain reaction was used to analyze several inflammatory cytokines in skin biopsy specimens from 53 patients with fibromyalgia and showed increases in interleukin 1β, interleukin-6, and tumor necrosis factor-α in approximately a third of test participants. Decreased coenzyme Q10, increased oxidative stress, and dysfunctional mitochondria also have been observed in the skin of patients with fibromyalgia, in addition to increased reactive oxygen species in the blood [13, 14]. Investigators have suggested that structural differences in skin may underlie the pathogenesis of fibromyalgia. A difference in collagen metabolism, with subsequent collagen deposition around peripheral nerves, has been hypothesized to lead to the reduction of pain tolerance in fibromyalgia patients [3]. A blinded electron microscopic analysis of skin biopsies of 13 patients with fibromyalgia compared with 5 matched controls showed ballooning of the unmyelinated Schwann cells in 9 of the 13 test participants—a finding that was not seen in any control biopsy specimen and was correlated to peripheral localization of axons within the unmyelinated Schwann cell sheaths [15]. Evidence has showed reduction in microcirculation and temperature in the skin overlying tender points in fibromyalgia, as well as decreased capillary density in the skin [4, 5]. Autonomic nervous system dysfunction also has been implicated in the pathogenesis of fibromyalgia [6–10]. From electroneuromyography, abnormalities in the sympathetic nervous system have been shown in the skin of patients with fibromyalgia [6]. Finally, when the levels of μ, κ, and δ opioid receptors in the skin of 25 patients with fibromyalgia were compared with controls, κ, and δ opioid receptor levels were an impressive 59.0- and 21.1-fold higher, respectively, than in
controls [11]. Table 3 summarizes data regarding differences in skin biopsy findings of patients who have fibromyalgia compared with patients who do not have the disorder. Findings in previous clinical literature To our knowledge, only one study looked specifically at skin disease in persons with fibromyalgia. This cross-sectional study included 66 fibromyalgia patients and 79 healthy controls who were seen on the same day by a sole dermatologist and identified an increased incidence of xerosis and neurotic excoriations in the patients with fibromyalgia [16]. An earlier study investigating clinical signs in fibromyalgia identified several cutaneous findings, including dermatographism, reticulated hyperpigmentation, hyperalgesia due to pressure, reactive hyperemia of the skin, and Raynaud phenomena [17]. Although no other studies have looked retrospectively at skin disease in patients with fibromyalgia, some studies have analyzed fibromyalgia incidence in both psoriasis and lupus erythematosus. Of 1,269 patients with a new diagnosis of psoriasis over a 3-year study period, 105 (8.3 %) were found to have concomitant fibromyalgia, with more female patients who had both diagnoses than male patients (93 women vs. 12 men) [18]. In a multicenter study of 60 patients with lupus erythematosus, 10 patients were found to have fibromyalgia, with an overrepresentation of systemic lupus erythematosus compared with other types of lupus [19]. Fibromyalgia has been shown to be increased in patients with lupus and psoriasis; yet, we did not observe an increase in these diseases in our cohort of patients with fibromyalgia. It is conceivable that the fibromyalgia symptoms may have been secondary to the lupus symptoms in a portion of these patients. Dermatologic diagnoses and symptoms In the present study, 845 patients with a confirmed diagnosis of fibromyalgia had 32 distinct dermatologic conditions or cutaneous symptoms. The most striking skin-related finding in this cohort was increased sweating, which in most patients was a subjective report noted on the intake form from their visit to the Fibromyalgia and Chronic Fatigue Clinic, rather than a clinical diagnosis of hyperhidrosis confirmed through thermoregulatory testing. Several reasons may explain the number of patients who noted increased sweating. First, the symptomology may be out of proportion to true disease. Second, an objective increase in sweating may occur in patients with fibromyalgia, given the evidence of dysautonomia having a role in fibromyalgia pathogenesis. Regardless, an interesting hypothesis is that a greater number of skin-related symptoms would be elicited from patients with fibromyalgia if these symptoms were listed on a questionnaire given to the patients.
Clin Rheumatol Table 3 Skin biopsy findings of patients with fibromyalgia compared with controls in the literature, listed in order of publication date Authors, year
Fibromyalgia patients, no. Controls, no. Findings in skin biopsy specimens
Beritze et al., 2010 [1] Cordero et al., 2010 [13] Kim et al., 2008 [15] Salemi et al., 2007 [11] Salemi et al., 2003 [2] Jeschonneck et al., 2000 [4] Enestrom et al., 1997 [12]
63 2 13 25 53 20 25
49 2 5 10 10 20 22
Increased mast cells CoQ10 deficiency, mitochondrial dysfunction, increased oxidative stress Peripheral localization of axons within unmyelinated Schwann cell sheaths Increased δ and κ opioid receptor expression Increased interleukin-1β, interleukin-6, and tumor necrosis factor α Vasoconstriction and decreased temperature within tender points Increased mast cell degranulation and intradermal IgG deposits
CoQ10 coenzyme Q10, IgG immunoglobulin G
Many additional skin diseases were identified in the study group of fibromyalgia patients, including dermatitis (n=77), psoriasis (n=19), and acne or rosacea (n=36). It is arguable whether these diagnoses were related in any way to the underlying pathophysiologic factors of fibromyalgia or were a result of the demographic characteristics of the sample population. Consistent with the prior cross-sectional study of skin findings in patients with fibromyalgia [16], we identified a number of patients with neurodermatitis, in addition to several other psychogenic dermatologic diseases, such as trichotillomania and acne excoriée. Neurodermatoses were not the predominant finding in our retrospective review, yet it is interesting to hypothesize whether similar findings could have been identified in our cohort on skin examination. No other additional overrepresentation of any one entity was apparent. However, we identified 44 patients when the sensation of burning and pain of the skin and oral cavity were combined with erythromelalgia. An additional 28 patients were identified who noted pruritus in the absence of an identified cause, with another 16 having a diagnosis of prurigo nodules, lichen simplex chronicus, excoriations, or neurodermatitis. Thus, in a sampling of fibromyalgia patients, one in ten might have cutaneous or mucosal symptoms without an identifiable cause. Although true dermatologic disease can and does exist in patients with a fibromyalgia diagnosis, the present study highlights that, after ruling out skin disease, the cutaneous symptoms of this cohort may be a result of the fibromyalgia itself. Fibromyalgia as the cause of skin and mucosal symptoms should be a diagnosis of exclusion. In some cases, it may be the only plausible explanation. Study limitations and future research The present study was a retrospective chart review, which limits our extraction of cutaneous findings and problems to what information is available in the chart. Additionally, while in some cases, the diagnosis of fibromyalgia may have preceded the evaluation by dermatology, in others it followed. It
is difficult to speculate whether this may have influenced the dermatologist’s assessment of the underlying cause for the cutaneous symptoms, although this is certainly a possibility. The previously published prospective controlled study looking at skin findings in patients with fibromyalgia showed increased dryness of the skin and excoriations, which indicates that differences were seen even in a blinded setting [16]. Furthermore, the study was limited to patients seen in the Fibromyalgia and Chronic Fatigue Clinic for confirmation of a fibromyalgia diagnosis, which may select for more severe cases of fibromyalgia. We acknowledge also that, because of the demographic characteristics of the patients reviewed (i.e., predominantly perimenopausal women), some of the categories of dermatologic diseases and cutaneous problems may have been a result of selection bias. Despite this potential, the present study highlights the relations between fibromyalgia and the skin and opens up many new avenues for research. Another limitation of this study is the lack of age and gendermatched controls with which to compare these various dermatologic diseases and skin-related symptoms. The authors acknowledge that some of the cutaneous findings in the fibromyalgia population may at least in part be represented in a control group and would be an interesting future study. For future study, one of the most exciting avenues involves looking at whether traditional treatments for fibromyalgia, such as antidepressants, analgesics, and antiepileptic agents, may have an effect on cutaneous problems in patients with fibromyalgia. This information would be particularly helpful for patients with cutaneous symptoms in the absence of an identifiable dermatologic diagnosis. In addition, although this study gives a good overview of skin disease in a cohort of patients with fibromyalgia, an age- and sex-matched comparison would be useful. Finally, an interesting exploration would be to investigate how many other patients with fibromyalgia identify cutaneous symptoms when this history is elicited from the patients.
Disclosures None.
Clin Rheumatol
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