Harunobu Iida

Comparison of renal response to four different induction therapies in Japanese patients with lupus nephritis class III or IV: A single-centre retrospective study

The recent recommendations for the management of lupus nephritis suggest that racial background should be considered while choosing induction therapy. However, the responses to different induction regimens have been poorly studied in Japanese population. Here, we assessed the renal response to different induction therapies in Japanese patients with lupus nephritis class III or IV. The records of 64 patients with biopsy-proven lupus nephritis class III or IV were retrospectively evaluated according to therapy received: monthly intravenous cyclophosphamide (IVCY), the Euro-lupus nephritis trial (ELNT) protocol-IVCY, tacrolimus (TAC), or mycophenolate mofetil (MMF). We investigated cumulative complete renal response (CR) rates and relapse rates for each group for 3 years. Organ damage was assessed with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). There were 22 patients on monthly IVCY, 18 on ELNT-IVCY, 13 on TAC, and 11 on MMF. Lower systemic lupus erythematosus disease activity index (SLEDAI) and higher CH50 were found in the TAC group at baseline (p<0.01 and p<0.01, respectively). There were no significant differences of cumulative CR rates and relapse free survival for 3 years among the four different therapeutic regimens (p = 0.2 and p = 0.2, respectively). There was a tendency to have early response and early relapse in TAC group and late response in MMF group. The SDI increase over 3 years was found more frequently in the TAC group than in the monthly-IVCY group (p = 0.04). Multivariate analysis indicated that CR at 3 months was independent prognosticator for low damage accrual. Regarding lower damage accrual, early CR achievement might be essential in induction therapy regardless of immunosuppressant choice.

Renal protective effect of antiplatelet therapy in antiphospholipid antibody-positive lupus nephritis patients without antiphospholipid syndrome

Objective We sought to evaluate the effect of antiplatelet therapy in addition to conventional immunosuppressive therapy for lupus nephritis (LN) patients positive for antiphospholipid antibodies (aPL) without definite antiphospholipid syndrome (APS). Methods Patients with biopsy-proven LN class III or IV were retrospectively evaluated. We selected patients positive for anticardiolipin antibody (aCL) or lupus anticoagulant (LA) who did not meet the criteria for a diagnosis of APS. The patients were divided into two subgroups according to whether antiplatelet therapy was received. The cumulative complete renal response (CR) rate, relapse-free rate, and change in estimated glomerular filtration rate (eGFR) over 3 years after induction therapy were calculated. Results We identified 17 patients who received antiplatelet therapy and 21 who did not. Baseline clinicopathological characteristics and immunosuppressive therapy did not show a significant difference between the two groups except for a higher incidence of LN class IV in the treatment group (p = 0.03). There was no difference in cumulative CR rate, relapse-free rate, or eGFR change between these subgroups. However, when data on LA-positive patients were assessed, an improvement in eGFR was found (p = 0.04) in patients receiving antiplatelet treatment. Conclusion Addition of anti-platelet therapy was associated with an improvement of eGFR in LA-positive patients with LN class III or IV.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) in a patient with microscopic polyangiitis following low-dose intravenous cyclophosphamide: a possible pathogenic link with disease activity

Abstract Syndrome of inappropriate antidiuretic hormone secretion (SIADH) induced by cyclophosphamide (CY) in rheumatology has been rarely described. Most reported cases developed SIADH at the first administration of high-dose CY. We report the case of a 76-year-old female with microscopic polyangiitis (MPA) who developed SIADH during the seventh course of low-dose intravenous cyclophosphamide (IVCY). Our report suggested that SIADH may be developed at any course of IVCY treatment and a process other than CY toxicity may be involved. An exacerbation of interstitial lung disease (ILD) and overexpression of inflammatory cytokines may have contributed to the development of SIADH in this case. Since the active phase of MPA might be a risk factor for SIADH, MPA patients should be evaluated for subclinical SIADH.

A positive direct Coombs’ test in the absence of hemolytic anemia predicts high disease activity and poor renal response in systemic lupus erythematosus

We determined the clinical utility of the direct Coombs’ test in the absence of hemolytic anemia as an indicator of disease activity and therapeutic response in systemic lupus erythematosus (SLE). SLE patients without hemolytic anemia who visited our hospital from January 2016 to November 2016 were retrospectively evaluated with a direct Coombs’ test. Clinical features, including SLE disease activity index (SLEDAI), treatment and laboratory findings were analyzed. For patients with lupus nephritis, we additionally evaluated the cumulative complete renal response rate over one year after induction therapy. Among 182 patients evaluated, 10 (5.8%) patients had a positive direct Coombs’ test in the absence of hemolytic anemia. They had a higher SLEDAI (p < 0.01), higher circulating immune complex levels (p = 0.01), higher anti-DNA titers (p < 0.01) and a lower complete renal response rate (p = 0.03) compared with those who were negative. Multivariate analysis indicated that SLEDAI was an independent factor correlated with the direct Coombs’ test without hemolytic anemia (odds ratio 2.4, 95% confidence interval 1.66–4.98, p < 0.01). A positive direct Coombs’ test in the absence of hemolytic anemia may therefore represent a useful biomarker for assessing disease activity and therapeutic response.

Rhabdomyolysis in a Patient with Polyarteritis Nodosa

Polyarteritis nodosa (PAN) is a medium vessel vasculitis affecting systemic organs. Muscle involvement of PAN usually lacks elevation of creatinine kinase (CK). We herein report a case of PAN with rhabdomyolysis. A 71-year-old man was hospitalized because of muscle weakness of the lower limbs that persisted for 1 month. On a physical examination, rapidly progressive lower proximal muscle weakness and bilateral drop foot were observed. His blood test showed an elevation in the C-reactive protein (19.5 mg/dL) and CK (13,435 IU/L) levels and negativity for anti-neutrophilic cytoplasmic antibody. Computed tomographic angiography showed stenosis of the left renal artery. Electromyogram indicated mono-neuritis multiplex pattern, and enhanced magnetic resonance imaging demonstrated discretely granular hyperintensities on T2 and slow tau inversion recovery in his femoral muscles. A femoral muscle-biopsy specimen showed fibrinoid necrosis of medium-sized vessels and disruption of the elastic lamina of the vessel wall in fascia. Furthermore, muscle necrosis was localized depending on the arterial distribution, suggesting ischemic changes in the muscles. Given these findings, he was diagnosed with PAN with rhabdomyolysis and treated with methyl-prednisolone pulse therapy followed by oral prednisolone at 50 mg/day. He was additionally treated with monthly intravenous cyclophosphamide at 500 mg. Sustained remission has been obtained for two months since the treatment. Although rhabdomyolysis rarely manifests with PAN, it should be included in a differential diagnosis of febrile patients presenting with acute myalgia and weakness with CK elevation.

Mycophenolate mofetil treatment with or without a calcineurin inhibitor in resistant inflammatory myopathy

To evaluate the efficacy and tolerability of mycophenolate mofetil (MMF) with or without calcineurin inhibitors (CNIs) in patients with inflammatory myopathy taking prednisolone, but refractory to conventional immunosuppressive therapy. The records of patients with inflammatory myopathy who had previously failed treatment with at least one immunosuppressant were retrospectively evaluated. We selected patients treated with MMF and divided them into two groups depending on whether or not there was concomitant use of CNIs. We investigated the efficacy by changes in creatine kinase (CK) levels, forced vital capacity (%FVC), prednisolone dose, and high-resolution computed tomography (HRCT) findings. Interstitial lung disease (ILD) progression was defined by more than 10% decline of %FVC from baseline. We identified 19 patients on MMF treatment. There were seven (36.8%) patients on MMF and CNIs, including five on cyclosporine and two on tacrolimus. At baseline, no significant difference was seen in the prevalence of ILD between patients taking or not taking CNIs (85.7% vs. 75.0%, P = 0.68). Improvement in CK was seen in patients treated with CNIs (P = 0.04) but not in those without (P = 0.39). No significant improvement in %FVC and HRCT findings were found in patients with ILD in either group, and there were no differences in death or ILD progression. The combination of CNIs and MMF might be more effective for decreasing CK levels than MMF alone. Neither treatment arm had a beneficial effect on ILD over a variable observation period.

Early achievement of deep remission predicts low incidence of renal flare in lupus nephritis class III or IV

Recommendations for lupus nephritis (LN) management specify that the therapeutic target should be a complete renal response (CR) [1], defined as a urine protein:Cr ratio (UPCR) of 0.5 g/gCr (50 mg/mmol) and normal or near-normal renal function. Earlier studies suggested that patients who achieved CR experienced fewer renal flares than those who achieved partial remission, defined as a 50% reduction of proteinuria [2]. Among patients who achieved CR (less than 0.50 g/gCr of UPCR), however, the renal outcome of those who achieved a value below the normal UPCR limit of 0.15 g/gCr was unclear. We recently reported that an early renal response may predict a good renal or systemic outcome [3, 4]. In this study, we investigated whether it is beneficial to achieve deep remission early by evaluating flare rate, Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), cumulative glucocorticoid dose, and eGFR level. We retrospectively assessed 69 patients with biopsyproven LN class III or IV who achieved CR in our hospital. We divided them into two groups based on whether deep remission was achieved, defined as less than 0.15 g/gCr UPCR, and compared cumulative flare rates [1], defined as estimated glomerular filtration rate (eGFR) decreasing by ≥ 10%, active urine sediment, or increasing UPCR > 1.0 g/gCr after achieving CR. Furthermore, we analyzed the additional effect of early achievement of CR, defined as CR within 3 months after induction therapy. Clinical characteristics between the two groups were compared using the non-parametric Mann-Whitney U-test. Frequencies of clinicopathological characteristics were compared using the Chi-square test. Cumulative flare free rates were calculated using the Kaplan-Meier method, and differences between the two groups were tested with a log-rank test. To identify independent parameters that predict CR at 3 years, we performed multivariate analysis. During the 3-year period, 55 of 69 CR patients achieved deep remission while 14 did not. Among clinical features at baseline, the proportion of females was significantly higher among patients with deep remission (p = 0.01; Table 1). We found a significantly higher flare-free rate among patients who achieved deep remission compared with those who did not (p = 0.001; Fig. 1a). For patients with deep remission, those with early CR had a higher flare-free rate than those without (p = 0.04) (Fig. 1b), but significant difference was found in those with non-deep remission (Fig. 1c). Multivariate analysis to predict sustained CR indicated that early achievement of deep remission was an independent factor (odds ratio 3.62, 95% confidence interval 1.1– 18.9, p = 0.05). Regarding SDI, cumulative glucocorticoid dose, and eGFR level at year 3, patients with early deep remission had the most favorable result compared to the other groups (Fig. 2). In this study, we found that achieving early and deep remission predicts a good renal outcome in patients with LN class III or IV. Since renal flare predicts a worse prognosis [5], determining the method of treatment to ensure long-term maintenance of CR is challenging. Our results suggest that deep remission might be a more beneficial therapeutic goal than that of the EULAR/ERA-EDTA recommendations regarding the prevention of renal flare. A future multi-center, prospective study is required to confirm our findings.

SAT0259 High plasma concentration of mycophenolate acid in early phase of induction therapy predicts good renal outcome in lupus nephritis class iii or iv

Background Mychophenolate mofetil (MMF) is recommended as initial induction treatment for most cases of lupus nephritis (LN) class III-IV. Although the association between area under the concentration-versus-time curve (AUC) of myochophenolate acid (MPA) and therapeutic efficacy has been well shown in renal transplantation, it has been poorly investigated in LN. Furthermore, MMF interacts with multiple factors and its concentration may be decreased by high prednisolone (PSL) dose, low serum albumin level and low creatinine clearance. Since these factors dramatically change in induction phase of LN, the plasma concentration of MPA may also change by fixed dose of MMF administration. Here, we measured AUC0–12 of MPA at different phases of induction treatment, early and middle, and prospectively investigated which concentration predicted future renal response in LN class III-IV. Objectives To investigate the relationship between the plasma concentration of MPA in early or middle phase of induction therapy and future renal response. Methods We prospectively enrolled patients with biopsy proven LN class III or IV who hospitalized from Apr to Oct 2016. As induction therapy, PSL was started at dose of 1mg/kg/day and tapered to 10mg/day by 12 weeks. Fixed dose of MMF at 2,000mg/day was continuously introduced. We measured 2 points of MPA plasma concentration depending on the phase of induction therapy, at early (week 2) and middle (week 12). We evaluated the association between these concentration and complete renal response (CR) rate at week 12. Results Six patients were enrolled. AUC0–12 between the early and the middle phase was not correlated (R2=0.17, p=0.7), but that of the early phase tended to be lower (47.4±25.6 vs 58.9±19.1 mgh/L). All the patients with high AUC0–12 (over 40mgh/L) at the early phase achieved CR at week 12 (Figure 1). But we could not find any association between AUC0–12 at middle phase and CR rate at week 12.Figure 1 Conclusions High AUC0–12 of MPA at the early phase of induction therapy might predict good renal response. Disclosure of Interest None declared