Current Rheumatology Reviews - Volume 3, Issue 2, 2007

Fibromyalgia (FM) is a syndrome and not a disease. Six million people in the United States have FM and it costs society $14 billion annually in lost productivity. Since patients don't succumb and are rarely hospitalized for FM, its evolution into an entity with a distinct epidemiology, etiopathogenesis, clinical presentation, laboratory abnormalities and therapy has lagged behind other conditions. Further compounding this is been the debate over provenance: should the primary treating physician for FM be in neurology, physical medicine, orthopedics, rheumatology, internal medicine or psychiatry? For example, the American College of Rheumatology (ACR) endorsed an ad hoc committee's preliminary criteria for FM, only to have the organization's president in his national address posit that the syndrome should not be treated by rheumatologists. Further, some practitioners published opinions that “feeling out of sorts” is a nondisease which does not deserve the cachet of even being a syndrome. The individuals who articulated these concerns wrote editorials but never conducted any evidence based studies validating these opinions. While the fibromyalgia dialog has been in full intercourse since the publication of the ACR criteria in 1990, some investigators have been quietly working to craft a biomedical model which embraces its pathophysiologic abnormalities and translationally apply it to the chronic widespread pain and fatigue our FM patients endure. Roland Staud is an outstanding example of a “bench to bedside” Renaissance man. His prescient work elucidated the mechanisms of the “wind up” phenomenon of pain experienced by FM patients in the Melzack/ Wall “gate theory” context. However, he has also able to convey to a lay audience appreciation of the syndrome with his popular work, “Fibromyalgia for Dummies”. Dr. Staud's contribution to this issue of Current Rheumatology Reports represents the most comprehensive and readable compendium published to date on the biomedical model of FM. In his summary, the chief autonomic, hormonal, muscular, local myofascial, neurotransmitter, cytokine, and stress facets of the syndrome are elegantly woven together in a reader friendly presentation which should help crystallize a practitioner's understanding of what FM constitutes. We are proud to be able to offer these insights to you.

In human adults, new blood vessels may form in two ways: via endothelial sprouting from pre-existing endothelial cells/angioblasts (angiogenesis) or via the peripheral recruitment of endothelial progenitor cells (EPCs) (vasculogenesis). EPCs, which have been recently discovered, are a population of bone marrow-derived cells capable of differentiating into mature endothelial cells, and participating in the formation of new blood vessels. The molecular phenotype of EPCs and processes leading to their mobilization from bone marrow and homing to neovascularization sites remain unclear. There is still debate regarding methods for their quantification and isolation. Evidence is growing for vascular involvement in inflammatory rheumatic diseases. Recent studies suggest that EPCs in rheumatoid arthritis are involved in synovial vascularization, and may contribute to the increased cardiovascular morbidity and mortality, known features of this disease. Data available in systemic sclerosis is consistent with the hypothesis that EPCs are recruited during active disease; however, their levels may be depleted as the disease progresses and under chronic ischemic conditions. Other inflammatory disorders have not yet been investigated. EPCs are important in vasculogenesis, and may be involved in other features of inflammatory rheumatic disorders. There are various interesting pathophysiological aspects to these cells, for example as pathogenic actors and/or biomarkers, and which may have therapeutic significance.

Procalcitonin (PCT), the precursor of the hormone calcitonin, is a new parameter of inflammation. This acutephase hormokine seems to be more accurate for differentiating between bacterial infections and viral or non-infective causes of inflammation than other serological markers. PCT, which is induced in invasive bacterial infections, is routinely assayed in some intensive care, surgery, haematological units and emergency rooms to help determine the cause of a systemic inflammatory response syndrome (SIRS). Patients with systemic autoimmune diseases have a higher risk of developing severe systemic bacterial infections due to the disease itself and to the immunosuppressive therapy received. Distinguishing between infection and a disease flare is sometimes difficult. Strategies to reach a precise diagnosis are decisive to establish early, adequate patient management. Studies in febrile patients with systemic autoimmune diseases (systemic lupus erythematosus, antineutrophil cytoplasmic antibody-associated systemic vasculitis, and rheumatoid arthritis) suggest that elevated PCT concentrations offer good sensitivity and specificity for diagnosing systemic bacterial infection. Nevertheless, there is little published information on PCT levels in other autoimmune diseases and inflammatory processes. In this review we summarise the current evidence regarding the pathophysiological basis of systemic PCT production in sepsis and the results from current case series on the response of this peptide to infectious and non-infectious SIRS in systemic autoimmune diseases.

Clinical symptoms of chronic muscle conditions like fibromyalgia (FM), include pain, stiffness, subjective weakness, and muscle fatigue. Pain in FM is usually described as fluctuating and always associated with local or generalized tenderness (hyperalgesia and/or allodynia). This tenderness related to FM pain depends on increased peripheral and/or central nervous system responsiveness to peripheral stimuli which can be either noxious (hyperalgesia) or nonnoxious (allodynia). For example, patients with muscle hyperalgesia will rate painful muscle stimuli higher than normal controls, whereas patients with allodynia may perceive light touch as painful, something that a “normal” individual will never describe as painful. The pathogenesis of such peripheral and/or central nervous system changes in FM is unclear, but peripheral tissue changes, specifically in muscles have been implicated. Indirect evidence from interventions that attenuate tonic peripheral impulse input in patients with FM suggest that overall FM pain is dependent on signals from deep tissues. More importantly, allodynia and hyperalgesia can be improved or abolished by removal of peripheral impulse input. Another potential mechanism for FM pain is central disinhibition. However, this pain mechanism also depends on tonic impulse input even if only inadequately inhibited. Thus a promising approach to understanding FM pain is to determine whether abnormal activity of receptors in deep tissues is fundamental to the development and maintenance of this chronic pain disorder.

Although patellofemoral osteoarthritis is common and a frequent cause of disability, its aetiology remains unknown. Biomechanical factors are believed to be important in the pathogenesis of the disease. Although the patellofemoral joint bears little axial load during normal walking, retropatellar load increases during knee flexion and can exceed three times body-weight during deep knee bends. The combination of large forces being transmitted to relatively incongruent articular surfaces during activities of daily living may explain why patellofemoral osteoarthritis is so common. Other patellofemoral pathologies considered to be biomechanically mediated, such as patellofemoral pain syndrome, may provide clues to helping understand the aetiology of patellofemoral osteoarthritis. For instance, patellofemoral pain syndrome is believed to be primarily due to abnormalities in bony geometry, neuromuscular patterns and tight fibromuscular support, which ultimately contribute toward lateral patella translation, maltracking and pain. Genu valgum has also been implicated as a factor that predates lateral patella pathologies, such as the progression of patellofemoral osteoarthritis. Nevertheless, it remains unclear whether common patellofemoral pathologies that occur in early life, such as subluxation/ dislocation and patellofemoral pain syndrome, are risk factors for degenerative changes, such as patellofemoral osteoarthritis, that occur in later life. This review examines the biomechanical factors associated with patellofemoral joint pathology, using patellofemoral osteoarthritis as a disease paradigm.

Increasing evidence suggests that common musculoskeletal diseases such as osteoporosis (OP), osteoarthritis (OA), and rheumatoid arthritis (RA) are increased in the presence of low vitamin D intake or low serum 25- hydroxyvitamin D (25(OH)D) levels. In addition, individuals with OP, OA, and RA carry an increased risk for falls and fractures, while anti-fall and anti-fracture efficacy of vitamin D has been demonstrated in the general older population. For patients with OA or RA, evidence suggests that maintenance of bone density could slow disease progression, while 25(OH)D and bone density are positively correlated among these individuals. Finally, anti-inflammatory effects of vitamin D have been proposed, which may contribute to decreased joint destruction among individuals with OA or RA. In addition, cardiovascular benefits by vitamin D may provide significant improvement to the care of patients with inflammatory rheumatologic diseases. Given the low cost of vitamin D, its excellent tolerability, combined musculoskeletal- and suggested antiinflammatory/ cardio-vascular benefits, vitamin D supplementation holds a significant public health potential. Thus, based on this review, a general supplementation with vitamin D in patients with OP, OA, and RA may be warranted, especially as a high prevalence of vitamin D deficiency has been documented among these individuals.

Tendinopathy is of distinct interest in rheumatology as it describes a painful tendon disease with local tenderness, swelling and pain associated with sonographic features such as hypoechogenic texture and diameter enlargement. Recent research elucidated microcirculatory changes in tendinopathy using laser Doppler flowmetry. Tendon capillary blood flow is increased at the point of pain correlating to neovascularisation. Tendon oxygen saturation as well as tendon postcapillary venous filling pressures, determined non-invasively using combined Laser Doppler flowmetry and spectrophotometry, can quantify, in real-time, how tendon microcirculation changes over with pathology or in response to therapy. Tendon oxygen saturation can be increased by repetitive, intermittent short-term ice applications; this corresponds to ‘ischemic preconditioning’, a method used to train tissue to sustain ischemic damage. Decreasing tendon oxygenation reflects local acidosis and deteriorating tendon metabolism. Eccentric training, a common therapy for tendinopathy decreases abnormal capillary tendon flow without compromising local tendon oxygenation. Combining an Achilles pneumatic wrap with eccentric training changes tendon microcirculation in a different way than does eccentric training alone; both approaches reduce pain in Achilles tendinopathy. Future research should focus on how novel therapies, such as non-invasive nitroglycerin application, non-invasive laser therapy, and invasive sclerosing therapy, influence vascularisation in tendinopathy.

Low level laser therapy (LLLT) is a promising tool for rheumatic diseases, and a systematic Cochrane review suggests that LLLT could be considered in rheumatoid arthritis management due to positive outcomes for pain and morning stiffness. The possible mechanisms behind LLLT are moving from myth to reality through an increasing number of controlled LLLT trials. A literature search revealed 82 laboratory trials and 11 randomized controlled clinical trials reporting about LLLT effects in inflammatory processes and impaired metabolism of ligament, tendons and muscle. 71 laboratory trials provided positive outcomes for one or more parameters, and 7 clinical trials yielded positive results for reduction PGE2 levels, reduction of edema inflammatory cell infiltration and reduction of ESR levels. In 4 head-to-head comparisons with non-steroidal anti-inflammatory drugs (NSAIDs), there were no significant difference between NSAIDs and LLLT. The observed LLLT effects occurred locally and distinct dose-response patterns and therapeutic windows were found for anti-inflammatory effects (1 to 12 Joules), fibroblast stimulation (0.2 to 4 Joules) and fibroblast inhibition (above 6 Joules). A possible systemic effect cannot be ruled out, but with the application techniques and doses used in the published material, the effect size seem small and of doubtful clinical value. Bearing in mind, that the laboratory trials were performed mainly in rats and mice, clinical use of LLLT should take into account energy loss if depth from skin surface is larger than 2-3 mm and that most of the pathological organ needs to be irradiated. Given the dual possibility of reducing inflammation alongside with the promotion of tissue repair and the superior safety of LLLT over NSAIDs, LLLT can be adopted in the clinical management of rheumatic diseases.

The efficacy of periarticular corticosteroid treatment of the sacroiliac (SI) joint was investigated in patients with chronic low back pain in the region of the SI joint in two double-blind, controlled studies. Twenty consecutive patients with spondylarthropathy (SpA) entered one study and correspondingly the other involved 24 consecutive nonspondylarthropathic patients with chronic pain in the SI joint region. The patients in both studies were randomised to receive a periarticular injection of methylprednisolone and lidocaine or isotonic sodium chloride and lidocaine to one affected SI joint. Clinical assessment at the onset and after the follow-up included the patient's estimation of pain in the SI joint region on a visual analogue scale (VAS) and by a pain index calculated from tenderness and stressing tests on the SI joint. For SpA patients the follow-up was 2 months and for non-spondylarthropatic patients 1 month. At the follow-up examination in both studies the VAS and pain index had improved significantly in patients treated with methylprednisolone compared to those receiving isotonic sodium chloride. These results suggest that periarticular injection of methylprednisolone may be effective in the treatment of pain in the region of the SI joint in this kind of patients.

Systemic lupus erythematosus (SLE) is an inflammatory autoimmune syndrome that may affect most organs in the body. Anti-dsDNA antibodies represent a classification criterion for SLE and are involved in lupus nephritis. Recently, the structures that bind lupus-related nephritogenic autoantibodies in vivo have been characterized by transmission electron microscopy (EM), immune-EM and co-localization immune-EM. By these methods, glomerular in vivo-bound autoantibodies were shown to co-localize with loci for binding of different experimental anti-chromatin antibodies, pointing at glomerular basement membrane-associated nucleosomes as target antigens. Lupus dermatitis has not been investigated in as much detail as lupus nephritis, but data indicate similarities between these two organ manifestations. The presence of granular antibody deposits at the dermo-epidermal junction suggests that the tissue injury is mediated by immune complexes. The deposits may be constituted by nucleosomes or chromatin and antibodies bound to them. The nucleosomes may be released locally or systemically from apoptotic cells; i.e. a process similar to that established for lupus nephritis. In this review we summarize current knowledge on immuno-pathological processes that are central in lupus nephritis, and discuss whether they may be similar to those occurring in lupus dermatitis.

Fibromyalgia syndrome is not a diagnosis in itself, but merely represents a set of classification criteria. It is possible to distinguish between different subgroups. Such a distinction can be made on the basis of psychopathological, clinical and laboratory tests. One subgroup reveals elevated level of different cytokines. The treatment of primary fibromyalgia can be optimized by taking these subgroups into consideration since one group responds better to 5-HT3 receptor antagonists, whereas another benefits more from antidepressants and a third group from psychotherapy. In socalled secondary fibromyalgia, 5-HT3 receptor antagonists may be used in the attempt to manage pain that might still persist after treatment of the primary disease.