Steroid-resistant protein-losing gastroenteropathy complicated with Sjögren’s syndrome successfully treated with mizoribine

A 64-year-old woman with leg edema was diagnosed with protein-losing gastroenteropathy and Sjögren’s syndrome. Central venous nutrition led to infection of her catheter, ascites, and deep vein thrombosis. Following successful treatment of these conditions with antibiotics and anticoagulants, she was treated unsuccessfully with prednisolone and steroid pulse therapy. Mizoribine add-on markedly reduced edema and normalized serum albumin. This is the first report of a steroid-resistant protein-losing gastroenteropathy patient with Sjögren’s syndrome successfully treated with mizoribine.     

Efficacy of mizoribine pulse therapy in patients with rheumatoid arthritis who show a reduced or insufficient response to infliximab

The efficacy of infliximab, a chimeric antibody against tumor necrosis factor-α used to treat patients with rheumatoid arthritis (RA), tends to decrease as patients develop human antichimeric antibody against infliximab (HACA). The clinical study reported here was designed to evaluate the efficacy of mizoribine (MZR) pulse therapy in patients who show a reduced or insufficient response to infliximab. Ten RA patients who had active arthritis despite infliximab therapy were treated with MZR pulse therapy at a dose of 100 mg MZR and methotrexate (MTX) and the disease activity assessed at baseline and at weeks 4–8, 12–16, and 20–24. The dose was increased to 150 mg in those patients who showed an insufficient response to MZR. The mean 28-joint disease activity score (DAS28) at weeks 12–16 and 20–24 of therapy was significantly lower than that at baseline. A moderate or good European League against Rheumatism (EULAR) response was achieved in seven patients (70%) at weeks 12–16 and in five patients (50%) at weeks 20–24. The dose of 150 mg MZR was effective in one of the three patients who showed an insufficient response to pulse therapy with 100 mg MZR. Based on these results, we propose that MZR pulse therapy should be attempted before the patient is switched to other biologics.     

Inhibitory effect of mizoribine on matrix metalloproteinase-1 production in synovial fibroblasts and THP-1 macrophages

Abstract

To investigate the mechanism of antirheumatic action of mizoribine (MZR), we examined the expression of matrix metalloproteinase-1 (MMP-1) and MMP-3 utilizing THP-1 derived macrophage-like cells (THP-1 macrophages) and human synovial fibroblasts (SFs). The cells were respectively stimulated with lipopolysaccharide (LPS) and interleukin-1β in the presence or absence of MZR in vitro. The concentrations of MMP-1 and MMP-3 in the supernatant were measured by enzyme-linked immunosorbent assay. The secretion of MMP-1 from SFs, as well as THP-1 macrophages, was inhibited by MZR in a dose-dependent manner. Furthermore, a quantitative real-time polymerase chain reaction revealed that MZR decreased the expression of MMP-1 messenger RNA. These findings may be an explanation for the clinical effect of MZR in patients with rheumatoid arthritis.     

A case of lupus nephritis improved after appropriately adjusting the dosage of mizoribine

Abstract

A 29-year-old male presenting nephrotic syndrome and facial skin erythema was admitted to our hospital in September of 2000. We diagnosed him as having systemic lupus erythematosus (SLE) accompanied by lupus nephritis (WHO class V). The disease activity had decreased after treatment with methylprednisolone (m-PSL) pulse therapy, which was followed by oral PSL. Thereafter, when tapering the dosage from 60 to 30 mg/day, the lupus nephritis flared up and he was re-hospitalized in February of 2001. After successful retreatment with m-PSL pulse therapy followed by the tapering of the dosage from 60 to 30 mg/day, we used mizoribine (MZR) as a combination therapy. The lupus nephritis flared up again after tapering down to 17.5 mg/day of PSL. Then, we changed the MZR dosage from 150 mg/day in three divided daily doses to 200 mg/day in two divided daily doses. This modification increased the peak blood concentration (Cmax) of MZR from 0.63 to 1.55 μg/ml. At present, we have been able to successfully taper the dosage to 7.5 mg/day of oral PSL and the patient has achieved a state of remission without any side effects. Monitoring of the serum concentration of MZR is thus considered to be important for achieving effective therapy of SLE, especially for steroid-resistant lupus nephritis. If the serum concentration of MZR does not reach an effective level, then the dosage of MZR should be adjusted appropriately in order to maintain an adequate serum concentration of MZR.     

Efficacy of tonsillectomy pulse therapy versus multiple-drug therapy for IgA nephropathy

We evaluated the efficacy of tonsillectomy plus pulse prednisolone, warfarin, and dipyridamole including methylprednisolone pulse (tonsillectomy plus pulse therapy), versus prednisolone, warfarin, and dipyridamole including mizoribine (PWDM) for the treatment diffuse IgA nephropathy (IgAN) in children. The patients were randomly assigned to be treated by tonsillectomy plus pulse therapy for 2 years (Group A, n=16) or PWDM for 2 years (Group B, n=16). The clinical features and pathological findings in both groups were analyzed prospectively. The mean urinary protein excretion after 6 months of treatment in both groups had decreased significantly compared with pre-therapy. The activity index (AI) in both groups was lower at the time of the second biopsy than at the time of the first biopsy. The chronicity index (CI) in Groups A and B did not differ between the first and second biopsy. At the latest follow-up examination none (0%) of the patients in either group had renal insufficiency. None of the patients in Group A, but six patients in Group B experienced an acute exacerbation of IgAN as a result of tonsillitis (P<0.05). In conclusion, although there was no untreated control group in this study, the results suggested that tonsillectomy plus pulse therapy is as effective as PWDM in ameliorating proteinuria and histological severity in IgAN patients and in preventing acute exacerbation of IgAN by tonsillitis.     

Induction therapy with low-dose intravenous cyclophosphamide, oral mizoribine, and steroids for severe lupus nephritis in children

Although immunosuppressive regimens of corticosteroids combined with high-dose intravenous cyclophosphamide (IVCY) have been reported to suppress the activity of lupus nephritis, there is controversy regarding its application for children and adolescents, because of its potential toxicity including gonadal dysfunction. On the basis of the recent finding that a low-dose IVCY regimen for induction therapy in adult lupus nephritis effectively achieves renal remission comparable with that achieved with a conventional high-dose IVCY regimen, we treated two children with severe lupus nephritis by low-dose (fixed dose of 500 mg m^–2, cumulative dose 3 g m^–2, approximately one-fourth of the conventional high-dose IVCY regimen) IVCY and oral mizoribine (5 mg kg^–1 day^–1) and steroids (3 methylprednisolone pulse followed by oral prednisolone). They responded well to this regimen, showing remarkable improvement in both histological and clinical manifestations in a short period of time. From these findings we suggest that the new low-dose IVCY regimen may be as effective as the conventional high-dose IVCY regimen, without significant adverse effect, for induction therapy in children with severe lupus nephritis (class III or IV).     

Mizoribine oral pulse therapy for steroid-dependent nephrotic syndrome

There have been reports of the use of mizoribine (MZB) oral pulse therapy for the treatment of systemic lupus erythematosus. We report its efficacy in a 9-year-old girl with steroid- and cyclosporine-dependent nephrotic syndrome (NS). The patient experienced relapses of NS when prednisolone was tapered to 20 mg/day after discontinuing cyclosporine due to biopsy proven toxicity. When methylprednisolone pulse therapy combined with prednisolone therapy (40 mg/day) failed to result in a complete remission after 3 weeks, oral MZB pulse therapy (total dose of 500 mg, 10 mg/kg per day in three divided daily doses twice a week) was given. This therapy was continued for 9 months and resulted in complete remission of the NS for 6 months despite the discontinuation of prednisolone. The serum concentration of MZB was above 2.5 g/ml for about 10 h (from 3 h after the first dose of MZB to 2 h after the final dose). Thus, our results suggest that this regimen may be effective for patients with steroid-dependent NS.     

A randomized open-label comparative study of conventional therapy versus mizoribine onlay therapy in patients with steroid-resistant nephrotic syndrome (postmarketing survey)

Background A previous double-blind 24-week clinical trial of mizoribine (MZ) vs placebo in steroid-resistant primary nephrotic syndrome (SRPNS) showed that MZ was more effective than placebo in reducing the rate of deterioration of renal function. The present study was conducted to evaluate the efficacy and safety of MZ in patients with SRPNS after 2 years treatment.Methods A multicenter randomized open-label controlled trial in patients with SRPNS was conducted as a 2-year prospective postmarketing study.Results There was a significant imbalance in the baseline serum albumin level (s-Alb) between the conventional therapy (CT) and MZ onlay therapy groups. Early dropouts were more frequent in the subset of patients in the CT group having a baseline s-Alb 3g/dl. Therefore, the primary analysis (urinary protein level (UP)-improving effect) was performed using a mixed-effects model, with stratification according to the baseline s-Alb value. The analysis revealed that, in the subset of 34 patients with membranous nephropathy (MN) within the stratum of patients with baseline s-Alb 3g/dl (n = 52), the rate of change (slope of change in the UP level/month), in terms of the log (UP+0.2), was –0.0577 in those allocated to the MZ group and –0.0227 in those allocated to the CT group (P = 0.058). In the stratum of patients with a baseline s-Alb >3g/dl (n = 97), there were no significant differences in the UP between the two treatment groups. Hence, MZ onlay therapy was not considered to be efficacious in this group of patients. No serious adverse reactions to the drug were observed.Conclusions The present study yielded significant results, in that it suggested the possibility that long-term MZ therapy may afford further reduction of the UP, in addition to that obtained following CT, in particular, in MN patients in a severe nephrotic state.     

Comparison of antiproteinuric effects of two different combination therapies in children with IgA nephropathy

Background Because moderate or severe proteinuria is a representative factor indicative of longterm poor prognosis in IgA nephropathy, an anti-proteinuric treatment which can be administered longterm with few side effects is necessary. We report here a comparison of antiproteinuric effects in two patient groups treated with different combination therapies.Methods Group A comprised 12 patients with IgA nephropathy, who had 24-h proteinuria of 0.5gm² or more, moderately severe renal histology, and normal renal function, and were treated with a combination of drugs, i.e., prednisolone, an immunosuppressant (mizoribine), an anti-platelet drug (dipyridamole), and an angiotensin-converting enzyme inhibitor. Group B consisted of 18 patients who had baseline characteristics similar to those of the patients in group A and were treated with our previous protocol (a combination of prednisolone, cyclophosphamide, and dipyridamole). Twenty-four-hour proteinuria and creatinine clearance were measured every 6 months. The primary endpoint was reduction of 24-h proteinuria by less than 25% compared with the baseline value.Results The proportion of patients that exhibited the primary endpoint, as assessed by the Kaplan-Meier method, was found to be significantly higher in group A than in group B (logrank test; P = 0.024). None of the patients in the two groups experienced serious adverse effects.Conclusions The results suggested that the use of drugs in combination with cyclophosphamide was beneficial for patients with moderately severe IgA nephropathy.