Rheumatoid Arthritis: Sigal LH

Sigal LH. · Pharmaceutical Research Institute, Bristol-Myers Squibb, Princeton, New Jersey 08543-4000, USA. · J Clin Rheumatol. · Pubmed #17762462 No free full text.

Abstract: I have often said "blessed be the splitters, for they shall inherit the earth." By that I mean that it is only by studying carefully culled populations, approaching, but never quite reaching, homogeneity that we can ever gain real insights into rheumatologic diseases. Differentiating tuberculous from gouty from rheumatoid arthritis was a good start, and when Moll and Wright identified the seronegative spondyloarthropathies, we were on our way to establishing "splitters" as leaders. Predictably, once T cells were identified as different from B cells, the floodgates opened. Subsets galore were described, with more isolated populations in the T-cell family, but we are now finding heterogeneity in B-cell populations, as well, which has been discussed in a previous article in this series. But as for T cells... well, it has not been smooth sailing. I initially trained in a laboratory that was firmly committed to the proposition that there were within the CD8 population not only cytotoxic cells but also "suppressor cells." Problem is, no one could ever isolate the little buggers, and so the idea of a suppressor or regulatory subpopulation of CD8+ T cells went the way of the Edsel. As noted in a previous article in this series, T regulatory cells were finally identified but not within the CD8+ population. And there are other regulatory subsets within both CD4+ and CD8+ T-cells populations and even new effector and memory populations that can be identified by their surface markers and functions. It is high time to review some of them; some of these populations may be involved in the immunopathogenesis of our diseases and undoubtedly will shortly be targets of immunotherapeutics. Although previous articles in this series discussed some of these subsets, I thought expanding on what is known about another recently described subset and putting them all together in one review might be helpful.

Sigal LH. · Pharmaceutical Research Institute, Bristol-Myers Squibb, Princeton 08543-4000, USA. · J Clin Rheumatol. · Pubmed #16891930 No free full text.

Abstract: 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.

Sigal LH. · Pharmaceutical Research Institute, Bristol-Myers Squibb, J.3100, PO Box 4000, Princeton, NJ 08543-4000, USA. · J Clin Rheumatol. · Pubmed #16601548 No free full text.

Abstract: 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.

Sigal LH. · Pharmaceutical Research Institute/Bristol-Myers Squibb, Princeton, New Jersey 08543-4000, USA. · J Clin Rheumatol. · Pubmed #16357743 No free full text.

Abstract: 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.

Sigal LH. · Pharmaceutical Research Institute/Bristol-Myers Squibb, J. 3100, PO Box 4000, Princeton, NJ 08543-4000, USA. · J Clin Rheumatol. · Pubmed #16357694 No free full text.

Abstract: As you saw in the first part of this description of interleukins, normal orchestration of wound healing, the protective immune response and inflammation involves many cells that must effectively communicate with each other. The means of this communication is often soluble messengers (cytokine) and many of them bear the title interleukin. Although all these messengers have a role in normal immune homeostasis, it is apparent that many are involved in tissue damage in a variety of disease, eg, rheumatoid arthritis, osteoarthritis. I dealt with interleukins (IL) 3 to 16 in the first part of this project. We now pick up the story with IL-17. Turns out, much of the most exciting recent work in rheumatology has focused on IL-17 and IL-18. The disparate effects of the interleukins may be confusing, often a single cytokine producing multiple effects seemingly at crossed purposes, but we are in our infancy when it comes to insights into the molecular biology of normal immune function, homeostasis, inflammation, and disease.

Setty AR, Sigal LH. · Massachusetts General Hospital, Department of Rheumatology, Boston, USA. · Semin Arthritis Rheum. · Pubmed #15942912 No free full text.

Abstract: 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.

Rullan E, Sigal LH. · Department of Medicine, Division of Rheumatology, UMDNJ-Robert Wood Johnson Medical School, 1 Robert Wood Johnson Place, PO Box 19, MEB-484, New Brunswick, NJ 08903-0019, USA. · Curr Rheumatol Rep. · Pubmed #11564377 No free full text.

Abstract: Rheumatic fever is a multisystem inflammatory disease that occurs as a delayed sequel to group A streptococcal pharyngitis. It is less common than it was 50 years ago but is still a major cause of heart disease in developing areas of the world. The relationship between the site of infection, the type of causative organism, and susceptibility of the host is essential in the development of the disease. Its major clinical manifestations include carditis, migratory polyarthritis, chorea, erythema marginatum, and subcutaneous nodules. It can manifest as an acute febrile illness consisting of migratory polyarthritis involving the large joints, as carditis and valvulitis, or as Sydenham's chorea with involvement of the central nervous system. The disorder in its milder form resolves itself without sequelae. Carditis is the condition most associated with increased mortality and morbidity and may be fatal in its severe forms. Penicillin is the most appropriate primary and secondary prophylaxis. Anti- inflammatory agents provide symptomatic relief but do not prevent rheumatic heart disease.

Sigal LH. · Department of Medicine, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, USA. · Rheum Dis Clin North Am. · Pubmed #10573763 No free full text.

Abstract: Design of rational therapy depends on knowledge of the causes of the disease, which is knowledge often lacking in rheumatology. There have been theories of infectious causes of many rheumatologic diseases but no proof. The seductive possibility of an infectious etiology has led to the use of antibiotics for treating these diseases. This article reviews the effectiveness of antibiotics against rheumatologic syndromes, including rheumatoid arthritis and Lyme disease.

Ruperto N, Lovell DJ, Quartier P, Paz E, Rubio-Pérez N, Silva CA, Abud-Mendoza C, Burgos-Vargas R, Gerloni V, Melo-Gomes JA, Saad-Magalhães C, Sztajnbok F, Goldenstein-Schainberg C, Scheinberg M, Penades IC, Fischbach M, Orozco J, Hashkes PJ, Hom C, Jung L, Lepore L, Oliveira S, Wallace CA, Sigal LH, Block AJ, Covucci A, Martini A, Giannini EH, Anonymous00184, Anonymous00185. · IRCCS G Gaslini, PRINTO, Genoa, Italy. · Lancet. · Pubmed #18632147 No free full text.

Abstract: 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.

Sigal LH. · Division of Rheumatology and Connective Tissue Research. · J Clin Rheumatol. · Pubmed #19078477 No free full text.

Abstract: ABSTRACT: T-cells are activated by their interaction with antigen-presenting cells. Antigen-presenting cells process and then express peptide fragments of the target protein in a complex with self-proteins known as major histocompatibility complex (MHC) proteins on the antigen-presenting cells' surface. However, the interaction of T-cell with antigen on the antigen-presenting cell is not sufficient to elicit T-cell activation. The T-cell must receive a second signal from the antigen-presenting cell. These "co-stimulatory signals" are mediated by other proteins on the antigen-presenting cell surface that interact with T-cell surface proteins other than the antigen receptor, the protein complex receiving the peptide fragment's specific antigen signal. Some of these co-stimulatory proteins are constitutively expressed, some are up-regulated during an immune response; some interactions stimulate activation, some suppress it. Thus, these receptor-ligand protein pairs represent new sites for blockade of immune responses in immunologically-mediated diseases, like rheumatoid arthritis, lupus, and transplant graft rejection.

Sigal LH. · Division of Rheumatology and Connective Tissue Research, Department of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903, USA. · J Clin Rheumatol. · Pubmed #17041387 No free full text.

Abstract: If we accept the perfectly reasonable premise that the mass of inflammatory tissue in rheumatoid arthritis (and psoriatic arthritis or any other inflammatory joint disease) requires oxygen and nutrition to survive and grow, we are confronted with a novel concept for therapy: if we can block the nutritional supply of the pannus, we can suppress or prevent its growth and the subsequent destruction of the joint. Thus, an understanding of how new blood vessels nourish the inflammatory mass could be pivotal in successfully treating our patients. Angiogenesis is the process whereby new blood vessels enter the site of inflammation or growing malignancy to supply the invading tissue. Many growth factors and local tissue conditions help to determine blood vessel growth, there being pro- and anti-angiogenetic influences. Thus, this is fertile ground for therapeutic molecular manipulations.

Hassett AL, Cone JD, Patella SJ, Sigal LH. · Department of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick 08903, USA. · Arthritis Rheum. · Pubmed #11083273 links to  free full text

Abstract: OBJECTIVE: Although 2 recent studies have found associations between catastrophizing and poor medical outcomes in patients with fibromyalgia syndrome (FMS), neither assessed these findings in comparison with a similar group of patients with chronic pain. Our study examined the complex relationships between depression, catastrophizing, and the multidimensional aspects of pain in women with FMS and compared these relationships with those in women with rheumatoid arthritis (RA). METHODS: Sixty-four FMS patients and 30 RA patients completed the Coping Strategies Questionnaire (CSQ), the Beck Depression Inventory II (BDI-II), and the McGill Pain Questionnaire. RESULTS: Compared with subjects with RA, FMS subjects scored significantly higher on the catastrophizing subscale of the CSQ. FMS patients also earned higher scores on overall depression and on the cognitive subscale of the BDI-II. Furthermore, the relationship between catastrophizing and depression was significant in the FMS group only. Regression analyses revealed that in FMS, catastrophizing as a measure of coping predicted patients' perception of pain better than demographic variables such as age, duration of illness, and education. CONCLUSION: Cognitive factors, such as catastrophizing and depressive self-statements, have a more pronounced role in the self-reported pain of patients with FMS than in patients with RA. Clinically, this indicates that treating pain and depression in FMS by adding cognitive therapy and coping skills components to a comprehensive treatment program may improve the outcomes obtained with pharmacologic interventions.