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ID PMID Title PublicationDate abstract
11550964 Improved functional ability in patients with rheumatoid arthritis--longterm treatment with 2001 Sep OBJECTIVE: We previously reported that the new disease modifying antirheumatic drug leflunomide resulted in significant improvement in functional ability compared with placebo and sulfasalazine in a 6 month double blind, randomized, Phase III trial in rheumatoid arthritis (RA). The current study compared functional disability in cohorts of patients with RA from the initial study who volunteered to continue treatment with leflunomide or sulfasalazine. METHODS: The Health Assessment Questionnaire (HAQ) was used to assess functional ability in patients completing 6 months of therapy who chose to continue in double blinded 12 and 24 month extensions. Patients on active regimens continued taking leflunomide 20 mg/day or sulfasalazine 2 g/day; those taking placebo were switched at Month 6 to sulfasalazine. RESULTS: Leflunomide significantly improved patients' functional ability compared to placebo (p < or = 0.0001) and sulfasalazine (p < or = 0.01) at 6 months. These changes were seen as early as Month 1, and continued improvements were seen in 12 and 24 month cohorts. Mean HAQ scores were significantly improved with leflunomide compared with sulfasalazine at 24 months (-0.65 vs -0.36; p = 0.0149); corresponding changes in HAQ Disability Index (DI) were -0.73 vs -0.56 and were not statistically different. Leflunomide is safe and well tolerated and no unexpected adverse events were noted during the 2 year period; diarrhea, nausea, and alopecia were less frequent with continued treatment. CONCLUSION: These longterm data confirm leflunomide improves functional ability as shown by reductions in HAQ scores. The benefit of leflunomide is reflected in other efficacy criteria, such as global assessments and the American College of Rheumatology response rates, all of which showed significantly more improvement with leflunomide than sulfasalazine at 24 months.
10431483 Interleukin-4 adenoviral gene therapy reduces production of inflammatory cytokines and pro 1999 Jul BACKGROUND: The rheumatoid arthritis (RA) joint is characterized by an inflammatory synovial pannus which mediates tissue destruction. Interleukin (IL)-4 reduces the production of many proinflammatory cytokines, particularly by activated macrophages. Therefore, we examined the ability of adenovirally delivered IL-4 for the treatment of human RA to reduce the secretion of proinflammatory molecules. METHODS: Adenoviral vectors encoding the genes for human IL-4 (AxCAIL-4) and bacterial beta-galactosidase (AxCAlacZ) were generated and examined for appropriate production and biological activity. RA synovial tissue (ST) explants or fibroblasts were infected with AxCAIL-4 or a beta-galactosidase producing vector, as a control, and conditioned medium (CM) was collected for ELISA analysis. RESULTS: AxCAIL-4 decreased the production of the inflammatory cytokines IL-1 beta and tumor necrosis factor-alpha in RA ST explant CM. IL-8 levels were significantly reduced by 71%, 88%, and 82% at 24, 48, and 72 hours, respectively, in RA ST explant CM. In the same CM, monocyte chemotactic protein-1 (MCP-1) levels decreased 60% at 48 hours. In contrast, RA synovial fibroblast CM levels of MCP-1 were increased by AxCAIL-4. Epithelial neutrophil activating peptide-78 levels produced by RA ST explants were significantly decreased by AxCAIL-4 by 88%, 92%, and 93% at 24, 48, and 72 hours, respectively. Growth related gene product-alpha levels were likewise decreased in RA ST explant CM. In ST explants as well as RA synovial fibroblasts, IL-4 treatment decreased prostaglandin E2 (PGE2) production. CONCLUSIONS: Increased expression of IL-4 via gene therapy may decrease RA-associated inflammation by reducing proinflammatory cytokines and PGE2.
10355057 [Immunosuppressive therapy in autoimmune diseases]. 1999 Mar Autoimmune diseases play an increasing role in daily practise. Advanced understanding of the pathogenesis and pathophysiology enables an outcome orientated therapy leading to a far better prognosis. Immunosuppressive drugs are essential for the treatment. The therapeutical concepts are adopted to the individual character and stage of the disease. In the meantime, therapeutical regimes combine certain drugs. Although it is not possible to cure these autoimmune diseases, a remission can be achieved in most cases. Further developments will concentrate on more selective strategies and the potentials of gene therapy.
11327244 The value of a continuous ambulatory activity monitor to quantify the amount and intensity 2001 Apr OBJECTIVE: To examine the reliability, validity, and responsiveness of a continuous ambulatory activity monitor in patients with rheumatoid arthritis (RA). METHODS: Forty-one patients with RA, participating in a randomized controlled trial examining the effect of an intensive exercise program, were assessed by means of the Dynaport ADL (activities of daily living) monitor (AM). The time spent on activities (locomotion, standing, and active sitting) during 24 hours and the intensity of trunk movement during these activities were recorded. To determine test-retest reliability 20 patients were reassessed with the AM one week after the first assessment. Construct validity of the AM was determined by comparing the AM results with physical fitness measures (muscle strength, endurance, joint mobility), disease activity, and functional status. As well, 37 patients were assessed 18 months after the first assessment to determine responsiveness. RESULTS: All AM measurements showed satisfactory test-retest reliability (ICC 0.63-0.76). AM measures were significantly associated with physical fitness, functional status, and disease activity, indicating construct validity of the AM. The AM could discriminate between patients with improvement and deterioration in physical fitness, indicating sufficient responsiveness of AM variables. CONCLUSION: This study shows the value of an ambulatory activity monitor to quantify both the amount and intensity of physical activity of patients with RA during a day in their own environment. The ambulatory activity monitor seems to be a promising instrument for research into rehabilitation of patients with RA.
10464550 Body image of women with rheumatoid arthritis. 1999 Jul OBJECTIVE: Physical disabilities generally cause severe disturbances in a patient's body image perception. The aim of the present study was to investigate different aspects of body image, including sexual dissatisfaction, in women with rheumatoid arthritis (RA) in relation to their subjective impression of handicap. METHODS: Forty women with RA were investigated using a series of instruments: Strauss and Appelt's questionnaire for assessing one's body (1), the body perception scale of Paulus (2), and an interview focusing on appearance, worries about health and sickness, and sexual dissatisfaction. In addition, clinical parameters and the subjective extent of morning stiffness were documented, and patients with a high degree of morning stiffness were compared to patients with a low degree of morning stiffness. RESULTS: In contrast to patients with a low degree of morning stiffness, patients with a high degree of morning stiffness worried significantly more about their bodies (p < or = 0.05) and reported significantly more problems in sexuality (p < or = 0.05). CONCLUSION: Our results suggest that morning stiffness plays a very important role in how severely a woman feels herself to be handicapped. Severely handicapped women have to deal with anxieties about health and have sexual problems. Physicians should not shy away from addressing these issues and in severe cases psychological therapy should be initiated.
9361153 The mechanism of action of methotrexate. 1997 Nov Because of methotrexate's well-documented efficacy in the treatment of rheumatoid arthritis, it is important that we understand the mechanism of action of this drug. There are two biochemical mechanisms by which methotrexate may modulate inflammation: (1) promotion of adenosine release and (2) inhibition of transmethylation reactions. Evidence is reviewed that favors the notion that the endogenous anti-inflammatory autocoid adenosine mediates the anti-inflammatory effects of methotrexate. This insight should aid in the design of new agents for the treatment of rheumatoid arthritis and other inflammatory diseases.
9377840 [Sulfasalazine: side effects and duration of therapy in patients with rheumatoid arthritis 1997 Jan Sulphasalazine (SSZ) is now recognised to be a useful agent in the management of rheumatoid arthritis (RA). We studied SSZ toxicity (2 g/die) and duration of therapy in 102 patients with RA. Adverse events occurred in 25.4% of all patients. In all patients the reactions subsided on either discontinuation of the drug or decrease of the dose. Gastrointestinal was the most common. At 5 years of follow-up the percentage of patients treated with SSZ still on drug was 29%, the inefficacy was 40% of the total drop-out.
9263137 In vitro modulation of cytokine, cytokine inhibitor, and prostaglandin E release from bloo 1997 Aug OBJECTIVE: To assess the effect of various antirheumatic drugs on cytokine, cytokine inhibitor, and prostaglandin E (PGE) production by normal blood mononuclear cells (MNC) and rheumatoid arthritis (RA) synovial fibroblasts in vitro. METHODS: MNC from healthy donors and RA synovial fibroblasts were preincubated with or without prostaglandin E2 (PGE2), indomethacin, dexamethasone, gold sodium thiomalate (GSTM), methotrexate (MTX), and cyclosporin A (CyA), and then cultured in the absence or presence of interleukin-1 beta (IL-1 beta) or tumor necrosis factor-alpha (TNF-alpha) for 48 h. We characterized cytokines such as IL-1 beta, IL-8, monocyte chemoattractant protein-1 (MCP-1), and cytokine inhibitors such as IL-1 receptor antagonist (IL-1ra) and soluble TNF receptors (sTNFR p55 + p75) as well as PGE in the cell-free culture supernatants. RESULTS: In MNC and synovial fibroblast cultures dexamethasone, GSTM, and PGE2 most markedly downregulated spontaneous and/or cytokine stimulated production of IL-1 beta, IL-14a, IL-8, and MCP-1, whereas sTNFR shedding was not affected. In contrast, MTX and CyA had only marginal or no effects on mediator release, whereas indomethacin inhibited only PGE production. CONCLUSION: Among several antirheumatic drugs examined, dexamethasone and GSTM exhibited the most potent inhibitory effects on inflammatory cytokine and cytokine inhibitor production by blood mononuclear cells and synovial fibroblasts. These drugs may exert their antiinflammatory actions by unspecific suppression of monocyte and fibroblast secretory function.
11361223 Genetic anticipation in rheumatoid arthritis in Europe. European Consortium on Rheumatoid 2001 May OBJECTIVE: To investigate whether there is evidence for genetic anticipation in rheumatoid arthritis (RA) in Europe. METHODS: Cross sectional comparison of data from all affected parent-offspring pairs identified among (1) the RA population attending our department and (2) a large cohort of families from RA probands with both parents alive recruited by the European Consortium on RA families (ECRAF) for association studies. Longitudinal comparison between probands with and without parental RA. We used prospectively collected data on disease activity, therapies, and radiological outcomes from our Dutch inception cohort of patients with early RA during the first 6 years of followup. RESULTS: From a total of 683 Dutch and 170 European patients we identified 28 Dutch and 21 European parent-offspring pairs with RA. Probands with parental RA had an earlier disease onset compared with affected parents (Dutch p < 0.002, European p < 0.0001). In Dutch patients, the prevalence of HLA-DR4, DR4 double dose, and shared epitope (SE) double dose was slightly higher in probands with parental RA than in those without [odds ratios (95% CI) 2.0 (0.7-5.8), 2.79 (0.8-9.4), and 2.12 (0.6-8.7), respectively]. The same was true for European probands concerning SE double dose [OR (95% CI) 1.76 (0.6-8.7)]. No other relevant differences in demographic or clinical indices were found between probands with affected parents and those without. Disease course (Disease Activity Score) and therapies used during the first 6 years of followup were similar in Dutch patients with and without parental RA. Radiological damage at baseline was lower in the former group and this difference persisted after 3 and 6 years. CONCLUSION: Our data suggest that genetic anticipation in RA does occur in terms of an earlier disease onset in the offspring. Despite a slightly higher prevalence of HLA alleles encoding for the SE, probands with confirmed parental RA had no worse outcome than those without.
9886436 The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies 1999 Jan 1 Antifilaggrin autoantibodies (AFA) are a population of IgG autoantibodies associated to rheumatoid arthritis (RA), which includes the so-called "antikeratin" Abs and antiperinuclear factor. AFA are the most specific serological markers of RA. We previously showed that they recognize human epidermal filaggrin and other profilaggrin-related proteins of various epithelial tissues. Here, we report further characterization of the protein Ags and epitopes targeted by AFA. All the Ags that exhibit numerous neutral/ acidic isoelectric variants were immunochemically demonstrated to be deiminated proteins. In vitro deimination of a recombinant human filaggrin by a peptidylarginine deiminase generated AFA epitopes on the protein. Moreover, two of three filaggrin-derived synthetic peptides with a citrulline in the central position were specifically and widely recognized by AFA affinity-purified from a series of RA sera. These results indicate that citrulline residues are constitutive of the AFA epitopes, but only in the context of specific amino acid sequences of filaggrin. In competition experiments, the two peptides abolished the AFA reactivity of RA sera, showing that they present major AFA epitopes. These data should help in the identification of a putative deiminated AFA-inducing or cross-reactive articular autoantigen and provide new insights into the pathogenesis of RA. They could also open the way toward specific immunosuppressive and/or preventive therapy of RA.
9697145 [Multiple surgical possibilities for the correction of acetabulum failure in rheumatoid ar 1998 Jun Pronounced osteoporosis of and surrounding the acetabulum commonly leads to early loosening of endoprosthetic hip replacements following implantation. Large osseous defects in the subimplant bed are the result and the reason why multiple revisions of loosened acetabular cups have to be performed so often in rheumatic surgery. The defects extend from the cranial to the central; ventral and dorsal anchorage losses may occur in addition to this. The anchorage of a new implant must be adapted to the individual circumstances. The new implant must be selected in accordance with point of surgical access, the patient's general status and osseous regenerationability. In the optimum case, osseous buildup of lost anatomical structures is the preferred method. If this is not possible, special implants, mostly custom-made prostheses, have to be incorporated. However, the survival time of the implants is much shorter than in patients with degenerative diseases.
11269535 Alendronate in rheumatoid arthritis patients treated with methotrexate and glucocorticoids 2001 Feb Rheumatoid arthritis (RA) is a systemic inflammatory disease. Along with synovial joint inflammation, extra-articular involvement is a common feature of RA. Periarticular and generalized osteoporosis are seen both as an extra-articular feature of the disease itself and due to various medications like glucocorticoids and methotrexate (MTX). In this study, we investigated the effects of oral alendronate in RA patients treated with MTX and prednisolone by comparing the effects of "alendronate+calcium" and "only calcium" on bone mineral density (BMD). Fifty RA patients classified according to American Rheumatism Association (ARA) criteria were included in the study. The control group consisted of 20 postmenopausal osteoporotic patients. The RA patients were divided randomly into two groups. All patients were started on MTX 7.5 mg/week, 2.5-mg daily folic acid, and 7.5-mg daily prednisolone. The first group, consisting of 25 female RA patients, was also given 10-mg daily alendronate and 1000-mg daily calcium. The second group also consisted of 25 female patients and was given only 1000-mg calcium per day. The postmenopausal control group was given daily 10-mg alendronate and 1000-mg calcium. Bone mineral densities were measured by dual-energy x-ray absorptiometry (DEXA) and again at the end of the sixth month. At the end of the study, RA patients given only calcium had reduced mean BMD, and patients treated with alendronate and calcium showed increased mean BMD almost in all regions. This increase was significant in the L2 and L1-4 total regions. In postmenopausal osteoporotic patients, we saw statistically significant increases in BMD in all regions. The increase in BMD values in RA patients treated with alendronate was smaller than in those of the control group of postmenopausal osteoporosis patients. In conclusion, RA itself has a risk factor for osteoporosis in addition to the risks of the medications like corticosteroids and MTX. In the prevention and treatment of RA-associated osteoporosis, alendronate and calcium therapy is effective and well tolerated.
9481588 Insufficiency and stress fractures of the long bones occurring in patients with rheumatoid 1997 Dec In patients with long standing rheumatoid arthritis and other rheumatoid disorders, stress fractures and insufficiency fractures are not uncommon. The cause may be osteoporosis due to rheumatoid arthritis, corticosteroid therapy, joint stiffness, and deformity of the joints caused by the inflammatory process. Also, unaccustomed exercise after reconstructive joint surgery may be a cause of fractures in these patients. Fractures can be documented on conventional X-ray-pictures and tomograms. Computed tomography can show the medullary extent of these fractures and gives, in several cases, additional information showing the combination of insufficiency fractures with fragmentations of parts of the involved bone. Reconstructive surgery with total joint replacement may be another cause of the development of these fractures. This unaccustomed increase in ambulation may lead to stress fractures in other joints of the same extremity or of contralateral extremity. Pain beginning in joint of the lower extremity in a patient with chronic rheumatoid arthritis should, besides arthritis, raise the possibility of a stress fracture. Also with cases of angular deformity of a joint and unaccustomed exercise after reconstructive surgery patients stress fractures may be seen and can be established by Plainfilm, Computed Tomography scintimetric bone scanning and MRI.
10447731 Do self-perpetuating B lymphocytes drive human autoimmune disease? 1999 Jun Normal immunological memory is thought to be underpinned by T lymphocytes. However, in rheumatoid arthritis there are indications that T-lymphocyte control has been subverted by self-perpetuating B lymphocytes. Potential mechanisms in other autoimmune states are less clear, but a number of observations suggest that misappropriation of immunological memory by B lymphocytes may be a common feature of human autoantibody-associated disease. Put simply, autoantibodies drive their own production. If so, the availability of safe B-lymphocyte-depleting agents provides a potential means for reversal of autoimmunity.
9734674 Direct cost of rheumatoid arthritis during the first six years: a cost-of-illness study. 1998 Aug The objective was to estimate the annual direct disease-related cost of rheumatoid arthritis (RA) during the first 6 yr and to determine which socio-demographic and clinical characteristics relate to these costs. The study population consisted of 424 RA patients who had participated in a (population-based) trial on therapeutic strategies for early RA since 1990 and were not lost to follow-up in April 1996. A questionnaire on costs due to RA was sent to these patients; 363 (86%) completed questionnaires were analysed. The total annual direct cost per patient was estimated by adding up the costs of health care workers, days admitted to care facilities, medication, monitoring for side-effects, alternative medicine, adaptations in the home, devices, and other direct costs such as travelling expenses. The mean annual direct cost due to RA was estimated to be Dfl. 11,550 per patient. An obvious increase in direct cost with increasing disease duration was not found. Patients with higher disease activity exhibited significantly higher costs compared to patients with lower disease activity. A multiple logistic regression model showed that greater disability and lower age increased the odds for high costs. The annual direct cost of RA averaged out at Dfl. 11,550 per patient (i.e. Pound Sterling 3680). A high total direct cost in the first 6 yr of disease is related to severe functional disability and lower age.
11136874 Cellular immune response to human cartilage glycoprotein-39 (HC gp-39)-derived peptides in 2000 Dec OBJECTIVE: To study the specificity of the peripheral blood mononuclear cell (PBMC) response to peptides derived from human cartilage glycoprotein-39 (HC gp-39) in patients with rheumatoid arthritis (RA) and the correlation between this response and disease activity. METHODS: RA patients, patients with systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD) or osteoarthritis (OA) and healthy controls were studied. All individuals were typed for HLA-DRB1 and their disease activity score was documented. Proliferation of PBMC was measured following incubation with five different HC gp-39-derived peptides, selected by the use of a DR4 (DRB1*0401) binding motif. RESULTS: A proliferative response to one of the five peptides (peptide 259-271 at 10 microg/ml) was more often observed in RA patients than in healthy controls (P=0.001). RA patients who expressed DRB1*0401 more often showed a response against this peptide than RA patients who did not express this RA-associated haplotype. This response was not RA-specific since patients with IBD or OA also showed a response significantly more frequently than healthy controls (P:=0.02 and P=0.03 respectively). However, the level of the response against peptide 259-271 correlated with disease activity in RA patients but not in patients with IBD or SLE. Increased responses to HC gp-39 263-275 were found in patients with IBD or OA; a trend towards such a response failed to reach significance in RA patients in this study. CONCLUSION: In RA patients as well as in patients with other inflammatory conditions, HC gp-39-derived peptides may be targets of the T-cell-mediated immune response. In the RA patient group the immune response to HC gp-39-derived peptide 259-271 correlated with disease activity.
9849316 Loss of laminin and of the laminin receptor integrin subunit alpha 6 in situ correlates wi 1998 Sep OBJECTIVE: To investigate in situ the expression of the integrin receptor subunits alpha 6 and beta 1 and the distribution of the ligand laminin in the synovia from osteoarthritis (OA) and rheumatoid arthritis (RA) patients and to study the effect of cytokines and antirheumatic drugs on the expression of the alpha 6 and beta 1 integrin subunits on long term cultures of fibroblast-like synoviocytes (FBS) derived from OA and RA. METHODS: The expression of the alpha 6 and beta 1 integrin subunits and the distribution of laminin were examined immunohistochemically in normal synovia and in synovia from patients with OA and RA. The effect of proinflammatory cytokines (IL1 beta and TNF alpha), and of antirheumatic drugs (salicylic acid, dexamethasone, and methotrexate) on the alpha 6 and beta 1 expression of cultured normal FBS and FBS from patients with OA and RA was determined by flow cytometry. RESULTS: In normal synovia and in OA synovia samples with a low grade of inflammation, synovial lining cells (SLC) showed a parallel expression and distribution of alpha 6 and laminin. In synovia samples of OA with a higher grade of inflammation and in the majority of RA synovia samples laminin was pericellularly distributed in a low number of SLC, whereas alpha 6 was expressed on the surface of a high number of SLC. In RA synovia samples with severe inflammatory changes the gradual loss of laminin generally corresponded to a decrease of the alpha 6 integrin subunit. beta 1 was always strongly expressed in all synovia samples detected. Proinflammatory cytokines up regulated the expression of alpha 6 and beta 1 on OA-FBS, whereas these effectors decreases alpha 6 and beta 1 on RA-FBS. In contrast, antirheumatic drugs, in particular methotrexate and dexamethasone, reduced the expression of alpha 6 and beta 1 on OA-FBS, whereas the same treatment on RA-FBS stimulated the expression of these integrin subunits. CONCLUSION: The gradual loss of laminin in chronic synovitis may contribute to the altered expression of alpha 6 in SLC. IL1 beta and TNF alpha down regulated the expression of the alpha 6 and beta 1 integrin subunits on long term cultures of FBS derived from RA. Therefore, these cytokines may be among the effectors regulating the expression of the alpha 6 integrin subunit in SLC in vivo. As antirheumatic drugs increase the expression of alpha 6 on RA-FBS, the presence of the laminin receptor may confer a protective effect on the synovia in vivo.
10585757 Intracytoplasmic Th1 and Th2 cytokines in rheumatoid arthritis blood and synovial tissue. 1999 Dec In rheumatoid arthritis (RA), T cells have been proposed either as a main actor or as an epiphenomenon in such a primarily synoviocyte-driven disease. A major issue remains the remarkable paradox between the T cell infiltrate and the relative failure to detect definite markers of their activity. To determine the Th1/Th2 cytokine profile in RA synovium, we used a single cell flow cytometric assay for interleukin-2 (IL-2), interferon-gamma (IFN-gamma), IL-4 and IL-10 in paired peripheral blood (PB) and synovial tissue (ST) lymphocytes from RA and osteoarthritis (OA) patients and PB lymphocytes from healthy controls. Cytokines were undetectable in unstimulated PB and ST lymphocytes. More stimulated PB and ST CD4(+)lymphocytes produced IFN-gamma than IL-4, for all individuals tested. RA PB CD4(+)lymphocytes showed the same Th1 cytokine pattern as normal controls. No increase of such a Th1 profile was observed for ST lymphocytes. A specific recruitment of T CD4(+)lymphocytes in the rheumatoid inflamed synovium could not be concluded on the basis of these results.
9002042 Analysis of the candidate gene NRAMP1 in the first 61 ARC National Repository families for 1997 Jan Maximum likelihood identity-by-descent (IBD) sib pair analysis using a 3 locus haplotype NRAMP1-IL8RB-VIL1, or NRAMP1 alone, provided preliminary evidence (maximum LOD score = 1.01, p = 0.024) for a gene in this region of human chromosome 2q35 contributing to susceptibility to rheumatoid arthritis (RA). Candidacy for NRAMP1 as the disease susceptibility gene was supported by a significant bias (p < 0.048) toward transmission of the NRAMP1 promoter region allele 3 in affected offspring.
10878393 Killer cell activating receptors function as costimulatory molecules on CD4+CD28null T cel 2000 Jul 15 Expansion of CD4+CD28null T cells is a characteristic finding in patients with rheumatoid arthritis. Despite lacking CD28 molecules, these unusual CD4 T cells undergo clonal proliferation and form large and long-lived clonal populations. They produce high levels of IFN-gamma, exhibit autoreactivity, and have cytolytic function. The mechanisms facilitating the expansion and longevity of CD4+CD28null T cell clones in vivo are unknown. Here, we report that CD4+CD28null, but not CD4+CD28+, T cells express MHC class I-recognizing receptors normally found on NK cells. CD4+CD28null T cells preferentially expressed killer cell activating receptors (KAR), often in the absence of killer cell inhibitory receptors. Cross-linking of KAR molecules enhanced the proliferative response to TCR-mediated stimulation, but not the cytolytic function of CD4+CD28null T cells, suggesting different signaling pathways in CD4 T cells and NK cells. Triggering of KAR signaling led to the phosphorylation of several cellular targets, although the pattern of phosphorylation differed from that induced by the TCR. Aberrant expression of KAR molecules in the absence of inhibitory receptors and in the appropriate HLA setting may lead to the clonal outgrowth of autoreactive CD4+CD28null T cells commonly seen in rheumatoid arthritis.