Dermatologic Manifestations of Fibromyalgia

Transcription

1 Dermatologic Manifestations of Fibromyalgia David A. Wetter, M.D. Professor of Dermatology, Mayo Clinic American Academy of Dermatology, Annual Meeting, Washington, D.C. F024: Advanced Management of the Dermatologic Manifestations of Connective Tissue Diseases March 1, MFMER

2 Disclosure I have no conflicts of interest 2015 MFMER

3 Patient vignette Overview Background on skin abnormalities in fibromyalgia Mayo Clinic study analyzing the dermatologic manifestations of fibromyalgia at a tertiary referral center Key Presentation Points ( take home messages ) 2015 MFMER

4 Genesis of a research idea Many research ideas begin from a patient encounter (as this idea did) 2. Our trainees (residents, medical students) constantly teach us (while we are simultaneously teaching them) 2015 MFMER

5 Patient Vignette 76-year-old woman with longstanding fibromyalgia Seen in dermatology on several occasions for nearly 2 years of intermittent (non-generalized) skin itching/burning Sometimes associated with rash Skin exam Mild dermatographism Mildly dry skin 2015 MFMER

6 Patient Vignette (continued) Skin biopsy Urticarial tissue reaction (routine microscopy) Direct immunofluorescence (DIF) - negative Normal/negative labs BP 180/230 Indirect immunofluorescence Anti-tissue transglutaminase antibodies 2015 MFMER

7 Patient Vignette (continued) Otherwise in good health, followed regularly by her general internist Treatments for skin Dry skin care Discontinuation of aspirin (only new medication prior to her itching) Topical corticosteroids Topical camphor/menthol Mirtazapine Multiple antihistamines (doxepin, cetirizine, ranitidine, fexofenadine) Gabapentin (prescribed, but patient did not take) 2015 MFMER

8 Daily Itch Score Diary Quantified by Patient as Large, Minimal, None 2015 MFMER

9 But You Need to Listen to Your Patients... On several occasions the patient brought me information from the Internet and asked Do you think my skin itching could be related to my fibromyalgia? My response: That is very interesting, but I am not sure (Sadly, I did not even review the literature despite her astute insight!) 2015 MFMER

10 And You Also Need to Listen to Your Students! Several months later I saw the patient with one of our first-year dermatology residents, and the patient again asked Do you think my skin itching could be related to my fibromyalgia? This time I didn t make the same mistake (but only because I was working with a bright and curious dermatology resident!) The resident asked me: Do you think her itching and fibromyalgia might be related? Should we explore the literature? 2015 MFMER

11 The Culmination of our Inquiry... 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 MFMER

12 Background: Fibromyalgia and Skin Basic Science Literature Fibromyalgia generally not thought to have related dermatologic findings However, skin studies in fibromyalgia patients compared to controls have shown* Increased mast cells and mast cell degranulation in the skin Increased inflammatory cytokines in the skin Collagen deposition around peripheral nerves Cutaneous microcirculatory abnormalities Autonomic nervous system dysfunction Increased cutaneous opioid receptors *Summarized in Laniosz et al: Clin Rheumatol, MFMER

13 Background: Fibromyalgia and Skin Clinical Literature Increased incidence of xerosis and neurotic excoriations in fibromyalgia compared to healthy controls (Yalcinkaya, 2009, Nobel Medicus Journal) Cutaneous findings in fibromyalgia: Dermatographism, reticulated hyperpigmentation, hyperalgesia due to pressure, reactive hyperemia of skin, and Raynaud phenomena (Granges and Littlejohn, 2003, J Rheumatol) Of 1,269 patients with new diagnosis of psoriasis: 105 (8.3%) had fibromyalgia (Thune, 2005, Acta Derm Venereol) Of 60 patients with lupus, 10 had fibromyalgia (16.7%), with an overrepresentation of systemic lupus erythematosus (SLE) (Grafe et al, 1999, Acta Derm Venereol) 2015 MFMER

14 Lupus and Fibromyalgia Patient had generalized discoid lupus and although had 4/11 American College of Rheumatology (ACR) criteria (discoid rash, oral ulcers, photosensitivity, positive ANA), she did not have clinically relevant SLE (per rheumatologic evaluation) Returns to dermatology office with new joint aches and fatigue despite ongoing methotrexate and chloroquine 1. Does she now have SLE? 2. Does she need more aggressive management of her lupus? Repeat rheumatologic evaluation revealed fibromyalgia (not SLE) as cause of her symptoms therefore do NOT need more aggressive treatment of lupus 2015 MFMER

15 What About Other Autoimmune Connective Tissue Diseases? Implication: A patient with clinically-amyopathic dermatomyositis (CADM) presenting with muscle pain, fatigue, and weakness could be falsely diagnosed as having developed active myositis (classic dermatomyositis) rather than having fibromyalgia in association with CADM Such a patient could have his/her dermatomyositis erroneously treated more aggressively with increased immunosuppression 2015 MFMER

16 Our Study Hypothesis Given aforementioned findings in basic science and clinical literature, we hypothesized that Patients with fibromyalgia have an increased burden of dermatologic disease and skin-related concerns 2015 MFMER

17 Inclusion Criteria Our Mayo Clinic Study Retrospective Review Diagnosis of fibromyalgia between January 1 and December 31, 2008 Diagnosis confirmed in the Fibromyalgia and Chronic Fatigue Clinic at Mayo Clinic in Rochester, Minnesota According to American College of Rheumatology (ACR) criteria 1990 criteria (Wolfe et al, 1990, Arthritis Rheum) 2010 preliminary diagnostic criteria (Wolfe et al, 2010, Arthritis Care Res [Hoboken]) 2011 modification of the ACR preliminary diagnostic criteria (Wolfe et al, J Rheumatol, 2011) 2015 MFMER

18 Collected Data Patient demographics Our Mayo Clinic Study Retrospective Review Dermatologic diagnoses in Department of Dermatology and primary care notes Patient reports of cutaneous problems in Fibromyalgia and Chronic Fatigue Clinic notes 2015 MFMER

19 ACR Diagnostic Criteria for Fibromyalgia J Rheumatol 38:1113, MFMER

20 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 270 (32.0) Dermatitis excluding neurodermatitis 77 (9.1) Pruritus 28 (3.3) Raynaud phenomenon 22 (2.6) Psoriasis 19 (2.2) Acne, other 18 (2.1) Rosacea 18 (2.1) Burning skin sensation 17 (2.0) Cutaneous pain/odd sensations 14 (1.7) Folliculitis 14 (1.7) Urticarial 13 (1.5) Burning/painful mouth/tongue 12 (1.4) Hair loss/telogen effluvium 12 (1.4) Rash, other 10 (1.2) Neurodermatitis/excoriations 8 (0.9) Oral ulcers 7 (0.8) Cutaneous lupus 6 (0.7) Prurigo nodules 4 (0.5) Lichen simplex chronicus 4 (0.5) Lichen planus 4 (0.5) Vasculitis 3 (0.4) Acne excoriée 3 (0.4) Lichen sclerosus 2 (0.2) Hidradenitis suppurativa 2 (0.2) Livedo reticularis 2 (0.2) Systemic sclerosis (limited) 1 (0.1) Morphea 1 (0.1) Dermatitis herpetiformis 1 (0.1) Darier disease 1 (0.1) Trichotillomania 1 (0.1) Calcinosis cutis 1 (0.1) Erythromelalgia 1 (0.1) 2015 MFMER

21 Demographics (845 total patients) 766 female (90.7%) Median age, 49 years (range, 17-84) Dermatologic diseases and symptoms [n (%)] Increased sweating 270 (32.0%) Itchy/burning dermatoses 87 (10.4%) Pruritus 28 (3.3) Burning skin sensation 17 (2.0) Cutaneous pain/odd sensations 14 (1.7) Burning/painful mouth/tongue 12 (1.4) Neurodermatitis/excoriations 8 (0.9) Prurigo nodules 4 (0.5) Lichen simplex chronicus 4 (0.5) Erythromelalgia 1 (0.1) 2015 MFMER

22 Other neurodermatoses 4 patients Acne excoriée 3 Trichotillomania 1 Other notable diseases Dermatitis (excluding neurodermatitis) 77 (9.1) Psoriasis 19 (2.2) Urticarial 13 (1.5) Cutaneous lupus 6 (0.7) 2015 MFMER

23 History Intake Questionnaire Mayo Clinic Fibromyalgia and Chronic Fatigue Clinic 1. Would other cutaneous symptoms be elicited in fibromyalgia patients if added to standard questionnaire? 2. CONVERSELY if dermatologists asked all patients with pruritus if there is a history of fibromyalgia, would this provide a more targeted therapy for this subgroup of pruritus patients? 2015 MFMER

24 Brief Thoughts on Clinical Findings Increased sweating 32% of Mayo cohort Autonomic nervous system dysfunction observed in fibromyalgia (Unlu et al, Rheum Int, 2006) could lead to increased sweating May also be a subjective finding due to intake questionnaire (as findings not confirmed on thermoregulatory sweat testing) 2015 MFMER

25 Brief Thoughts on Clinical Findings Itchy/burning dermatoses 10.4% of Mayo cohort Supports previous study showing increased neurotic excoriations in fibromyalgia compared to controls Highlights skin and mucosal symptoms may occur as a result of the fibromyalgia itself Should be a diagnosis of exclusion 2015 MFMER

26 Could some fibromyalgia patients have a small-fiber neuropathy leading to abnormal skin sensations (which in turn could be detected by TST)? Thermoregulatory sweat testing (TST) 2015 MFMER

27 2015 MFMER

28 41% of skin biopsies from fibromyalgia patients (versus 3% from control subjects) were diagnostic for small-fiber polyneuropathy 2015 MFMER

29 Patients may have coexistent autoimmune connective tissue disease (ACTD) (such as Sjögren syndrome or SLE), fibromyalgia, and small fiber neuropathy - autoimmune neuropathic fibromyalgia May respond to treatment with intravenous immunoglobulin (IVIg) 2015 MFMER

30 Skin Itching and Burning in Fibromyalgia Indicative of a Bigger Knowledge Gap in Dermatology? Pruritus was one of 3 areas selected by the American Academy of Dermatology (AAD) as a research gap that needs to be filled 2015 MFMER

31 Chronic pruritus Primary skin lesions with or without chronically scratched lesions present No primary skin lesions; chronically scratched lesions present or absent Dermatologic cause Atopic eczema Psoriasis Xerosis Scabies Contact dermatitis Insect bite Lichen planus Systemic cause Chronic kidney disease Cholestasis Hodgkin s lymphoma Polycythemia vera HIV infection Hyperthyroidism Nondermatologic cause Neuropathic cause Brachioradial pruritus Notalgia paresthetica Postherpetic itch Psychogenic cause Obsessive-compulsive disorder Delusions of parasiotsis Substance abuse Complete blood count and differential count Creatinine level Liver-function test Thyroid-function test Erthrocyte sedimentation rate HIV serologic analysis Chest radiography Drug history Based on Mayo study and other research, should fibromyalgia be added as a neuropathic cause of pruritus? 2015 MFMER

32 Abnormal Skin Findings in Fibromyalgia 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, Increased mast cells Cordero et al, Kim et al, CoQ10 deficiency, mitochondrial dysfunction, increased oxidative stress Peripheral localization of axons within unmyelinated Schwann cell sheaths Salemi et al, Increased interleukin δ and κ opioid receptor expression Salemi et al, Increased interleukin-1β, interleukin-6, and tumor necrosis factor α Jeschonneck et al, Vasoconstriction and decreased temperature within tender points Enestrom et al, Increased mast cell degranulation and intradermal IgG deposits 2015 MFMER

33 Abnormal Skin Findings in Fibromyalgia Skin biopsy findings in fibromyalgia Increased mast cells (Bertize et al, Clin Rheumatol, 2010) Increased mast cell degranulation and IgG intradermal deposits (Enestrom et al, Scand J Rheumatol, 1997) suggestive of neurogenic inflammation Increased cytokines (IL-1β, IL-6, TNF-α) (Salemi et al, J Rheumatol, 2003) Increased oxidative stress and mitochondrial dysfunction (Cordero et al, Clin Biochem, 2010) Ballooning of unmyelinated Schwann cells peripheral localization of axons (Kim et al, Clin Rheumatol, 2008) Increased opioid receptor expression (κ 59.0 higher; δ 21.1 higher) (Salemi et al, Arthritis Rheum, 2007) 2015 MFMER

34 Abnormal Skin Findings in Fibromyalgia Other skin findings in fibromyalgia Collagen deposition around peripheral nerves reduction in pain tolerance (Sprott et al, Z Rheumatol, 1998) Decreased microcirculation and temperature in skin overlying tender points (Jesschonneck et al, Rheumatology [Oxford], 2000) Autonomic nervous system dysfunction (Ulas et al, Rheumatol Int, 2006) 2015 MFMER

35 Melding Basic Science With Clinical Practice in Fibromyalgia... Medication Common dose Side effects Medical condition Comments Anticonvulsants Gabapentin Pregabalin Antidepressants Paroxetine Mirtazapine Amitriptyline 100 to 200 mg orally three times daily 25 to 200 mg orally twice daily 10 to 40 mg orally once daily 7.5 to 15 mg orally once daily 25 to 150 mg once daily or up to 3 divided doses Opioids Mu antagonist Naltrexone, 12.5 to 50 mg orally once daily Kappa agonist and mu antagonist Commonly Used Topical and Systemic Medications for Chronic Pruritus Butorphanol, 1 to 4 mg inhaled at bedtime Drowsiness, constipation, leg swelling Drowsiness, leg swelling Insomnia, dry mouth, sexual dysfunction Drowsiness, dry mouth, increase in appetite, weight gain Drowsiness, dizziness, constipation, dry mouth, blurred vision Nausea and vomiting, abdominal cramps, diarrhea, hepatoticity Drowsiness, dizziness, nausea, vomiting Neuropathic itch (high dose, up to 3600 mg daily); pruritus from chronic kidney disease (low dose, 100 to 300 mg three times a week after dialysis) Generalized pruritus, paraneoplastic itch, psychogenic pruritus Generalized pruritus, nocturnal itch Neuropathic itch Intractable itch, cholestatic pruritus, possibly pruritus from chronic kidney disease Intractable itch Urinary retention, heart palpitations, low blood pressure, confusion in elderly NEJM 368:17, MFMER

36 Melding Basic Science With Clinical Practice in Fibromyalgia... Abnormalities found in skin biopsies of fibromyalgia patients provide rationale for pursuing certain classes of pruritus treatments in those with fibromyalgia AND pruritus or skin dysesthesias Anticonvulsants ( neuropathic itch) Antidepressants Opioid (antagonists) 2015 MFMER

37 Limitations and Future Directions Limitations of Mayo study Retrospective Diagnosis of fibromyalgia occurred after dermatologic evaluation in some patients Only patients seen in Fibromyalgia and Chronic Fatigue Clinic - may have selected for more severe cases of fibromyalgia Lack of age and gender-matched controls 2015 MFMER

38 Limitations and Future Directions Future research avenues Are traditional fibromyalgia treatments (antidepressants: amitriptyline, duloxetine; anticonvulsants: gabapentin, pregabalin; analgesics) helpful for cutaneous problems in fibromyalgia patients? Are other treatments (such as IVIg) better for patients with autoimmune neuropathic fibromyalgia associated with cutaneous dysesthesias/pruritus in setting of ACTD? Age and gender-matched comparison of dermatologic disease in fibromyalgia cohort 2015 MFMER

39 Key Presentation Points Patients with fibromyalgia have a variety of abnormal skin findings compared to controls, including: Increased mast cells and mast cell degranulation; increased inflammatory cytokines; altered collagen deposition around peripheral nerves; microcirculatory abnormalities; autonomic nervous system dysfunction; and increased levels of cutaneous opioid receptors Dermatologic symptoms and findings are common in fibromyalgia patients, including: A subjective increase in sweating, and dermatoses manifesting as itching or burning of the skin 2015 MFMER

40 Key Presentation Points (continued) Cutaneous symptoms can occur directly as a result of fibromyalgia (but this is a diagnosis of exclusion) Fibromyalgia and ACTD may coexist Further studies are needed to determine if traditional fibromyalgia treatments may have a beneficial effect on cutaneous problems in patients with fibromyalgia 2015 MFMER