Rheumatoid Arthritis: Huizinga TW

Pincus T, Huizinga TW, Yazici Y. · No affiliation provided · J Rheumatol. · Pubmed #17304647 links to  free full text

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Huizinga TW, Ioan-Facsinay A. · No affiliation provided · J Rheumatol. · Pubmed #12966588 No free full text.

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Klarenbeek NB, Allaart CF, Kerstens PJ, Huizinga TW, Dijkmans BA. · Department of Rheumatology, C-01-R, Leiden University Medical Center, PO Box 9600, Leiden 2300 RC, The Netherlands. · Curr Opin Rheumatol. · Pubmed #19318946 No free full text.

Abstract: PURPOSE OF REVIEW: To give an overview of recent strategy trials for the treatment of rheumatoid arthritis. RECENT FINDINGS: Strategy studies showed a clear benefit of dynamic result-driven treatment towards tight control of disease activity compared with 'usual care' in rheumatoid arthritis patients. In addition, treatment given after short symptom duration gives better outcomes than later initiation of treatment. In many trials, combination therapies, especially combinations with prednisolone or biologicals, were superior to monotherapies. Moreover, combination therapies were more effective if given early in the disease as compared with a delayed introduction, giving support to the window of opportunity hypothesis. In the BeSt study, initial combination therapy could be successfully discontinued in half of the patients, emphasizing that 'initial' would mean 'temporary'. Less evidence is available about initial combination in comparison with combination therapy with a shorter delay. Larger tight-controlled, goal-steered, dynamic strategy trials comparing initial combination therapy with a short-delay combination therapy will help to translate the use of initial (temporary) combination therapy into normal daily practice. SUMMARY: Treatment strategy trials have demonstrated that in the majority of patients with rheumatoid arthritis, the following approach is the most beneficial: goal-steered, dynamic treatment towards tight control of disease activity, including early introduction of (an) effective disease-modifying antirheumatic drug(s) in combination with prednisone or antitumor necrosis factor, which includes tapering of the medication if remission or low disease activity is achieved.

Aletaha D, Huizinga TW. · Division of Rheumatology, Department of Internal Medicine 3, Medical University of Vienna, Vienna, Austria. · Best Pract Res Clin Rheumatol. · Pubmed #19233051 No free full text.

Abstract: Many early arthritis clinics have been started in the past decade. A major objective of these clinics is to improve our understanding of early arthritis in its undifferentiated form and to help provide guidance, recommendations, or criteria for diagnostic and therapeutic decision-making in patients with such presentation. Increasingly, they will allow aspects of pathogenesis - including autoantibodies and potential genetic markers - to be included in the set of clinical predictors that a rheumatologist is presented with. From an analytical perspective, usually logistic regression modelling is used to identify the best predictors of potentially long-lasting and/or erosive disease. Classification tree analysis might be another way to analyse data, and has the advantage that the results are easier to interpret than statistical parameters. In the past, many such projects have been published, none of which has achieved widespread use. Currently, the American College of Rheumatology and the European League Against Rheumatism are in the process of defining new criteria for rheumatoid arthritis that will allow earlier diagnosis and treatment of patients and definition of patients with early disease for inclusion in clinical trials.

Feitsma AL, van der Helm-van Mil AH, Huizinga TW, de Vries RR, Toes RE. · Department of Rheumatology, LUMC, Leiden, The Netherlands. · Ann Rheum Dis. · Pubmed #19022816 No free full text.

Abstract: Rheumatoid arthritis (RA) is a complex genetic disorder in which the HLA region contributes most to the genetic risk. HLA-DRB1 molecules containing the amino acid sequence QKRAA/QRRAA/RRRAA (ie, HLA-DRB1*0101, *0102, *0401, *0404, *0405, *0408, *0410, *1001 and *1402) at position 70-74 in the third hypervariable region of the DRB1 chain are associated with susceptibility to RA. HLA-DRB1 molecules containing the amino acids "DERAA" (ie, HLA-DRB1*0103, *0402, *1102, *1103, *1301, *1302 and *1304) at the same position are associated with protection from RA. Interestingly, not only inherited but also non-inherited HLA-antigens from the mother can influence RA susceptibility. A protective effect of "DERAA"-containing HLA-DRB1 alleles as non-inherited maternal antigen (NIMA) has recently been described. The underlying mechanism of this protective effect is currently unknown, although a possible explanation is covered below. In this review, an overview of the current knowledge on protection against RA is given and the inherited and NIMA effect of "DERAA"-containing HLA-DRB1 alleles are compared.

van der Woude D, Huizinga TW. · Leiden University Medical Center, Department of Rheumatology, Albinusdreef 2, 2300 RC Leiden, The Netherlands. <> · Best Pract Res Clin Rheumatol. · Pubmed #18455686 No free full text.

Abstract: Findings from basic research in combination with precise clinical observations of the disease course in rheumatoid arthritis (RA) have led to the development of a multistage model to explain the pathophysiology of RA. Different cellular and soluble mediators, which play principal roles at different phases of the disease, have been identified. New therapeutic agents, which specifically target these factors, now allow us to intervene at several levels of the pathogenesis. This has already resulted in significant improvements for patients suffering from RA, and the development of new promising agents continues at a high pace. However, many questions concerning the optimal use of the new therapies remain unanswered. Combined efforts of basic research and clinical trials investigating the optimal timing and combination of the new treatments will be necessary to allow them to achieve their full potential and to result in the maximum benefit for patients.

van der Helm-van Mil AH, Huizinga TW. · Department of Rheumatology, Leiden University Medical Center, PO Box 9600, 2300RC Leiden, The Netherlands. · Arthritis Res Ther. · Pubmed #18394179 links to  free full text

Abstract: In the past few years considerable advances have been made in the genetics of susceptibility to rheumatoid arthritis (RA). For decades the HLA-DRB1 alleles were the only extensively replicated genetic factor, but more genetic risk factors have now been identified that predispose to RA. Interestingly, several of the observed genetic variants conferred risk to anticitrulline-peptide antibody (ACPA)-positive RA and two variants may be restricted to ACPA-negative RA, pointing to the need for subclassification of RA. The current manuscript reviews recently identified genetic factors predisposing to ACPA-positive RA and ACPA-negative RA. Additionally, although being scarcely explored, genetic variants affecting the severity of disease course are discussed.

Wessels JA, Huizinga TW, Guchelaar HJ. · Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. · Rheumatology (Oxford). · Pubmed #18045808 No free full text.

Abstract: This review presents recent data supporting the methotrexate (MTX) mechanisms of action, which are likely to account for its anti-proliferative and immunosuppressive effects in rheumatoid arthritis (RA). The effects of MTX in vivo may be mediated by reducing cell proliferation, increasing the rate of apoptosis of T cells, increasing endogenous adenosine release, altering the expression of cellular adhesion molecules, influencing production of cytokines, humoral responses and bone formation. Several reports indicate that the effects of MTX are influenced by genetic variants, specific dynamic processes and micro-environmental elements such as nucleotide deprivation or glutathione levels. The challenge for the future will be linking biological and genetic markers relevant to the response to MTX in RA.

van der Helm-van Mil AH, Huizinga TW, de Vries RR, Toes RE. · Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #17534941 links to  free full text

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Kooloos WM, de Jong DJ, Huizinga TW, Guchelaar HJ. · Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, PO Box 9600, NL 2300 RC Leiden, The Netherlands. · Drug Discov Today. · Pubmed #17275732 No free full text.

Abstract: Etanercept, infliximab and adalimumab have shown clinical benefit in immune-mediated inflammatory diseases; however, the outcome of treatment with these tumour-necrosis factor inhibitors remains insufficient in approximately 40-60% and approximately 25-40% of individuals with rheumatoid arthritis and Crohn's disease, respectively. Moreover, their use is accompanied by adverse events and unintentional immune suppression. Pharmacogenetics has the potential to increase efficacy and ameliorate adverse events and immune suppression, and its application might be of clinical benefit for patients with rheumatoid arthritis and Crohn's disease. Pharmacogenetic studies have shown associations between single nucleotide polymorphisms in genes encoding enzymes related to the pharmacodynamics of these drugs and treatment outcome. As we discuss here, replication and prospective validation are warranted before pharmacogenetics can be used in clinical practice.

Wesoly J, Wessels JA, Guchelaar HJ, Huizinga TW. · Department of Rheumatology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. · Curr Rheumatol Rep. · Pubmed #16973111 No free full text.

Abstract: Rheumatoid arthritis patients exhibit a considerable interindividual variability in response to drug treatment. Although many disease-related and demographic factors have been studied to predict treatment outcome, the effective disease-modifying antirheumatic drug (DMARD) therapy is not yet allocated based on factors that predict efficacy. Individual genetic characteristics are thought to play an important role in treatment response; therefore, current research aims to identify these genetic predictors for clinical response. Pharmacogenetic studies are beginning to provide results, which suggests that personalized treatment maximization of DMARD efficacy and minimization of adverse drug reactions are feasible.

van der Helm-van Mil AH, Breedveld FC, Huizinga TW. · Department of Rheumatology, Leiden University Medical Center, The Netherlands. · Arthritis Res Ther. · Pubmed #16879719 links to  free full text

Abstract: With regard to rheumatoid arthritis, remission as currently used in the literature can have two meanings: either a state with persistent absence of clinical and radiological signs of disease activity without being treated for a specific time period, or it may point to a disease state with minimal disease activity during antirheumatic treatment. A risk factor for the first is absence of autoantibodies, with the anti-CCP-antibodies as best predictors, whereas risk factors for achieving a drug-induced state of minimal disease activity are not well defined. These definitions of remission refer to different disease states; therefore, we propose that the term remission is reserved for patients that are not treated with antirheumatic drugs.

de Vries RR, Huizinga TW, Toes RE. · Department of Immunohematology/Bloodtransfusion, Leiden University Medical Center, The Netherlands. · Hum Immunol. · Pubmed #16728269 No free full text.

Abstract: An obvious way to unravel the apparently complex association between human leukocyte antigen (HLA) and rheumatoid arthritis (RA) is to reduce the heterogeneity of this multifactorial disease. Recently we have discovered that shared epitope (SE)-positive HLA-DRB1 alleles are exclusively associated with a subgroup of RA patients that test positive for auto-antibodies against cyclic citrullinated peptides. Further studies suggested that SE-positive alleles are classical immune response genes for the development of these antibodies. On the basis of these and other data we formulated a two-hit model for the pathogenesis of RA which incorporates a novel "citrullinated" SE hypothesis. About 5 years ago Zanelli et al. reported that HLA-DR6 (*1301 and *1302) and some other DR alleles that share the DERAA-sequence on amino acids 70-74 of their third hypervariable region are associated with protection from (severe) RA. Recently we corroborated these data in a large prospective cohort study and demonstrated that protection was observed both in the presence and in the absence of a SE susceptibility allele on the other haplotype. Finally we review the state of the art of the association of noninherited maternal HLA antigens with both susceptibility to and protection from RA.

de Vries RR, Huizinga TW, Toes RE. · Department of Immunohematology and Bloodtransfusion, Leiden University Medical Center, Building 1, E3-Q, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. · J Autoimmun. · Pubmed #16257178 No free full text.

Abstract: Rheumatoid Arthritis (RA) is the most common chronic inflammatory joint disease. The overall prevalence is 1% and in people older than 60 it is more than 2%. RA has auto-immune features: auto-antibodies against the Fc part of IgG, so-called Rheumatoid Factor (RF) are found more often in RA patients and more recently RA-specific auto-antibodies directed against Cyclic Citrunilated Peptides (CCP) have been discovered. Based on twin studies the contribution of genetic factors to the pathogenesis has been estimated to be about 60%. The main genetic contribution (about 40%) comes from the HLA complex. An association between HLA-DR4 and RA was already documented almost 30 years ago. This association was more prominent for severe forms of the disease. Because more HLA-DRB1 alleles appeared to be associated with RA and the products of these alleles shared a 5AA sequence in a peptide-binding pocket the so-called Shared Epitope (SE) hypothesis was formulated, the prediction being that these DRB1 molecules would bind an RA inducing peptide(s). Thus far however such (a) peptides remain elusive. Because the risk for RA associated with different but SE-identical DRB1 alleles varies considerably this SE can also not be the whole explanation for the HLA contribution to RA susceptibility/severity. A modified SE has been postulated and a role for DQ has been postulated. There is also evidence for a contribution of non-class II genes to susceptibility. About 5 years ago we have reported that certain HLA-DRB1 alleles are associated with protection from (severe) RA. The products of these alleles carry instead of the SE sequence another peptide anchor region consisting of the amino acid DERAA. In a large prospective cohort study we showed recently that these alleles indeed confer (dominant) protection both against developing RA and a severe course of the disease. This protection was observed both in the presence and the absence of SE susceptibility alleles. We are presently exploring the hypothesis that this protection is mediated by regulatory T cells reactive with the DERAA epitope. An obvious way to unravel the apparently complex association between HLA and RA is to reduce the heterogeneity of this multifactorial disease. Recently, we have discovered that SE positive DRB1 alleles are exclusively associated with CCP positive RA. The previously reported association with RF positive RA appeared to be secondary to the association with anti-CCP pos. RA. This was the case both for the association found for susceptibility and severity. Interestingly, DRB1*03 was exclusively associated with anti-CCP neg. RA. Because recent evidence puts the immune response against citrunilated proteins (CCP) as prime suspect for disease induction and progression in this subgroup of RA these observations are a big leap forwards in solving the HLA-RA puzzle.

van Gaalen F, Ioan-Facsinay A, Huizinga TW, Toes RE. · Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands. · J Immunol. · Pubmed #16237041 links to  free full text

Abstract: Rheumatoid arthritis is a chronic inflammatory autoimmune disease of unknown cause. The immune response against citrullinated Ags has recently become the prime suspect for disease pathogenesis. Immunity against citrullinated Ags is thought to play a pivotal role in the disease for several reasons: 1) citrullinated Ags are expressed in the target organ, the inflamed joint; 2) anti-citrullinated protein Abs are present before the disease becomes manifest; and 3) these Abs are highly specific for rheumatoid arthritis. In this review, data from clinical, genetic, biochemical, and animal studies is combined to create a profile of this remarkable autoantibody response. Moreover, a model is proposed of how the anti-citrullinated proteins response is generated and how it could eventually lead to chronic inflammation.

van der Helm-van Mil AH, Wesoly JZ, Huizinga TW. · Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. · Curr Opin Rheumatol. · Pubmed #15838240 No free full text.

Abstract: PURPOSE OF REVIEW: The identification of the genetic variants that mediate the risk for susceptibility and severity of rheumatoid arthritis will allow the development of new drug targets and also increase the ability to predict disease course. Technical and methodologic progress has fueled the advances in this field. RECENT FINDINGS: The second risk factor for rheumatoid arthritis, the PTPN22 polymorphism, has been identified. This genetic variant regulates the threshold of T cell activation. Intriguingly, this variant is a risk factor for diabetes as well. Moreover, it has been shown that multiple genetic variants in one pathway (both in a transcription factor, RUNX-1, as in the transcription factor binding site of RUNX1 in the SLC22A4 gene) can each confer very small risks but by gene-gene interactions can confer a ninefold risk for rheumatoid arthritis. These genetic risk factors have been found to confer risk for multiple autoimmune diseases. Phenotype-genotype interactions were described by the enhanced prevalence of a rheumatoid arthritis-specific autoantibody (anti-cyclic citrullinated peptide antibodies) in rheumatoid arthritis patients that harbor the rheumatoid arthritis-associated human leukocyte antigen class II genes, the shared epitope alleles. An environmental factor, smoking was demonstrated to confer risk for rheumatoid arthritis, especially in patients positive for both shared epitope and rheumatoid arthritis-specific anti-cyclic citrullinated peptide antibodies. SUMMARY: Two new pathways, T cell receptor signaling and a hematopoietic-specific signal transduction pathway, have been discovered that allow future pharmacologic interventions. The description of the new genetic risk factors and the interaction with environmental triggers as well as phenotypic features are gradually expanding the ability to predict disease susceptibility and course.

Verpoort KN, van Dongen H, Allaart CF, Toes RE, Breedveld FC, Huizinga TW. · Department of Rheumatology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. · Clin Exp Rheumatol. · Pubmed #15552509 No free full text.

Abstract: The prognosis of patients with undifferentiated arthritis (UA) may vary from self-limited to severe destructive rheumatoid arthritis (RA). Because early aggressive treatment might offer an effective means to slow disease progression in RA, it is important to identify UA patients who will develop RA and treat them as early as possible. At the same time, inappropriate treatment of patients with a more benign disease course should be avoided. Here, an overview is given of the characteristics and numbers of patients with UA who evolve into RA. UA is defined as any arthritis that has the potential for a persistent course, without fulfilling the classification criteria for specific rheumatic disorders. To compare endpoints in the different databases, the 1987 ACR criteria for RA were used. In the nine databases employing a similar definition for undifferentiated arthritis, the proportion of patients with UA that evolved into RA within 1 year varied from 6% to 55%. These differences arise in large part from differences in the inclusion criteria and in the definitions used for UA and RA. The data from the various cohorts support a hypothesis that a considerable proportion of UA patients are actually patients with RA in a very early stage. Controlled intervention studies with early antirheumatic treatment in these patients are mandatory in order to provide further insight into the natural course of UA and to define a treatment strategy that will successfully slow or prevent disease progression.

van Aken J, van Bilsen JH, Allaart CF, Huizinga TW, Breedveld FC. · Leiden University Medical Center, Leiden, The Netherlands. · Clin Exp Rheumatol. · Pubmed #14969059 No free full text.

Abstract: In 1993 a special Early Arthritis Clinic (EAC) was established at the Department of Rheumatology of the Leiden University Medical Center in order to detect and treat inflammatory disorders early in the disease state, especially early rheumatoid arthritis. Patients with confirmed arthritis of recent onset (less than 2 years) were included by rheumatologists and trained research nurses. Parameters of first and follow-up visits (3, 6 and 9 months and yearly) that were entered in the EAC-database include the medical history, physical-diagnostic examination, laboratory tests, questionnaires, radiographic joint scores and diagnosis. This database enables us to conduct research on arthritis, with an emphasis on rheumatoid arthritis, in many ways. Physicians and basic scientists have studied cellular immunology and genetic, environmental and clinical risk factors in order to determine the pathophysiologic mechanisms of inflammatory arthritis. The present article is a review on reports published from the EAC. Over the past ten years, these reports have been highly relevant for both daily clinical practice and research. Present and planned future studies, as described in this article, reconfirm the importance of an EAC framework to ensure that research continues on this disease in the Leiden EAC area.

Huizinga TW. · Department of Rheumatology, C4-R, Leiden University Medical Center, P.O. Box 9600, RC 2300, Leiden, The Netherlands. · Best Pract Res Clin Rheumatol. · Pubmed #12915153 No free full text.

Abstract: This chapter reviews the latest original research on the genetics of rheumatoid arthritis (RA), with a focus on its relevance for the clinical rheumatologist. The following questions will be dealt with in order to appreciate the recent progress in this field. * Why is a knowledge of genetics useful for an understanding of the pathogenesis of RA? * Is a knowledge of genetic risk factors relevant for day-to-day clinical practice? * What methods are used for identifying genetic risk factors? * Which genetic regions have been identified in susceptibility to RA? * What risk factors have been identified? * What are the future prospects and research agenda?

Huizinga TW, Machold KP, Breedveld FC, Lipsky PE, Smolen JS. · Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #12115216 links to  free full text

This publication has no abstract.

Goossens PH, Huizinga TW. · Department of Rheumatology, Leiden University Medical Center, The Netherlands. · Clin Exp Rheumatol. · Pubmed #12102483 No free full text.

Abstract: In various animal models gene transfer to the synovial tissue has been shown after intraarticular injection of adenoviral vectors. Safety of the transfer of therapeutic genes to the synovial tissue depends on multiple factors, including the mode of administration, the vector and the gene used, and the immune system of the host. In this article, data on the biodistribution and induction of inflammation after the intraarticular administration of adenoviral vectors are summarized and discussed. The ultimate goal of gene therapy will be the injection of a vector that has a specific target cell. Such a goal will require major improvements in the currently available delivery systems or the development of novel vectors. In this article new strategies are proposed in which gene transfer efficiency to the synovial tissue increases, whereas simultaneously the effect of neutralization of the adenoviral vector by the synovial fluid is circumvented.

Huizinga TW. · Leiden University Medical Center, Department of Rheumatology, C4-R, PO Box 9600, 2300 RC Leiden, The Netherlands. · Curr Rheumatol Rep. · Pubmed #12010603 No free full text.

Abstract: The data from the human genome project were published in 2001. Although this achievement will boost research in the genetics of rheumatoid arthritis (RA), most of the work is in progress. Three of the four consortia that are performing linkage studies to identify loci that are transmitted more often to patients than controls have published data on genome-wide searches in few families. Of all the possible candidate genes, the human leukocyte antigen (HLA) class II region was found in the pan-European and the US linkage studies, confirming the previous data from association studies that HLA class II alleles confer risk to RA. Although HLA as a risk factor for RA has been known for a long time, the mechanism by which HLA alleles affect disease risk are controversial. Several papers have been published recently that support the RA-protection hypothesis. Several candidate loci/genes have been suggested from association studies. However, these associations have not been reproduced by different groups in several different cohorts.

van der Bijl AE, Emmer BJ, Breedveld FC, Middelkoop HA, Jurgens CK, van Buchem MA, Huizinga TW, van der Grond J. · Departments of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. · Clin Exp Rheumatol. · Pubmed #17543158 No free full text.

Abstract: OBJECTIVE: Neurological symptoms have been reported in patients treated with anti-TNF-alpha. In a pilot study we evaluated the effect of anti-TNF-alpha on cerebral parenchyma using advanced Magnetic Resonance (MR) techniques. METHODS: Seven patients with a systemic inflammatory disease (5 rheumatoid arthritis, 2 psoriatic arthritis) had Magnetization Transfer Imaging, Diffusion Weighted Imaging (DWI) and Magnetic Resonance Spectroscopy (MRS) of the brain before and after administration of anti-TNF-alpha. Four patients were neuropsychologically evaluated. RESULTS: After treatment with TNF-alpha blocking agents the Magnetization Transfer Ratio histogram Peak-heights (MTR-Pht) of the white and gray matter decreased (p < 0.01 and p < 0.05 respectively). The Apparent Diffusion Coefficient for the white and gray matter and the metabolite ratios in the centrum semiovale did not significantly change after therapy. Neuropsychological assessment showed no difference before and after anti-TNF-alpha. CONCLUSION: The decrease of the MTR-Pht after anti-TNF-alpha therapy suggests loss of parenchyma integrity; however, these changes could not be attributed to inflammation or demyelination based on our complementary DWI and MRS data. The decrease of the MTR-Pht did not result in decreased cognitive function.

van Oosterhout M, Levarht EW, Sont JK, Huizinga TW, Toes RE, van Laar JM. · Leiden University Medical Centre, Department of Rheumatology, PO Box 9600, 2300 RC Leiden, Netherlands. · Ann Rheum Dis. · Pubmed #15769913 links to  free full text

Abstract: BACKGROUND: Tumour necrosis alpha (TNF alpha) blocking agents lead to pronounced clinical effects and reduced synovial infiltrate in rheumatoid arthritis. Laboratory and clinical studies suggest that TNF alpha independent pathways play a role in the disease. OBJECTIVES: To evaluate the immunopathological effects of combination therapy on rheumatoid synovial tissue in order to identify TNF alpha independent mechanisms. METHODS: 12 rheumatoid patients, including four DMARD (disease modifying antirheumatic drug) naive patients with early disease, were studied for the effect of combination therapy with infliximab and methotrexate on the synovial infiltrate. Biopsies and clinical assessments (DAS28) were carried out before the first and after the third infusion of infliximab. Synovial inflammation was scored semiquantitatively. Co-expression of CD38(+) cells was studied by an immunofluorescent double labelling technique. RESULTS: Marked clinical responses were associated with a global reduction in the synovial infiltrate and expression of cytokines, notably interleukin 18 and TNF alpha, but low grade disease activity persisted. There was no effect on the expression of CXC chemokine ligand (CXCL12), and germinal centre-like structures were still detectable in synovial tissue in two patients after treatment. CD38(+) activated T cells were more resistant to treatment than CD38(+) plasma cells. No differences in clinical response or effects on synovial infiltrate were observed between DMARD refractory and DMARD naive patients. CONCLUSIONS: Persistent expression of CXCL12 and incomplete resolution of lymphocytic infiltrates after infliximab plus methotrexate indicates that TNF alpha independent mechanisms are operative in rheumatoid arthritis. This may contribute to low grade disease activity, even in DMARD naive patients with early disease.

de Jong Z, Munneke M, Zwinderman AH, Kroon HM, Ronday KH, Lems WF, Dijkmans BA, Breedveld FC, Vliet Vlieland TP, Hazes JM, Huizinga TW. · Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands. · Ann Rheum Dis. · Pubmed #15479889 links to  free full text

Abstract: OBJECTIVE: To investigate the effect of long term high intensity weightbearing exercises on radiological damage of the joints of the hands and feet in patients with rheumatoid arthritis (RA). METHODS: Data of the 281 completers of a 2 year randomised controlled trial comparing the effects of usual care physical therapy (UC) with high intensity weightbearing exercises were analysed for the rate of radiological joint damage (Larsen score) of the hands and feet. Potential determinants of outcome were defined: disease activity, use of drugs, change in physical capacity and in bone mineral density, and attendance rate at exercise sessions. RESULTS: After 2 years, the 136 participants in high intensity weightbearing exercises developed significantly less radiological damage than the 145 participants in UC. The mean (SD) increase in damage was 3.5 (7.9) in the exercise group and 5.7 (10.2) in the UC group, p = 0.045. Separate analysis of the damage to the hands and feet suggests that this difference in rate of increase of damage is more pronounced in the joints of the feet than in the hands. The rate of damage was independently associated with less disease activity, less frequent use of glucocorticoids, and with an improvement in aerobic fitness. CONCLUSION: The progression of radiological joint damage of the hands and feet in patients with RA is not increased by long term high intensity weightbearing exercises. These exercises may have a protective effect on the joints of the feet.