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 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 58: IgG subclasses.

In evolutionary terms, IgG is the most recent addition to the human humoral immune response, the most recent of the 5 isotypes (classes). The IgG 4 subclasses and their multiple receptors, each with a unique structure and functions, speak to their broad repertoire of often overlapping functions. The IgG subclasses differ only slightly in structure, but therein lies their unique qualities. Focusing solely on the clinical niches filled by each and the clinical correlations thereof allows one to clearly see nature in its abhorrence of, and skill in filling, vacuums. One of the IgG subclasses, IgG4, the least in serum concentration, has recently become the topic of intense interest, as the linkage of certain diseases with IgG4 becomes apparent. As this association is studied, the molecular biology at the root of these diseases becomes the predominant cytokines explaining the pattern of histopathology.

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 56: inducible T-cell costimulator--the world of costimulation gets more complicated and interesting.

They say that nothing is assured in this world but change. And this applies in a cynical way to immunology: nothing is assured--we can never rest with an assumption that we know it all because there are always more apparent complications when analyzing immune mechanisms (someday, perhaps we will arrive on a "grand scheme" that elegantly explains it all, just as our brethren in particle physics seek the Higgs boson and the completion of a better model--I am not holding my breath awaiting completion of our task!). In a recent article in this series, we explored CTLA4 as a counterregulator of the CD28-CD80/86 costimulatory pathway. However, treatment with CTLA4 does not entirely shutdown the immune system; engineering animals so that the CD28-CD80/86 pathway no longer functions does not prevent functional protective immune responses. Thus, there must be yet another pathway. And there is--an "inducible T-cell costimulator" (ICOS) is found on T cells (activated, not naive), which has a single ligand on antigen-presenting cells (ICOS ligand, B7-RP-1). The rapid induction of ICOS speaks to its importance in T-cell function; however, ICOS is more relevant to the stimulation of effector and memory T cells than is CD28 signaling. There are similarities and differences, interactions, and overlaps between the 2 pathways, some of which are very useful in understanding the immunopathogenesis of immune diseases.

Basic science for the clinician 55: CTLA-4.

In physiological systems, for every "yang," there must be a "yin," for uncontrolled systems can run amok. This is the case for the T-cell compartment of the immune system, where activation must be modulated, dampened, and ultimately reversed; to not apply the brakes leads to dire consequences. In less than 20 years, CTLA-4 has emerged from being an orphan, next becoming a physiological star with ever-emerging effects, and finally to being a therapeutic target-an impressive example of evolution and one that continues. Understanding the costimulatory effects and mechanisms of CTLA-4 and the redundancies intrinsic to costimulation is important in understanding T-cell function and dysfunction in disease. A future article in this series will describe inducible T-cell costimulator, which is a normal by-pass to CTLA-4's effects.

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.

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 51: the inflammasome.

The innate immune system is packaged in a number of discrete, but intercommunicating, systems. The inflammasome is a multimolecular complex that detects intracellular foreign molecules of a variety of sorts and promptly promotes the secretion of IL-1ß and IL-18. When all goes well, defense of the organism in the early period of infection is enhanced by this system; when certain elements of the inflammasomal systems go awry, inflammatory diseases of a variety of sorts result. A family of multimolecular detection systems are activated at times of infection and tissue damage; it is the dysfunction of this innate immune defense system that intrigues rheumatologists, as this is the cause of a series of newly described autoinflammatory diseases.

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.

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.

Autobiographical Case Report: A Rubber Band, a Glass of Orange Juice.

Seemingly simple procedures can go desperately wrong. Physicians are used to "knowing" and "being in charge". When a physician is suddenly the profoundly ill patient, the inversion of roles can be frustrating, frightening, and disorienting.

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.

Basic science for the clinician 49: expanding the description of the RNA universe.

We have come a long way in paying RNA its due respect. Originally thought to be nothing more than a shuttle of information from DNA to protein, a bearer of amino acids to the ribosome, and a splicer of messenger RNA, we now know that other RNA species are pivotal in controlling cellular functions that assure normal development and differentiation of immune cells, modulation of inflammatory mechanisms, control of proliferation of a number of hematologic lineages, and spermatogenesis (clearly, vital for the maintenance of the species!). In the future, ribozymes, antisense RNA and oligonucleotides, decoy RNA, peptide-nucleic acid chimeras, and other RNAs will probably be part of the routine armamentarium in a variety of medical practices. Targeting these to the appropriate cell may allow for highly directed therapies, maximizing efficacy and minimizing toxicity. It is a new world, an RNA world, and we will all benefit from the insights broadly outlined in this article. When I was in college and medical school, RNA was known to come in only a few varieties. There was messenger RNA, ribosomal RNA, transfer RNA, and double-stranded RNA in some viruses. And that was that! My, how times have changed!! The truth, as always, is much more complicated than we had thought. We now know that RNA is involved in splicing of mRNA and in cleaving RNA. And, recent studies have revealed even more: DNA transcription, mRNA stability, and levels of protein synthesis are all, to some degree, controlled by an entirely different set of RNAs, such as small RNAs, which come in at least 3 different broad varieties. Thus, there are now at least 10 varieties of RNAs of which I am aware at the time I write these words, and who is to say that there are not more out there? Just as the entire repertoire of the known classes of small RNAs has not yet been described, there may be different RNAs out there yet to be identified. If, in fact, the bio-universe was initially determined by RNA, not DNA, there may be new RNAs with unexpected mechanisms and consequences.

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.

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.

Reactive arthritis.

ReA consists of sterile axial or peripheral articular inflammation,enthesitis, and extra-articular manifestations. Most patients are HLA-B27 positive, although determining the B27 status of an individual patient is irrelevant. Exposure to specific bacterial antigens is usually the inciting factor. Diagnosis usually can be made by clinical examination and history. The current standard therapy is NSAIDs and physiotherapy, but molecular biologic treatment may ultimately become the mainstay in recalcitrant and severe ReA.

Contributions of societal and geographical environments to "chronic Lyme disease": the psychopathogenesis and aporology of a new "medically unexplained symptoms" syndrome.

Lyme disease is a relatively well-described infectious disease with multisystem manifestations. Because of confusion over conflicting reports, anxiety related to vulnerability to disease, and sensationalized and inaccurate lay media coverage, a new syndrome, "chronic Lyme disease," has become established. Chronic Lyme disease is the most recent in a continuing series of "medically unexplained symptoms" syndromes. These syndromes, such as fibromyalgia, chronic fatigue syndrome, and multiple chemical sensitivity, meet the need for a societally and morally acceptable explanation for ill-defined symptoms in the absence of objective physical and laboratory findings. We describe factors involved in the psychopathogenesis of chronic Lyme disease and focus on the confusion and insecurity these patients feel, which gives rise to an inability to adequately formulate and articulate their health concerns and to deal adequately with their medical needs, a state of disorganization termed aporia.