Effects of low-dose tacrolimus therapy in combination with methotrexate in patients with methotrexate-refractory rheumatoid arthritis.

The aim of the present clinical trial was to determine the efficacy and safety of low-dose administration of tacrolimus in combination with methotrexate (MTX) in rheumatoid arthritis (RA) patients with an insufficient clinical response to MTX alone. Eleven patients with active RA, despite treatment with MTX, were enrolled and given tacrolimus in combination with MTX for 24 weeks. The primary endpoint was the assessment of clinical improvement using the European League against Rheumatism criteria. Administration of tacrolimus to RA patients with an insufficient response to MTX produced significant improvement in the Disease Activity Score 28 after 8-24 weeks. In addition, after 24 weeks, 50% and 25% of patients had achieved moderate and good responses, respectively, and there were significant reductions in the Modified Health Assessment Questionnaire, the rheumatoid factor and serum matrix metalloproteinase-3 levels. The present preliminary study suggests that low-dose tacrolimus in combination with MTX is well tolerated and provides both clinical and economic benefits.

A case of rheumatoid arthritis with bucillamine-induced yellow nail syndrome initially manifesting as pulmonary disease.

We report a case of a 67-year-old woman with rheumatoid arthritis with yellow nail syndrome (YNS) that was caused by bucillamine. All three signs (yellow fingernails, lymphatic edema, and bronchiectasis) of YNS manifested, with characteristic timing, first with the nails turning yellow after when bronchiectasis was noticed. We reviewed 10 case reports from Japan and compared the periods until the appearance of yellow nails after starting bucillamine treatment, as well as those until lung disease and leg edema appeared.

Effects of low-dose mizoribine pulse therapy in combination with methotrexate in rheumatoid arthritis patients with an insufficient response to methotrexate.

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.

Clinical features of hemophagocytic syndrome in patients with dermatomyositis.

OBJECTIVE: To investigate the clinical features of patients with dermatomyositis (DM) complicated by hemophagocytic syndrome (HPS). METHODS: Twenty-four patients diagnosed with DM and treated at our hospital between January 2002 and April 2007 were enrolled for study. Serum levels of various parameters including cytokines were determined during the active disease states. RESULTS: Levels of serum ferritin, creatine kinase, and immune complexes were all significantly higher in all patients with HPS than in those without HPS. Levels of soluble interleukin-2 receptor, macrophage colony stimulating factor, and the chemokine CX3CL1 were significantly elevated in DM patients with HPS. CONCLUSION: Our findings suggest that mechanisms related to both circulating immune complexes and circulating cytokines are involved in the pathogenesis of HPS complicating DM.

Effect of the H2 receptor antagonist nizatidine on xerostomia in patients with primary Sjögren's syndrome.

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.

Tacrolimus-induced lung injury in a rheumatoid arthritis patient with interstitial pneumonitis.

A 74-year-old woman was experiencing rheumatoid arthritis complicated with interstitial pneumonitis (IP), and tacrolimus treatment was started. She presented with dyspnea. Chest X-ray and computed tomography (CT) showed ground-glass opacity and IP. Although tacrolimus was stopped, she died of respiratory failure. At autopsy, both the upper and lower lung fields showed usual IP and the organizing stage of diffuse alveolar damage. The former is common, but the latter is uncommon, suggesting tacrolimus may cause severe alveolar damage.

Increased serum levels of soluble fractalkine (CX3CL1) correlate with disease activity in rheumatoid vasculitis.

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.

Clinical evaluation of patients with inflammatory connective tissue diseases complicated by cytomegalovirus antigenemia.

We evaluated the occurrence of cytomegalovirus (CMV) infection and the background characteristics in twenty-three hospitalized patients with inflammatory connective tissue diseases including systemic lupus erythematosus, polymyositis/dermatomyositis, rheumatoid vasculitis, microscopic polyangitis, and Takayasu's arteritis. Cytomegalovirus antigenemia was demonstrated in 10 of 23 evaluable patients. Five of ten patients with CMV antigenemia developed symptomatic CMV disease (all cases of fever, two cases of liver involvement, two cases of interstitial pneumonia, and one case of unknown organ involvement), whereas the remaining five patients were asymptomatic. Most of CMV antigenemia-positive patients had been administered intravenous steroid pulse, or in combination with immunosuppressive agents intravenously or orally because of refractory disease activity. Particularly, in patients who received intravenous methylprednisolone pulse in combination with additional intravenous cyclophosphamide pulse, the incidence of CMV antigenemia was markedly higher (four out of four). Four of ten CMV antigenemia-positive patients simultaneously showed detection of Pneumocystis jiroveci in induced sputum by PCR, increase in level of serum beta-D-glucan and the finding of geographical ground-glass opacities on chest computed tomography. These findings suggested that patients with connective tissue diseases under intensive immunosuppressive therapies (intravenous steroid pulse in combination with additional intravenous cyclophosphamide pulse in particular) are highly susceptible to CMV infection and disease, and that patients complicated by CMV antigenemia are susceptible to combined opportunistic infection such as Pneumocystis pneumonia.

Elevated levels of soluble fractalkine in active systemic lupus erythematosus: potential involvement in neuropsychiatric manifestations.

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 (SLEDAI) 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, anti-double-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.

Enhanced expression of interferon-inducible protein 10 associated with Th1 profiles of chemokine receptor in autoimmune pulmonary inflammation of MRL/lpr mice.

MRL/Mp-lpr/lpr (MRL/lpr) mice spontaneously develop systemic lupus erythematosus (SLE)-like disease. The natural history of the pulmonary involvement and the underlying mechanism of leukocyte infiltration into the lungs of MRL/lpr mice and SLE patients remains elusive. We aimed to investigate the expression profiles of chemokines and chemokine receptors in the lung of the SLE-prone mouse. We examined the correlation between lung inflammation and expression of IP-10 (interferon-gamma-inducible protein 10), a CXC chemokine, and TARC (thymus- and activation-regulated chemokine), a CC chemokine, in MRL/lpr mice, MRL/Mp-+/+ (MRL/+) mice, and C57BL/6 (B6) control mice. The extent of cell infiltration in the lung was assessed histopathologically. Reverse transcriptase PCR showed up-regulation of IP-10 mRNA expression in the lungs (P < 0.05) of MRL/lpr mice, in comparison with MRL/+ or B6 mice. The increase paralleled increased expression of a specific IP-10 receptor, CXCR3, and correlated with the degree of infiltration of mononuclear lymphocytes. In contrast, lung expression of TARC and its specific receptor, CCR4, were suppressed in MRL/lpr mice. Immunohistology showed that macrophage-like cells were the likely source of IP-10. Flow cytometric analyses revealed that the CXCR3-expressing cells were mainly infiltrating CD4 T cells and macrophages, which correlated with the degree of mononuclear lymphocyte infiltration. Recent data suggest that Th1 cells and Th1-derived cytokines play an important role in the development of SLE-like disease in MRL/lpr mice. Our results suggest that IP-10 expression in the lung is involved, through CXCR3, in the pathogenesis of pulmonary inflammation associated with migration of Th1 cells.

Peripheral T cell lymphoma-associated hemophagocytic syndrome in a patient with human adjuvant disease.

Hemophagocytic syndrome (HPS) is a rare complication of lymphoma. We report a 70-year-old woman with human adjuvant disease who developed lymphoma-associated HPS (LAHPS) and elevated serum soluble interleukin (IL)-2 receptor. Despite intensive therapy, she died of pneumonia. Necropsy revealed a prominent spleen containing atypical T cells and many erythrophagocytizing histiocytes.

A novel mechanism for the regulation of IFN-gamma inducible protein-10 expression in rheumatoid arthritis.

Chemokines play an essential role in the progression of rheumatoid arthritis (RA). In the present study we examined the expression and regulatory mechanisms of IFN-gamma inducible protein (IP)-10 in RA synovitis. RA synovial fluid contained greater amounts of IP-10 than did synovial fluid from patients with osteoarthritis. Immunolocalization analysis indicated that IP-10 was associated mainly with infiltrating macrophage-like cells, and fibroblast-like cells in the RA synovium. The interaction of activated leukocytes with fibroblast-like synoviocytes resulted in marked increases in IP-10 expression and secretion. Moreover, induction of IP-10 was mediated via specific adhesion molecules, as indicated by the finding that both anti-integrin (CD11b and CD18) and intercellular adhesion molecule-1 antibodies significantly inhibited IP-10 induction. These results suggest that IP-10 expression within inflamed joints appears to be regulated not only by inflammatory cytokines but also by the physical interaction of activated leukocytes with fibroblast-like synoviocytes, and that IP-10 may contribute to the recruitment of specific subpopulations of T cells (Th1 type) from the bloodstream into the synovial joints.

[A case with systemic lupus erythematosus presenting with reversible edematous lesion in cerebellum].

We report the case of a 24-year-old woman with systemic lupus erythematosus (SLE). The patient presented with cervical erythema and multiple arthralgia in December, 1996. Based on the high level of antinuclear antibody and the positivity for anti-double-stranded-DNA antibody, we diagnosed the patient as having SLE. Her symptoms improved and her condition was maintained following steroid treatment. In August 2000, the patient suddenly had headache, nausea, vertigo, cerebellar ataxia, fixation nystagmus, and intention tremor. She was negative for the anti-phospholipid antibody. The cerebrospinal fluid IgG index and the IL-6 level were high. MRI of the right cerebellar hemisphere showed an equal-signal-intensity region in the T 1-enhanced image, and a high-signal-intensity region with a diffuse undefined border in the T 2-enhanced image. The increased cerebral blood flow at the site corresponding to a cerebellar lesion detected by magnetic resonance imaging (MRI) was observed by brain single photon emission computed tomography (SPECT). The central nervous system (CNS) lupus was confirmed by the presence of a lesion in the cerebellum. The abnormalities detected in MRI and SPECT images of the brain disappeared immediately after the steroid pulse therapy, and symptoms such as ataxic gait were improved. This patient was diagnosed as having acute neuropsychiatric SLE with cerebellar symptoms that are rarely observed as a localized neural sign of SLE. The MRI and SPECT images suggested the presence of an inflammatory edematous lesion that was confined in the cerebellar hemisphere. This is considered to be due to the increase of vasopermeability.

[A case of rheumatoid arthritis complicated with a pneumonitis during concomitant treatment with methotrexate and bucillamine].

A 70-year-old female was diagnosed as having rheumatoid arthritis (RA) in 1971, which was then treated with steroid and nonsteroidal anti-inflammatory drugs. In 1999, after total replacement of her knee joint, 4 mg of methotrexate (MTX) per week was administered. Two months after the MTX administration, 200 mg of bucillamine per day was administered. On May 10, 2001, the patient was rushed to the hospital due to fever and difficulty in breathing. Chest X-ray and computed tomography (CT) revealed shadows of ground-glass-like opacity occurring sporadically in many places in the upper lung field bilaterally and interstitial shadows mainly on the lateral side of the lower lung field bilaterally. Instead of MTX and bucillamine, which were withheld, an MTX antagonist was administered and oxygen-supported therapy was performed; consequently, the patient recovered without the need to increase the amount of steroid. The percentage of lymphocytes in the broncholaveolar lavage fluid increased to 72%, and the CD4/CD8 ratio to 3.13. The level of serum KL-6 increased while that of serum SP-D returned to the normal level at different time. Following MTX and bucillamine administration, shadows of ground-glass-like opacity occurred sporadically in many places in the upper lung field bilaterally, which is not usually observed. It is suggested that such an unusual pulmonary disorder occurred due to concomitant use of drugs or other factors.

Interaction of monocytes with vascular endothelial cells synergistically induces interferon gamma-inducible protein 10 expression through activation of specific cell surface molecules and cytokines.

To further understand the regulatory mechanisms involved in the process of angiogenesis, the present study was designed to determine the expression and regulation of interferon gamma-inducible protein 10 (IP-10) in peripheral blood monocytes and human umbilical vein endothelial cells (HUVECs). We found that the interaction of monocytes with HUVECs resulted in synergistic increases in IP-10 expression and secretion, which consequently inhibited endothelial tube formation in vitro. Induction of IP-10 was mediated via specific cell surface molecules, as indicated by the finding that IP-10 secretion was significantly inhibited by anti-CD40 ligand antibody, and to a lesser extent by anti-CD40 antibody. Furthermore, we examined the effects of soluble mediators, such as inflammatory and immune cytokines on IP-10 secretion. Addition of interleukin (IL)-1, as well as interferon gamma, induced a marked augmentation of IP-10 secretion by unstimulated monocytes, unstimulated HUVECs, and co-cultures of the two cell types. In contrast, IL-10, recognized as an anti-inflammatory cytokine, significantly inhibited IP-10 secretion by co-cultures. Our results suggest that the interaction of monocytes with endothelial cells results in synergistic increases in IP-10 expression and secretion, which contribute to the regulation of angiogenesis and initiation of inflammatory vascular diseases.