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An obese 30-year-old African-American woman presents at a rheumatology clinic with muscle pain and tenderness to touch throughout her body. The patient, a mechanical engineer, has been referred by her primary care physician for a second assessment of diffuse myalgia accompanied by elevated inflammatory markers. She has a long and complex medical history.

She has a body-mass index of 41, and does not smoke or drink alcohol. She says that she has muscle pain all over her body, but that her joints are not painful. She also reports extreme fatigue.

Her medical history is marked by conditions often associated with obesity, including high blood pressure, acid reflux, and untreated sleep apnea. She says that she also suffers from migraine headaches and has a history of asthma.

She reports that she has not had any fever, rash, bowel symptoms, claudication, or giant cell arteritis symptoms. Regarding family history, she notes that her younger sister developed complex regional pain syndrome following foot surgery.

At the time of her evaluation, she has been tapered off the latest of several courses of prednisone for 3 weeks. She reports increasing aches.

Patient's 1-Year Medical History

She explains that her symptoms emerged about a year previously, when she suddenly began to have trouble swallowing. At the same time, she developed sore tender muscles and sensitive lymph nodes in her neck.

She received treatment from her family physician with antibiotics (for unknown reasons) and a tapered course of prednisone, after which she said she felt much better while receiving treatment.

However, her sore muscles returned when the prednisone was discontinued. Treatment was reinstated at an average dose of 25–35 mg daily for about 3 months, while she waited to be assessed by a rheumatologist. Her muscle symptoms became more widespread during this time.

The rheumatologist performed an extensive autoimmune workup, which yielded negative results except for an erythrocyte sedimentation rate (ESR) of 100 mm/h (normal <29) and C-reactive protein (CRP) level of 35 mg/L (normal is less than 8.0 mg/L). A magnetic resonance imaging scan of her neck showed early signs of degenerative disk disease.

Polymyalgia rheumatica (PMR) was suspected as a cause of the symptoms. Because she required a minimum prednisone dose of 20 mg daily to maintain function (higher doses further relieved but did not resolve the symptoms), she was prescribed methotrexate to allow tapering.

A computed tomography (CT) scan of the chest, abdomen, and pelvis for potential malignancy was reportedly negative. She was referred to a neurologist due to orthostatic symptoms, but evaluations, including tilt-table testing, were all negative. As a result of the steroid treatment during this period, she developed hypertension, diabetes, and peripheral edema. She also gained 30 pounds.

Back at the Clinic

Clinical examination to provide a second opinion revealed a Cushingoid female with diffuse areas of tenderness to touch. Her joints were free of synovitis, with full range of motion. She was able to rise from a seated position without difficulty and had normal muscle strength. Peripheral pulses were strong and symmetrical.

Results of extensive autoimmune testing, including a MyoMarker panel and serum protein electrophoresis were negative. The patient's ESR was 53 mm/h (normal is less than 20 mm/h), and CRP was 27 mg/L (normal is less than 8 mg/L).

Her clinicians ordered further evaluations while she was not taking immunosuppressive therapy. Neurological examination ruled out underlying muscle disease. Findings of electromyography of the left upper extremity were also unremarkable, and there was no evidence of inflammation or malignancy on a positron emission tomography (PET)/CT scan.

The patient's original clinicians diagnosed her with fibromyalgia. Immunosuppressive treatment with methotrexate was discontinued, and she was advised not to resume the prednisone.

The clinicians also instructed her about how to manage fibromyalgia and recommended treatment of her sleep apnea, as well as muscle relaxants, dietary modifications, and physical activity.

Several weeks later, she reported that her symptoms improved somewhat and that she is no longer taking immunosuppressive agents. Her inflammatory markers continue to be variably elevated.

Discussion

Clinicians reporting this ¹ of an initial misdiagnosis of fibromyalgia note that it highlights the confounding influence of obesity-related elevation of CRP/ESR on medical decision-making.

The authors emphasize the importance of understanding the association between obesity (which affects an estimated 40% of the U.S. population²) and elevated CRP and ESR, and being aware that obese patients with fibromyalgia may present with elevated inflammatory markers. However, before identifying obese patients with elevated inflammatory markers as having fibromyalgia -- which affects an estimated 2-4% of the general population³ -- an appropriate clinical workup should be pursued to exclude other conditions, the authors stated.

Key factors that help differentiate PMR and fibromyalgia include age of onset and race, as well as symptomatology, inflammatory markers, and response to prednisone.

PMR is diagnosed almost exclusively in patients over age 50, with an annual incidence of up to 50/100,000 population, peaking at above age 70.⁴ The case authors note that age above 50 is a required criterion for PMR classification.⁵ However, PMR has been reported occasionally in 40-year-old patients, as confirmed by PET imaging,⁶ which has good diagnostic accuracy for PMR, the authors stated.⁷

PMR often affects people of northern European ancestry -- more females than males -- and is very rare in African-Americans.⁸ In addition, PMR pain and stiffness primarily affects the shoulder and hip girdles, and the condition is marked by significant elevations in inflammatory markers such as CRP and ESR.

These all differ from fibromyalgia, which can occur in people of any race and at any age, although it tends to be most common in women from age 20 through 55.

Fibromyalgia is characterized by chronic widespread musculoskeletal pain, often accompanied by fatigue; some patients with fibromyalgia have concomitant cognitive disturbance, psychiatric symptoms, and a variety of somatic symptoms.

The primary clinical sign of fibromyalgia is muscle tenderness. Synovitis is not a feature, and steroids are not effective in management.⁹ In patients who present with chronic muscle pain and stiffness, fibromyalgia may be diagnosed after exclusion of conditions such as spondyloarthritis, systemic autoimmune disorders, polymyalgia rheumatica, inflammatory myopathy, and hypothyroidism.

Unlike typical fibromyalgia patients, those with PMR also respond quickly to low-dose glucocorticoids -- specifically, a 75% improvement in clinical and laboratory parameters within 7 days of treatment with 15 mg of prednisone equivalent.¹⁰

The case report authors also described atypical PMR, which may be a manifestation of occult malignancy,¹¹ and note that these patients should be investigated for disseminated cancer, connective tissue disease, or other vasculitic disorders.¹²

Characteristics of atypical PMR include the following:

• Onset before age 50

• No prolonged morning stiffness

• Involvement limited to one site

• ESR less than 40 mm/h or greater than 100 mm/h

• Peripheral arthritis

• Asymmetric involvement at atypical sites

• Partial or delayed response to steroids¹²

Potential misreading of diagnostic clues for PMR in this case include that the patient was under age 50, African-American, had diffuse muscle pain as opposed to shoulder and hip girdle stiffness and pain, and had a poor response (with significant adverse effects) to extended prednisone treatment. Elevated CRP and ESR served as red herrings leading to an initial misdiagnosis in this patient's case, the authors stated.

Although the classic teaching is that CRP and ESR are not elevated in fibromyalgia, the authors said that they reported this case to highlight the potential for elevations of these inflammatory markers in a subset of patients with obesity and fibromyalgia, which are both very common.

The patient's initial response to prednisone is puzzling, and might be attributed in part to the placebo effect, the authors stated, adding that the potential role of steroids in the management of pain in fibromyalgia patients with obesity-related inflammation needs to be clarified.

Obesity has been ¹³ to elevated inflammatory markers.¹⁴ In particular, abdominal adipose tissue is a major source of cytokines, including tumor necrosis factor-alpha and interleukin-6, which result in increased production of hepatic CRP.¹⁵

In addition, the case report authors wrote, inflammatory foci have been found in the skin of a subset of fibromyalgia patients and have been proposed as a theoretical explanation of the response to non-steroidal anti-inflammatory drugs noted in some fibromyalgia patients.¹⁶

Given the increasing evidence that obesity is characterized by chronic and low-grade systemic inflammatory response, and the between CRP and obesity and comorbidity reported in fibromyalgia patients,¹⁷ inflammatory fibromyalgia remains an open area for further research, the authors concluded.

References

1. Cheema R, et al "Myalgia with Elevated Inflammatory Markers in an Obese Young Female: Fibromyalgia or Polymyalgia Rheumatica?" Am J Case Rep 2019; 20: 659-663.

2. Hales CM, et al "Trends in obesity and severe obesity prevalence in U.S. youth and adults by sex and age, 2007–2008 to 2015– 2016" JAMA 2018; 319(16): 1723-1725.

3. Queiroz LP "Worldwide epidemiology of fibromyalgia" Curr Pain Headache Rep 2013; 17(8): 356.

4. Salvarani C, et al "Epidemiology of polymyalgia rheumatica in Olmsted County, Minnesota, 1970–1991" Arthritis Rheum 1995; 38(3): 369-373.

5. Dasgupta B, et al "2012 provisional classification criteria for polymyalgia rheumatica: A European League Against Rheumatism/American College of Rheumatology collaborative initiative" Ann Rheum Dis 2012; 71(4): 484-492.

6. Park J, Sung DH "Early onset polymyalgia rheumatica: Two rare cases under age of 50" Skeletal Radiol 2017; 46(6): 837-840.

7. Kubota K, et al "Clinical value of FDG-PET/CT for the evaluation of rheumatic diseases: Rheumatoid arthritis, polymyalgia rheumatica, and relapsing polychondritis" Semin Nucl Med 2017; 47(4): 408-424.

8. Raheel S, et al "Epidemiology of polymyalgia rheumatica 2000–2014 and examination of incidence and survival trends over 45 years: A population-based study" Arthritis Care Res (Hoboken) 2017; 69(8): 1282-1285.

9. Clark S, et al "A double blind crossover trial of prednisone versus placebo in the treatment of fibrositis" J Rheumatol 1985; 12(5): 980-983.

10. Salvarani C, et al "Epidemiology of polymyalgia rheumatica in Olmsted County, Minnesota, 1970–1991" Arthritis Rheum 1995; 38(3): 369-373.

11. Al-Kaabi J, et al "Non-hodgkin lymphoma mimicking polymyalgia rheumatica in a young patient" Oman Med J 2008; 23(3): 189-191.

12. Naschitz JE "Rheumatic syndromes: Clues to occult neoplasia" Curr Opin Rheumatol 2001; 13(1): 62–66.

13. George MD, et al "Impact of obesity and adiposity on inflammatory markers in patients with rheumatoid arthritis" Arthritis Care Res (Hoboken) 2017; 69(12): 1789-1798.

14. Choi J, et al "Obesity and C-reactive protein in various populations: A systematic review and meta-analysis" Obes Rev 2013; 14(3): 232-244.

15. Saijo Y, et al "Relationship between C-reactive protein and visceral adipose tissue in healthy Japanese subjects" Diabetes Obes Metab 2004; 6(4): 249-258.

16. Salemi S, et al "Detection of interleukin 1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha in skin of patients with fibromyalgia" J Rheumatol 2003; 30(1): 146-150.

17. Feinberg T, et al "Potential mediators between fibromyalgia and C-reactive protein: Results from a Large U.S. Community Survey" BMC Musculoskelet Disord 2017; 18(1): 294.

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