The current standard induction therapy for antineutrophil cytoplasm antibody (ANCA)–associated vasculitis is the combination of high-dose glucocorticoids and cyclophosphamide or rituximab. Although these regimens have high remission rates, they are associated with considerable adverse events presumably due to high-dose glucocorticoids.
Objective
To compare efficacy and adverse events between a reduced-dose glucocorticoid plus rituximab regimen and the standard high-dose glucocorticoid plus rituximab regimen in remission induction of ANCA-associated vasculitis.
Design, Setting, and Participants
This was a phase 4, multicenter, open-label, randomized, noninferiority trial. A total of 140 patients with newly diagnosed ANCA-associated vasculitis without severe glomerulonephritis or alveolar hemorrhage were enrolled between November 2014 and June 2019 at 21 hospitals in Japan. Follow-up ended in December 2019.
Interventions
Patients were randomized to receive reduced-dose prednisolone (0.5 mg/kg/d) plus rituximab (375 mg/m2/wk, 4 doses) (n = 70) or high-dose prednisolone (1 mg/kg/d) plus rituximab (n = 70).
Main Outcomes and Measures
The primary end point was the remission rate at 6 months, and the prespecified noninferiority margin was −20 percentage points. There were 8 secondary efficacy outcomes and 6 secondary safety outcomes, including serious adverse events and infections.
Results
Among 140 patients who were randomized (median age, 73 years; 81 women [57.8%]), 134 (95.7%) completed the trial. At 6 months, 49 of 69 patients (71.0%) in the reduced-dose group and 45 of 65 patients (69.2%) in the high-dose group achieved remission with the protocolized treatments. The treatment difference of 1.8 percentage points (1-sided 97.5% CI, −13.7 to ∞) between the groups met the noninferiority criterion (P = .003 for noninferiority). Twenty-one serious adverse events occurred in 13 patients in the reduced-dose group (18.8%), while 41 occurred in 24 patients in the high-dose group (36.9%) (difference, −18.1% [95% CI, −33.0% to −3.2%];P = .02). Seven serious infections occurred in 5 patients in the reduced-dose group (7.2%), while 20 occurred in 13 patients in the high-dose group (20.0%) (difference, −12.8% [95% CI, −24.2% to −1.3%];P = .04).
Conclusions and Relevance
Among patients with newly diagnosed ANCA-associated vasculitis without severe glomerulonephritis or alveolar hemorrhage, a reduced-dose glucocorticoid plus rituximab regimen was noninferior to a high-dose glucocorticoid plus rituximab regimen with regard to induction of disease remission at 6 months.
Abstract Background Patients with systemic lupus erythematosus (SLE) are associated with pre-eclampsia. Pre-eclampsia can have systemic manifestations, such as ascites. Lupus peritonitis, a rare condition in patients with SLE, can also cause ascites. Case presentation A 31-year-old woman, primigravida, with SLE had a blood pressure of 170/110 mmHg and proteinuria at 29 weeks of gestation. She was diagnosed with pre-eclampsia. Her blood pressure was stabilized by an antihypertensive drug. At 30 weeks of gestation, a cesarean section was performed for maternal safety because of decreased urine output and massive ascites. Postoperatively, re-accumulation of ascites was observed. On the fourth postoperative day, ascites (approximately 3 L) was discharged from the cesarean section wound. A decrease in serum complement concentrations was observed, and she was diagnosed as having lupus peritonitis. The steroid dose was increased and she recovered well thereafter. Conclusions Ascites occurs in pre-eclampsia and SLE, but determining which of these conditions causes ascites can be difficult. However, careful observation is necessary because of the differences in treatment of these two conditions.
The clinical efficacy of mizoribine (MZR; 4-carbamoyl-1-b-d-ribofuranosylimidazolium) in patients with lupus nephritis was investigated. Thirteen Japanese patients with biopsy-proved lupus nephritis were enrolled in this study. A change in global assessments score, total protein (TP) of serum, serum creatinine, creatinine clearance (Ccr), proteinuria, titers of serum anti-ds DNA antibody, C3, C4, and hemolytic complement activity (CH50) were examined. Following MZR treatment, the level of urinary protein decreased (P < 0.05), whereas the level of Ccr increased (P < 0.05). Moreover, the level of TP significantly increased from 5.5 g/dl to 6.3 g/dl (P < 0.01) and the level of C3 increased significantly (P < 0.01). However, there was no change in the levels of both C4 and CH50. The titer of anti-ds DNA antibody significantly decreased (P < 0.05). The dosage of prednisolone could be tapered from 24.8 mg to 14.9 mg daily during the period. The clinical effects associated with MZR concentration in the blood revealed that there was a significant correlation between the peak MZR blood concentration of more than 0.66 µg/ml and clinical improvement (P = 0.021). Our results suggest that an optimal MZR blood concentration was important for the treatment of lupus nephritis.
The kidney is a major target organ for systemic amyloidosis, which results in proteinuria and an elevated serum creatinine level. The clinical manifestations and precursor proteins of amyloid A (AA) and light-chain (AL) amyloidosis are different, and the renal damage due to amyloid deposition also seems to differ.
Objectives
The purpose of this study was to clarify haw the difference in clinical features between AA and AL amyloidosis are explained by the difference in the amount and distribution of amyloid deposition in the renal tissues.
Methods
A total of 119 patients participated: 58 patients with an established diagnosis of AA amyloidosis (AA group) and 61 with AL amyloidosis (AL group). We retrospectively investigated the correlation between clinical data, pathological manifestations, and the area occupied by amyloid in renal biopsy specimens. In most of the renal specimens the percentage area occupied by amyloid was less than 10%. For statistical analyses, the percentage area of amyloid deposition was transformed to a common logarithmic value (Log10%amyloid).
Results
The results of sex-, age-, and Log10%amyloid-adjusted analyses showed that systolic blood pressure (SBP) was higher in the AA group. In terms of renal function parameters, serum creatinine, creatinine clearance (Ccr) and estimated glomerular filtration rate (eGFR) indicated significant renal impairment in the AA group, whereas urinary protein indicated significant renal impairment in the AL group. Pathological examinations revealed amyloid was predominantly deposited at glomerular basement membrane (GBM) and easily transferred to the mesangial area in the AA group, and it was predominantly deposited at in the AL group. The degree of amyloid deposition in the glomerular capillary was significantly more severe in AL group. The frequency of amyloid deposits in extraglomerular mesangium was not significantly different between the two groups, but in AA group, the degree amyloid deposition was significantly more severe, and the deposition pattern in the glomerulus was nodular. Nodular deposition in extraglomerular mesangium leads to renal impairment in AA group. There are significant differences between AA and AL amyloidosis with regard to the renal function, especially in terms of Ccr, eGFR and urinary protein, even after Log10%amyloid was adjusted; showing that these inter-group differences in renal function would not be depend on the amount of renal amyloid deposits.
Conclusions
These differences could be explained by the difference in distribution and morphological pattern of amyloid deposition in the renal tissue.
References
[1] Kuroda T, et al. Significant association between renal function and area of amyloid deposition in kidney biopsy specimens in reactive amyloidosis associated with rheumatoid arthritis. Rheumatol Int. 2012;32:3155–3162. [2] Kuroda T, et al. Significant association between renal function and area of amyloid deposition in kidney biopsy specimens in both AA amyloidosis associated with rheumatoid arthritis and AL amyloidosis. Amyloid2017:14:1–8.
Acknowledgements
This work was supported by JSPS KAKENHI Grant Number 17 K09973.
Background: The risk for opportunistic infections in patients with autoimmune diseases requiring intensive immunosuppressive therapy is high and cytomegalovirus (CMV) infection is one of the most common opportunistic infections. Since 2011, we have performed weekly CMV pp65 antigen testing for patients at risk of opportunistic infections owing to autoimmune diseases to ensure appropriate patient management. Objectives: To evaluate the risk factors that predict CMV infection in patients that received remission-induction therapy for autoimmune diseases. Methods: We enrolled 254 patients (93 male, 161 female) from our hospital with autoimmune disease and who received remission-induction therapy with prednisolone at a dose greater than 0.5 mg/kg/day between January 2011 and December 2018. We retrospectively analysed their clinical characteristics and laboratory data, including treatment regimens and CMV pp65 antigen test results. The presence of more than five CMV pp65 antigen-positive cells over two slides was considered a positive result. We conducted univariate and multivariate analyses to extract CMV risk factors. Results: Of the patients we evaluated, 60 suffered from systemic lupus erythematosus (SLE), 55 from anti-nucleolar cytoplasmic antibody-associated vasculitis (AAV), 31 from dermatomyositis (DM), 14 from interstitial pneumonia with anti-aminoacyl tRNA synthetase antibody, 14 from adult-onset Still’s disease (AOSD), 14 from rheumatoid arthritis (RA), 11 from mixed connective tissue disease (MCTD), 10 from Takayasu’s aortitis, and 45 suffered from other autoimmune diseases. Pulse therapy with methylprednisolone (mPSL) and immunosuppressive reagents were administered to 103 (40.6 %) and 97 (38.2 %), respectively. The median follow-up period was 61.0 days, and 66 patients became CMV pp65 antigen-positive during this period (SLE, 15; DM, 14; AAV, 9; AOSD, 8; and other, 20). Univariate analysis revealed that when compared to patients testing negative for the CMV pp65 antigen patients testing positive had lower total lymphocyte count (TLC) (825 /uL vs. 1220 /uL; p < 0.01), a lower serum albumin level (2.70 g/dL vs. 3.30 g/dL; p < 0.01), a higher HbA1c level (6.3 % vs. 5.9 %; p<0.01), and were older (66.0 vs. 59.5 year old; p < 0.01). Forty-nine of the 66 patients in the positive group received mPSL pulse therapy (p < 0.01), and 38 received immunosuppressive reagents (p < 0.01). Logistic regression analyses indicated that a higher age by decade (OR; 1.46 [95%CI 1.06 - 2.00]), a lower TLC per 100/uL (OR; 0.83 [95%CI 0.73 -0.94]), a higher HbA1c level per 1% (OR; 2.37 [95%CI 1.25-4.53]), and mPSL pulse therapy (OR; 3.92 [95%CI 1.33-11.5]) were risk factors for CMV pp65 antigen positivity. Conclusion: Higher age, lower TLC, higher HbA1c, and treatment with mPSL pulse therapy were risk factors for acquiring CMV infection, as measured by the presence of the CMV pp65 antigen, in patients receiving remission-induction therapy for autoimmune diseases. Careful monitoring of these, at risk, patients is necessary. Disclosure of Interests: None declared
Pulmonary alveolar proteinosis (PAP) is a rare lung disorder characterized by abnormal accumulation of surfactant materials in the lower respiratory tracts. It is classified into three distinct types according to etiology; autoimmune, secondary, and congenital PAP. Secondary PAP (SPAP) comprises ten percent of acquired PAP. Previously, we reported 40 cases of SPAP, in whom more than 70% occurred secondary to hematological disorders, with the majority being myelodysplastic syndrome (MDS). The present study focused clinical features of five patients (four female and one male) who developed PAP during 6 months to 18 years after the onset of Behcet9s disease (BD), with underlying trisomy 8-positive MDS in four of them. Oral and cutaneous BD lesions were involved in all cases, but ocular lesions were observed in only one case. Intestinal BD was recognized in three patients who had undergone potent immunosuppressive therapy that resulted in overwhelming sepsis. In the two surviving patients, PAP and BD were managed successfully, although both individuals had a high risk of MDS at diagnosis. Thus, we figure out the common and different points among SPAP patients complicated with BD. The differential diagnoses of SPAP should be ruled out when lung complications are encountered during the course of BD.
Reactive amyloid A (AA) amyloidosis is a serious and life-threatening systemic complication of rheumatoid arthritis (RA).Recently, therapy with biologic agents such as anti- tumor necrosis factor (TNF) and anti- interleukin (IL)-6 antibodies has developed against a background of increased understanding of the pathogenesis of rheumatoid arthritis (RA), representing a tremendous advance in the management of RA. However, the prognosis of amyloid patients treated with biologics has not yet been clearly investigated.
Objectives
Our purpose was to examine the safety of therapy with anti-tumor necrosis factor and anti-interleukin-6 biologic agents in RA patients with reactive AA amyloidosis, together with prognosis and hemodialysis (HD)-free survival, in comparison with AA amyloidosis patients without such therapy.
Methods
One hundred thirty-three patients with an established diagnosis of reactive AA amyloidosis participated in the study. Clinical data were assessed from the patient records at the time of amyloid detection and administration of biologics. Survival was calculated from the date when amyloid was first demonstrated histologically until the time of death, or up to end of 2010, for the patients who were still alive. Patients who had been started on HD were selected for inclusion only after the presence of amyloid had been demonstrated. Assessment of the association of various factors with survival was performed on the date of the original diagnosis.
Results
Fifty-three patients were treated with biologic agents (biologic group) and 80 were not (non-biologic group). Survival rate was significantly higher in the biologic group than in the non-biologic group (p=0.001). Nine patients in the biologics group and 33 in the non-biologic group were started on HD. HD-free survival was significantly higher in the biologic group (p=0.00004).
Conclusions
Patients with amyloidosis have a higher mortality rate, but that the use of biologic agents reduces mortality among them. Additionally, the use of biologics improves the HD-free survival rate.
References
[1]Lunt M, et al. Arthritis Rheum 2010; 62: 3145-53. [2]Dixon WG, et al. Ann Rheum Dis 2010; 69: 1180-91. [3]Kuroda T, et al. Clin Rheumatol 2006; 25: 498-505. [4]Kuroda T, et al. J Rheumatol 2009; 36:2409-15.
Atypical femoral fracture (AFF) is generally a rare complication of long-term use of bisphosphonate (BP); glucocorticoid (GC) use and Asian race are also risk factors. Femoral localized periosteal thickening (LPT, also termed "beaking") of the lateral cortex often precedes AFF. This cohort study investigated the incidence of LPT and AFF and their clinical courses over 10 yr in patients with autoimmune inflammatory rheumatic diseases (AIRDs) treated with BP and GC. The study population consisted of 121 patients with AIRDs taking BP and GC. LPT was screened by X-ray, and the LPT shape was evaluated. Prednisolone (PSL) dose was 10 (8-12) mg/d at enrollment and 9 (6-10) mg/d at the last observation. LPT was evident in 10 patients at enrollment and increased linearly to 31 patients (26%) at the last observation. AFF occurred in 9 femurs of 5 patients with LPT. All patients with AFF had bilateral LPT, and the prevalence of pointed type and LPT height were higher in the AFF-positive group than in the AFF-negative group. AFF occurred before BP discontinuation in 2 patients, 1 yr after BP discontinuation in 1, after BP discontinuation followed by 7 yr of alfacalcidol use in 1, and after switching from alfacalcidol to denosumab in 1. The prevalence rates of AFF and LPT associated with long-term BP use with concomitant use of GC (mostly PSL ≥ 6 mg/d) in Japanese patients with AIRD increased over time. The selection of long-term osteoporosis treatment for LPT-positive patients is difficult in some cases.
