Cumulative Glucocorticoid Use Research Articles

Efficacy and Safety of Inebilizumab in IgG4-Related Disease: Protocol for a Randomized Controlled Trial.

Immunoglobulin G4-related disease (IgG4-RD) is a debilitating multiorgan disease characterized by recurring flares leading to organ dysfunction, decreased quality of life, and mortality. Glucocorticoids, the standard of care for IgG4-RD, are associated with substantial treatment-related toxicity. Inebilizumab, an antibody directed against CD19, mediates the rapid and durable depletion of CD19+ B cells thought to be involved in IgG4-RD pathogenesis. We describe the first international, prospective, double-blind, placebo-controlled trial to evaluate the safety and efficacy of B-cell depletion for flare prevention in IgG4-RD (MITIGATE). The study was designed by an international panel of physicians with expertise in IgG4-RD. Critical trial design decisions included the selection of participants, definition of clinically meaningful primary and secondary endpoints, accommodation of standard of care, and development of flare diagnostic criteria. The study is approved for conduct in 22 countries. The primary efficacy endpoint is time from randomization to the occurrence of the first centrally adjudicated and investigator-treated disease flare during the 1-year randomized controlled period. A set of novel, organ-specific flare diagnostic criteria were developed specifically for this trial, incorporating symptoms and signs, laboratory findings, imaging study results, and pathology data. MITIGATE aims to accrue 39 flares for the primary endpoint, which provides sufficient power to detect a relative risk reduction of 65% in the inebilizumab group. It is anticipated that enrollment of 160 participants will achieve this goal. Additional endpoints include safety, annualized flare rate, flare-free complete remission, quality-of-life measures, and cumulative glucocorticoid use. MITIGATE represents the first randomized, double-blind, placebo-controlled trial of any treatment strategy conducted in IgG4-RD. Data from this study will provide insights into the natural history and pathophysiology of IgG4-RD and the efficacy and safety of B-cell depletion as a therapeutic avenue. NCT04540497.

Low disease activity state associated with fewer incident vertebral fractures in Mestizo women with systemic lupus erythematosus.

Low disease activity state (LDAS) has been linked to a significant reduction in flares and damage accrual in patients with systemic lupus erythematosus (SLE); however, the effect of LDAS on the risk of vertebral fractures (VFs) in subjects with SLE is unknown, considering that low bone mineral density (BMD) and VF are frequent in SLE. to evaluate whether achieving LDAS ≥50% of the observation time prevents new VF and BMD changes in Mestizo women. We carried out a longitudinal, observational, and retrospective study. Mestizo women with SLE were included for a median of an 8-year follow-up. LDAS was described as Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score ≤4, prednisone ≤7.5mg/day, and stable immunosuppressive therapies. BMD measurements and lateral thoracic and lumbar radiographs for a semiquantitative analysis for VF were assessed at baseline and during the follow-up. Uni- and multivariable interval-censored survival regression models were carried out. We included 110 patients: 35 (31.8%) had new VF. A total of 56 patients (50.1%) achieved LDAS ≥50% of the time during the follow-up and achieved a significantly lesser risk of incident VF (HR = 0.16; 95% CI, 0.06-0.49). After adjusting by age, BMI, menopause, prevalent VF, baseline BMD, cumulative glucocorticoid use, and anti-osteoporotic therapy, LDAS-50 was significantly related to a decrease in the risk of a new VF (HR = 0.39; 95% CI, 0.16-0.98). There was no association between LDAS and BMD measurement changes. When only patients on LDAS but not in remission (n = 43) were evaluated for the risk of incident VF, both uni- and multivariate analyses were significant (HR = 0.12; 95 CI, 0.04-47; p = 0.001, and HR = 0.26; 95% CI, 0.7-0.88; p = 0.03). LDAS ≥50% of the time was significantly associated with a diminished risk of new VF in Mestizo women with SLE, even in patients not in remission. However, LDAS did not help modify BMD changes over time.

Fibroscan detection of fatty liver and liver fibrosis in patients with systemic lupus erythematosus.

Although liver dysfunction is not considered the main organ involvement in Systemic Lupus Erythematosus (SLE), the frequency of liver dysfunction or abnormal liver enzyme values may be observed in 50-60% of patients. The aim of this study was to assess fatty liver and liver fibrosis in SLE patients using Fibroscan as well as determine associated factors such as immunosuppressive medications. Sixty SLE patients and 30 healthy controls were included. Patients with HBV, HCV or cirrhosis, malignancy, cardiac disease, or patients on dialysis were excluded. All participants underwent Fibroscan measurements. The prevalence of fatty liver disease was similar between SLE patients and healthy controls (21.7 vs 26.7%, p = .597). Liver fibrosis was also similar between the two groups (26.7 vs 10.0%, p = .069). Since the majority of SLE patients were female, we performed a subgroup analysis in female patients (n = 51) and controls (n = 25). Fatty liver disease was similar between female SLE patients and controls (23.5 vs 24.0%, p = .964). However, liver fibrosis in female patients with SLE was increased compared to female controls (29.4 vs 4.0%, p = .011) and was associated with age (Exp (B) 95% CI: 1.083 (1.006-1.166), p = .034) and low-dose cumulative glucocorticoid use (Exp (B) 95% CI: 14.116 (1.213-164.210), p = .034). The prevalence of fatty liver was similar between SLE patients and controls, while liver fibrosis was increased in the female patient group as compared to controls. Furthermore, liver fibrosis was associated with age and low dose cumulative glucocorticoid use. Interestingly, fatty liver did not precede liver fibrosis in the majority of cases, contrary to what is observed in the general population. Larger studies are needed to confirm our findings and determine whether immunosuppressive use has any impact on the development of liver fibrosis in SLE patients.

MO174FIBROSCAN DETECTION OF FATTY LIVER AND LIVER FIBROSIS IN SYSTEMIC LUPUS ERYTHEMATOSUS

Abstract Background and Aims Systemic Lupus Erythematosus (SLE) is a chronic, multi-organ, systemic autoimmune disease that is more common in women than men and is typically diagnosed during the reproductive age. Although liver dysfunction is not considered the main organ pathology in SLE, the frequency of liver dysfunction or abnormal liver enzyme values may be observed in 50-60% of patients. Liver-related complications may present as asymptomatic hepatomegaly, subclinical steatosis and abnormal liver enzymes. The most common causes are drug-associated liver injury, lupus-associated hepatitis, and fatty liver disease. The aim of this study was to assess fatty liver and liver fibrosis in SLE patients using the FibroScan method as well as associated factors such as immunosuppressive medications. Method Sixty SLE patients and 30 healthy controls were included. Patients with HBV, HCV or cirrhosis, malignancy, cardiac disease, or patients on dialysis were excluded. All participants underwent FibroScan measurements. Demographic data and cumulative doses of immunosuppressive medications were extracted from patient charts. Fasting blood was collected for analysis Results Demographic and clinical characteristics of the study groups are shown in Tables 1. The prevalence of fatty liver disease was similar between SLE patients and healthy controls (21.7% vs 26.7%, p= 0.597) and was associated with body mass index (BMI) (p= 0.026) and C-reactive protein (CRP) (p= 0.046) in multivariate analysis. Liver fibrosis was also similar between the two groups (26.7% vs 10.0%, p= 0.069). There was no relationship between cumulative drug doses including glucocorticoids with either fatty liver disease or liver fibrosis. Since the majority of SLE patients were female, we performed a subgroup analysis in female patients (n=51) and healthy controls (n=25). Fatty liver disease was similar between female SLE patients and healthy controls (23.5% vs 24.0%, p= 0.964). However, liver fibrosis in female patients with SLE was increased compared to the female healthy population (29.4% vs 4.0%, p= 0.011) and was associated with age (p= 0.034) and low-dose cumulative glucocorticoid use (p = 0.034). Low-dose cumulative glucocorticoid use was defined as less than 17.45 g, which was the 75th percentile value. Only 1 out of 15 female patients with fibrosis had high-dose cumulative glucocorticoid use (>17.45 g), while the remaining 14 patients had used lower doses (<17.45 g). Conclusion The prevalence of fatty liver was similar between SLE patients and healthy controls, while liver fibrosis was increased in the female patient group as compared to controls. Furthermore, liver fibrosis was associated with age and low dose cumulative glucocorticoid use. Interestingly, fatty liver did not precede liver fibrosis in the majority of cases, contrary to what is observed in the general population. We hypothesized that liver fibrosis may be the result of subclinical inflammation and autoimmunity associated with SLE itself and the use of steroids may prevent or prolong fibrosis formation in the liver.

Dual trajectories of fatigue and disease activity in an inception cohort of adults with systemic lupus erythematosus over 10 years.

Fatigue is one of the most common symptoms reported in patients living with SLE. We aim to: 1) determine if different trajectories of fatigue associate with specific latent classes of disease activity and 2) define the patient characteristics and associated factors in different latent classes. Data from an inception cohort of adult patients from the Toronto Lupus Clinic from 1997-2018 were analyzed. Fatigue levels were measured using Fatigue Severity Scale (FSS) and disease activity by the Adjusted Mean Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) (AMS). Dual latent class trajectory analysis, for fatigue and AMS, was performed. Univariable and multivariable logistic regression analyses assessed the association of baseline variables with class membership. Among 280 patients, 4 dual classes (C) of fatigue and disease activity were identified: C1- lowest disease activity and second highest fatigue trajectory (27%); C2- second highest disease activity and highest fatigue trajectory (30%); C3-moderate disease activity and lowest fatigue trajectory (33%); and C4- highest disease activity and moderate fatigue trajectory (10%). 4 distinct latent classes of dual fatigue and disease activity trajectories were identified. Fatigue and disease activity follow distinct trajectories and disease activity alone cannot fully explain fatigue trajectories. Trajectories with higher FSS scores were associated with more fibromyalgia and trajectories with higher disease activity were associated with higher cumulative glucocorticoid use. Higher baseline glucocorticoid use was more likely associated with more fatigue while older age at SLE diagnosis was associated with less fatigue.

Mortality, causes of death and influence of medication use in patients with systemic lupus erythematosus vs matched controls.

ObjectivesWe wanted to estimate the magnitude of the risk from all-cause, cause-specific and sex-specific mortality in patients with SLE and relative risks compared with matched controls and to evaluate the influence of exposure to medication on risk of mortality in SLE.MethodsWe conducted a population-based cohort study using the Clinical Practice Research Datalink, Hospital Episode Statistics and national death certificates (from 1987 to 2012). Each SLE patient (n = 4343) was matched with up to six controls (n = 21 780) by age and sex. Cox proportional hazards models were used to estimate overall and cause-specific mortality rate ratios.ResultsPatients with SLE had a 1.8-fold increased mortality rate for all-cause mortality compared with age- and sex-matched subjects [adjusted hazard ratio (HR) = 1.80, 95% CI: 1.57, 2.08]. The HR was highest in patients aged 18–39 years (adjusted HR = 4.87, 95% CI: 1.93, 12.3). Mortality rates were not significantly different between male and female patients. Cumulative glucocorticoid use raised the mortality rate, whereas the HR was reduced by 45% with cumulative low-dose HCQ use. Patients with SLE had increased cause-specific mortality rates for cardiovascular disease, infections, non-infectious respiratory disease and for death attributable to accidents or suicide, whereas the mortality rate for cancer was reduced in comparison to controls.ConclusionBritish patients with SLE had a 1.8-fold increased mortality rate compared with the general population. Glucocorticoid use and being diagnosed at a younger age were associated with an increased risk of mortality. HCQ use significantly reduced the mortality rate, but this association was found only in the lowest cumulative dosage exposure group.

Rheumatoid arthritis and cognition dysfunction: lack of association with cumulative glucocorticoid use

Aim: To study if cumulative glucocorticoid use could be related to cognitive impairment in rheumatoid arthritis (RA) patients.Methods: A sample of 60 RA patients and 64 controls were studied for the Mini Mental State Examination (MMSE) and depression scale (using CES-D or Center for Epidemiological Studies Depression scale). RA patients also filled a visual analogic scale (VAS) of pain and had disease activity evaluated by DAS-28 ESR (disease activity score using erythrocyte sedimentation rate). Clinical and treatment data, including cumulative dose of glucocorticoid, were collected from the charts.Results: Patients with RA had more cognitive impairment and depression than controls (p = .002 and .03, respectively). A weak and negative association of MMSE with VAS of pain was found (rho= −0.16; 95%CI = 0.49–0.004; p = .04) but not with depression and cumulative glucocorticoid doses (p = .22 and p = .52, respectively).Conclusion: Although RA patients have more cognitive impairment than controls, no correlation of this problem with cumulative glucocorticoid doses was found.

Reviewing the Pathophysiology Behind the Advances in the Management of Giant Cell Arteritis.

Improving understanding of the underlying pathophysiology of giant cell arteritis (GCA) is transforming clinical management by identifying novel avenues for targeted therapies. One key area of concern for both clinicians and patients with GCA is glucocorticoid (GC) morbidity. The first randomised controlled trials of targeted treatment to reduce cumulative GC use in GCA have been published, with tocilizumab, an interleukin (IL)-6 receptor inhibitor, now the first ever licensed treatment for GCA. Further potential therapies are emerging owing to our enhanced understanding of the pathophysiology of the disease. Other improvements in the care of our patients are rapid access pathways and imaging techniques, such as ultrasound, which are becoming part of modern rheumatology practice in the UK, Europe and beyond. These have been highlighted in the literature to reduce delay in diagnosis and improve long-term outcomes for those investigated for GCA.

Long-term efficacy of remission-maintenance regimens for ANCA-associated vasculitides

ObjectiveTo compare long-term efficacy of remission-maintenance regimens in patients with newly diagnosed or relapsing antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides.MethodsThe 28-month Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis trial...

Glucocorticoid treatment and damage in the anti-neutrophil cytoplasm antibody-associated vasculitides: long-term data from the European Vasculitis Study Group trials.

Granulomatosis with polyangiitis and microscopic polyangiitis are ANCA-associated vasculitides (AAVs). The Vasculitis Damage Index (VDI) quantifies damage. This study aims to determine the factors associated with long-term damage in the AAVs. Data from 535 patients from four European Vasculitis Study Group trials were studied. A long-term follow-up (LTFU) questionnaire at 7 years post-diagnosis was completed. The associations between baseline (age, creatinine and BVAS score) and cumulative (number of relapses and duration of glucocorticoid use) factors and damage accrued (total VDI scores and individual treatment-related damage items) during follow-up were explored. Multiple regressions identified independent associations between baseline measures, cumulative factors and VDI scores at LTFU. Two hundred and ninety-six patients had glucocorticoid use and VDI data available at LTFU, with the mean length of glucocorticoid use being 40.4 months (S.D. 16.7). High levels of damage were independently associated with older age at baseline (P = 0.051), lower glomerular filtration rate (P = 0.041), higher BVAS scores (P = 0.046), increased cumulative glucocorticoid use (P = 0.016) and increasing number of relapses. Patients with longer duration of glucocorticoid treatment were more likely to have a total VDI score ≥5 [odds ratio 1.26 per 12 months of glucocorticoid use (95% CI 1.03, 1.53), P = 0.022]. The main limitation is that approximately half of the patients enrolled had no LTFU data available; these patients were older with more severe initial disease. Long-term damage in the AAVs may be associated with severity of initial disease, age, number of relapses and duration of glucocorticoid use.

Prevalence and risk factors associated with low-impact fractures in men with rheumatoid arthritis

The aim of this study is to describe the prevalence of fractures in men with rheumatoid arthritis (RA) and identify potential risk factors associated with skeletal fragility. We consecutively studied 50 men with RA. Clinical risk factors were evaluated by clinical questionnaire, functional capacity by M-HAQ1, and disease activity by DAS-28. RA men were compared to 52 healthy controls paired for age and BMI. Bone mineral density (BMD) and quantitative ultrasound (QUS) at the heel were performed in all participants. Morphometric vertebral fractures (VF) were classified by a semiquantitative method. Men with RA were 51.7 years old on average and had mean disease duration of 115 months. Fragility fractures were found in 40% of individuals, of which 36% were VF, significantly higher than in healthy controls (p < 0.01). Age, anthropometric data, and lifestyle were similar between RA men with and without fractures. About 94% of the men with RA were on long-term glucocorticoid (GC) use. Patients with fractures were more frequently positive for rheumatoid factor (RF), had longer morning stiffness, and higher DAS-28 when compared to patients without fractures (p ≤ 0.05). In addition, they had significantly lower spine and hip BMD as well as a lower stiffness index (p ≤ 0.05). There was no statistically significant correlation between fracture and cumulative GC use. The final model of logistic regression showed a significant association and interaction between lower weight and physical activity in men with RA and fragility fractures. RA in men as well as in women is a risk factor for fragility fractures. The risk of fractures is higher in patients with positive RF, prolonged morning stiffness, higher scores of disease activity, and lower values of BMD and QUS.

Population‐based assessment of adverse events associated with long‐term glucocorticoid use

The frequency of many adverse events (AEs) associated with low-dose glucocorticoid use is unclear. We sought to determine the prevalence of glucocorticoid-associated AEs in a large US managed care population. Using linked administrative and pharmacy claims, adults receiving >or=60 days of glucocorticoids were identified. These individuals were surveyed about glucocorticoid use and symptoms of 8 AEs commonly attributed to glucocorticoid use. Of the 6,517 eligible glucocorticoid users identified, 2,446 (38%) returned the mailed survey. Respondents were 29% men with a mean +/- SD age of 53 +/- 14 years; 79% were white and 13% were African American. Respondents had a mean +/- SD of 7 +/- 3 comorbid conditions and were prescribed a mean +/- SD prednisone-equivalent dosage of 16 +/- 14 mg/day. More than 90% of individuals reported at least 1 AE associated with glucocorticoid use; 55% reported that at least 1 AE was very bothersome. Weight gain was the most common self-reported AE (70% of the individuals), cataracts (15%) and fractures (12%) were among the most serious. After multivariable adjustment, all AEs demonstrated a strong dose-dependent association with cumulative glucocorticoid use. Among users of low-dose therapy (<or=7.5 mg of prednisone per day), increasing duration of use was significantly associated with acne, skin bruising, weight gain, and cataracts. The prevalence of 8 commonly attributed self-reported glucocorticoid-associated AEs was significantly associated with cumulative and average glucocorticoid dose in a dose-dependent fashion. Physicians should be vigilant for glucocorticoid-related AEs and should counsel patients about possible risks, even among low-dose long-term users.

Bone mineral density changes within six months of renal transplantation.

The effective use of new steroid-sparing immunosuppressive regimens may lower cumulative glucocorticoid use among renal transplant recipients. However, it is unknown what effect this therapeutic trend has had on bone disease. Unselected newly transplanted inpatients (n=45) were identified and comprehensively evaluated for metabolic bone disease at a median of 16 days (range 9-33) posttransplant. A follow-up evaluation was conducted a median of 5.7 months (range 4.8-9.3) later. Follow-up values for bone mineral density (BMD) and select laboratories were compared with baseline values using nonparametric statistics. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to describe the associations of baseline characteristics, select laboratory values, and cumulative prednisone and cyclosporine use with spinal BMD loss and were calculated using logistic regression. A significant decrease in intact parathyroid hormone (P<0.001) and a significant increase in calcitriol (P=0.02) were noted postengraftment. At follow-up, subjects had lost a mean of 2.4% BMD at the lumbar spine (P=0.003) but did not experience significant declines at the femoral neck. The highest tertiles of cumulative prednisone (OR=28.4; 95% CI 2.5-329 and OR=15.8; 95% CI 1.4-179, respectively) and past alcohol use (OR=9.3; 95% CI 1.46-58.5) were significantly associated with spinal BMD loss. Significant loss in lumbar BMD occurred within 6 months of transplantation in more than one third of a prospective cohort of renal transplant recipients. Lumbar bone loss seemed to be mediated primarily by glucocorticoid dose and a history of alcohol use.