Polymorphonuclear neutrophils (PMNs) are usually thought of as the leukocyte population involved in acute inflammatory responses, acting as a first line of defense against invading microorganisms. These terminally differentiated cells are generally not thought of as an important source of de novo synthesis of polypeptide mediators. Recent progress has shown, however, that PMNs are able to synthesize cytokines in response to a variety of inflammatory stimuli and during certain pathological conditions. The expression profiles of PMN-derived cytokines are similar with those of monocytes/macrophages, major professional phagocytes. Like monocytes, PMNs are able to secrete proinflammatory cytokines [e.g., tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta], both CC and CXC chemokines [e.g., IL-8, interferon-inducible protein 10 (IP-10) and macrophage inflammatory protein (MIP)-1alpha], and angiogenic factors [e.g., vascular endothelial growth factor (VEGF)]. The secretion of cytokines by activated PMNs is regulated by immunoregulatory cytokines such as interferon (IFN)-gamma, IL-4, IL-10 and IL-13. In addition to acute inflammatory responses, PMNs and PMN-derived cytokines appear to be involved in the pathogenesis of such chronic inflammatory disorders as rheumatoid arthritis, inflammatory bowel diseases and mycobacterial infections. Conceivably, these findings place PMNs at a pivotal position where they regulate and orchestrate not only acute inflammatory responses but also chronic inflammation and immune regulation. As such, inhibition of PMN-derived cytokines is viewed as a potentially useful strategy for therapeutic immunointervention.

Objective. To determine levels of the soluble form of the chemokine fractalkine (sFkn) and its receptor, CX 3 CR1, in patients with systemic lupus erythematosus (SLE) with neuropsychiatric involvement (NPSLE) and in SLE patients without neuropsychiatric involvement, and to assess their relationship with disease activity and organ damage.Methods. Levels of sFkn in serum and cerebrospinal fluid (CSF) were measured by enzyme-linked immunosorbent assay. Expression of Fkn and CX 3 CR1 was quantified using real-time polymerase chain reaction. Surface expression of CX 3 CR1 on peripheral blood mononuclear cells (PBMCs) was determined by flow cytometry. Disease activity and organ damage were assessed using the SLE Disease Activity Index (SLE-DAI) and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ ACR) Damage Index, respectively.Results. Serum sFkn levels were significantly higher in patients with SLE than in patients with rheumatoid arthritis (RA) or healthy controls. In addition, significant correlations between serum sFkn levels and the SLEDAI, the SLICC/ACR Damage Index, antidouble-stranded DNA and anti-Sm antibody titers, immune complex levels (C1q), and serum complement levels (CH50) were observed. Expression of CX 3 CR1 was significantly greater in PBMCs from patients with active SLE than in those from RA patients or healthy controls. Levels of sFkn were also significantly higher in CSF from untreated patients with newly diagnosed NPSLE than in SLE patients without neuropsychiatric involvement; treatment reduced both serum and CSF levels of sFkn in patients with SLE.Conclusion. Soluble Fkn and CX 3 CR1 may play key roles in the pathogenesis of SLE, including the neuropsychiatric involvement. Soluble Fkn is also a serologic marker of disease activity and organ damage in patients with SLE, and its measurement in CSF may be useful for the diagnosis of NPSLE and followup of patients with NPSLE.

Objective. To determine levels of soluble fractalkine (sFkn) in rheumatoid arthritis (RA) patients with and without rheumatoid vasculitis (RV), and to assess the relationship of sFkn levels to disease activity.Methods. Serum was obtained from 98 RA patients (54 without vasculitis, 36 with extraarticular manifestations but without histologically proven vasculitis, and 8 with histologically proven vasculitis) and from 38 healthy individuals. Levels of sFkn were measured by enzyme-linked immunosorbent assay. Expression of Fkn and CX 3 CR1 was quantified by real-time polymerase chain reaction. Vasculitis disease activity was assessed using the Birmingham Vasculitis Activity Score and the Vasculitis Activity Index.Results. Serum sFkn levels were significantly higher in patients with RA than in controls and were significantly higher in RA patients with RV than in those without vasculitic complications. Statistically significant correlations were observed between serum sFkn levels in RA patients and levels of C-reactive protein, rheumatoid factor, immune complex, and complement. In the RV group, sFkn levels also correlated with disease activity. Immunohistochemical analysis indicated that Fkn levels were associated mainly with endothelial cells in vasculitic arteries. In addition, expression of CX 3 CR1 messenger RNA was significantly greater in peripheral blood mononuclear cells from patients with active RV than in those from other RA patients or controls. Notably, serum sFkn levels were significantly diminished following successful treatment and clinical improvement.Conclusion. These findings suggest that Fkn and CX 3 CR1 play crucial roles in the pathogenesis of RV and that sFkn may serve as a serologic inflammatory marker of disease activity in RA patients with vasculitis.

Our results suggest that the CX3CL1-CX3CR1 system in patients with active RA may be sensitive to anti-tumor necrosis factor-alpha therapy, and confirm that CX3CL1 plays a crucial role in the pathogenesis of RA.

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The aim was to determine the efficacy of low-dose intermittent pulse administration of mizoribine (MZR), a purine synthesis inhibitor, in combination with methotrexate (MTX) to control the symptoms of rheumatoid arthritis (RA) in patients with an insufficient clinical response to MTX alone. Twenty-seven patients with active RA, despite treatment with MTX, were enrolled and given MZR in combination with MTX and continued for 24 weeks. The primary endpoint was assessment of clinical improvements using the European League against Rheumatism (EULAR) criteria. Administering MZR to RA patients with an insufficient response to MTX produced significant improvements in the Disease Activity Score 28 (DAS28) after 8-24 weeks. In addition, after 24 weeks, 60.0% and 8.0% of patients had achieved moderate and good responses, respectively, and there were significant reductions in Modified Health Assessment Questionnaire and serum matrix metalloproteinase-3 levels. The present preliminary study suggests that low-dose MZR in combination with MTX is well tolerated and provides both clinical and economic benefits.

Macrophage migration inhibitory factor (MIF) is recognized to be an important mediator in several inflammatory disorders, including rheumatoid arthritis (RA) and vasculitis. To evaluate the role of MIF in rheumatoid vasculitis (RV), we determined serum levels of MIF by enzyme-linked immunosorbent assay in RA patients with and without vasculitis and assessed their relationship to disease activity. Serum was obtained from 95 RA patients during active disease states [49 without vasculitis, 35 with extra-articular manifestations without histologically proven vasculitis, and 11 with histologically proven vasculitis] and from 22 healthy individuals. Vasculitis disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS). MIF levels were significantly higher in RA patients than in controls. Moreover, MIF levels were significantly higher in RA patients with vasculitis than in those without vasculitic complications. In all RA patients, a statistically significant positive correlation was observed between serum MIF levels and each of the following: serum levels of C-reactive protein, rheumatoid factor, and thrombomodulin; and the erythrocyte sedimentation rate. In the RV group, the elevation of MIF levels correlated with the BVAS. Our findings suggest that MIF may serve as an additional serologic inflammatory marker of disease activity in RV, and it may be implicated in the pathogenesis of RV.

In Sjögren's syndrome (SS), oral dryness (xerostomia) is frequently the most bothersome symptom. An H2 histamine receptor antagonist is often administered to SS patients to treat associated superficial gastritis. The aim of the present study was to assess the ability of nizatidine, an H2 receptor antagonist, to also relieve xerostomia in patients with primary SS. Twenty-seven patients with primary SS were randomly assigned to receive nizatidine (n=14, 300 mg a day) or another H2 blocker, famotidine (n=13, 40 mg a day; control), were followed for eight weeks, and were asked for both subjective and objective assessments of oral dryness using a visual analog scale (VAS; 1-100 mm) and the Saxon's test, respectively. Patients receiving oral nizatidine, but not famotidine, obtained significant objective relief from their xerostomia (Saxon's test; baseline, 0.57 g/2 min; after eight weeks, 0.90 g/2 min, P<0.05). VAS scores indicated that nizatidine also provides mild improvement (20% improvement over baseline) of xerostomia-related clinical conditions, including mouth dryness and difficulty in chewing, tasting and swallowing food. Both drugs were generally well tolerated, without adverse effects. The present preliminary study suggests that nizatidine may represent a new option for the treatment of xerostomia in SS.