Early Untreated Rheumatoid Arthritis Research Articles

Expression of survivin in rheumatoid arthritis

To detect the correlation between survivin and rheumatoid arthritis (RA) to determine the possible mechanism of RA and multidrug resistance in refractory rheumatoid arthritis (RRA). We collected 15 normal controls, 35 early untreated RA patients, 20 effectively treated RA patients and 25 RRA patients according to selection standard. The expression of survivin in the peripheral blood lymphocytes was detected by immunocytochemical method. There was significant difference in the survivin expression in the peripheral blood lymphocytes between the early untreated and normal control group (χ(2)=29.59, P<0.01). The survivin expression in the peripheral blood lymphocytes of effectively treated RA group slightly elevated, but had no significant difference with the normal control group (χ(2)=1.591, P>0.05). The survivin expression in the peripheral blood lymphocytes of the RRA group was significantly stronger than in the effectively treated RA group (χ(2)=24.35, P<0.01), and normal control group (χ(2)=26.53, P<0.01), with no significant difference compared with early untreated group (χ(2)=0.014,P>0.05). Survivin has an influential role in the occurrence and development of rheumatism arthritis. Survivin might be involved in refractory multidrug resistance of RA and be one of the multidrug resistance mechanism of RRA.

Infliximab for 6 months added on combination therapy in early rheumatoid arthritis: 2-year results from an investigator-initiated, randomised, double-blind, placebo-controlled study (the NEO-RACo Study)

ObjectiveEarly treatment of patients with rheumatoid arthritis (RA) with combination treatment starting with methotrexate, sulfasalazine, hydroxychloroquine and prednisolone (FIN-RACo strategy) is superior to monotherapy. A study was undertaken to determine...

Rheumatoid arthritis synovial fibroblasts produce a soluble form of the interleukin-7 receptor in response to pro-inflammatory cytokines

We previously demonstrated that baseline synovial overexpression of the interleukin-7 receptor α-chain (IL-7R) is associated with poor response to tumour necrosis factor (TNF) blockade in rheumatoid arthritis (RA). We found that IL-7R gene expression is induced in fibroblast-like synovial cells (FLS) by the addition of TNF-α, IL-1β and combinations of TNF-α+ IL-1β or TNF-α+ IL-17, thereby suggesting that these cytokines play a role in the resistance to TNF blockade in RA. Because FLS and CD4 T cells also produce a soluble form of IL-7R (sIL-7R), resulting from an alternative splicing of the full-length transcript, we wondered whether expression of sIL-7R is similarly regulated by pro-inflammatory cytokines. We also investigated whether sIL-7R is detectable in the serum of RA patients and associated with response to TNF blockade. RA FLS were cultured in the presence of pro-inflammatory cytokines and sIL-7R concentrations were measured in culture supernatants. Similarly, sIL-7R titres were measured in sera obtained from healthy individuals, early untreated RA patients with active disease and disease-modifying anti-rheumatic drug (DMARD)-resistant RA patients prior to initiation of TNF-blockade. Baseline serum sIL-7R titres were correlated with validated clinical measurements of disease activity. We found that exposure of RA FLS to pro-inflammatory cytokines (TNF-α, IL-1β and combinations of TNF-α and IL-1β or TNF-α and IL-17) induces sIL-7R secretion. Activated CD4 T cells also produce sIL-7R. sIL-7R serum levels are higher in RA patients as compared to controls. In DMARD-resistant patients, high sIL-7R serum concentrations are strongly associated with poor response to TNF-blockade. In conclusion, sIL-7R is induced by pro-inflammatory cytokines in RA FLS. sIL-7R could qualify as a new biomarker of response to therapy in RA.

Subclinical remodelling of draining lymph node structure in early and established rheumatoid arthritis assessed by power Doppler ultrasonography

To investigate the suitability of power Doppler ultrasonography (PD-US) for the assessment of lymph node (LN) status in RA, evaluating the existence of structural and dynamic modifications in well-characterized stages of the disease. Ten patients with active disease and five patients in clinical remission underwent complete clinical and PD-US examination of hands, wrists, axillary and cervical LNs on the same day. Synovitis and PD were graded 0-3. LN assessment included maximum short axis, cortical hypertrophy (CH) and PD signal distribution. All patients with active disease were re-evaluated prospectively 3 months after initiation of therapy. PD-US signs of axillary LN remodelling were observed in 7 out of 10 patients with active disease despite the absence of clinical lymphoadenopathy. Subclinical alterations were detected in both early untreated RA and in established disease. Characteristic structural changes consisted of hypertrophy of the LN cortex and PD signal amplification in cortical and hilar regions. Cervical LNs in active disease and axillary LNs in clinical remission were unaffected. LN PD amplification returned to normal ranges in patients with baseline alterations re-evaluated 3 months after therapy with TNF-α blocking agents and/or MTX. Draining LNs in RA are subjected to subclinical intra-parenchymal changes and vascular flow modulation detectable by PD-US. Sonographic signs of LN involvement associate with disease activity and are reversible upon treatment. These data point at LN reactivity as a dynamic component of RA inflammatory cascade and an attractive platform to be explored in prognostic and response to therapy evaluations.

Identification of a cytokine network sustaining neutrophil and Th17 activation in untreated early rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by sustained synovitis. Recently, several studies have proposed neutrophils and Th17 cells as key players in the onset and perpetuation of this disease.

Identification of a cytokine network sustaining neutrophil and Th17 activation in untreated early rheumatoid arthritis

IntroductionRheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by sustained synovitis. Recently, several studies have proposed neutrophils and Th17 cells as key players in the onset and perpetuation of this disease. The main goal of this work was to determine whether cytokines driving neutrophil and Th17 activation are dysregulated in very early rheumatoid arthritis patients with less than 6 weeks of disease duration and before treatment (VERA).MethodsCytokines related to neutrophil and Th17 activation were quantified in the serum of VERA and established RA patients and compared with other very early arthritis (VEA) and healthy controls. Synovial fluid (SF) from RA and osteoarthritis (OA) patients was also analyzed.ResultsVERA patients had increased serum levels of cytokines promoting Th17 polarization (IL-1β and IL-6), as well as IL-8 and Th17-derived cytokines (IL-17A and IL-22) known to induce neutrophil-mediated inflammation. In established RA this pattern is more evident within the SF. Early treatment with methotrexate or corticosteroids led to clinical improvement but without an impact on the cytokine pattern.ConclusionsVERA patients already display increased levels of cytokines related with Th17 polarization and neutrophil recruitment and activation, a dysregulation also found in SF of established RA. 0 Thus, our data suggest that a cytokine-milieu favoring Th17 and neutrophil activity is an early event in RA pathogenesis.

Insulin resistance in early untreated rheumatoid arthritis patients

Objectives To assess insulin resistance in early untreated rheumatoid arthritis patients and its relation to the clinical, inflammatory and biochemical characteristics of these patients. Patients and methods Sixty-six untreated rheumatoid arthritis (RA) patients with disease duration less than 1 year along with age and sex matched controls were studied. Disease activity score (DAS28) was used to assess disease activity. Plasma levels of C- reactive protein (CRP), glucose, insulin and complete lipid profile were measured. Insulin resistance (IR) was estimated by the homeostasis model assessment for insulin resistance (HOMA-IR). Results RA patients revealed high grade systemic inflammation compared to control group p < 0.0001. Patients with high disease activity were more insulin resistant than patients with moderate disease activity P < 0.0001. Conclusion The findings of the present study showed that early untreated RA patients are characterized by a severe insulin resistant state that is driven primarily by disease activity and systemic inflammation.

Invited Commentary

Invited Commentary

Early and long-standing rheumatoid arthritis: distinct molecular signatures identified by gene-expression profiling in synovia

IntroductionRheumatoid arthritis (RA) is a heterogeneous disease and its underlying molecular mechanisms are still poorly understood. Because previous microarray studies have only focused on long-standing (LS) RA compared to osteoarthritis, we aimed to compare the molecular profiles of early and LS RA versus control synovia.MethodsSynovial biopsies were obtained by arthroscopy from 15 patients (4 early untreated RA, 4 treated LS RA and 7 controls, who had traumatic or mechanical lesions). Extracted mRNAs were used for large-scale gene-expression profiling. The different gene-expression combinations identified by comparison of profiles of early, LS RA and healthy synovia were linked to the biological processes involved in each situation.ResultsThree combinations of 719, 116 and 52 transcripts discriminated, respectively, early from LS RA, and early or LS RA from healthy synovia. We identified several gene clusters and distinct molecular signatures specifically expressed during early or LS RA, thereby suggesting the involvement of different pathophysiological mechanisms during the course of RA.ConclusionsEarly and LS RA have distinct molecular signatures with different biological processes participating at different times during the course of the disease. These results suggest that better knowledge of the main biological processes involved at a given RA stage might help to choose the most appropriate treatment.

Candidate autoantigens identified by mass spectrometry in early rheumatoid arthritis are chaperones and citrullinated glycolytic enzymes

IntroductionThe aim of our study was to identify new early rheumatoid arthritis (RA) autoantibodies.MethodsSera obtained from 110 early untreated RA patients (<6 months) were analyzed by western blot using HL-60 cell extract, separated on one-dimensional and two-dimensional gel electrophoresis (1-DE, 2-DE). Sera from 50 healthy blood donors and 20 patients with non-RA rheumatisms were used as controls for 1-DE and 2-DE, respectively. The immunoreactive proteins were identified by MALDI-TOF mass spectrometric analysis and the presence of potential sites of citrullination in each of these proteins was evaluated. FT-ICR mass spectrometry was used to verify experimentally the effect of citrullination upon the mass profile observed by MALDI-TOF analysis.ResultsThe 110 1-DE patterns allowed detection of 10 recurrent immunoreactive bands of 33, 39, 43, 46, 51, 54, 58, 62, 67 and 70 kDa, which were further characterized by 2-DE and proteomic analysis. Six proteins were already described RA antigens: heterogeneous nuclear ribonucleoprotein A2/B1, aldolase, α-enolase, calreticulin, 60 kDa heat shock protein (HSP60) and BiP. Phosphoglycerate kinase 1 (PGK1), stress-induced phosphoprotein 1 and the far upstream element-binding proteins (FUSE-BP) 1 and 2 were identified as new antigens. Post-translational protein modifications were analyzed and potentially deiminated peptides were found on aldolase, α-enolase, PGK1, calreticulin, HSP60 and the FUSE-BPs. We compared the reactivity of RA sera with citrullinated and noncitrullinated α-enolase and FUSE-BP linear peptides, and showed that antigenicity of the FUSE-BP peptide was highly dependent on citrullination. Interestingly, the anti-cyclic citrullinated peptide antibody (anti-CCP2) status in RA serum at inclusion was not correlated to the reactivity directed against FUSE-BP citrullinated peptide.ConclusionsTwo categories of antigens, enzymes of the glycolytic family and molecular chaperones are also targeted by the early untreated RA autoantibody response. For some of them, and notably the FUSE-BPs, citrullination is involved in the immunological tolerance breakdown observed earlier in RA patients. Autoantibodies recognizing a citrullinated peptide from FUSE-BP may enhance the sensibility for RA of the currently available anti-CCP2 test.

Finger Tendon Disease in Untreated Early Rheumatoid Arthritis: A Comparison of Ultrasound and Magnetic Resonance Imaging

Finger Tendon Disease in Untreated Early Rheumatoid Arthritis: A Comparison of Ultrasound and Magnetic Resonance Imaging

Finger tendon disease in untreated early rheumatoid arthritis: A comparison of ultrasound and magnetic resonance imaging

To investigate the frequency and distribution of finger tenosynovitis in patients with early, untreated rheumatoid arthritis (RA) using gray-scale ultrasound (US) and magnetic resonance imaging (MRI). Fifty patients underwent US and MRI of metacarpophalangeal (MCP) joints 2-5. Twenty healthy controls underwent US only. Flexor and extensor involvement was documented for each joint. Intrareader reliability (IRR) was calculated by rereading static images. Flexor tenosynovitis was found in 57 (28.5%) of 200 joints in 24 (48%) of 50 patients on US compared with 128 (64%) of 200 joints in 41 (82%) of 50 patients on MRI. Periextensor tenosynovitis was found in 14 (7%) joints in 9 (18%) patients on US compared with 80 (40%) joints in 36 (72%) patients on MRI. No controls had imaging tenosynovitis. Using MRI as the gold standard, the sensitivity, specificity, and negative and positive predictive values for US were 0.44, 0.99, 0.49, and 0.98, respectively, for flexor tenosynovitis and 0.15, 0.98, 0.63, and 0.86 for extensor tenosynovitis, respectively. The IRR was 0.85 and 0.8 for US and MRI, respectively. The most frequently involved joints on US and MRI were the second and third MCP joints. This is the first study to compare US and MRI for the detection of tenosynovitis in the fingers of patients with early untreated RA. Tenosynovitis was found to be common using both modalities, with MRI being more sensitive. A negative US scan does not exclude inflammation and an MRI should be considered. Further work is recommended to standardize definitions and image acquisition for both US and MRI images.

The ratio of circulating osteoprotegerin to RANKL in early rheumatoid arthritis predicts later joint destruction

Rheumatoid arthritis (RA) is a chronic inflammatory disease that may result in debilitating joint deformities with destruction of bone and cartilage. Inflammation is still considered the pivotal inducer of both components of joint damage. Results of recent animal studies suggested a prominent contribution of osteoclastic bone resorption that could be dissociated from inflammation. RANKL and its natural decoy receptor, osteoprotegerin (OPG), play key roles in osteoclast activation. In a group of patients with early RA not treated with disease-modifying drugs, we tested the hypothesis that osteoclast activation, reflected by the serum OPG:RANKL ratio at baseline, is negatively associated with progression of bone damage, independent of inflammation. OPG and RANKL levels, together with a parameter of inflammation (first-year time-averaged erythrocyte sedimentation rate [tESR]), were measured in 92 patients with newly diagnosed early active RA who were participants in a randomized study. The tESR and the OPG:RANKL ratio were evaluated for the ability to predict 5-year radiographic progression of joint damage. The first-year tESR and the OPG:RANKL ratio, as measured at baseline, independently predicted 5-year radiographic progression of joint damage (both P < or = 0.001). Progression of radiographic damage was greatest in patients with a high tESR and a low OPG:RANKL ratio and was lowest in patients with a low tESR and a high OPG:RANKL ratio. This study in patients with early untreated RA is the first to confirm the findings in animal models of arthritis, that radiographic progression of the bone component of joint destruction is dependent on both inflammation (tESR) and osteoclast activation (the OPG:RANKL ratio).

Apolipoprotein A-I infiltration in rheumatoid arthritis synovial tissue: a control mechanism of cytokine production?

The production of tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) by monocytes is strongly induced by direct contact with stimulated T lymphocytes, and this mechanism may be critical in the pathogenesis of rheumatoid arthritis (RA). Apolipoprotein A-I (apoA-I) blocks contact-mediated activation of monocytes, causing inhibition of TNF-α and IL-1β production. This study examined the hypothesis that apoA-I may have a regulatory role at sites of macrophage activation by T lymphocytes in inflamed RA synovial tissue. Synovial tissue samples were obtained after arthroscopy from patients with early untreated RA or treated RA and from normal subjects. As determined by immunohistochemistry, apoA-I was consistently present in inflamed synovial tissue that contained infiltrating T cells and macrophages, but it was absent from noninflamed tissue samples obtained from treated patients and from normal subjects. ApoA-I staining was abundant in the perivascular areas and extended in a halo-like pattern to the surrounding cellular infiltrate. C-reactive protein and serum amyloid A were not detected in the same perivascular areas of inflamed tissues. The abundant presence of apoA-I in the perivascular cellular infiltrates of inflamed RA synovial tissue extends the observations in vitro that showed that apoA-I can modify contact-mediated macrophage production of TNF-α and IL-1β. ApoA-I was not present in synovium from patients in apparent remission, suggesting that it has a specific role during phases of disease activity. These findings support the suggestion that the biologic properties of apoA-I, about which knowledge is newly emerging, include anti-inflammatory activities and therefore have important implications for the treatment of chronic inflammatory diseases.

Cellular and humoral markers of systemic inflammation in acute reactive arthritis and early rheumatoid arthritis

Objective: To compare systemic inflammation in reactive arthritis (ReA), rheumatoid arthritis (RA), and sepsis using novel markers of systemic inflammation, and to study whether they are helpful in distinguishing between ReA and RA.Methods: In 28 patients with acute ReA, 16 patients with early untreated RA, and 25 patients with blood culture‐positive sepsis, phagocyte CD11b expression was measured by flow cytometry, serum procalcitonin (PCT) levels by immunoluminometric assay, and soluble E‐selectin (sE‐selectin) levels by enzyme‐linked immunosorbent assay (ELISA).Results: Neutrophil and monocyte CD11b expression and serum levels of PCT and sE‐selectin were higher in patients with sepsis than patients with ReA or RA, or in healthy subjects (all p<0.01). They were comparable in healthy subjects, ReA, and RA.Conclusion: Patients with acute ReA and early RA have normal CD11b expression levels on phagocytes and normal PCT and sE‐selectin levels in serum. Elevated levels suggest possible sepsis.

Serum MMP-3 and MMP-1 and progression of joint damage in early rheumatoid arthritis.

Expression and activation of matrix metalloproteinases such as MMP-3 (stromelysin-1) and MMP-1 (collagenase-1) are increased in patients with rheumatoid arthritis (RA). Previous negative reports of their value as predictors of joint damage may be due to the lack of a large longitudinal study of early RA patients. This study evaluated their use in assessing early untreated patients with RA and predicting subsequent joint damage. Ninety-eight patients with early untreated RA of less than 12 months duration and 20 normal controls had baseline serum samples tested with a double-antibody enzyme-linked immunosorbent assay for each of MMP-1 and MMP-3. The subsequent changes in Larsen score (DeltaLarsen) and Health Assessment Questionnaire (DeltaHAQ) over the first 12 months were recorded. Baseline serum levels of MMP-3 and MMP-1 correlated significantly with baseline C-reactive protein (CRP) (r=0.42 and 0.49, P<0.001), DeltaHAQ (r=0.32 and 0.30, P<0.01) and DeltaLarsen (r=0.23 and 0.32, P<0.05) respectively. Analysis of the group of patients with a normal CRP at presentation (n=21) showed correlation of the baseline MMP-3 and MMP-1 with the presence of erosive disease during the first 12 months (r=0.52 and 0.65 respectively, P<0.05). Logistic regression analysis, in the patients who were non-erosive at presentation, showed that the strongest correlation with progression in Larsen score was the baseline MMP-3 level (r=0.30, P=0.01). Baseline serum MMP-1 and MMP-3 levels correlate with disease activity and predict functional and radiographic outcome in early untreated RA. They may have a particular value in predicting the progression of erosive disease in patients who are not erosive at presentation.

The bias for Th1 cell differentiation of rheumatoid arthritis T cells is characteristic of memory but not of naive T cells

An impaired ability of CD4 memory T cells to differentiate into immunomodulatory Th2 cells has been documented in patients with rheumatoid arthritis (RA) and has been implicated in the initiation and perpetuation of the characteristic Th1 dominated rheumatoid inflammation. To determine the stage of T-cell maturation at which the bias for Th1 cell differentiation becomes manifest, we investigated Th cell differentiation from resting CD4 CD45RA (naive) and CD45RO (memory) T cells in patients with untreated early RA (mean disease duration <8 months) and in age- and sex-matched healthy controls in vitro. No differences in the cytokine secretion profile, as assessed by flow cytometry, between patients and control subjects were detected in freshly isolated naive or in freshly isolated memory T cells. Th2 cells could be induced from naive T cells in all healthy donors and in all RA patients by priming with monoclonal antibodies (mAbs) to CD3 and CD28. Exogenous IL-4 was not required for Th2 differentiation from naive cells and did not consistently increase Th2 priming efficacy. In contrast to naive cells, Th2 effectors were effectively generated from memory T cells by stimulation with anti-CD28 without ligation of the T-cell recceptor. This mode of stimulation generated Th2 cells from memory T cells of all healthy controls but in only one third of the RA patients. The data suggest that CD4 memory T cells from the majority of patients with early RA manifest a deficiency in their capacity to differentiate into Th2 effectors. In contrast, naive T cells are capable of differentiating into Th2 cells with appropriate stimulation suggesting that the bias in Th1 differentiation of most RA patients may be acquired during T-cell maturation presumably in response to antigenic stimulation.

Relationship between interleukin-6 (IL-6) and hypothalamic-pituitary-adrenal axis hormones in rheumatoid arthritis.

Systemic symptoms in rheumatoid arthritis (RA) are mediated, at least in part, by elevated levels of circulating interleukin 6 (IL-6), which is a potent activator of the human hypothalamic-pituitary-adrenal (HPA) axis. In a recent study, we observed that the 24 h time-integrated plasma ACTH and cortisol, as well as urinary free cortisol levels of untreated RA patients were not significantly different from control subjects, in spite of their active disease. However, an earlier morning surge of plasma ACTH and cortisol in RA patients was found. Plasma ACTH and cortisol responses to oCRH were similar between RA patients and controls. Plasma IL-6 levels showed a pronounced circadian variation and were significantly increased in the RA patients, compared to control subjects. In the RA patients, we detected a positive temporal correlation between plasma levels of IL-6 and ACTH/cortisol, with IL-6 preceding ACTH and cortisol by 1 and 2 h, respectively. In the same patients, we detected a negative effect of cortisol upon IL-6 exerted with a delay of 5 h. In patients with early untreated RA--although endogenous IL-6 stimulates the ACTH and cortisol secretion--the overall secretory activity of the HPA axis remains "inappropriately" normal despite elevated plasma IL-6 levels. The resulting "inappropriately" normal cortisol levels are apparently insufficient to satisfactorily limit the inflammation in these patients. In patients with Sjögren's syndrome the ACTH and cortisol response after CRH stimulation has been found to be blunted. On the other hand, patients suffering from systemic lupus erythematosus, when subjected to insulin tolerance testing, showed a lower cortisol response compared to healthy controls. These data indicate a direct and/or indirect involvement of a defective HPA axis in the pathogenesis of certain autoimmune-related pathologic entities.

The relationship between synovitis and bone changes in early untreated rheumatoid arthritis: a controlled magnetic resonance imaging study.

The interrelationship between synovitis and bone damage in rheumatoid arthritis (RA) is a subject of controversy. Using magnetic resonance imaging (MRI), this study followed the bone changes in early RA and determined their relationship to synovitis. Thirty-one patients with early RA who had swelling of the metacarpophalangeal (MCP) joints and 31 healthy control subjects with no clinical evidence of arthritis underwent MRI of the second through fifth MCP joints of the dominant hand by use of a 1.5T scanner. Coronal T1-weighted and T2-fat suppressed (FS) sequences were performed to evaluate bone edema, and gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) pulse sequences were obtained to evaluate synovitis. Bony abnormalities were described as bone edema (low signal on T1-weighted sequences and intermediate/high signal on T2 FS sequences adjacent to the bone cortex) or as bone cysts (circular juxtacortical abnormalities with low signal on T1-weighted images and with very high signal on T2 FS sequences). Contrast and noncontrast MRI films were scored in a blinded manner, and Fisher's exact probability test was used to determine differences between groups. Twenty-one of the 31 RA patients (68%) had bone edema, which was seen in 43 of 124 joints (35% of joints) and 3 of the 31 control subjects had bone edema seen in 3 of 124 joints (2% of joints) (P < 0.0001). Thirty RA patients (97%) had Gd-DTPA-confirmed MCP joint synovitis, and bone edema was seen in 40 of the 75 joints with Gd-DTPA-proven synovitis (53%), but in only 3 of 49 without (6%) (P < 0.0001). MCP joint bone edema is present in the majority of patients with RA at presentation, but is seen only occasionally in normal control subjects. The fact that bone edema occurred rarely in the absence of synovitis in patients with RA suggests that bony changes in RA are secondary to synovitis.

Altered Memory T Cell Differentiation in Patients with Early Rheumatoid Arthritis

The chronic immune response in rheumatoid arthritis (RA) might be driven by activated Th1 cells without sufficient Th2 cell differentiation to down-modulate inflammation. To test whether disordered memory T cell differentiation contributes to the typical Th1-dominated chronic inflammation in RA we investigated differentiation of resting CD4+ memory T cells in patients with early (6 wk to 12 mo) untreated RA and in age- and sex-matched healthy controls in vitro. No difference in cytokine secretion profiles of freshly isolated memory T cells was detected between patients and controls. A cell culture system was then employed that permitted the differentiation of Th effectors from resting memory T cells by short term priming. Marked differences were found in response to priming. Th2 cells could be induced in all healthy controls by priming with anti-CD28 in the absence of TCR ligation. By contrast, priming under those conditions resulted in Th2 differentiation in only 9 of 24 RA patients. Exogenous IL-4 could overcome the apparent Th2 differentiation defect in seven patients but was without effect in the remaining eight patients. In all patients a marked decrease in IL-2-producing cells and a significant increase in well-differentiated Th1 cells that produced IFN-gamma but not IL-2 were evident after priming with anti-CD3 and anti-CD28. The data suggest that CD4+ memory T cells from patients with early untreated RA manifest an intrinsic abnormality in their ability to differentiate into specific cytokine-producing effector cells that might contribute to the characteristic Th1-dominated chronic (auto)immune inflammation in RA.