Diagnostic Performance of a Temporal Artery Biopsy for the Diagnosis of Giant Cell Arteritis in Japan-A Single-center Retrospective Cohort Study.

Objectives To investigate the sensitivity and specificity of a temporal artery biopsy (TAB) in the diagnosis of giant cell arteritis (GCA) in a single-center retrospective cohort in Japan. Methods A retrospective chart review was performed on consecutive patients who visited our hospital between April 2009 and October 2018 and underwent a TAB. The sensitivity and specificity were calculated for the three pathological standards for a TAB, predetermined according to the pathological criterion of the 1990 American College of Rheumatology (ACR) criteria: A) vasculitis characterized by predominant mononuclear cell infiltration; B) vasculitis with granulomatous inflammation; and C) vasculitis with multinucleated giant cells. We also analyzed the clinical parameters predicting the diagnosis of GCA and the impact of a diagnostic delay of ≥3 months on cardiovascular complications of GCA. Results Our study population was 16 cases in the GCA group and 13 in the non-GCA group. The sensitivity and specificity for Standard A of a TAB were 81% and 85%, respectively, while those for stricter Standards B or C were identical, at 75% and 100%, respectively. These pathological standards, but not any other parameters, significantly predicted the diagnosis. A diagnostic delay tended to cause cardiovascular complications (p=0.057). Conclusion The sensitivity and specificity of the pathological standards of a TAB were favorable in our cohort and were the only predictors for the diagnosis of GCA. Considering the possible impact of a diagnostic delay on cardiovascular complications, the early recognition and prompt initiation of glucocorticoid therapy is needed, even in Japan, where GCA is uncommon.

A report of three cases with lupus myelitis.

Lupus myelitis (LM) is a rare but serious complication of systemic lupus erythematosus (SLE). In 2009, Birnbaum et al. suggested that LM could be classified into two subtypes, namely gray and white matter myelitis, based on neurological examination findings. Here we describe three cases of this disorder, one with signs of white matter dysfunction and two with signs of gray matter dysfunction. We discuss the potential role of autoantibodies in the development of LM.

[Efficacy and safety of combination therapy with mizoribine and methotrexate for rheumatoid arthritis resistant with methotrexate].

Background. MZB is a purine analog, and is used as a disease modifying anti-rheumatic drug (DMARD). We conducted an open label uncontrolled clinical trial to evaluate the efficacy and safety of combination therapy with methotrexate (MTX) and mizoribine (MZB). Methods. Thirty one RA patients (9 males, 22 females, 68±12 year-old) who fulfilled ACR criteria of RA and did not show sufficient clinical response to MTX were included. MZB (150 mg/day, once a day) were added to MTX. DAS28-CRP was measured at day 0 and 1, 3, 6, and 12 months after the treatment. Adverse events were recorded. Results. Overall DAS28-CRP was significantly decreased from 4.4±1.0 to 3.1±1.3 at 3 months (p<0.01), 2.7±0.68 at 6 months (p<0.01), 2.4±1.4 at 12 months (p<0.01). Seventeen patients (55%) achieved significant improvement of DAS28-CRP. Number of swollen joints of responders before the treatment was significantly fewer than that of non-responders. Improvement of DAS28-CRP was significantly different between the responders (0.91±0.74) and non-responders (0.18±0.66) at 1 month (p<0.01). Nine patients (29%) could achieve remission Four patients experienced adverse events. Conclusions. MTX and MZB combination therapy was effective and relatively safety.

Role of IL-17 in the Th1 systemic defects in rheumatoid arthritis through selective IL-12Rbeta2 inhibition.

BACKGROUND: Patients with rheumatoid arthritis (RA) have a systemic Th1 defect associated with inflammation. OBJECTIVE: To examine the hypothesis that interleukin 17 (IL-17) contributes to this defect. METHODS: IL-17 effects on Th1 markers were examined on T-bet and interferon gamma (IFNgamma) expression in peripheral blood mononuclear cells (PBMCs) from patients with RA or healthy controls (HC). Receptor specificities were determined by analysis of the Th1-specific IL-12 receptor beta2 (IL-12Rbeta2), Th17-specific IL-23R and the common IL-12Rbeta1 chain expression. Effects of IL-17 or IFNgamma on IL-6, IL-1, IL-8, matrix metalloproteinase-8 (MMP-8) were measured by real-time RT-PCR in RA synovial cells. RESULTS: RA PBMCs were less responsive to IL-12-induced IFNgamma than HC PBMCs. IL-12 hyporesponsiveness was increased by IL-17 treatment associated with a selective reduction in IL-12Rbeta2, but not IL-23R, IL-12Rbeta1 or T-bet, which was reversed with IL-17R inhibition. IL-17 inhibited IL-12Rbeta2 expression in developing Th1 cells. In RA synovial cells, IL-17 induced IL-6, IL-1, IL-8 and MMP-8, whereas IFNgamma had minimal or inhibitory effects. CONCLUSION: In RA, IL-12 hyporesponsiveness is associated with IL-17R-mediated downregulation of IL-12Rbeta2 expression. IL-17 may reinforce Th17 lineage commitment and proinflammatory and destructive effects through Th1 inhibition and positive feedback effects in RA synovial cells. Anti-inflammatory effects of IL-17/IL-17R antagonism may include the restoration of protective Th1 responses.

IL-17 inhibits human Th1 differentiation through IL-12R beta 2 downregulation.

Th17 cells are critical in adaptive immunity and autoimmune disease. The polarized development of Th17, Th1 and Th2 cells is dependent on counterregulatory effects on each other. Whereas IFN-gamma inhibits Th17 development, the effect of IL-17 in human Th1 development is not known. We report a novel negative regulatory role of IL-17 on IL-12R beta 2 expression associated with reduced IL-12 responsiveness. IL-17 decreased IL-12-induced IFN-gamma expression in PBMC and developing Th1 cells, associated with a selective reduction in IL-12R beta 2, and not IL-23R, IL-12R beta 1 or T-bet. Counterregulatory effects of human Th17 on Th1 lineage cytokines may contribute to lineage divergence. In autoimmune disease, IL-17 may reinforce its own developmental programme by reducing IL-12 responsiveness, thus limiting inhibitory effects of IFN-gamma on Th17 development.

Recruitment of CD16+ monocytes into synovial tissues is mediated by fractalkine and CX3CR1 in rheumatoid arthritis patients.

CD16+ monocytes, identified as a minor population of monocytes in human peripheral blood, have been implicated in several inflammatory diseases, including rheumatoid arthritis (RA). Fractalkine (FKN, CX3CL1), a member of the CX3 C subfamily, is induced by pro-inflammatory cytokines, while a receptor for FKN, CX3CR1, is capable of mediating both leukocyte migration and firm adhesion. Here, we investigated the role of FKN and CX3CR1 in activation of CD16+ monocytes and their recruitment into synovial tissues in RA patients. High levels of soluble FKN were detected in the synovial fluid and sera of RA patients. Circulating CD16+ monocytes showed a higher level of CX3CR1 expression than CD16- monocytes in both RA patients and healthy subjects. High level expression of CX3CR1 was also seen in CD16+ monocytes localized to the lining layer in RA synovial tissue. In the in vitro culture experiments, IL-10 induced CX3CR1 expression on the surface of monocytes, and TNFalpha induced membrane-bound FKN as well as soluble FKN expression in synovial fibroblasts. Moreover, soluble FKN was capable of inducing IL-1beta and IL-6 by activated monocytes. These results suggest that FKN might preferentially mediate migration and recruitment of CD16+ monocytes, and might contribute to synovial tissue inflammation.

Manifestation of rheumatoid arthritis after transsphenoidal surgery in a patient with acromegaly.

Acromegalic arthropathy is one of the most frequent manifestations occurring in acromegaly patients. In contrast, rheumatoid arthritis (RA) is a rare clinical complication in acromegaly patients. Here, we report a 70-year-old Japanese woman with acromegaly, who complained of bilateral finger stiffness and polyarthralgia two months after transsphenoidal surgery of a growth hormone (GH)-secreting pituitary adenoma. Postoperative levels of serum GH and insulin-like growth factor-1 (IGF-1) were markedly decreased without any secretory deficiency of other anterior pituitary hormones. Hand X-ray did not show typical RA changes; however, erosive changes in carpal bones were clearly detected by magnetic resonance imaging with gadolinium enhancement. Based on the levels of serological markers in the patient following surgery including C-reactive protein, rheumatoid factor and matrix metalloproteinase-3, anti-rheumatic therapy was subsequently commenced. Regardless of the levels of GH and IGF-1, acromegaly patients frequently complain about joint-related symptoms even after remission. Therefore, careful observation of bone erosive changes and immunological activity in acromegaly patients is required when joint-related symptoms persist.

Induction of tumour necrosis factor receptor-expressing macrophages by interleukin-10 and macrophage colony-stimulating factor in rheumatoid arthritis.

Despite its potent ability to inhibit proinflammatory cytokine synthesis, interleukin (IL)-10 has a marginal clinical effect in rheumatoid arthritis (RA) patients. Recent evidence suggests that IL-10 induces monocyte/macrophage maturation in cooperation with macrophage-colony stimulating factor (M-CSF). In the present study, we found that the inducible subunit of the IL-10 receptor (IL-10R), type 1 IL-10R (IL-10R1), was expressed at higher levels on monocytes in RA than in healthy controls, in association with disease activity, while their expression of both type 1 and 2 tumour necrosis factor receptors (TNFR1/2) was not increased. The expression of IL-10R1 but not IL-10R2 was augmented on monocytes cultured in the presence of RA synovial tissue (ST) cell culture supernatants. Cell surface expression of TNFR1/2 expression on monocytes was induced by IL-10, and more efficiently in combination with M-CSF. Two-color immunofluorescence labeling of RA ST samples showed an intensive coexpression of IL-10R1, TNFR1/2, and M-CSF receptor in CD68+ lining macrophages. Adhered monocytes, after 3-day preincubation with IL-10 and M-CSF, could produce more IL-1beta and IL-6 in response to TNF-alpha in the presence of dibutyryl cAMP, as compared with the cells preincubated with or without IL-10 or M-CSF alone. Microarray analysis of gene expression revealed that IL-10 activated various genes essential for macrophage functions, including other members of the TNFR superfamily, receptors for chemokines and growth factors, Toll-like receptors, and TNFR-associated signaling molecules. These results suggest that IL-10 may contribute to the inflammatory process by facilitating monocyte differentiation into TNF-alpha-responsive macrophages in the presence of M-CSF in RA.

Hypokalemic paralysis and osteomalacia secondary to renal tubular acidosis in a case with primary Sjögren's syndrome.

A 39-year-old Japanese woman was admitted to our hospital for severe weakness owing to potassium deficiency caused by type 1 renal tubular acidosis (RTA1). Sicca complex, serological tests, and lip biopsy revealed that she had Sjögren's syndrome (SS). Acidosis was corrected by alkali supplement treatment. She also had an impaired renal function with proteinuria, and high absorbance on Ga scintigram was recognized in both kidneys. She was taking warfarin potassium after aortic valve substitution due to aortic regurgitation, therefore renal biopsy was not performed. Prednisone (20 mg/day) was administered for renal inflammation. One month later, she suffered severe chest wall pains with some local tender points over the costae of both sides, which was presumed to be due to pseudo-fractures based on osteomalacia. Hypokalemic paralysis and osteomalacia should be taken into consideration in the diagnosis of SS with RTA1.

The S100A8/A9 heterodimer amplifies proinflammatory cytokine production by macrophages via activation of nuclear factor kappa B and p38 mitogen-activated protein kinase in rheumatoid arthritis.

S100A8 and S100A9, two Ca2+-binding proteins of the S100 family, are secreted as a heterodimeric complex (S100A8/A9) from neutrophils and monocytes/macrophages. Serum and synovial fluid levels of S100A8, S100A9, and S100A8/A9 were all higher in patients with rheumatoid arthritis (RA) than in patients with osteoarthritis (OA), with the S100A8/A9 heterodimer being prevalent. By two-color immunofluorescence labeling, S100A8/A9 antigens were found to be expressed mainly by infiltrating CD68+ macrophages in RA synovial tissue (ST). Isolated ST cells from patients with RA spontaneously released larger amounts of S100A8/A9 protein than did the cells from patients with OA. S100A8/A9 complexes, as well as S100A9 homodimers, stimulated the production of proinflammatory cytokines, such as tumor necrosis factor alpha, by purified monocytes and in vitro-differentiated macrophages. S100A8/A9-mediated cytokine production was suppressed significantly by p38 mitogen-activated protein kinase (MAPK) inhibitors and almost completely by nuclear factor kappa B (NF-kappaB) inhibitors. NF-kappaB activation was induced in S100A8/A9-stimulated monocytes, but this activity was not inhibited by p38 MAPK inhibitors. These results indicate that the S100A8/A9 heterodimer, secreted extracellularly from activated tissue macrophages, may amplify proinflammatory cytokine responses through activation of NF-kappaB and p38 MAPK pathways in RA.

Increased expression of receptor for advanced glycation end products by synovial tissue macrophages in rheumatoid arthritis.

OBJECTIVE: The accumulation of advanced glycation end products (AGEs), S100A12, and high mobility group box chromosomal protein 1 has been associated with joint inflammation in rheumatoid arthritis (RA). This study was undertaken to determine the induction of the receptor for these proteins, termed receptor for AGEs (RAGE), in synovial tissue (ST) macrophages from RA patients. METHODS: RAGE and CD68 expression in ST were determined by 2-color immunofluorescence labeling. Cell surface and messenger RNA (mRNA) expression of RAGE were examined by flow cytometry and reverse transcriptase-polymerase chain reaction (PCR) or real-time PCR, respectively. RESULTS: CD68+ lining macrophages, like the vasculature, expressed high levels of RAGE in inflamed ST from RA patients. RAGE mRNA expression was significantly higher in RA ST than in ST from patients with osteoarthritis. RAGE mRNA levels were significantly higher in ST macrophages and normal endothelial cells than in ST CD4+ T cells and synovial fibroblasts stimulated with tumor necrosis factor alpha and interleukin-1beta (IL-1beta). Cell surface RAGE was highly induced on normal monocytes after a 24-hour incubation with a 20% concentration of RA ST cell culture supernatants. RAGE mRNA expression in adherent monocytes was augmented by various cytokines, most potently by IL-1beta. CONCLUSION: These results indicate that RAGE overexpression in lining macrophages may be induced, at least in part, by cytokines such as IL-1, leading to the amplification of inflammatory responses mediated by RAGE ligands that are abundant in RA joints.

mRNA quantification of T-bet, GATA-3, IFN-gamma, and IL-4 shows a defective Th1 immune response in the peripheral blood from rheumatoid arthritis patients: link with disease activity.

A T helper (Th)1 cytokine profile is predominant in the inflamed synovium of rheumatoid arthritis (RA). Since the situation in the blood is more controversial, we studied the Th1/Th2 balance in the peripheral blood of RA patients using mRNA markers. Total RNA was isolated directly from whole blood from 20 RA patients and 14 healthy controls. T-bet and GATA-3 transcription factors associated with Th1 and Th2 responses respectively, and IFNgamma and IL-4 mRNA levels were measured by real-time PCR. In RA but not in control samples, T-bet mRNA levels correlated positively with IFNgamma mRNA levels, and negatively with CRP levels. Accordingly, RA patients were divided into two groups according to CRP levels. In comparison to RA patients with a low CRP (CRP < 40 mg/l), patients with a high CRP (CRP>or=40 mg/l) had lower IFNgamma/beta-actin, T-bet/beta-actin mRNA levels and T-bet/GATA-3 expression ratios. In conclusion, RA blood cells showed a decreased Th1 situation as indicated by low IFNgamma and T-bet mRNA expression. This pattern was found only in patients with the most active disease.

Regulation of interleukin-18 binding protein production by blood and synovial cells from patients with rheumatoid arthritis.

OBJECTIVE: To study the regulation of interleukin-18 binding protein (IL-18BP) production by rheumatoid arthritis (RA) or control peripheral blood mononuclear cells (PBMCs) and by RA synovial tissue cells, and to compare the levels of IL-18BP messenger RNA (mRNA) expression in whole blood from RA patients and controls. METHODS: Unstimulated or phytohemagglutinin and phorbol myristate acetate (PHA/PMA)-stimulated PBMCs from 10 RA patients and 12 healthy controls and unstimulated or PHA/PMA-stimulated synovial tissue cells from 8 RA patients were cultured with or without IL-12 (1 ng/ml) and IL-18 (5 ng/ml) alone or in combination. IL-18BP and interferon-gamma (IFN gamma) levels in supernatants were measured by enzyme-linked immunosorbent assay. Levels of IL-18BP and IFN gamma mRNA expression in whole blood samples from 22 RA patients and 12 healthy controls were determined by quantitative reverse transcriptase-polymerase chain reaction. RESULTS: IL-12 decreased the basal levels of IL-18BP production by freshly isolated RA or control PBMCs, but increased those of synovial cells or PHA/PMA-stimulated PBMCs. IL-18 alone had no direct effect on IL-18BP production by PBMCs or RA synovial cells, with or without stimulation. Unstimulated whole blood samples from RA patients showed lower levels of IL-18BP mRNA expression than those from healthy controls. CONCLUSION: The production of IL-18BP in response to IL-12 and IL-18 was regulated differently in blood and synovial cells. The difference appears to be related to the level of cell activation.

Expression of interleukin 12 receptor (IL-12R) and IL-18R on CD4+ T cells from patients with rheumatoid arthritis.

OBJECTIVE: Interleukin 12 (IL-12) and IL-18 synergistically induce interferon-gamma (IFN-gamma) production by T cell infiltrates in rheumatoid arthritis (RA). To investigate this synergism, we examined the expression and regulation of IL-12 receptor (IL-12R) and IL-18R on peripheral blood (PB) and synovial tissue (ST) CD4+ T cells from patients with RA. METHODS: The mRNA and cell surface expression of IL-12R and IL-18R in CD4+ T cells were determined by reverse transcriptase-polymerase chain reaction and flow cytometry, respectively. IFN-gamma and IL-4 production by CD4+ T cells stimulated with phorbol myristate acetate (PMA) and calcium ionophore A23187 was measured by intracellular cytokine staining and flow cytometry. RESULTS: Despite the negligible expression of IL-12R on fresh cells, PB CD4+ T cells from RA patients expressed higher levels of both IL-12Rbeta1 and beta2 subunits after stimulation with anti-CD3 antibody (Ab) than the cells of healthy controls. ST CD4+ T cells contained mRNA transcripts encoding IL-12Rbeta1 and beta2, and expressed detectable levels of these 2 subunits on the cell surface. Their IL-12R expression was markedly augmented by costimulation with anti-CD3 Ab and IL-18. In contrast, IL-18Ralpha was expressed on freshly isolated PB CD4+ T cells from RA patients and controls, and the level of expression was higher in RA. IL-18Ralpha+ CD4+ T cells were further increased in the ST lesion, where IL-18Rbeta mRNA was constitutively detected. IL-12Rbeta1 and beta2 were induced mainly on IL-18Ralpha+ CD4+ T cells after anti-CD3 Ab stimulation. PMA and A23187-activated ST CD4+ T cells mostly expressed IL-18Ralpha and produced high levels of IFN-gamma. CONCLUSION: These results indicate that IL-18R-expressing CD4+ T cells are accumulated in the ST of patients with RA, where the functional IL-12R is locally induced by stimuli such as CD3 activation and IL-18. Activation of both cytokine receptors may be necessary for the IFN-gamma-dominant cytokine response.

Decreased response to IL-12 and IL-18 of peripheral blood cells in rheumatoid arthritis.

Inflamed synovium of rheumatoid arthritis (RA) has been associated with a T helper (Th)1 cytokine profile but the blood situation remains to be clarified. We studied the differential IFN-gamma producing activity of peripheral blood mononuclear cells (PBMCs) from RA patients (RA-PBMCs) and from healthy controls (H-PBMCs) in response to IL-12 and IL-18. RA-PBMCs had a decreased IFN-gamma production in response to IL-12 and IL-18 when compared with H-PBMCs. RA-PBMCs activated with phytohemagglutinin and phorbol 12-myristate 13-acetate showed an increased sensitivity to IL-12 and IL-18, but still the RA-PBMC response was lower. IL-18 increased IL-12-stimulated IFN-gamma production from RA synovium cells obtained after collagenase digestion more effectively than that of RA- or H-PBMCs. A specific inhibitor of IL-18 bioactivity, IL-18-binding protein (IL-18BP), down-regulated IL-12-induced IFN-gamma production by RA- or H-PBMCs and had a remarkable effect on RA synovium cells. In conclusion, RA disease combines a polarized immune response with an active Th1 in inflamed joints and a reduced Th1 pattern in peripheral circulation.

Heterogeneity of response of rheumatoid synovium cell subsets to interleukin-18 in relation to differential interleukin-18 receptor expression.

OBJECTIVE: To examine the differential response of rheumatoid arthritis (RA) synovium cell subsets to interleukin-18 (IL-18), the effect of IL-18 on Th1-cytokine production, and the regulation of IL-18 by IL-18 binding protein (IL-18BP). METHODS: RA fibroblast-like synoviocytes were stimulated with IL-1 beta, IL-12, and IL-18, and levels of IL-6 were measured by enzyme-linked immunosorbent assay (ELISA). Expression of IL-18 receptor alpha and beta chains (IL-18R alpha and IL-18R beta, respectively), interferon-gamma (IFN gamma), and IL-17 messenger RNA (mRNA) by peripheral blood mononuclear cells, by total RA synovium cells containing T cells obtained after collagenase digestion, and by RA fibroblast-like synoviocytes was determined by reverse transcription-polymerase chain reaction. Levels of IFN gamma were measured by ELISA. RESULTS: IL-1 beta and, less effectively, IL-12 could induce RA fibroblast-like synoviocytes to produce IL-6, but IL-18 failed to have an effect. Although IL-18R alpha mRNA was constitutively expressed by RA fibroblast-like synoviocytes, IL-18R beta could not be detected, either with or without stimulation with IL-1 or IL-12. Total RA synovium cells containing T cells showed a strong expression of both IL-18R alpha and IL-18R beta mRNA, and only IL-18R beta was up-regulated by IL-12. The combination of IL-12 and IL-18 synergistically up-regulated IFN gamma mRNA expression by total RA synovium cells containing T cells, but down-regulated that of IL-17. IL-12-induced IFN gamma production by total RA synovium cells containing T cells was increased by additional IL-18 and decreased by IL-18BP. CONCLUSION: These results indicate that IL-18 plays an important role in RA inflammation and joint destruction via T cells and macrophages, but it does not have a direct effect on fibroblast-like synoviocytes. IL-18BP may be a tool for RA therapy because of its ability to neutralize endogenous IL-18.

Pathophysiological functions of CD30+ CD4+ T cells in rheumatoid arthritis.

High levels of soluble CD30 (sCD30) were detected in the serum and synovial fluid of patients with rheumatoid arthritis (RA), indicating the involvement of CD30+ T cells in the pathogenesis. We investigated the induction of CD30 and its functions in CD4+T cells from patients with established RA (disease duration >_2 years). CD4+ T cells from both the peripheral blood (PB) and synovial tissue (ST) of RA patients expressed surface CD30 when stimulated with anti-CD3 antibody (Ab) and anti-CD28 Ab, but their CD30 induction was slower and weaker compared with PB CD4+ T cells of healthy controls (HC). Immunohistochemical analysis showed that only a small proportion of lymphocytes expressed CD30 in the ST (-1%). RA PB CD4+ T cells, after recovery from 6-day stimulation with anti-CD3 Ab and anti-CD28 Ab, showed in intracellular cytokine staining that CD30+ T cells could produce more interleukin-4 (IL-4) but less interferon-gamma. In the culture of RA PB CD4+ T Cells with anti-CD3 Ab and anti-CD28 Ab, blocking anti-CD30 Ab similarly inhibited the cell proliferation and activation of nuclear factor-kappaB on day 4 in RA and HC, but inhibited the apoptotic cell death on day 6 only in RA. These results indicate that despite high-level expression of sCD30, the anti-inflammatory activity of IL-4-producing CD30+ CD4+ T cells may be limited in the ST due to a poor induction of surface CD30 and a susceptibility to CD30-mediated cell death.

CD14+,CD16+ blood monocytes and joint inflammation in rheumatoid arthritis.

OBJECTIVE: CD14+,CD16+ monocytes, identified as a minor population of monocytes in human peripheral blood (PB), have been implicated in several inflammatory diseases. We undertook this study to investigate the relevance of this phenotype to joint inflammation in rheumatoid arthritis (RA). METHODS: The expression of CD14, CD16, CC chemokine receptor 1 (CCR1), CCR5, and intercellular adhesion molecule 1 (ICAM-1) on monocytes was measured by flow cytometric analysis. Concentrations of the cytokines known to induce CD16 (including transforming growth factor beta1 [TGFbeta1], macrophage colony-stimulating factor [M-CSF], and interleukin-10 [IL-10]) and concentrations of the soluble form of CD14 (sCD14) in plasma and synovial fluid (SF) samples were measured by enzyme-linked immunosorbent assay. The induction of CD16 on RA blood monocytes cultured for 18 hours with 1 or with all 3 cytokines was determined. RESULTS: The mean +/- SD frequency of CD14+,CD16+ blood monocytes was significantly increased in RA patients (11.7 +/- 5.6%; n = 105) compared with healthy controls (9.5 +/- 2.2%; n = 15) (P < 0.01), and the patient group with an increased frequency of CD16+ monocytes (> or =13.9%) had active disease, as defined by increased counts of tender and swollen joints, levels of acute-phase reactants, and titers of rheumatoid factor. The response to drug therapy correlated with changes in the frequency of this phenotype. The expression of CD16 on SF monocytes from RA patients was markedly elevated compared with the expression on PB monocytes. CD16 expression on RA blood monocytes was augmented in vitro by IL-10, M-CSF, and TGFbeta1. Plasma concentrations of these cytokines and of sCD14 were significantly higher in RA patients with high CD16+ monocyte frequencies than in those with low CD16+ monocyte frequencies or in healthy controls. CD14+,CD16+ monocytes expressed higher levels of CCR1, CCR5, and ICAM-1 than did regular CD14++,CD16- monocytes, particularly in active RA. CONCLUSION: These results indicate that the maturation of blood monocytes into tissue-infiltrative CD16+ cells before entry into the joint, induced by cytokine spillover from the inflamed joint, may contribute to the persistent joint inflammation of RA.