Rheumatoid Arthritis: Bijlsma JW

Zhang W, Doherty M, Leeb BF, Alekseeva L, Arden NK, Bijlsma JW, Dincer F, Dziedzic K, Hauselmann HJ, Kaklamanis P, Kloppenburg M, Lohmander LS, Maheu E, Martin-Mola E, Pavelka K, Punzi L, Reiter S, Smolen J, Verbruggen G, Watt I, Zimmermann-Gorska I, Anonymous00031. · Dr W Zhang, Academic Rheumatology, University of Nottingham, Clinical Sciences Building, City Hospital, Nottingham NG5 1PB, UK. · Ann Rheum Dis. · Pubmed #18250111 No free full text.

Abstract: OBJECTIVES: To develop evidence-based recommendations for the diagnosis of hand osteoarthritis (OA). METHODS: The multidisciplinary guideline development group, representing 15 European countries, generated 10 key propositions regarding diagnosis using a Delphi consensus approach. For each recommendation, research evidence was searched for systematically. Whenever possible, the sensitivity, specificity and likelihood ratio (LR) were calculated; relative risk and odds ratios were estimated for risk factors for hand OA. Quality of evidence was categorised using the European League Against Rheumatism (EULAR) hierarchy, and strength of recommendation was assessed by the EULAR visual analogue scale. RESULTS: Diagnostic topics included clinical manifestations, radiographic features, subgroups, differential diagnosis, laboratory tests, risk factors and comorbidities. The sensitivity, specificity and LR varied between tests depending upon the cut-off level, gold standard and controls. Overall, no single test could be used to define hand OA on its own (LR <10) but a composite of the tests greatly increased the chance of the diagnosis. The probability of a subject having hand OA was 20% when Heberden nodes alone were present, but this increased to 88% when in addition the subject was over 40 years old, had a family history of nodes and had joint space narrowing in any finger joint. CONCLUSION: Ten key recommendations for diagnosis of hand OA were developed using research evidence and expert consensus. Diagnosis of hand OA should be based on assessment of a composite of features.

Bijlsma JW, Weinblatt ME. · No affiliation provided · Ann Rheum Dis. · Pubmed #17934080 No free full text.

Abstract: The CAMERA study shows that using methotrexate in a tight control setting might lead to considerable improvement in disease activity in early rheumatoid arthritis See linked article p 1443.

van der Zant FM, Boer RO, Moolenburgh JD, Jahangier ZN, Bijlsma JW, Jacobs JW. · Department of Nuclear Medicine, Hospital Medical Center Alkmaar, The Netherlands. · Clin Exp Rheumatol. · Pubmed #19327243 No free full text.

Abstract: OBJECTIVE: To perform a systemic review and meta-analysis on the effectiveness of radiosynoviorthesis (RSO). METHODS: A search of medical databases was conducted. Criteria for inclusion: articles in English, minimum follow-up of 6 months, specification of joint disease, reported outcome of at least 5 RSOs. The studies were scored for quality by the Oxford Centre of Evidenced-based Medicine Levels of Evidence, from 1 to 4. RESULTS: Twenty-one (21) studies were included (3 quality 1b, 5 2b and 13 4), analysing 169Erbium/186Rhenium-RSO used predominantly in small joints and 49 (1 quality 1b, 10 2b and 38 4) on 90Yttrium-RSO used predominantly in knee joints. The reported success rates of 169Erbium/186Rhenium-RSO ranged from 69-100% at 6 months, and from 54-100% at > or =12 months; for 90Yttrium they were 24-100% and 29-94%, res-pectively. Studies comparing the effect of RSO with that of glucocorticoid (GC) or saline injection alone were pooled. At 6 months, the pooled odds ratio favouring RSO of the knee with Yttrium over control is 4 (confidence interval (CI) 95% 1.2-14), p=0.02, but at 12 months the ratio was 1.7 (CI95% 0.69-4), p=0.26. For RSO of small joints with Erbium/Rhenium compared to controls, the pooled odds ratio at 6 months is 2 (CI95% 0.66-6), p=0.22 and at 12 months 2 (CI95% 1.09-3.5), p=0.03. CONCLUSION: Reported success rates of RSO are high, but differences in effect with GC injection are less evident, although there is marked heterogeneity in study design of the (small number of) comparative studies.

Cutolo M, Straub RH, Bijlsma JW. · Department of Rheumatology, University of Genova, Viale Benedetto XV, 6-16132 Genova, Italy. · Nat Clin Pract Rheumatol. · Pubmed #17968333 No free full text.

Abstract: Synovial tissue lines the noncartilaginous surfaces of synovial joints and supplies these avascular structures with nutrients. In diseases such as rheumatoid arthritis, inflammation of the synovial tissue--synovitis--induces diffuse damage to the joints. The presence of functional receptors for glucocorticoids, androgens and estrogens in synoviocytes might link inflammation and the endocrine system at the local level. Synovial tissue could be regarded as an intracrine tissue, whereby active steroids influence the cells in which they are synthesized, without their release into the extracellular space. An increase in the peripheral metabolism of sex steroids is characteristic of rheumatoid synovitis, with an augmented ratio of estrogen to androgen occurring in both male and female patients. Changes in the peripheral nervous system at the site of local inflammation are also hallmarks of synovitis in rheumatoid arthritis. In the chronic phase of synovitis, sympathetic nerve fibers are lost; by contrast, sensory nerve fibers sprout into the inflamed tissue. Complex interactions occur between the endocrine, nervous and immune systems during synovitis. In particular, studying neuroendocrine-immune interactions in the inflamed synovium will potentially uncover new mechanisms in the pathophysiology of rheumatoid arthritis and might lead to new methods of therapeutic intervention.

Bakker MF, Jacobs JW, Verstappen SM, Bijlsma JW. · University Medical Center Utrecht, Department of Rheumatology & Clinical Immunology, F02.127, PO Box 85500, 3508 GA Utrecht, The Netherlands. · Ann Rheum Dis. · Pubmed #17934098 No free full text.

Abstract: OBJECTIVE: To evaluate the available evidence on the efficacy and feasibility of the new concept of tight control in randomised trials in patients with rheumatoid arthritis (RA). Tight control is a treatment strategy tailored to the individual patient with RA, which aims to achieve a predefined level of low disease activity or remission within a certain period of time. METHODS: The literature database PubMed was searched and yielded four trials: the FIN-RACo trial, the TICORA study, the BeSt study and the CAMERA study. RESULTS: Tight control resulted in greater improvement and a higher percentage of patients meeting the preset aim of low disease activity or remission when compared to the control intervention. In the FIN-RACo trial, analysing the subset of patients completing the study, 68% in the tight control group achieved remission (DAS28<2.6) verus 41% in the contrast group [corrected] In the TICORA study, 65% of patients in the tight control group versus 16% of the contrast group achieved remission, based on DAS<1.6 (p<0.0001). In the CAMERA study, 50% of patients in the tight control group using a computer decision model achieved remission, versus 37% in the contrast group (p = 0.029). The BeSt study consisted of only tight control groups aimed at a DAS<1.6; remission was achieved in 38-46% of patients. This is higher than the range of remission in earlier trials of 13-36%. CONCLUSION: Tight control aiming for low disease activity or even better still, remission, seems a promising option in treating patients with RA in clinical trials and probably also in daily practice.

Kirwan JR, Bijlsma JW, Boers M, Shea BJ. · Liverpool Women's Hospital, Crown Street, Liverpool, UK, L8 7SS. · Cochrane Database Syst Rev. · Pubmed #17253590 No free full text.

Abstract: BACKGROUND: Glucocorticoid use in rheumatoid arthritis (RA) is widespread. Two Cochrane Reviews have been published examining the short term clinical benefit of low dose glucocorticoids compared to non-steroidal anti-inflammatory drugs and demonstrate good short term and medium term clinical benefits. The possibility that glucocorticoids may have a fundamental 'disease modifying' effect in RA, which would be seen by a reduction in the rate of radiological progression, has been raised by several authors. OBJECTIVES: To perform a systematic review of studies evaluating glucocorticoid efficacy in inhibiting the progression of radiological damage in rheumatoid arthritis. SEARCH STRATEGY: A search of MEDLINE (from 1966 to 22 February 2005) and the Cochrane Controlled Trials Register was undertaken, using the terms 'corticosteroids' and 'rheumatoid arthritis' expanded according to the Cochrane Collaboration recommendations. Identified abstracts were reviewed and appropriate reports obtained in full. Additional reports were identified from the reference lists and from expert knowledge. SELECTION CRITERIA: Randomized controlled or cross-over trials in adults with a diagnosis of rheumatoid arthritis in which prednisone or a similar glucocorticoid preparation was compared to either placebo controls or active controls (i.e. comparative studies) and where there was evaluation of radiographs of hands, or hands and feet, or feet by any standardised technique. Eligible studies had at least one treatment arm with glucocorticoids and one without glucocorticoids. DATA COLLECTION AND ANALYSIS: Standardised data extraction obtain the mean and standard deviation (SD) of change in erosion scores over 1 year or 2 years. (Where SD for change was not given a conservative estimate was taken from baseline data.) At least two authors selected the studies and extracted the data. Radiographic erosion scores were expressed as a percentage of the maximum possible score for the method used. The results were pooled after weighting in a random effects model to provide a standardised mean difference (SMD). MAIN RESULTS: The initial search produced 217 citations, and 15 were added from experts, abstracts and review of reference lists. Authors of 4 trials being prepared for publication (and subsequently published) kindly shared their data. After application of eligibility criteria 15 studies and 1,414 patients were included. The majority of trials studied early RA (disease duration up to 2 yrs), and the mean cumulative dose of glucocorticoid was 2,300 mg prednisone equivalent (range 270 mg - 5,800 mg) over the first year. Glucocorticoids were mostly added to other disease modifying anti-rheumatoid drug (DMARD) treatment. The standardised mean difference in progression was 0.40 in favour of glucocorticoids (95% CI 0.27, 0.54). In studies lasting 2 years (806 patients included), the standardised mean difference in progression in favour of glucocorticoids at 1 year was 0.45 (0.24, 0.66) and at 2 years was 0.42 (0.30, 0.55). All studies except one showed a numerical treatment effect in favour of glucocorticoids. The beneficial effects of glucocorticoids were generally achieved when used in conjunction with other DMARD treatment. AUTHORS' CONCLUSIONS: Even in the most conservative estimate, the evidence that glucocorticoids given in addition to standard therapy can substantially reduce the rate of erosion progression in rheumatoid arthritis is convincing. There remains concern about potential long-term adverse reactions to glucocorticoid therapy, such as increased cardiovascular risk, and this issue requires further research.

Hartgring SA, Bijlsma JW, Lafeber FP, van Roon JA. · Rheumatology and Clinical Immunology (F02.127), University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, the Netherlands. · Ann Rheum Dis. · Pubmed #17038478 No free full text.

Abstract: Interleukin (IL)-7 is a potent immunoregulatory cytokine that is detected in joints of patients with rheumatoid and juvenile idiopathic arthritis and which correlates with parameters of disease. Several synovial cell types that play an important role in inflammation and immunopathology, such as macrophages, dendritic cells, and fibroblasts, produce IL-7. IL-7 induces cytokines produced by arthritogenic T cells (for example, interferon gamma (IFNgamma), IL-17), T cell differentiating factors (for example, IL-12), chemokines capable of attracting inflammatory cells (for example, macrophage induced gene (MIG), macrophage inflammatory protein (MIP)-1alpha) as well as molecules involved in cell adhesion, migration, and costimulation (for example, lymphocyte function associated antigen (LFA)-1, CD40, CD80). In addition, IL-7 can induce bone loss by stimulating osteoclastogenesis that is dependent on receptor activator of nuclear factor kappaB ligand (RANKL). IL-7 induces tumour necrosis factor alpha (TNFalpha) secretion by T cells and by monocytes after T cell dependent monocyte/macrophage activation. Importantly, induction of both IL-7 and IL-7 induced effects seems to be able to operate independent of TNFalpha. Together this suggests that IL-7 is an important cytokine in several rheumatic conditions, capable of inducing inflammation and immunopathology. Thus it may be an important target for immunotherapy.

van Roon JA, Bijlsma JW, Lafeber FP. · Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands. · Best Pract Res Clin Rheumatol. · Pubmed #16980213 No free full text.

Abstract: During follow-up of the suppressive functions of CD4+ T helper (Th) 2 cells in recent years, the suppressive capacities of newly recognised CD4+ Th cells with more widespread suppressive potential have been extensively investigated. These Th cells, collectively termed regulatory T cells, are characterised by the secretion of specific cytokines, such as interleukin (IL)-10 (Tr1 Th cells), transforming growth factor (TGF)beta (Th3 cells) or the constitutive expression of CD25 (naturally occurring T regulatory cells, nTregs). The balance of these regulatory T cells with pro-inflammatory effector T cells, such as Th1 (interferon (IFN)gamma secreting), Th17 (IL-17 secreting) and CD25- Th cells, has been shown to be of pivotal importance for the development and persistence of autoimmune diseases. The high potential of regulatory T cells (in particular nTregs), to efficiently suppress several arthritic responses both in humans and in animal models of arthritis, make them therapeutic targets of interest in arthritic conditions such as rheumatoid arthritis.

Furst DE, Breedveld FC, Kalden JR, Smolen JS, Burmester GR, Bijlsma JW, Dougados M, Emery P, Keystone EC, Klareskog L, Mease PJ. · 1000 Veteran Avenue Rehabilitation Centre, Room 32-59, Los Angeles, CA 90024, USA. · Ann Rheum Dis. · Pubmed #16239380 links to  free full text

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Da Silva JA, Jacobs JW, Kirwan JR, Boers M, Saag KG, Inês LB, de Koning EJ, Buttgereit F, Cutolo M, Capell H, Rau R, Bijlsma JW. · Reumatologia, Hospitais da Universidade, 3000-075 Coimbra, Portugal. · Ann Rheum Dis. · Pubmed #16107513 links to  free full text

Abstract: Adverse effects of glucocorticoids have been abundantly reported. Published reports on low dose glucocorticoid treatment show that few of the commonly held beliefs about their incidence, prevalence, and impact are supported by clear scientific evidence. Safety data from recent randomised controlled clinical trials of low dose glucocorticoid treatment in RA suggest that adverse effects associated with this drug are modest, and often not statistically different from those of placebo.

Buttgereit F, Saag KG, Cutolo M, da Silva JA, Bijlsma JW. · Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany. · Scand J Rheumatol. · Pubmed #15903020 No free full text.

Abstract: Glucocorticoids (GCs) have powerful and potent anti-inflammatory and immunomodulatory effects in rheumatoid arthritis (RA) and many other diseases. These effects are mediated by up to four different mechanisms of action: cytosolic glucocorticoid receptor (cGCR)-mediated classical genomic and rapid non-genomic effects, membrane-bound glucocorticoid receptor (mGCR)-mediated non-genomic effects and non-specific non-genomic effects. On the basis of this detailed knowledge of mechanisms there are currently interesting approaches being considered that may lead to the development of GC drugs and GCR ligands with an improved benefit to side-effect ratio. Another interesting field of GC research is the phenomenon of GCR resistance. Several different mechanisms may mediate this phenomenon; among them are alterations in number, binding affinity, or phosphorylation status of the GCR. Other mechanisms of GC resistance being investigated are polymorphic changes and/or overexpression of (co-)chaperones, the increased expression of inflammatory transcription factors, overexpression of the GCR beta isoform, the multidrug resistance pump, and an altered mGCR expression.

Straub RH, Dhabhar FS, Bijlsma JW, Cutolo M. · Laboratory of Neuroendocrinoimmunology, Division of Rheumatology, Dept. of Internal Medicine I, University Hospital Regensburg, 93042 Regensburg, Germany. · Arthritis Rheum. · Pubmed #15641084 links to  free full text

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Bijlsma JW, Saag KG, Buttgereit F, da Silva JA. · Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Box 85500, 3508 GA Utrecht, The Netherlands. · Rheum Dis Clin North Am. · Pubmed #15639052 No free full text.

Abstract: Recent evidence for a disease-modifying potential of low-dose glucocorticoids (GCs) in the treatment of rheumatoid arthritis has renewed the debate on the risk benefit ratio with this therapy. Two recent developments are described that might have a positive influence on these risk benefit ratios. One is the improvement in new GC compounds--designer GCs, alterations in bioactivity, and alterations in formulations. The other is a better understanding and management of the toxicity of GCs.

Verstappen SM, Bijlsma JW, Verkleij H, Buskens E, Blaauw AA, ter Borg EJ, Jacobs JW, Anonymous00105. · Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands. · Arthritis Rheum. · Pubmed #15188338 links to  free full text

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Furst DE, Breedveld FC, Kalden JR, Smolen JS, Antoni CE, Bijlsma JW, Burmester GR, Cronstein B, Keystone EC, Kavanaugh A, Klareskog L. · University of California, Los Angeles, CA, USA. · Ann Rheum Dis. · Pubmed #12379612 links to  free full text

This publication has no abstract.

van Roon JA, Bijlsma JW. · UMC Utrecht, The Netherlands. · Ann Rheum Dis. · Pubmed #12379513 links to  free full text

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van Roon JA, Bijlsma JW, Lafeber FP. · Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, The Netherlands. · Curr Opin Investig Drugs. · Pubmed #12186260 No free full text.

Abstract: A predominance of T-helper 1 (Th1) activity and a lack of Th2 activity has been documented in the inflamed joints of patients with rheumatoid arthritis (RA). This imbalance is suggested to contribute to activation of, particularly, inflammatory macrophages and B-cells. Th2-mediated immunity, like atopy, is associated with amelioriated inflammation and joint damage in RA patients. Despite the potent anti-inflammatory capacities of two prominent Th2 cytokines in many experimental studies, clinical trials with either human IL-4 or IL-10 in RA patients did not lead to substantial disease suppression. Based on a thorough evaluation of the actions of IL-4 and IL-10 in these studies, it is hypothesized that disease suppression of RA may require the concerted action of suppressive Th2 cytokines or Th2 activity.

Bijlsma JW, Van Everdingen AA, Huisman M, De Nijs RN, Jacobs JW. · Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, the Netherlands. · Ann N Y Acad Sci. · Pubmed #12114262 No free full text.

Abstract: Recently, four prospective placebo-controlled studies have further evaluated the disease-modifying properties of glucocorticoids in the treatment of rheumatoid arthritis. These studies irrefutably show that the use of (low) doses of glucocorticoids leads to a significant retardation of the progression of erosions, especially in early rheumatoid arthritis. This effect on erosions seems more impressive and probably more persistent than the well-known relief during low-dose glucocorticoid therapy of symptoms, such as pain, stiffness, and joint scores. The management of the (side) effects of glucocorticoids on bone has clearly improved in the last years. These two developments lead to a further optimizing of glucocorticoid treatment in patients with rheumatoid arthritis.

Cutolo M, Bijlsma JW, Lahita RG, Masi AT, Straub RH, Bradlow HL. · University of Genova, Italy. · Ann N Y Acad Sci. · Pubmed #12114252 No free full text.

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Derksen RH, Bijlsma JW. · Universitair Medisch Centrum Utrecht, afd. Reumatologie & Klinische Immunologie, Postbus 85.500, 3508 GA Utrecht. · Ned Tijdschr Geneeskd. · Pubmed #12109305 No free full text.

Abstract: Monoclonal antibodies are increasingly used to modulate immunologically mediated diseases such as rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, Crohn's disease, multiple sclerosis and systemic vasculitis. Constructs of monoclonal antibodies to tumour necrosis factor (TNF) alpha differ with respect to their structure, effects and immunogenic side effects. Clinical experience with TNF alpha-neutralizing therapy has revealed several other side effects over the past few years. The most important is increased infection rates, especially the activation of (latent) tuberculosis, although other opportunistic infections such as listeriosis, Pneumocystis carinii pneumonia, histoplasmosis, candidiasis and aspergillosis have also been reported. Furthermore, results from clinical studies indicate that TNF alpha-neutralizing therapy should not be given to patients with cardiac failure (NYHA class III or IV) or a history of demyelinating disease. An increased incidence of malignancies has not been observed up to now, but data from the long-term follow-up are not yet available.

van Roon JA, Lafeber FP, Bijlsma JW. · Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, The Netherlands. · Arthritis Rheum. · Pubmed #11212172 links to  free full text

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Bijlsma JW, Jacobs JW. · Department of Rheumatology and Clinical Immunology, University Medical Center, Utrecht, The Netherlands. · Rheum Dis Clin North Am. · Pubmed #11084950 No free full text.

Abstract: Bone loss is a hallmark of RA. Factors influencing generalized bone loss include RA-specific factors such as the influence of disease activity and deficient sex hormone status and more general mechanisms (e.g., due to the use of glucocorticoids). Reducing disease activity has a positive effect on bone. Estrogens or androgens can restore deficiency of the sex hormones with a small positive effect on BMD. The more pronounced bone loss occurs when RA patients are being treated with glucocorticoids. This bone loss can be reduced by the concomitant use of calcium and vitamin D and, in most patients, by the use of bisphosphonates as well.

Da Silva JA, Bijlsma JW. · Department of Rheumatology, Coimbra University, Portugal. · Rheum Dis Clin North Am. · Pubmed #11084948 No free full text.

Abstract: Glucocorticoids have a profound effect on the immune system and also on the HPA axis. Present insights into these mechanisms are discussed. Glucocorticoid resistance and clinical efficacy in the treatment of RA are reviewed. There is growing evidence for a positive effect of low-dose glucocorticoids on the retardation of erosive joint damage. Side effects of glucocorticoids on bone are now better controlled. Some guidelines to optimize glucocorticoid therapy in RA are given regarding dosage, timing, managing of side effects, and (new) types of glucocorticoids.

Jacobs JW, Blaauw AA, Dijkmans BA, van Riel PL, Bijlsma JW. · Universitair Medisch Centrum, afd. Reumatologie en Klinische Immunologie, Utrecht. · Ned Tijdschr Geneeskd. · Pubmed #10682647 No free full text.

Abstract: As soon as the diagnosis 'early rheumatoid arthritis (RA)' is made, a disease-modifying antirheumatic drug (DMARD) should be prescribed without delay. Methotrexate in dosages up to 30 mg once weekly is being used more frequently than in the past, also in early RA. Combination therapy with DMARDs is indicated in case of insufficient effect of a single DMARD. Combinations with methotrexate appear to be especially effective, like methotrexate and cyclosporin. A novel effective DMARD is leflunomide. In the near future promising biologicals will probably be applied in clinical daily practice, presumably in combination with conventional DMARDs. New non-steroidal anti-inflammatory drugs (NSAIDs) have been developed that are probably safer than conventional NSAIDs. If the recent finding that glucocorticoids are able to inhibit joint damage in (early) RA will be confirmed, prednisone might be used more often in (early) RA. Bone marrow transplantation in RA is still experimental.

Masi AT, Bijlsma JW, Chikanza IC, Pitzalis C, Cutolo M. · Department of Medicine, University of Illinois College of Medicine at Peoria, 61656-1649, USA. · Semin Arthritis Rheum. · Pubmed #10553979 No free full text.

Abstract: OBJECTIVE: To review the "core" systems interactions in rheumatoid arthritis (RA): neuroendocrine, immunologic, and microvascular, and to interpret an integrated physiopathogenesis of the disease, beginning at a preclinical phase of risk factors to the later stages of manifest clinical inflammation. METHODS: Publications on stress reactions, serum hormonal levels, biological mediators of inflammation and vascular alterations in RA during its preclinical phase, course of active disease, including pregnancy, and hormonal therapy of active disease were retrieved. In addition, experimental reports on biological models of the disease were considered. Levels of adrenal and gonadal steroids (ie, glucocorticosteroids [GCS], dehydroepiandrosterone [DHEA], its sulfate [DHEAS], estradiol [E2], and testosterone [T]), as well as prolactin (PRL) and other hormones, biological mediators, vascular endothelial system (VES) interactions with hormones, and immunologic mediators of inflammation in RA, were reviewed and interpreted. RESULTS: Women with premenopausal onset of RA not previously treated with GCS had lower basal serum levels of adrenal androgens, that is, DHEA or DHEAS, both before and after onset of clinical disease, compared with controls. Risk factors, including hormonal, immunologic, and hereditary indicators, were found to be uniformly present many years before clinical onset in such younger women, as compared with a frequency of circa 15% in matched controls. Also, a history of heavy cigarette smoking significantly predicted the onset of RA in perimenopausal women, and in men, suggesting that vascular endothelial alterations predispose to the disease. In the same prospective study, 1 or more of 4 risk factors were present an average of 12 years before clinical onset of disease in 83% of male RA cases versus 26% in matched controls (ie, sensitivity of 83% and specificity of 74%). Early RA patients may have lower serum cortisol levels than normal controls, and less than expected for the degree of ongoing inflammation, as well as having upregulated PRL levels. CONCLUSION: Among persons genetically prone to RA, the "core" systems are hypothesized to become "remodeled" during a long preclinical phase as a result of chronic imbalances in their interactive homeostasis. This hypothesis needs to be critically assessed in further studies of such physiological precursors of disease as well as stressors in the development and course of RA. Optimal hormonal management of biological mediators of RA is also a priority challenge for disease control in the future. Relevance: Evidence indicates that men and women who are susceptible to premenopausal onset of RA can each be identified long before their clinical onsets of disease, and that productive research in primary prevention is an achievable objective. Disease prevention objectives are central in the public health strategy of the National Arthritis Action Plan and of the US Public Health Service "Healthy People 2000" (and 2010 proposed). Success in such prevention goals can be expected to significantly reduce the enormous burden of this common disease, which affects all segments of the population.