Biological/targeted synthetic DMARDs do not arrest bone loss in patients with rheumatoid arthritis: a multicenter prospective observational study.

OBJECTIVE: To elucidate the differential effects of biological/target synthesized DMARDs (b/tsDMARDs) on bone metabolism in patients with rheumatoid arthritis (RA) in a real-world cohort. METHODS: This was a multicentre prospective observational study of RA patients enrolled at the time of 1st b/tsDMARDs administration. Bone mineral density (BMD) and bone turnover markers (BTMs) were measured during the 52-week observation. The study was designed to enrol all eligible RA patients. The end-points were differences in changes in BMD according to b/tsDMARD type, and the correlation between BMD and BTMs. RESULTS: A total of 1,164 patients were enrolled in this study. b/tsDMARDs improved RA disease activity from mean CDAI 25.5 at baseline to 4.5 at week 26. Patients not receiving anti-osteoporotic agents (anti-OP) at baseline with no history of fracture experienced a significant decrease in both femoral neck (F: mean 0.666-0.655 g/cm3) and radial (R: 0.518-0.514) BMD at week 26. Despite maintaining low CDAI levels during weeks 26-52 (5.3-4.4), there was a continued decline in BMD (F: 0.653, R: 0.509. Weeks 52). None of b/tsDMARDs type preserved BMD. Conversely, patients receiving anti-OP at baseline maintained stable BMD throughout the study (Weeks 0/26/52. F: 0.551/0.551/0.555, R: 0.415/0.416/0.415). Although BTMs were changed by b/tsDMARDs, the changes were unrelated to those in BMD. CONCLUSION: Our study suggested the progression of osteoporosis in RA patients during b/tsDMARDs treatment without anti-OP. BTMs may not reflect BMD change. Regular monitoring of BMD in RA should be considered for early management of osteoporosis.

Low complements and high titre of anti-Sm antibody as predictors of histopathologically proven silent lupus nephritis without abnormal urinalysis in patients with systemic lupus erythematosus.

OBJECTIVE: The aim of this study was to clarify the clinical characteristics and predictors of silent LN (SLN), a type of LN in SLE without abnormal urinalysis or renal impairment. METHODS: Of 182 patients who underwent renal biopsy, 48 did not present with abnormal urinalysis or renal impairment at the time of biopsy. The patients with LN (SLN group, n = 36) and those without LN (non-LN group, n = 12) were compared with respect to their baseline characteristics. Bivariate analysis comprised Fisher's exact test and the Mann-Whitney test, whereas multivariate analysis employed binomial logistic regression analysis. RESULTS: LN was histopathologically identified in 36 of 48 patients. According to the International Society of Nephrology/Renal Pathology Society classification, 72% of the SLN patients were classified as having class I/II, with a further 17% having class III/IV. Bivariate analyses indicated that platelet count, serum albumin, complement components (C3 and C4), complement haemolytic activity (CH50), anti-Sm antibody titre and anti-ribonucleoprotein antibody titre were significantly different between groups. Multivariate analysis indicated that CH50 and C3 titres were significantly lower in the SLN group, whereas anti-Sm antibody titre was significantly higher. The cut-off titre, calculated based on the receiver operating characteristic curve for CH50, was 33 U/ml, with a sensitivity and specificity of 89% and 83%, respectively. The cut-off titre for anti-Sm antibodies was 9 U/ml, with a sensitivity and specificity of 74% and 83%, respectively. CONCLUSION: Low titres of CH50 and C3 and a high titre of anti-Sm antibody were identified as predictors of SLN.

C5a promotes migration, proliferation, and vessel formation in endothelial cells.

OBJECTIVES: The goal of this paper is to investigate the effects of activated complement C5a on vascular endothelium during vessel formation. METHODS: A human microvascular endothelial cell line (HMEC-1) derived from post-capillary venules in skin was used to measure DNA synthesis, proliferation and cell-cycle progression. In vitro ring-shaped formation by the cells was assessed by using type I collagen gel matrix and a cell-migration assay using the Chemotaxicell chamber. A Matrigel plug assay was performed to confirm the effect of C5a in vivo. RESULTS: C5a progressed the cell cycle of HMEC-1 into G2/M phases, and induced DNA synthesis and proliferation in a dose-dependent manner. C5a efficiently induced migration and ring-shaped structure formation both in vitro and in vivo. Furthermore, a C5a receptor antagonist (W-54011) suppressed all HMEC-1 activities including proliferation and migration. CONCLUSIONS: Proliferation, migration, and ring-shaped formation by HMEC-1 cells was induced by C5a. The actions were efficiently inhibited by a specific antagonist against C5a. Our results implicated C5a in vessel formation and as a potent target for management of inflammatory diseases.

[Successful treatment of intravenous cyclophosphamide pulse therapy for lupus myelitis with urinary disturbance and acute confusional state].

A 18-year-old female had low grade fever, butterfly rush, proteinuria, leukocytopenia and hypocomplimentemia in 1988, and she was diagnosed as systemic lupus erythematosus (SLE) with lupus nephritis (WHOIIb). Treatments with prednisolone and mizoribine resulted in the remission for three years. In May 2001, she presented neurosis and polakisuria despite of the increase of prednisolone to 20 mg/day. Finally, she admitted in our hospital because of manic and repressive state and disorientaion. A brain MRI revealed high intensity lesions in bilateral basal ganglia in T2 weighted images, and cerebrospinal fluid showed elevated protein and IFN-alpha (421 IU/ml). In addition, she manifested neurogenic bladder, muscle weakness and hyperactive deep tendon reflex of bilateral lower limbs due to both supranuclear disorder and hypesthesia under the Th 10 level. Spinal MRI revealed marked atrophy and high intensity signals at the middle to lower thoracic spinal cord in T2 weighted images, indicating complication of lupus myelitis as well as cerebral involvement. Although the symptoms of CNS lupus did not respond to prednisolone, twelve monthly cyclophosphamide pulse therapy (IV-CY) has resolved urinary disturbance, muscle weakness and sensory loss, along with the improvement of both cerebral and spinal MRI images. Lupus myelitis and neurogenic bladder are the rare, but very refractory manifestation among CNS involvement of SLE. We here propose IV-CY as an invaluable choice for the treatment of not only active lupus myelitis but also neurogenic bladder resisted for steroid.

[Successful treatment of intravenous cyclophosphamide pulse therapy for systemic lupus erythematosus complicated with steroid-resistant hemolytic anemia].

(Case 1) A 13-years-old female had multiple arthralgia and butterfly rush, when she admitted in our hospital in May 2001. Nephropathy, hemolytic anemia (Hb 6.3 g/dl and direct Coombs 3+) and high titers of antinuclear antibodies and anti-ds-DNA antibody were disclosed and she was diagnosed as systemic lupus erythematosus (SLE). Although combination therapy of PSL 60 mg/day with a steroid pulse therapy, cyclosporine or an immunosorbent treatment, severe hemolytic anemia remained. However, monthly cyclophosphamide pulse therapy (IV-CY), which was started for the steroid-resistant hemolytic anemia, has gradually become effective and Hb improved up to 11.4 g/dl after 6 courses of IV-CY. (Case 2) A 53-years-old woman diagnosed as SLE in 1978 and she had PSL 5 mg for over 10 years. Severe anemia (Hb 5.9 g/dl) was disclosed with a slight fever in June 2001, and she admitted in our hospital for further examinations. Progressive hemolytic anemia was revealed with marked decrease of Hb (3.4 g/dl) and high titer of direct Coombs (3+). Neither PSL (50 mg/day) nor steroid pulse therapy were effective against hemolytic anemia. In contrast, 3 courses of monthly IV-CY (500 mg/day) resulted in the resolution of hemolysis. It is well known that the steroid-resistant hemolytic anemia is extremely hard to treat and leads to miserable prognosis, but we here propose IV-CY as an alternative and invaluable choice for the treatment of refractory hemolytic anemia complicated with SLE.

[Active arthritis due to cryoglobulinemia based on HCV infection in a patient with RA improvement of arthritis with IFN-alpha].

A 49-year-old Japanese woman was diagnosed with rheumatoid arthritis (RA) based on ACR criteria in May 1999. She developed liver injury after initiation of disease-modifying antirheumatic drugs (DMARDs) and was found to have contracted HCV infection. RA disease activity worsened following restriction of medication due to liver dysfunction. However, 3 mg/day of prednisolone (PSL) resulted in a temporary but marked improvement of RA in December 2001; but arthritis recurred along with Raynaud's phenomenon and palpable purpura. Differential diagnosis between arthritis caused by cryoglobulinemia and exacerbation of RA was important for the selection of appropriate treatment. She manifested non-erosive arthritis on medium and large joints with proteinuria, hematuria and hypocomplementemia. In addition, type III cryoglobulin was detected and chronic active hepatitis was observed on liver biopsy in March 2002. We considered that the main cause for the arthritis was HCV-related mixed cryoglobulinemia. Administration of IFN-alpha resulted in the disappearance of HCV-RNA and cryoglobulin followed by amelioration of arthritis without exacerbation of RA.

Phenotypic changes of lymphocytes in patients with systemic lupus erythematosus who are in longterm remission after B cell depletion therapy with rituximab.

OBJECTIVE: Rituximab has recently emerged as a novel treatment strategy for systemic lupus erythematosus (SLE). We investigated longitudinally the differentiation and phenotypic changes of peripheral B cells and T cells in patients with SLE after rituximab treatment. METHODS: Phenotypic changes on B cells and T cells in 10 patients with SLE treated with rituximab were analyzed before, 28 days after, and 2 years after rituximab treatment, and at relapse. RESULTS: Rituximab rapidly depleted naive and memory B cells from the peripheral blood. In the patients with prolonged remission, the memory B cells remained depleted while naive B cells recovered within 3-9 months, and the expression levels of CD40 and CD80 remained downregulated for 2 years. There was also a decrease of memory T cells relative to naive T cells, and the expression of CD40L and inducible costimulator (ICOS) on CD4-positive T cells rapidly decreased and remained downregulated for 2 years. In 1 patient, an increase in the number of memory B cells with upregulation of CD40 and CD80 expression was noted just before relapse. In another patient with relapse, however, recovery of CD4-positive memory T cells with upregulation of ICOS expression was noted, with no change in the number of memory B cells. CONCLUSION: Our results suggest that the phenotypic changes of peripheral B cells result in inhibition of T cell differentiation and activation mediated by B cells and thereby bring about longterm remission of SLE. Activated memory B cells or ICOS-positive CD4-positive memory T cells reappeared in association with relapse, probably reflecting the heterogeneity of SLE.

Efficacy of rituximab (anti-CD20) for refractory systemic lupus erythematosus involving the central nervous system.

AIM: Neuropsychiatric systemic lupus erythematosus (NPSLE) is a serious treatment-resistant phenotype of systemic lupus erythematosus. A standard treatment for NPSLE is not available. This report describes the clinical and laboratory tests of 10 patients with NPSLE before and after rituximab treatment, including changes in lymphocyte phenotypes. METHODS: Rituximab was administered at different doses in 10 patients with refractory NPSLE, despite intensive treatment. RESULTS: Treatment with rituximab resulted in rapid improvement of central nervous system-related manifestations, particularly acute confusional state. Rituximab also improved cognitive dysfunction, psychosis and seizure, and reduced the SLE Disease Activity Index Score at day 28 in all 10 patients. These effects lasted for >1 year in five patients. Flow cytometric analysis showed that rituximab down regulated CD40 and CD80 on B cells and CD40L, CD69 and inducible costimulator on CD4+ T cells. CONCLUSIONS: Rituximab rapidly improved refractory NPSLE, as evident by resolution of various clinical signs and symptoms and improvement of radiographic findings. The down regulation of functional molecules on B and T cells suggests that rituximab modulates the interaction of activated B and T cells through costimulatory molecules. These results warrant further analysis of rituximab as treatment for NPSLE.

Overcoming treatment unresponsiveness mediated by P-glycoprotein overexpression on lymphocytes in refractory active systemic lupus erythematosus.

P-glycoprotein (P-gp) expels various drugs from cells, resulting in multidrug resistance, including against glucocorticoids. Here, we present a case of systemic lupus erythematosus (SLE) that suggests the importance of initial intensive treatment in overcoming unresponsiveness due to P-gp overexpression on activated lymphocytes. A 28-year-old woman had been diagnosed with highly active SLE including severe pericarditis, hemolytic anemia, lupus nephritis, and retinopathy. The disease activity of SLE progressed despite 1 mg/kg per day oral prednisolone. At the time, P-gp expression was extremely high, as evaluated by flow cytometric analysis on peripheral lymphocytes. After intensive treatment with three courses of methylprednisolone pulse therapy and plasmapheresis, we succeeded in controlling disease activity in association with marked reduction of P-gp overexpression; namely, the clinical symptoms immediately improved along with the reduction of P-gp expression. These results imply that patients with highly active SLE might have drug unresponsiveness that is mediated by P-gp overexpression on lymphocytes. Therefore, downregulation of P-gp by initial intensive immunosuppressive therapy might be important for overcoming glucocorticoid resistance. We also propose that measurement of P-gp on lymphocytes is a useful test for prediction of drug resistance and may assist in the selection of appropriate initial treatment.

[A case of rheumatoid arthritis with secondary amyloidosis in urinary bladder].

We document a case of 61-year-old woman with a 24 year history of rheumatoid arthritis (RA), who developed severe polyarthralgia, dry cough, paresthesia in the legs, frequent micturition, and severe macrohematuria. We diagnosed as severe RA with extraarticular manifestations based on interstitial pneumonia, mononeuritis multiplex, subcutaneous nodules, and high titer of rheumatoid factor. Ultrasonography demonstrated an intravesical mass lesion. A histological examination of the urinary bladder by endoscopic biopsy revealed marked deposition of AA amyloid. The diagnosis of secondary amyloidosis and bacterial cystitis were made based on histological findings and urine culture. At first, we administered antibiotics by intravenous infusion, which resulted in cure of cystitis and partial improvement of macrohematuria. Then combination therapy of corticosteroids and cyclophosphamide successfully reduced the disease activity of RA. There have only been a few reports published so far on the vesical amyloidosis in patients with RA. However, 5 of 10 patients (50%) in vesical amyloidosis died because of continuous massive hematuria, which induced disseminated intravascular coagulation and multiple organ failure. In conclusion, secondary amyloidosis of the urinary bladder should be considered as a possible cause of hematuria in patients with long-term RA and as an important prognosis factor of RA.

Efficacy of mizoribine treatment in patients with Sjögren's syndrome: an open pilot trial.

Abstract The aim of this study was to evaluate the efficacy and safety of mizoribine in patients with Sjögren's syndrome. Forty patients with sicca syndrome, whose conditions were definitely diagnosed as Sjögren's syndrome, were given mizoribine orally at a dosage of 150 mg/day for 12 months. The percentage change in salivary secretion after 3, 6, and 12 months of the therapy increased to +112.2% (P < 0.001), +119.9% (P < 0.01), and +147.3% (P < 0.001), respectively, compared with the baseline. Serum IgG levels decreased significantly throughout the study, and the level was 1969.4 ± 620.0 mg/dl after treatment for 12 months compared with the pretreatment value of 2094.3 ± 746.6 mg/dl (P < 0.05). The patient's assessment of clinical signs and symptoms on a 10-cm visual analog scale improved significantly from 7.2 ± 2.3 cm at the start of the treatment to 5.0 ± 1.9 cm after 12 months (P < 0.001). There was a similar improvement in the physician's assessment using the 10-cm visual analog scale: 7.1 ± 1.6 cm at the start of the treatment and 5.2 ± 1.9 cm after 12 months (P < 0.001). With regard to safety, no serious adverse reactions were observed. Although a controlled study would be required to clarify the efficacy of mizoribine, these preliminary observations indicate its efficacy for ameliorating glandular symptoms through improvements in immune abnormalities in patients with Sjögren's syndrome.