A 34-year-old woman is referred by her primary physician for musculoskeletal pain and stiffness involving joints and muscles which has been present for approximately 1 year, but has worsened to the point that the patient is frequently missing work over the last 2 months. The patient states that she was previously healthy, taking only oral contraceptives and intermittent medications for migraine headaches before the onset of symptoms. She initially developed pain in her neck and shoulders that she associated with her work in an automobile parts assembly plant. She was told that she had a rotator cuff injury and was treated with physical therapy that worsened her symptoms. She states that the pain began to spread to her arms and back, and she now has marked functional impairment related to the pain. She states she has a very difficult time with function in both morning and evening with “a few good hours” in the middle of the day. Exercise worsens her symptoms. Her symptoms do not respond well to over-the-counter analgesic or anti-inflammatory medications. Her primary care physician has given her a prescription for hydrocodone-acetaminophen, which she states provides minimal relief, but its use is associated with nausea.
Review of symptoms reveals debilitating fatigue that she relates to lack of sleep from pain. She complains of pain in the neck, back, shoulders, elbows, and hips but has not identified joint swelling. She states that she is diffusely stiff. Her headaches have increased in frequency and severity. There are no cardiopulmonary complaints, but the patient has frequent bouts of diarrhea. She denies any additional symptoms of connective tissue diseases, including absence of ocular and mucosal symptoms. She complains of anxiety related to her inability to fulfill her responsibilities at work and at home.
Past medical history reveals G2, P2. She has regular menstrual periods while on oral contraceptives, but reports a diagnosis of endometriosis. She was diagnosed with postpartum depression following the birth of her second child 5 years previously. The patient reports no other chronic medical problems.
Regarding her social history, the patient lives with her husband and sons ages 7 and 5. Daycare for her children is provided through her church, and her older son was recently diagnosed with attention-deficit disorder. Her husband works in construction. The patient works full time. She does not smoke, but her husband smokes 1 pack of cigarettes daily. She consumes alcohol on social occasions, but her husband consumes approximately 3 to 4 glasses of beer every evening.
Family history is significant because her mother was frequently “down” with “arthritis in her back” and thyroid disease. Her father passed away due to myocardial infarction at the age of 58. Her four younger siblings are healthy.
Physical examination reveals a pleasant, anxious woman. Vital signs are normal. Body Mass Index (BMI) is 31. Examination of the head and neck are normal. Cardiopulmonary examination is normal. There is mild abdominal tenderness without rebound and there is no organomegaly. Skin shows no rash and examination of the musculoskeletal system reveals limited range of motion in all planes at the cervical spine, tenderness in the cervical and lumbar paraspinal regions and the trapezius musculature, absence of synovitis, and presence of 16 of 18 tender points for fibromyalgia (FM) ( Fig. 28-1 ). The neurologic examination is normal, including muscle strength testing.
Laboratory evaluation demonstrated a normal complete blood count (CBC) and metabolic profile. Thyroid-stimulating hormone (TSH) was normal. Rheumatoid factor (RF) and antinuclear antibody (ANA) drawn by her primary care physician were negative. There was a slightly elevated C-reactive protein (CRP) of 1.3. Erythrocyte sedimentation rate (ESR) was normal.
Discussion of Differential Diagnosis
The features of the above-mentioned case that are frequently observed in patients with FM include the combination of widespread musculoskeletal pain and stiffness worsened by physical activity, fatigue, and sleep disturbance. A triggering pain generator (rotator cuff injury) is identifiable. The patient has a history of a pain syndrome (migraine) that may also serve as a pain generator, and mood disorder (postpartum depression). She has significant emotional comorbidity (anxiety) associated with her symptoms and the accompanying inability to fulfill roles and responsibilities. There is significant and ongoing psychosocial stress (son with attention-deficit disorder). There is a family history of chronic pain. Physical examination is negative for features of inflammatory arthritis and connective tissue disease, but evidence of widespread allodynia (as detected using the digital tender point examination to detect diffusely lowered mechanical pain threshold) is present. Laboratory testing does not reveal evidence of significant inflammation, autoimmunity, or endocrine disorder.
Although the patient under discussion appears straightforward, a thorough history and physical examination (H&P) of patients with diffuse, chronic myalgias and arthralgias is essential to avoid missing a diagnosis that requires specific treatment and to avoid overuse of laboratory and radiographic tests. Furthermore, inaccuracy in the referring diagnosis is surprisingly frequent. The differential diagnosis is broad ( Table 28-1 ), but narrowing the possibilities can be done relatively easily with a thorough H&P and a few laboratory tests. It is imperative to distinguish between a non-FM primary diagnosis and the presence of FM triggered by an alternate diagnosis ( Table 28-2 ). Patients with Lyme disease who need treatment with antibiotics must be distinguished from patients with post-Lyme FM.
| Inflammatory |
| Polymyalgia rheumatica |
| Inflammatory arthritis: rheumatoid arthritis, spondyloarthritidies |
| Connective tissue diseases |
| Systemic vasculitidies |
| Infectious |
| Hepatitis C |
| Human immunodeficiency virus |
| Lyme disease |
| Parvovirus B19 |
| Epstein-Barr virus |
| Noninflammatory |
| Degenerative joint/spine disease |
| Fibromyalgia |
| Myofascial pain syndromes |
| Metabolic myopathies |
| Endocrine |
| Hypothyroidism or hyperthyroidism |
| Hyperparathyroidism |
| Addison’s disease |
| Neurologic Diseases |
| Multiple sclerosis |
| Neuropathic pain |
| Psychiatric Disease |
| Major depressive disorder |
| Drugs |
| Statins |
| Aromatase inhibitors |
| Musculoskeletal |
| Osteoarthritis and spondylosis |
| Other spinal disorders: Disk disease, spinal stenosis, scoliosis |
| Inflammatory arthritis: Rheumatoid arthritis, spondyloarthritis (psoriatic arthritis, reactive arthritis, ankylosing spondylitis) |
| Connective tissue diseases: Systemic lupus erythematosus, Sjögren’s syndrome, inflammatory myopathies, systemic sclerosis, mixed connective tissue disease |
| Joint hypermobility |
| Injuries/Trauma: whiplash, repetitive strain disorders, bursitis, tendonitis, postsurgical |
| Myofascial pain disorders: Temporomandibular disorders, muscular back pain |
| Neurologic |
| Neuropathies: Post-herpetic neuralgia, diabetic neuropathy, sciatica and other peripheral neuropathies |
| Chronic headache: Migraine, tension |
| Endocrine Disorders Associated with Chronic Pain |
| Hypothyroidism |
| Hyperparathyroidism |
| Visceral Pain Syndromes |
| Irritable bowel syndrome |
| Irritable bladder/interstitial cystitis |
| Chronic pelvic pain disorders: Endometriosis, vulvar vestibulitis |
| Infections Associated with Chronic Musculoskeletal Pain |
| Hepatitis C |
| Lyme disease |
One should initially determine if the patient has an autoimmune inflammatory etiology or not. Patients with more than 6 to 12 months of symptoms typically have a relatively easily identifiable autoimmune inflammatory disorder if it is present. If the patient under consideration were older than 50 years of age, then polymyalgia rheumatica should be considered; a normal ESR and CRP significantly reduces the likelihood of that diagnosis. Rheumatoid arthritis is unlikely in this patient given the absence of synovitis, minimal evidence of systemic inflammation, and negative rheumatoid factor. If the patient’s symptom profile or laboratory tests were more suggestive of rheumatoid arthritis (RA), an anti-CCP antibody and radiographs should be added to the work-up. More difficult to exclude is a seronegative spondyloarthropathy including inflammatory bowel disease–associated reactive arthritis. The patient gives a history of back pain and diarrhea with a slight elevation of CRP, a finding common in individuals with a BMI higher than 30. The symptoms, however, are not typical of inflammatory back pain given the lack of clear morning predominance and worsening (rather than improving) with exercise. Of all the inflammatory disorders, spondyloarthropathies are the most frequently overlooked in patients with fibromyalgia-like symptoms. The clinician should evaluate the patient for presence of ocular inflammation, mucosal ulceration, psoriasis, enthesitis, dactylitis, and inflammatory bowel disease. Early sacroiilitis can be difficult to diagnose and if suspicion for a spondyloarthritis is high, plain films or MRI may be needed.
The patient under consideration does not meet criteria for a systemic connective tissue disorder given lack of connective tissue disease (CTD) symptoms and the negative ANA. In this patient, however, careful evaluation for presence of SICCA complaints should be performed and consideration should be given to evaluating antibodies to SSA and SSB if these symptoms are present. No objective proximal muscle weakness was identified. However, if concern for a primary muscle disease is present, measurement of creatine phosphokinase (CPK) and aldolase should be performed. If the patient did have a positive ANA (low-titer), no further testing or evaluation would be required. A high-titer ANA in this patient should be further evaluated for other autoantibodies that might signal a need for close monitoring for development of a connective tissue disease.
Infectious etiologies that should be considered include Lyme disease, parvovirus B-19, human immunodeficiency virus (HIV), and hepatitis C virus (HCV). Given the relatively high prevalence of HCV, the clinician should inquire into risk factors for HCV and screen when present. Epstein-Barr virus infection can also lead to chronic (> 3 months) symptoms, although other myotropic viruses would be shorter lived.
Noninflammatory conditions include FM, myofascial pain syndromes (a more limited musculoskeletal pain syndrome with significant overlap in symptom domains), and generalized osteoarthritis/spondylosis. Endocrine disorders, particularly hypothyroidism and hyperthyroidism but also including parathyroid and adrenal gland dysfunction, can cause widespread myalgias and arthralgias. Vitamin D deficiency is also associated with these symptoms and questioning the patient about diet and sun exposure followed by screening for at-risk patients is recommended. Patients should be screened for major depressive disorder by query for depressed mood (feeling down, depressed, or hopeless) and anhedonia (little interest or pleasure in activities). Drug-induced myalgias are seen in patients taking statins and aromatase inhibitors among many others, and a careful history should be able to determine a temporal association between onset of symptoms and the offending drug.
A 28-year-old woman with a 4-year history of systemic lupus erythematosus (SLE) presents complaining of a “flare” of her lupus characterized by pain in her shoulders and back with a marked increase in fatigue. She was initially diagnosed following the birth of her first child when she developed a malar rash, alopecia, oral ulcers, Raynaud’s phenomenon, arthritis, and serositis. Laboratory evaluation at that time revealed mild normochronic anemia and leukopenia. Her creatinine and urinalysis were normal. ESR was elevated at 46 mm/hr. Serologic testing revealed a positive fluorescent ANA at a titer of 1:640, positive anti-ds-DNA at 1:80, and positive SSA. Complement levels were normal. The patient was treated with prednisone 20 mg daily and hydroxychloroquine 400 mg daily. She responded quickly to this treatment and prednisone was tapered off over the ensuing 3 months.
Over the next several years, the patient had intermittent exacerbations of her symptoms typified by increasing fatigue, malar rash, arthritis in her elbows, wrists, metacarpophalangeal (MCP), and peripheral interphalangeal (PIP) joints, and oral ulcers. She usually responded to reinstitution of prednisone at doses of 10 to 15 mg. No nephritis, central nervous system disease, severe hematologic manifestations, or vasculitis has been identified. Flares were usually accompanied by elevation of ESR, increased anti-ds-DNA, and mild leukopenia.
At the present time, the patient reports a marked increase in her fatigue and musculoskeletal pain in the shoulders and low back. She states that the symptoms are disrupting her attempt to return to school and would like a prescription for prednisone.
On further questioning, the patient denies swelling in her peripheral joints, although she has had a malar flush and a few recent oral ulcers. On physical examination, the vital signs are normal. The patient does not have a visible rash nor mucosal ulcerations. Joints reveal no swelling, but there is diffuse tenderness of the joints and muscles. There was increased tone of the cervical and lumbar paraspinal musculature and the trapezius muscles. FM tender points were positive in 16 of 18 sites. Neurologic examination is normal including muscle strength testing.
The patient reports that she has recently returned to school to complete her bachelor’s degree in history and plans to go to law school. She is married and her husband is a physician.
Laboratory testing reveals a white blood cell (WBC) count of 3900, unchanged from her last visit. Urinalysis is normal, ESR is 25 mm/h, anti-ds-DNA is 1:10, and complements are normal.
Discussion of Differential Diagnosis
FM is a frequent comorbid condition with autoimmune inflammatory rheumatic diseases. It is thought that the increased incidence relative to the population at large reflects the capacity of these disorders to function as pain generators (see Table 28-2 ), although the possibility of shared genetic vulnerability between autoimmune diseases and FM (through altered function of the hypothalamic-pituitary-adrenal axis, as is postulated for mood disorders, for example) cannot be excluded. The challenge is to distinguish between exacerbation of the underlying autoimmune inflammatory disease and comorbid FM. In general, it is preferable to assure, as best as possible, that the underlying autoimmune or inflammatory disorder is treated before attributing symptoms to FM. However, in cases in which characteristic FM symptoms are present, concomitant therapy may be beneficial. It is also necessary to evaluate the patient for other new disease, particularly including a new autoimmune disease such as thyroid disease.
In the case under discussion, the patient’s clinical manifestations are different from previous flares. She specifically had no signs of arthritis in peripheral joints and rash, and mucosal ulcers were not clinically evident. Laboratory tests were unchanged from her baseline values. It is useful to discuss with the patient the differences between her current symptoms and symptoms of lupus and in this case, it is preferable to treat the patient for FM symptoms without intensifying treatment for SLE.
PRINCIPLES OF TREATMENT
FM has a substantial negative impact on social and occupational function as assessed in a recent qualitative study. Patients reported disrupted relationships with family and friends, social isolation, reduced activities of daily living and leisure activities, avoidance of physical activity, and loss of career or inability to advance in careers or education. This impact should be understood by the clinician and return to function and improved health-related quality of life should be emphasized as the primary treatment goal. Accordingly, it is essential to recognize that multiple symptom domains contribute to the functional deficits experienced by patients with FM. In a recent study designed to determine the relevant symptom domains, patients and clinicians participated in an exercise to achieve group consensus using the Delphi method, a structured process of consensus building via questionnaires together with systematic and controlled opinion feedback. The relevant symptom domains identified included pain, stiffness, fatigue, sleep, cognition, depression, and quality of life. In approaching the treatment of an individual patient with FM, determining the most important symptom domains and functional goals is critical to designing a treatment plan.
In approaching the treatment plan, it is useful to think of the symptoms and their consequences as needing different but complementary approaches ( Fig. 28-2 ). For example, the physiologic alterations that lead to altered pain processing may by amenable to drug treatment, but the decreased activity associated with musculoskeletal pain and postexertional malaise should be approached using nonpharmacologic therapies. In discussing this dual approach to treatment, patients with FM should be engaged as active participants in the treatment program and clearly understand what each treatment is designed to address.
There has been controversy as to whether making a diagnosis of FM or avoiding a diagnostic label is more beneficial to the patient. Studies directly addressing this hypothesis fail to support the assertion that labeling a patient as having FM increases the likelihood of persistent symptoms. Furthermore, absence of a clear diagnosis leads the patient to seek out additional clinicians and treatments, and solidifies maladaptive health behaviors. Recent studies have demonstrated that use of health care resources is decreased significantly following diagnosis of FM, although effective treatment is needed to achieve long-term reductions in the medical costs of FM.
Providing a diagnosis is an essential first step in discussion of an intellectual framework by which the patient may understand his or her symptoms and treatment ( Table 28-3 ). This framework can provide increased control and self-efficacy for the patients that may, in turn, improve self-management of symptoms. Furthermore, there is substantial and growing evidence that physiologic alterations in FM patients can be treated pharmacologically. Explanation of why specific types of treatments are used requires a discussion of the diagnosis and its underpinnings.
| Diagnosis |
| Education |
| Diagnose and treat associated conditions and pain generators |
| Exercise and other physical strategies |
| Cognitive behavioral strategies: sleep hygiene, stress management, pain coping |
| Pharmacologic treatment of syndrome symptoms |
| Treatment of specific symptoms |
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