Basic science for the clinician 59: polymorphonuclear cells: mechanisms in human defense and in the pathogenesis of autoimmune disease.

When I learned about polymorphonuclear neutrophils (PMNs) in medical school, they were presented as pretty much 1-trick ponies: PMNs were phagocytes with no intrinsic specificity; their only specificity was supplied by the Fcγ receptors on their surfaces and that would then be the specificity of the bound immunoglobulin G, nothing intrinsic to the PMN. My, how simple life was in those days! And how wrong! Turns out, these circulating cells are involved in bridging the innate immune system and the acquired immune response in some very interesting ways and may play a crucial role in the immunopathogenesis of some of "our" diseases. Polymorphonuclear neutrophils are often underappreciated as drivers of inflammatory diseases, which is why I think it is time for us to turn our attention to this underappreciated component of the immune response.

Basic science for the clinician 57: transforming growth factor ß.

As is so often the case, a molecule gets named for its first identified activity or apparent role and then that initial name sticks, even as new and perhaps fundamentally different activities emerge from later studies. It is the special power of evolution that takes a certain activity and then uses it over and over again in pursuit of apparently disparate goals in a maturing or mature organism. In general terms, transforming growth factor ß (TGF-ß) is intimately involved in a variety of differentiation and growth inhibition processes, in apoptosis, and in deposition of the extracellular matrix. Initially identified in its role in oncogenesis, TGF-ß is now implicated in a number of vascular and rheumatologic disorders, perhaps most notably the scleroderma. TGF-ß has been identified as a powerful influence in angiogenesis, wound healing, joint inflammation, tumor growth and metastasis, and, of course, immunoregulation. So "what is in a name?" A rose by any other name would smell as sweet and would still be immunologically active, even if the name is "misleading."

Basic science for the clinician 54: CD5.

The full story of what surface markers mean about the cells on which they reside twists and turns as the days go by, with previously accepted "truth" changing in light of new findings. Such is the case with CD5, a surface marker on most murine T cells, many thymocytes, and a subset of B cells. The precise role of CD5 in the murine and human immune responses has been a matter of intense speculation for many years. Recent work suggests that CD5 may have a fine-tuning or suppressive effect on signaling through the antigen receptors on both B and T cells. These CD5 B cells were initially thought to be a major source of autoantibodies and/or "natural antibodies," targeting broad arrays of carbohydrate and protein antigens. More recent studies support the latter contention-CD5 B cells do produce "natural antibodies," but the former is far from true-CD5 B cells are not the major source of autoantibodies. In fact, CD5 may be a major negative influence on antigen receptor driven-B-cell function and may serve to control autoimmunity rather than encourage it. Furthermore, another subset of CD5 B cells may represent a distinct regulatory population. CD5 expression is noted on more than three fourths of all T-cell lymphomas. CD5 may be a receptor of pathogen-associated molecular patterns; CD5 may be a marker of decreased dependence of B cells on certain circulating factors. Elevated levels of CD5 are found in a number of autoimmune disorders. Thus, although the precise mechanism is unclear, there is at the very least circumstantial evidence of a role for CD5 in the pathogenesis of autoimmunity and perhaps T cell-derived lymphoid malignancy. New findings put old claims to rest and open up new avenues for research, both basic and clinical, with therapeutic applications not far behind.

Basic science for the clinician 53: mast cells.

Mast cells stand at the interface between the innate immune system and the acquired (adaptive) immune response, serving as sentinels detecting invaders and directing a concerted and coordinated response. Mast cells reside immediately under body surfaces and within lymph nodes, near blood vessels and nerves, perfectly situated to for early detection and defense. They secrete a wide array of prostanoids, cytokines, chemokines, and other proteins mediators and modifiers of a variety of immune and inflammatory functions and bear surface markers suggesting broad functions, including as antigen-presenting cells. Although usually not given their due in medical school lectures, there is great likelihood that mast cells will be implicated in the pathogenesis of rheumatoid arthritis, scleroderma, multiple sclerosis, and perhaps cancer. Thus, better insights into mast cell functions and mast cell-derived effector molecules should command our attention as we move forward in better understanding disease immunopathogenesis and directed intelligent therapeutics development.

Musculoskeletal features of Lyme disease: understanding the pathogenesis of clinical findings helps make appropriate therapeutic choices.

Patients with Lyme disease, that is, active infection with Borrelia burgdorferi, experience many types of musculoskeletal complaints, with different explanatory mechanisms. Appropriate therapy depends on understanding the underlying cause of the complaint and addressing that specific root cause. In the case of active infection the dosage, duration, drug, and method of administration of antibiotics should be determined by the state of the infection and history of prior therapy, according to the established and validated recommendations of the Infectious Disease Society of America. Many patients have musculoskeletal complaints not attributable to active infection; some patients have residual complaints following a documented infection that has been adequately treated with antibiotics previously, and others never had true B. burgdorferi infection in the first place. For such patients, antibiotics are not warranted and in fact may be physically and emotionally harmful. Complaints following an episode of Lyme disease are not necessarily due to ongoing infection, especially adequately treated. Consideration of other diagnoses may suggest use of other effective modalities, including physical therapy and emotional support. Appropriate ordering and interpretation of the various validated seroconfirmatory tests available to study B. burgdorferi infection are critical, as these tests are often misapplied and misconstrued in pursuit of strategies aimed at eliminating patients' suffering. Although seronegative Lyme disease has been reported, seronegativity in a reputable laboratory makes the likelihood of Lyme arthritis very low. On the other hand, a positive result from certain unvalidated laboratories or novel assays proves nothing and should not be viewed as substantiating the diagnosis.

Basic Science for the Clinician 52: adipokines.

Adipocytes, the cells that maintain fat stores and influence energy metabolism, produce a variety of messengers, called adipokines (or adipocytokines). These proteins have broad reaching effects on glucose and fat metabolism, but also influence inflammation, by modulating the production of inflammatory cytokines and modifying how established cytokines such as interleukin 6 and tumor necrosis factor α themselves induce or modulate inflammation; some of these proteins are produced by synovial tissue adipocytes, suggesting a very direct effect on the modification of local inflammation. Adipokines provide mechanisms that might explain accelerated atherosclerosis and impaired glucose metabolism in some of our chronic inflammatory diseases and offer potential unique therapeutic approaches to control these and other manifestations of inflammation.

Long-term safety and efficacy of abatacept in children with juvenile idiopathic arthritis.

OBJECTIVE: We previously documented that abatacept was effective and safe in patients with juvenile idiopathic arthritis (JIA) who had not previously achieved a satisfactory clinical response with disease-modifying antirheumatic drugs or tumor necrosis factor blockade. Here, we report results from the long-term extension (LTE) phase of that study. METHODS: This report describes the long-term, open-label extension phase of a double-blind, randomized, controlled withdrawal trial in 190 patients with JIA ages 6-17 years. Children were treated with 10 mg/kg abatacept administered intravenously every 4 weeks, with or without methotrexate. Efficacy results were based on data derived from the 153 patients who entered the open-label LTE phase and reflect >or=21 months (589 days) of treatment. Safety results include all available open-label data as of May 7, 2008. RESULTS: Of the 190 enrolled patients, 153 entered the LTE. By day 589, 90%, 88%, 75%, 57%, and 39% of patients treated with abatacept during the double-blind and LTE phases achieved responses according to the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30), Pedi 50, Pedi 70, Pedi 90, and Pedi 100 criteria for improvement, respectively. Similar response rates were observed by day 589 among patients previously treated with placebo. Among patients who had not achieved an ACR Pedi 30 response at the end of the open-label lead-in phase and who proceeded directly into the LTE, 73%, 64%, 46%, 18%, and 5% achieved ACR Pedi 30, Pedi 50, Pedi 70, Pedi 90, and Pedi 100 responses, respectively, by day 589 of the LTE. No cases of tuberculosis and no malignancies were reported during the LTE. Pneumonia developed in 3 patients, and multiple sclerosis developed in 1 patient. CONCLUSION: Abatacept provided clinically significant and durable efficacy in patients with JIA, including those who did not initially achieve an ACR Pedi 30 response during the initial 4-month open-label lead-in phase.

Role of psychiatric comorbidity in chronic Lyme disease.

OBJECTIVE: To evaluate the prevalence and role of psychiatric comorbidity and other psychological factors in patients with chronic Lyme disease (CLD). METHODS: We assessed 159 patients drawn from a cohort of 240 patients evaluated at an academic Lyme disease referral center. Patients were screened for common axis I psychiatric disorders (e.g., depressive and anxiety disorders); structured clinical interviews confirmed diagnoses. Axis II personality disorders, functional status, and traits like negative and positive affect and pain catastrophizing were also evaluated. A physician blind to psychiatric assessment results performed a medical evaluation. Two groups of CLD patients (those with post-Lyme disease syndrome and those with medically unexplained symptoms attributed to Lyme disease but without Borrelia burgdorferi infection) were compared with 2 groups of patients without CLD (patients recovered from Lyme disease and those with an identifiable medical condition explaining symptoms attributed to Lyme disease). RESULTS: After adjusting for age and sex, axis I psychiatric disorders were more common in CLD patients than in comparison patients (P = 0.02, odds ratio 2.64, 95% confidence interval 1.30-5.35), but personality disorders were not. Patients with CLD had higher negative affect, lower positive affect, and a greater tendency to catastrophize pain (P < 0.001) than comparison patients. All psychological factors except personality disorders were related to level of functioning. A predictive model based on these psychological variables was confirmed. Fibromyalgia was diagnosed in 46.8% of CLD patients. CONCLUSION: Psychiatric comorbidity and other psychological factors distinguished CLD patients from other patients commonly seen in Lyme disease referral centers, and were related to poor functional outcomes.

Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial.

BACKGROUND: Some children with juvenile idiopathic arthritis either do not respond, or are intolerant to, treatment with disease-modifying antirheumatic drugs, including anti-tumour necrosis factor (TNF) drugs. We aimed to assess the safety and efficacy of abatacept, a selective T-cell costimulation modulator, in children with juvenile idiopathic arthritis who had failed previous treatments. METHODS: We did a double-blind, randomised controlled withdrawal trial between February, 2004, and June, 2006. We enrolled 190 patients aged 6-17 years, from 45 centres, who had a history of active juvenile idiopathic arthritis; at least five active joints; and an inadequate response to, or intolerance to, at least one disease-modifying antirheumatic drug. All 190 patients were given 10 mg/kg of abatacept intravenously in the open-label period of 4 months. Of the 170 patients who completed this lead-in course, 47 did not respond to the treatment according to predefined American College of Rheumatology (ACR) paediatric criteria and were excluded. Of the patients who did respond to abatacept, 60 were randomly assigned to receive 10 mg/kg of abatacept at 28-day intervals for 6 months, or until a flare of the arthritis, and 62 were randomly assigned to receive placebo at the same dose and timing. The primary endpoint was time to flare of arthritis. Flare was defined as worsening of 30% or more in at least three of six core variables, with at least 30% improvement in no more than one variable. We analysed all patients who were treated as per protocol. This trial is registered, number NCT00095173. FINDINGS: Flares of arthritis occurred in 33 of 62 (53%) patients who were given placebo and 12 of 60 (20%) abatacept patients during the double-blind treatment (p=0.0003). Median time to flare of arthritis was 6 months for patients given placebo (insufficient events to calculate IQR); insufficient events had occurred in the abatacept group for median time to flare to be assessed (p=0.0002). The risk of flare in patients who continued abatacept was less than a third of that for controls during that double-blind period (hazard ratio 0.31, 95% CI 0.16-0.95). During the double-blind period, the frequency of adverse events did not differ in the two treatment groups. Adverse events were recorded in 37 abatacept recipients (62%) and 34 (55%) placebo recipients (p=0.47); only two serious adverse events were reported, both in controls (p=0.50). INTERPRETATION: Selective modulation of T-cell costimulation with abatacept is a rational alternative treatment for children with juvenile idiopathic arthritis. FUNDING: Bristol-Myers Squibb.

The relationship between affect balance style and clinical outcomes in fibromyalgia.

OBJECTIVE: Affective balance, relative levels of negative affect (NA) and positive affect (PA), better describes emotional functioning than NA or PA alone. Affect balance styles and their relationship to clinical outcomes were compared between patients with fibromyalgia (FM) and controls. METHODS: FM patients (n = 79) were compared with patients with other medical conditions (controls; n = 92). Patients underwent a physical examination, completed questionnaires, and were screened for clinical disorders such as depression, with diagnoses confirmed by structured interview. Affect balance style categories were calculated as follows: healthy (high PA/low NA), low (low PA/low NA), reactive (high PA/high NA), and depressive (low PA/high NA). RESULTS: Compared with controls, FM patients had lower levels of PA (P = 0.0031; P values are adjusted for multiple testing), higher levels of NA (P = 0.0061), lower levels of functioning (P < 0.0001), and more clinical disorders (P = 0.0031). Groups differed regarding affect balance style (P = 0.0061), with FM patients being more likely than controls to be categorized as depressive (odds ratio 5.60) and reactive (odds ratio 3.81). FM patients and controls with reactive and depressive affect balance styles reported poorer functioning (P < 0.0001) compared with patients with healthy affect balance style. Finally, there was an association between affect balance style and psychiatric comorbidity (P < 0.0001), with patients with depressive and reactive affect balance styles having a 9.00 and 4.75 odds ratio, respectively, of having psychiatric comorbidity compared with patients with healthy affect balance style. CONCLUSION: Depressive (low PA, high NA) and reactive (high PA, high NA) affect balance styles were predominant in FM patients and related to poor functioning and psychiatric comorbidity.

Basic science for the clinician 48: tyrosine kinases in disease: the potential for inhibitors in the treatment of immunologic diseases.

The magic bullet--a compound that will stop a disease dead in its tracks by specifically targeting the underlying pathogenic principle of that disease--is what every designer/developer of drugs wants. As cellular and molecular biology research delves deeper into how cells are activated by their ligands, the intracellular pathways of activation of individual cellular processes become better known and more attractive therapeutic targets. The receptors for transforming growth factor beta (TGFbeta) and platelet-derived growth factor (PDGF) activate a variety of cells via a series of tyrosine kinases; inhibition of specific tyrosine kinases has until recently been within the domain of oncologists, treating leukemia, and certain gastrointestinal tumors, but now there is mounting evidence that these agents might be of value in rheumatologic and autoimmune diseases. This is another example of "Better living (and curing!) through chemistry" that we as clinicians need to master to render optimal care.

A pilot study of the efficacy of heart rate variability (HRV) biofeedback in patients with fibromyalgia.

UNLABELLED: Fibromyalgia (FM) is a non-inflammatory rheumatologic disorder characterized by musculoskeletal pain, fatigue, depression, cognitive dysfunction and sleep disturbance. Research suggests that autonomic dysfunction may account for some of the symptomatology of FM. An open label trial of biofeedback training was conducted to manipulate suboptimal heart rate variability (HRV), a key marker of autonomic dysfunction. METHODS: Twelve women ages 18-60 with FM completed 10 weekly sessions of HRV biofeedback. They were taught to breathe at their resonant frequency (RF) and asked to practice twice daily. At sessions 1, 10 and 3-month follow-up, physiological and questionnaire data were collected. RESULTS: There were clinically significant decreases in depression and pain and improvement in functioning from Session 1 to a 3-month follow-up. For depression, the improvement occurred by Session 10. HRV and blood pressure variability (BPV) increased during biofeedback tasks. HRV increased from Sessions 1-10, while BPV decreased from Session 1 to the 3 month follow-up. CONCLUSIONS: These data suggest that HRV biofeedback may be a useful treatment for FM, perhaps mediated by autonomic changes. While HRV effects were immediate, blood pressure, baroreflex, and therapeutic effects were delayed. This is consistent with data on the relationship among stress, HPA axis activity, and brain function.

Basic Science for the clinician 41: tails of cytokine receptor activation and control: JAKs, STATs, PIASs, and SOCSs.

We now have an emerging sense of the details of how cytokines deliver their signals through the specific receptors to which they bind and the means by which these messages are modulated. Using common mechanisms, many of which have been described in past articles in this series, tight controls are maintained over this signaling. A better understanding of the molecular details of these pathways has provided insights into the pathogenesis of some malignancies and immunodeficiency syndromes and may ultimately yield therapeutic agents of use in the treatment of inflammatory and autoimmune diseases.

Basic science for the clinician 40: ubiquitin, programmed protein degradation, and the proteasome.

mRNA is made from DNA. Protein is made from mRNA. Although one might say that "DNA is forever," the same cannot be said for mRNA or protein. These molecules are made in response to the cell's present needs; once the cell's circumstances change, a whole new repertoire of proteins may be needed and the previous set of proteins may be unnecessary, perhaps even deleterious. So, the cell must be able to eliminate the characters in the previous act in favor of the actors needed for the current act. In addition, there is good evidence that the DNA to mRNA to protein flow may not be efficient; abnormal proteins, as well as damaged or misfolded proteins, are quite common and must also be eliminated. This process depends on the ability of the cell to tag the protein to be eliminated with a small protein (or chain of these proteins) that targets the protein to a special structure for digestion into its constituent amino acids for recycling into new proteins. This very common protein tag was identified in the 1970s and called "ubiquitin"--it truly was everyplace! In addition, ubiquitin is crucial to targeting normal proteins to their appropriate place in or on the cell and for recycling of proteins. Ubiqutination of proteins and what follows this tagging are crucial to the normal function of cells. The complexity of these processes is being used for therapy in oncology now and perhaps in immunology and rheumatology in the near future.

Basic science for the clinician 39: NF-kappaB-function, activation, control, and consequences.

Were there to be a crossroads through which all inflammatory signaling passed, controlling that junction would provide the ultimate therapeutic target for rheumatoid arthritis and many, if not all, autoimmune diseases. It now seems likely that no single cytokine or cytokine family represents such a crucial nexus. However, there is reason to believe that there may be an intracellular bottleneck that does: the family of NF-kappaB proteins. This family of proteins allows cytokine-receptor signals to enter the nucleus and either enhance or suppress the transcription of many genes involved in inflammation and in cellular survival itself. The same set of proteins is also involved in apoptosis and likely in carcinogenesis. The delicate choreography of control systems, balancing the effects of NF-kappaB proteins on the multiple DNA sites that are targeted, is also a prime target for specific therapies. Moreover, the NF-kappaB system interdigitates with other intracellular systems, eg, kinases, ubiquitin-associated protein degradation, that are critical to the normal function of cells, involved in homeostasis and inflammation, in autoimmune diseases and malignancy.

Basic science for the clinician 38: B cells, factories, and immunomodulators.

In a previous article in this series, we explored how developing pre-T cells learn how to be well-behaved T cells that recognize and honor the "self versus nonself" dichotomy of the universe. B cells do much of the same sort of thing, with multipotent stem cells becoming committed to ultimately becoming B cells within the bone marrow and then, after judicious culling of the flock, going off to the spleen to learn the final lessons needed to become "well-behaved" B cells. Like with T cells, there are a large number of things that can, and do, go wrong. If there is a failure of the system and B cells do not develop properly, hypogammaglobulinemia may develop as a result of a number of immune deficiency syndromes that can be quite devastating. If autoreactive cells survive to emerge into the periphery, autoimmunity, either organ-specific or more global, may occur. If B cells in the periphery proliferate in an uncontrolled fashion, a variety of B cell lymphoproliferative syndromes may develop, recognizable by the phenotypic markers of their originating B cell lineage level of differentiation. The full details of how autoreactive B cells survive and thrive, only to cause disease, are not yet clear, but identification of many of the phenotypic surface markers and circulating growth factors identified to this point have borne therapeutic fruit.

Basic science for the clinician 37: Protecting against autoimmunity-tolerance: mechanisms of negative selection in the thymus.

As noted in previous articles in this series, tolerance, the ability of the immune system to differentiate self from nonself and leave the former alone, is a vital characteristic of a successful (and safe) immune system. With the detection of the molecule called aire (autoimmune regulator), the mechanism whereby autoreactive thymocytes encounter extrathymic proteins within the thymus and therefore are deleted, is now far better understood; aire was the subject of a prior article in this series. The absence of aire leads to autoimmune polyendocrinopathy, proof that aire is the center of an amazing "filtering" system. However, there are other mechanisms at work. Irregularities in expression of other proteins such as hypoxia-induced factor-1 (HIF-1) and CTLA4, have been implicated in autoimmune disease, the former in rheumatoid arthritis, the latter in autoimmune thyroid disease and lupus. Defects in intracellular factors involved in transcription of key apoptotic proteins have also been implicated in the escape of autoreactive thymocytes from the thymus, leading to autoimmune and lymphoproliferative syndromes as well. Changes in the proteins that oversee acetylation of histone lead to differential patterns of gene expression. At least 2 proteins involved in this process, HDAC and nur77, have been implicated in changes in survival of thymocytes. Yet again, there are multiple layers at work in the immune system; I have no idea how many more will be brought to light, which are phylogenetically most ancient or which will prove the most clinically relevant. For now, it is enough to bask in our new-found knowledge and know that the time from laboratory oddity, to animal model development, to therapeutic and/or diagnostic applications grows shorter each year since the molecular biologic revolution.

Basic science for the clinician 27: Toll-like receptors and nucleotide oligomerization domains.

Ancient protective mechanisms are in place, deep within our defenses against infection and malignancy, often unappreciated until homologous proteins found within less phylogenetically advanced organisms are identified. Such is the case with 2 major recent finds, the Toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD) families of innate immunity molecules. These families of receptors have high specificity, limited heterogeneity, and no plasticity; nonetheless, they play a pivotal role in rapid initial defenses against pathogens. Moreover, studies of the mechanisms of TLRs and NODs show how they and IL-1 and IL-18 stand at the threshold of the adaptive immune response and help to accelerate specific immune responsivity. Nonspecific reactivity of these preprogrammed receptors may be how relatively nonpathogenic organisms like yersinia and chlamydia may drive the inflammation of reactive arthritis and atherosclerosis. The inflammation of rheumatoid arthritis may be magnified, if not initiated, by these innate mechanisms as well.

Lyme arthritis synovial gammadelta T cells instruct dendritic cells via fas ligand.

gammadelta T cells participate in the innate immune response to a variety of infectious microorganisms. They also link to the adaptive immune response through their induction of maturation of dendritic cells (DC) during the early phase of an immune response when the frequency of Ag-specific T cells is very low. We observe that in the presence of Borrelia burgdorferi, synovial Vdelta1 T cells from Lyme arthritis synovial fluid potently induce maturation of DC, including production of IL-12, and increased surface expression of CD40 and CD86. The activated DC are then able to stimulate the Vdelta1 T cells to up-regulate CD25. Both of these processes are initiated primarily by Fas stimulation rather than CD40 activation of DC via high expression of Fas ligand by the Vdelta1 T cells. DC are resistant to Fas-induced death due to expression of high levels of the Fas inhibitor c-FLIP. This effect serves to divert Fas-mediated signals from the caspase cascade to the ERK MAPK and NF-kappaB pathways. The findings affirm the importance of the interaction of certain T cell populations with DC during the early phases of the innate immune response. They also underscore the view that as levels of c-FLIP increase, Fas signaling can be diverted from induction of apoptosis to pathways leading to cell effector function.

Herbal medications commonly used in the practice of rheumatology: mechanisms of action, efficacy, and side effects.

OBJECTIVE: To review the literature on herbal preparations commonly utilized in the treatment of rheumatic indications. METHODS: Search of MEDLINE (PubMed) was performed using both the scientific and the common names of herbs. Relevant articles in English were collected from PubMed and reviewed. RESULTS: This review summarizes the efficacy and toxicities of herbal remedies used in complementary and alternative medical (CAM) therapies for rheumatologic conditions, by elucidating the immune pathways through which these preparations have antiinflammatory and/or immunomodulatory activity and providing a scientific basis for their efficacy. Gammalinolenic acid suppresses inflammation by acting as a competitive inhibitor of prostaglandin E2 and leukotrienes (LTs) and by reducing the auto-induction of interleukin1alpha (IL-1alpha)-induced pro-IL-1beta gene expression. It appears to be efficacious in rheumatoid arthritis (RA) but not for Sjogrens disease. The antiinflammatory actions of Harpagophytum procumbens is due to its action on eicosanoid biosynthesis and it may have a role in treating low back pain. While in vitro experiments with Tanacetum parthenium found inhibition of the expression of intercellular adhesion molecule-1, tumor necrosis factor alpha (TNF-alpha), interferon-gamma, IkappaB kinase, and a decrease in T-cell adhesion, to date human studies have not proven it useful in the treatment of RA. Current experience with Tripterygium wilfordii Hook F, Uncaria tomentosa, finds them to be efficacious in the treatment of RA, while Urtica diocia and willow bark extract are effective for osteoarthritis. T. wilfordii Hook F extract inhibits the production of cytokines and other mediators from mononuclear phagocytes by blocking the up-regulation of a number of proinflammatory genes, including TNF-alpha, cyclooxygenase 2 (COX-2), interferon-gamma, IL-2, prostaglandin, and iNOS. Uncaria tomentosa and Urtica diocia both decrease the production of TNF-alpha. At present there are no human studies on Ocimum spp. in rheumatic diseases. The fixed oil appears to have antihistaminic, antiserotonin, and antiprostaglandin activity. Zingiber officinale inhibits TNF-alpha, prostaglandin, and leukotriene synthesis and at present has limited efficacy in the treatment of osteoarthritis. CONCLUSIONS: Investigation of the mechanism and potential uses of CAM therapies is still in its infancy and many studies done to date are scientifically flawed. Further systematic and scientific inquiry into this topic is necessary to validate or refute the clinical claims made for CAM therapies. An understanding of the mechanism of action of CAM therapies allows physicians to counsel effectively on their proper and improper use, prevent adverse drug-drug interactions, and anticipate or appreciate toxicities. RELEVANCE: The use of CAM therapies is widespread among patients, including those with rheumatic diseases. Herbal medications are often utilized with little to no physician guidance or knowledge. An appreciation of this information will help physicians to counsel patients concerning the utility and toxicities of CAM therapies. An understanding and elucidation of the mechanisms by which CAM therapies may be efficacious can be instrumental in discovering new molecular targets in the treatment of diseases.