implications for diagnosis and management

  Robert Bennett MD 

It is increasingly evident that fibromyalgia is a common accompaniment of lupus. In North America fibromyalgia is amongst the 3 most frequent diagnoses made by rheumatologists (1,2). Many physicians feel uncomfortable with this diagnosis as there are no confirmatory investigations and current treatment is not very effective (3). Even when the diagnosis is correctly considered, physicians may search for some alternative (and more acceptable) explanation. If an abnormal test is found, it may be seized upon with an unrestrained zeal. Often this abnormal test is a weakly positive antinuclear antibody test (ANA) and the patient is told she/he may have lupus. Even when it is apparent that the diagnosis of SLE is incorrect, the patient is often reluctant to abandon this diagnosis. Two common clinical situations are seen in relation to these issues: (i) fibromyalgia in a lupus patient may be missed or denied, and (ii) fibromyalgia may be misdiagnosed as lupus.

The association of SLE and Fibromyalgia

Lupus patients often have a concurrent fibromyalgia syndrome. Wallace reported a 22% prevalence in 464 lupus patients (4), Middleton reported a 22% prevalence of fibromyalgia meeting the ACR criteria with another 23% having probable fibromyalgia (5), and Morand reported a 25% prevalence of fibromyalgia in a cohort of 87 lupus patients (6). The latter authors noted that having concurrent fibromyalgia interfered with the rating of lupus activity using the SLAM assessment questionnaire. Middleton's report noted that lupus patients with fibromyalgia were much more likely to have the following symptoms compared to lupus patients without fibromyalgia: widespread pain, myalgias, non-restorative sleep, depression, abdominal pain/bloating, dysmenorrhea and sensitivity to light and noise. Furthermore the fibromyalgia group were less likely to be able to perform daily activities or be employed. Interestingly lupus activity was the same in the two groups (using SLAM) after the data were corrected for subjective fibromyalgia symptoms. Wysenbeek evaluated 77 lupus patients using factor analysis to identify distinctive subgroups (7). Six factors accounted for 64% of the variance. They were, in descending order of the percentage of the total variance attributed to each feature: (i) skin disease, (ii) renal involvement, (iii) thrombotic disease, (iv) lymphopenia, (v) fibromyalgia and (vi) abnormal serology. The individual components of the fibromyalgia group were: myalgias, arthralgias, muscle tenderness, headaches and nervousness.

These studies indicate that fibromyalgia is a common accompaniment of lupus and has a considerable impact on morbidity. Lupus is not alone in having an association with fibromyalgia; about 25% of patients with rheumatoid arthritis (8) and about 50% of Sjogren's have been reported to have concurrent fibromyalgia (9). In some patients with mild primary Sjogren's syndrome fibromyalgia may be the presenting problem (10).

Misdiagnosis of SLE

Wallace has noted (4): "the implications of telling a patient that he or she has lupus are tremendous. In addition to the emotional and psychological effects, receiving a diagnosis of lupus opens up new worlds of powerful and expensive medications, influences career planning and family life -- and makes it difficult to obtain health, life or disability insurance."

An interesting study from the University of Alabama analyzed 230 patients being followed for a presumptive diagnosis of lupus (11). It turned out that only 39% fulfilled the 1982 ACR criteria for lupus. The remaining 61% were readily divisible into 3 groups; (i) 16% had probable SLE (classical organ involvement but not fulfilling = 4 criteria), (ii) 26% had fibromyalgia and (iii) 58% could not be classified or had cutaneous lupus (n=8) or a non-lupus anti-phospholipid antibody syndrome (n=3). The fibromyalgia group had predominantly arthralgias/myalgias, self reported skin problems, fatigue and a positive ANA. This was a different clinical profile from the definite and probable lupus groups who most often presented with clinically evident arthritis, serositis, renal disease and observable skin findings.

There are 2 major reasons for mistaking fibromyalgia for lupus.

(i) Fibromyalgia patients have a high prevalence of lupus like symptoms (12,13). All have musculoskeletal pain, which in about 25% of fibromyalgia patients has a peripheral distribution (14), and is often described as coming from their joints (13). However fibromyalgia patients are negative on radioactive joint scans (15). About 40% of fibromyalgia patients have cold induced vasospasm (16), but this is not due to digital vessel pathology as is seen in secondary Raynaud's (17). Some fibromyalgia patients have IgG deposits at the dermal-epidermal junction (18). However this finding can be differentiated from a classical lupus band test by the absence of other immunoglobulins and complement components (19). Sicca symptoms are very common in fibromyalgia patients (13,20); this appears to be a primary feature in many, but may also be due to anticholinergic medications (e.g. tricyclic antidepressants). It may also be a clue to an association with primary Sjogren's syndrome (10). One study has noted a 50% prevalence of fibromyalgia in patients with primary Sjogren's syndrome (9). Cognitive dysfunction and fatigue are common complaints in both conditions (13,21); the extent to which a concurrent fibromyalgia contributes to these symptoms in lupus has not been evaluated.

2. Fibromyalgia is not a popular diagnosis with many physicians; they therefore seek an alternative diagnosis. Repeated ANA testing may eventually disclose a weakly positive ANA. It should be stressed that several careful studies have not found an increased prevalence of positive ANAs in fibromyalgia patients (22,23). Wallace describes 44 patients seen over a 3 month period for a "rule out lupus" consultation (4). All patients had tested ANA positive on at least one occasion. After retesting, using multiple substrates, 20% had a true negative ANA. At 6 month follow-up the diagnoses were: lupus - 43%, fibromyalgia - 32%, RA - 9%, myasthenia gravis - 2% and 15% were undiagnosed. Another potential cause for misdiagnosis is the association of fibromyalgia with infections. Three infectious diseases have been linked to the development of fibromyalgia; all may develop clinical and serological features suggesting a diagnosis of lupus. They are hepatitis-C (24,25), HIV (26,27), and Lyme disease (28,29). All three have increased immune reactivity with a tendency to auto-antibody production (25,30,31). Hepatitis-C in particular may develop a low grade synovitis and an associated Sjogren's syndrome (32). Thus patients with these infections and concurrent fibromyalgia may be misdiagnosed as having lupus.

One might wonder whether the ANA positive fibromyalgia patients will develop lupus at some later date? Long term follow up studies of fibromyalgia patients have never shown an increased predilection for the development of any another rheumatic disorder (33-35). It is obviously important not to misdiagnose lupus in fibromyalgia patients, as its treatment with steroids and cytotoxic drugs puts patients at an increased risk for iatrogenic disease. Steroid withdrawal may mimic fibromyalgia symptoms (36) and make fibromyalgia worse. One controlled study of steroids in fibromyalgia showed no therapeutic efficacy (37). Although there are currently no effective medications for treating fibromyalgia patients, a conservative approach stressing life-style modification and gentle exercise is very different that the usual approach to treating lupus (38,39)

Consequences of having fibromyalgia and lupus

The development of fibromyalgia in a lupus patient will complicate the differential diagnosis of new symptoms and make effective treatment more difficult. Fibromyalgia is more than a muscle pain syndrome, as most patients have an array of other somatic complaints (12) which adversely impact their quality of life (40). Nearly all fibromyalgia patients have severe fatigue, poor sleep, and post-exertional pain (13). Other symptoms include: tension type headaches, cold intolerance, sicca symptoms, unexplained bruising, fluid retention, chest pain, jaw pain, dyspnea, dizziness, abdominal pain, paresthesiae, and low grade depression and anxiety (20,41-47). Some symptoms relate to specific syndromes whose prevalence appears to be increased; these include: irritable bowel syndrome, migraine, premenstrual syndrome, Raynaud’s, female urethral syndrome, and restless leg syndrome (17,48-53). The restless leg syndrome, which occurs in about 60% of fibromyalgia patients, has prominent symptoms of paresthesiae that may easily be mistaken for a neuropathic process.

These problems often impact a patient’s ability to lead a normal life. Muscular pain and fatiguability influence motor performance. Henriksson, et al, have noted that every-day activities take longer in fibromyalgia patients, they need more time to get started in the morning and often require extra rest periods during the day (54). They have difficulty with repetitive sustained motor tasks, unless frequent time-outs are taken. Tasks may be well tolerated for short periods of time, but when carried out for prolonged periods become aggravating factors (55). Activities such as prolonged sitting or standing and environmental stressors such as coldness, excessive noise and rigid time/performance expectations (55,56) often aggravate fibromyalgia symptoms. Lastly fibromyalgia patients describe a diurnal variation in energy level and alertness that is different from healthy individuals.(57). They describe a "window of opportunity" for constructive work that typically extends from about 10 am to 2 p.m. The net result of having fibromyalgia, especially when added to the burden of having lupus, may render individuals non-competitive in the work force and adversely impact their marital and social interactions.  

The fibromyalgia process

Fibromyalgia is a readily recognized syndrome, but cannot currently be regarded as a distinctive disease -- in the sense of having a uniform pathophysiogical basis. It is better conceived of as a "spectrum" disorder (58,59) that occurs in some patients as a continuing process of neurophysiological and psychological changes. Recent epidemiological studies from the UK and the USA indicate that fibromyalgia is at one end of the spectrum of chronic pain. Croft et al in the U.K. found widespread pain in 13% and regional pain in 43% of all responders to a postal survey (60) . When subjects with widespread pain were examined, 81.5% had 11 or more tender points and 14.7% had no tender points. Wolfe et al in Wichita U.S.A., found that a history of widespread musculoskeletal pain increased progressively from ages 18 to 70 -- with a 23% prevalence in the seventh decade (61). The overall (M+F) prevalence of fibromyalgia in the total Wichita population was 2%, with a prevalence of 3.4% in women and 0.5% in men. These findings suggest that fibromyalgia is at one end of a continuous spectrum of chronic pain that extends from well tolerated regional pain syndromes to distressing total body pain experiences. An increased understanding of chronic pain mechanisms, at a basic level, has provided some insights into the "fibromyalgia process".

The cardinal symptom of fibromyalgia is widespread body pain (13). The cardinal finding is the presence of focal areas of hyperalgesia, the tender points (13). Tender points imply that the patient has a local area of reduced pain threshold – suggesting a peripheral pathology (62). In general tender points occur at muscle tendon junctions, a site where mechanical forces are most likely to cause micro-injuries (63). Many, but not all fibromyalgia patients, have tender skin and a overall reduction in pain threshold (64). These latter observations suggest that some fibromyalgia patients have a generalized pain amplification state. An objective demonstration that fibromyalgia patients have a generalized increase in pain sensitivity has been provided by somatosensory evoked action potential studies. Gibson et al reported an increased nociceptive evoked EEG somatosensory response in 10 fibromyalgia patients compared to 10 matched controls following CO₂ laser stimulation of the skin (65). Lorenz et al reported an increased amplitude of the N170 brain somatosensory potential evoked by laser stimulation of the skin in fibromyalgia patients compared to controls (66). Furthermore they observed a spreading of the brain impulse to the other side of the cerebral cortex – in controls the somatosensory potential was strictly localized to the side of the brain opposite the stimulus. These 2 studies provide objective evidence that fibromyalgia patients experience an enhanced pain response to a given stimulus. This is usually referred to as hyperalgesia. Hyperalgesia is the fundamental symptom of the fibromyalgia syndrome. Its pathogenesis is now understood to involve long lasting changes in the central nervous system referred to as "neural plasticity" (67-69). A crucial concept in understanding neural plasticity is that the same intensity of pain stimulus will not always elicit the same degree of nerve stimulation and hence the same subjective experience of pain. In other words the nervous system is not "hard wired".

The first demonstration of neural plasticity was in 1965 (70). Mendell and Wall noted that repeated stimulation of a peripheral nerve at sufficient intensity to activate C-fibers led to a progressive build up of the amplitude of the electrical response recorded in the second order dorsal horn neurons of the spinal cord. They termed this phenomenon "wind-up". It is now appreciated that the phenomenon of wind-up is crucial to understanding the problem of chronic pain. Wind-up is one cause of increased pain susceptibility called "central sensitization". It is now thought that central sensitization is an important mechanism in the pain experience of fibromyalgia patients.
 --- see table 1. 

Furthermore the biochemical basis for this phenomenon is now known to be a result of activated NMDA receptors (N-methyl D-aspartate) (68). Synergism between substance P and NMDA receptors play a major role in the perpetuation of secondary hyperalgesia (71). The finding of a threefold increase in cerebrospinal fluid levels of substance-P in fibromyalgia patients is probably an indirect reflection of these central events (72). A recent study from Sweden provided evidence that activation of NMDA receptors is relevant to pain in fibromyalgia patients. Sorensen et al reported that intravenous ketamine (an NMDA receptor antagonist) attenuates pain and pain threshold, as well as improving muscle endurance in fibromyalgia patients (73). Pain related functional CNS changes can now be demonstrated by imaging techniques. Mountz et al reported that fibromyalgia patients, characterized by low pain thresholds, had a decreased regional cerebral flow compared to healthy controls (74). The decreased perfusion was particularly prominent in the thalamic and caudate nuclei (structures involved in the processing of nociceptive stimuli).

Most fibromyalgia patients have varying degrees of psychological distress associated with their condition (47,75-81). Whereas lifetime psychiatric disorders are more prevalent in fibromyalgia patients than fibromyalgia non-patients, they are not intrinsically related to the pathophysiology of the fibromyalgia syndrome. Rather, psychological distress in fibromyalgia patients appears to be mainly a result of symptom severity (78,82).

The International Association for the Study of Pain (IASP) defines pain as follows (83): 

"Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage". One component of pain is a reflex avoidance behavior that can occur before the conscious appreciation of pain, this accounts for the wince or grimace elicited by fibromyalgia tender point examination.. In terms of brain physiology this implies that more primitive parts of the brain are being activated (i.e. the areas below the cerebral cortex). These sub-cortical areas of the brain contain several discrete nuclei (e.g. the thalamus, cingulate gyrus, hippocampus, amygdyala, locus coerulus) which interact to form a functional unit called the limbic system. This is the part of the brain that subserve many reflex phenomenon, including the association of sensory input with specific mood states (e.g. sexual pleasure, migraine displeasure etc.). These subcortical areas of the brain show increased activity in chronic pain states (84). These facts form the psychophysiological basis for understanding the emotional aspect of pain.

Many fibromyalgia patients are reluctant to consider the psychological component of pain as in the past they had been led to believe that the pain was all in their head – i.e. the pain was purely psychological in nature. Some health care professionals still convey this impression. However pain is both a sensory and an emotional experience (83). To consider just the sensory component is equally as wrong as to focus entirely on the psychological component. The emotional component of pain is multifactorial and includes past experiences, genetic factors, general state of health, the presence of depression and other psychological diagnoses, coping mechanisms, and beliefs and fears surrounding the pain diagnosis. The unsettling realization that pain may well be life-long generates a varied mix of emotions and behaviors that are often counterproductive to coping with a chronic problem. An improvement in the behavioral consequences of having continuous pain can often be attained by modifying how the patient interprets their pain – this is the underlying principle of cognitive-behavioral therapy (39,85-89). Mastering these concepts will present a new challenge to some physicians who care for lupus patients.  

Conclusions

The development of fibromyalgia in a lupus patient complicates the clinical picture and treatment decisions several fold. Some physicians are reluctant to make a diagnosis of fibromyalgia as they view with suspicion any symptoms that do not conform to the classical "biomedical model" of disease (90). However, the increasing recognition that fibromyalgia is at one end of a spectrum of central neurophysiological changes and psychological distress, should provide a more rational basis for understanding these patients.