Cumulative Glucocorticoid Dose Research Articles

High prevalence of steroid-induced glucose intolerance with normal fasting glycaemia during low-dose glucocorticoid therapy: an oral glucose tolerance test screening study.

To evaluate the prevalence and risk factors of new-onset glucose metabolism impairment using an oral glucose tolerance test (OGTT) in patients with normal fasting glycaemia on long-term glucocorticoid (GC) treatment. An OGTT was performed in 150 patients without a previous history of pre-diabetes or diabetes who were diagnosed with inflammatory rheumatic diseases and treated with GCs >3 months. All participants underwent clinical and biochemical evaluation for risk factors of diabetes: age, sex, current and cumulative dose of steroids, treatment duration, waist circumference, BMI, Homeostatic Model Assessment for Insulin Resistance, fasting insulin concentration, family history of diabetes, CRP, 28-joint DAS with CRP, type of connective tissue disease and trunk fat percentage measured by DXA. Logistic regression analysis was conducted to evaluate the association between the presence of impaired glucose tolerance (IGT) in the OGTT and analysed risk factors. A total of 102 patients (68%) had fully normal glucose tolerance. Diabetes, isolated impaired fasting glucose, isolated IGT and combined impaired fasting glucose + IGT was diagnosed in 3.3, 4.67, 19.33 and 4.67% of patients, respectively; 20% of participants had IGT or diabetes despite normal fasting glucose concentration. The median cumulative dose and current dose (5 mg) of GCs and treatment duration were similar compared with the normal glucose tolerance group. In a multivariate logistic regression model, only older age (particularly ≥50 years of age) and trunk fat percentage remained significant factors predicting IGT or diabetes in the OGTT. New-onset GC-induced glucose intolerance, even in patients on long-term low-dose treatment, is prevalent despite normal fasting glucose concentration and patients should be screened with an OGTT despite the absence of classic risk factors of diabetes.

Prevalence of osteoporosis in patients with systemic lupus erythematosus: A multicenter comparative study of the World Health Organization and fracture risk assessment tool criteria

ObjectivesOsteoporosis and fracture are known complications of systemic lupus erythematosus (SLE). We assessed the prevalence and risk factors for osteoporosis in patients with SLE. MethodsA total of 155 female SLE patients were recruited retrospectively in 5 university hospitals. The bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry, and the fracture risk assessment tool (FRAX) for high-risk osteoporotic fractures was calculated with and without BMD. ResultsThe mean age was 53.7 ± 6.8 years, and osteoporotic fractures were detected in 19/127 (15.0%) patients. The proportion of patients having a high-risk for osteoporotic fractures in the FRAX with and without BMD, and osteoporosis by the World Health Organization (WHO) criteria were 25 (16.1%), 24 (15.5%), and 51 (32.9%), respectively, and 48.0–68.6% of them were receiving treatment. On multivariate logistic analysis, nephritis (odds ratio [OR] 11.35) and cumulative dose of glucocorticoid (OR 1.1) were associated with high-risk by the FRAX with BMD, and low complement levels (OR 4.38), erythrocyte sedimentation rate (ESR) (OR 1.04), and cumulative dose of glucocorticoid (OR 1.05) were associated with osteoporosis by the WHO criteria in patients with SLE. ConclusionsAmong Korean female patients with SLE, the proportion of patients having a high-risk of osteoporotic fractures by the FRAX tool was 15.5%–16.1% and the proportion of patients having osteoporosis by the WHO criteria was 32.9%. In SLE, nephritis, low level of complement, ESR, and cumulative dose of glucocorticoids may contribute to fracture risk.

The effect of glucocorticoids on serum cystatin C in identifying acute kidney injury: a propensity-matched cohort study

BackgroundGlucocorticoids may impact the accuracy of serum cystatin C (sCysC) in reflecting renal function. We aimed to assess the effect of glucocorticoids on the performance of sCysC in detecting acute kidney injury (AKI) in critically ill patients.MethodsA prospective observational cohort study was performed in a general intensive care unit (ICU). Using propensity score matching, we successfully matched 240 glucocorticoid users with 960 non-users among 2716 patients. Serum creatinine (SCr) and sCysC were measured for all patients at ICU admission. Patients were divided into four groups based on cumulative doses of glucocorticoids within 5 days before ICU admission (Group I: non-users; Group II: 0 mg < prednisone ≤50 mg; Group III: 50 mg < prednisone ≤150 mg; Group IV: prednisone > 150 mg). We compared the performance of sCysC for diagnosing and predicting AKI in different groups using the area under the receiver operator characteristic curve (AUC).ResultsA total of 240 patients received glucocorticoid medication within 5 days before ICU admission. Before and after matching, the differences of sCysC levels between glucocorticoid users and non-users were both significant (P < 0.001). The multiple linear regression analysis revealed that glucocorticoids were independently associated with sCysC (P < 0.001). After matching, the group I had significantly lower sCysC levels than the group III and group IV (P < 0.05), but there were no significant differences in sCysC levels within different glucocorticoids recipient groups (P > 0.05). Simultaneously, we did not find significant differences in the AUC between any two groups in the matched cohort (P > 0.05).ConclusionsGlucocorticoids did not impact the performance of sCysC in identifying AKI in critically ill patients.

Predictors of Vertebral Deformity in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia: The PETALE Study.

The prevalence of vertebral deformities in long-term survivors of childhood acute lymphoblastic leukemia (ALL) is unknown. Our objectives were to identify the prevalence of vertebral deformities and their risk factors among long-term childhood ALL survivors. We recruited 245 (49% male) long-term childhood ALL survivors from the Preventing Late Adverse Effects of Leukemia Cohort (French-Canadian ALL survivors treated between the years 1987 and 2010 with the Dana Farber Cancer Institute clinical trials protocols, who did not experience disease relapse and/or receive hematopoietic stem cell transplant). Median age at recruitment was 21.7 years (range, 8.5-41) and median time since diagnosis was 15.1 years (range, 5.4-28.2). All participants underwent spine radiograph and dual-energy X-ray absorptiometry scans. The prevalence of vertebral deformity was 23% with 88% classified as grade 1 according to the Genant method. The majority of vertebral deformities were clinically silent. Regression analysis confirmed male sex (risk ratio [RR] = 1.94; 95% confidence interval [CI], 1.16-3.24; P = 0.011), higher glucocorticoid cumulative dose (RR = 1.05; 95% CI, 1.00-1.10; P = 0.032), and back pain (RR = 2.44; 95% CI, 1.56-3.84; P < 0.001) as predictors of prevalent vertebral deformity. Sex differences in vertebral deformity predictors emerged. We report a significant prevalence of vertebral deformities in this young cohort. Male sex, cumulative glucocorticoid dose, and back pain were identified as predictors of prevalent vertebral deformity. Back pain emerging as a strong predictor of vertebral deformity underscores the importance of ongoing bone health surveillance in survivors with persistent vertebral deformities treated with these earlier protocols.

Impact of age at diagnosis in polymyalgia rheumatica: A retrospective cohort study of 218 patients

Polymyalgia rheumatica (PMR) is a common musculoskeletal inflammatory disease that may occur with giant-cell arteritis (GCA) or in an isolated form. While the incidence is highest in the elderly, there is a paucity of data on its presentation, clinical course and response to treatment in younger individuals. We conducted a retrospective review of 40 patients who were diagnosed with isolated PMR under the age of 60 and 178 patients diagnosed above this age, taking into account clinical and laboratory data and treatment history. Patients who were diagnosed at a younger age had lower acute-phase reactant levels at diagnosis but not after initiation of treatment or at the time of relapse. The risk of relapse was lower in the group diagnosed under age 60 (35% vs 55%). Cumulative and maximal glucocorticoid doses, use of glucocorticoid-sparing agents and duration of glucocorticoid treatment, did not differ between the groups. In multivariate analysis, younger age at diagnosis was associated with cervical pain and male gender. Compared to patients diagnosed above age 60, patients diagnosed with PMR at a younger age have a lower risk of relapse, but similar long-term outcomes with regards to continued need for treatment.

Is concomitant treatment with steroids and radiotherapy more favorable than sequential treatment in moderate-to-severe graves orbitopathy?

Glucocorticoids (GCs) and external radiotherapy (RT) are used for treating moderate-to-severe Graves' orbitopathy (GO). We aimed to assess whether GCs and RT were more effective when administered concomitantly or sequentially. We retrospectively analyzed clinical outcomes [assessed by Clinical Activity Score (CAS) and NOSPECS classification] in 73 patients treated with both i.v. GCs and RT. The patients were divided in two groups: In group A (53 patients), RT was delivered concomitantly with GCs, and in group B (20 patients) RT was administered subsequently to the end of methylprednisolone. At baseline, CAS (median 4.0) and the percentage of patients encompassing the various grades of the classes 2, 3 and 4 of the NOSPECS score were similar in both groups. Six months after RT, CAS decreased to 2 in both groups (p = 0.0003 vs baseline) as well as NOSPECS class 4 (p < 0.0001 vs baseline). NOSPECS class 2 improved more in group A than in group B (p = 0.016). The median cumulative dose of GCs was lower in group A than in group B (median 4.500 vs 6000mg, p < 0.007); the overall length of therapy was shorter in group A than in group B (68 vs 106days, p < 0,02). The most common acute adverse effect was transient conjunctivitis (five in group A and three in group B); seven patients (five in group A and two in group B, age between 60 and 66years) developed cataract, requiring surgery in five cases. Concomitant administration of GC and RT showed a favorable effect in moderate-to-severe GO, thus suggesting that RT should be carried out early during steroid therapy, when clinical symptoms do not improve or deteriorate after the first i.v. administrations of GCs.

Glucocorticoid dose-dependent risk of type 2 diabetes in six immune-mediated inflammatory diseases: a population-based cohort analysis

IntroductionIn immune-mediated inflammatory diseases, there is a lack of -estimates of glucocorticoid dose–response diabetes risk that consider changes in prescribed dose over time and disease activity.Research design and methodsPopulation-based longitudinal...

Clinical phenotypes of IgG4-related disease reflect different prognostic outcomes.

Four clinical phenotypes of IgG4-related disease (IgG4-RD) have been recently identified by latent class analysis (LCA): pancreato-biliary (group 1); retroperitoneum/aortitis (group 2); head and neck limited (group 3); and Mikulicz/systemic (group 4). The reproducibility of this classification in clinical practice and its relevance for patient management, however, remain unknown. The study included 179 patients. Four IgG4-RD experts were asked to classify a validation cohort of 40 patients according to published LCA-derived phenotypes based on clinical judgement. Agreement between LCA and clinical clustering was calculated. To assess differences among disease phenotypes, the following variables were recorded on an additional 139 patients: serum IgG4 and IgE; inflammatory markers; eosinophils; plasmablasts; IgG4-RD responder index (RI); history of atopy, diabetes, osteoporosis, relapses and malignancy; cumulative dose of glucocorticoids; and use of rituximab. Clinical judgement replicated LCA classification with strong agreement among IgG4-RD experts (κ = 0.841, P < 0.0005). At disease onset, group 1 showed the highest levels of serum IgG4 and IgE. Groups 2 and 4 had the lowest and highest IgG4-RD RI, respectively. At 2 years' follow-up, group 3 received the highest cumulative dose of glucocorticoids, but higher incidences of diabetes mellitus were observed in groups 1 and 4, consistent with the higher likelihood of pancreatic involvement in groups 1 and 4. No difference among the four groups was observed in terms of disease recurrence, time to relapse and frequency of rituximab infusion. Clinical phenotypes of IgG4-RD reflect differences in epidemiological features and prognostic outcomes.

Effect of exogenous glucocorticoids on male hypogonadism.

The aim of the present study was to investigate the effects of exogenous glucocorticoids (GCs), a potent cause of male hypogonadism, on the function of the hypothalamic-pituitary-gonadal axis, and to determine their secondary effects in male patients. The present study was a case-controlled study conducted in Basrah, Iraq. Of the 152 participants who met the inclusion criteria, 100 patients used different types of GCs. Of these 100 patients, 57 patients (57%) were current GC users, and 43 patients (43%) were not currently using GCs (had not used GCs in the past 30 days). The control group was comprised of 52 men (34.21%), considered as healthy participants, although 7 men (13.65%) were biochemically diagnosed with hypogonadism. Current GC exposure significantly decreased the total and free testosterone levels, whereas previous GC exposure increased estradiol (E2) levels, with the 31 patients on oral dexamethasone (cumulative dose, 18.9 mg) exhibiting a 7.5-fold increased risk of being diagnosed with hypogonadism. For previous GC users, a significant increase in the E2 level was observed, whereas all other gonadal hormonal levels were within normal reference ranges, including the total and free testosterone levels. The total cumulative dose of equivalent GCs was 240 mg, which resulted in a decrease in total testosterone levels, and subsequent hypogonadism. Oral dexamethasone at a lower total cumulative dose resulted in hypogonadism.

Factors associated with active tuberculosis in Colombian patients with systemic lupus erythematosus: a case-control study.

To identify factors associated with active tuberculosis (TB) in patients with systemic lupus erythematosus (SLE). We performed a retrospective case-control study in two tertiary care teaching hospitals in Medellín, Colombia. From January 2007 to December 2017, a total of 268 patients with SLE were included. SLE patients with TB (cases) were matched 1:3 with SLE patients without TB (controls) by disease duration and the date of the hospitalization in which the diagnosis of TB was made (index date of cases) to the nearest available rheumatology hospitalization in the matched controls (± 2years). Conditional univariable and multivariable logistic regression analyses were performed. Sixty-seven cases and 201 controls were assessed. Only pulmonary TB occurred in 46.3%, only extrapulmonary TB in 16.4% and disseminated TB in 37.3% of cases. Multivariable logistic regression analysis showed that lymphopenia (OR, 2.91; 95% CI 1.41-6.03; P= 0.004), 12-month cumulative glucocorticoid dose ≥1830mg (OR, 2.74; 95% CI 1.26-5.98; P= 0.011), and having been treated with ≥2 immunosuppressants during the last 12months (OR, 2.81; 95% CI 1.16-6.82; P= 0.022) were associated with TB after adjusting for age, sex, ethnicity, disease duration, disease activity, and comorbidity index. A trend towards an association of kidney transplantation with TB was also found (OR, 3.77; 95% CI 0.99-14.30; P= 0.051). Among SLE patients, cumulative glucocorticoid dose, lymphopenia, and the use of ≥2 immunosuppressants during the last 12months were associated with active TB infection. Key Points • Among SLE patients, a cumulative dose of glucocorticoids equivalent to 5mg/day of prednisone during the last 12months is independently associated with the development of TB. • The use of two or more immunosuppressants during the last 12months is also a risk factor for TB infection development is SLE patients. • Lymphopenia is predominant in SLE patients with TB, being especially profound in those with disseminated TB. • Renal transplant recipients with SLE also have an elevated risk of TB.

THU0308 COMPARISON OF CHILDHOOD-ONSET VERSUS ADULT-ONSET TAKAYASU ARTERITIS: A STUDY OF 141 PATIENTS FROM TURKEY

Background:Childhood-onset Takayasu Arteritis (c-TAK) may differ from adult-onset Takayasu Arteritis (a-TAK) in clinical maaifestations and treatment.Objectives:To compare c-TAK with a-TAK patients for vascular involvement, disease activity, damage, and treatment.Methods:Patient charts from two tertiary-care centers of a pediatric and adult clinic were reviewed. Adult patients diagnosed before the age of 18 were included in the c-TAK group. The activity was assessed with the physician’s global assessment (PGA) and Indian Takayasu Clinical Activity Score (ITAS). The damage was evaluated with Takayasu Arteritis Damage Score (TADS) and Vasculitis Damage Index (VDI).Results:Twenty four c-TAK and 121 a-TAK patients were compared. 21 (88%) of the c-TAK group and 104 (89%) of the a-TAK group were female. Age at symptom onset was 14 (IQR: 9-15) for c-TAK and 30 (IQR: 24-43) for a-TAK patients. Diagnostic delay in months was shorter for c-TAK patients [c-TAK: 3 (1-10) vs. a-TAK: 12 (5-58)]. Follow-up duration was similar [53 months (IQR: 16-131) vs. 68 (IQR: 30-102), p=0.763].ITAS was comparable for c-TAK and a-TAK patients on the first visit [14 (SD: 7) vs. 13 (SD: 5), p=0.362, respectively]. However, the PGA score was higher in the c-TAK group compared to the a-TAK group [9 (IQR 7-10) vs. 7 (IQR 6-8), p&lt;0.001].14 (64%) of c-TAK patients and 10 (9%) of a-TAK patients received pulse glucocorticoids, p= 0.002. Cumulative glucocorticoid dose was 10 grams (IQR: 6-13) for c-TAK patients and 7 grams (IQR: 4-12) for a-TAK patients (p=0.128).After diagnosis, children had more vascular interventions than the adults did [9 (38%) vs. 20 (18%), p=0.031, respectively].Rates of achieving at least one remission were lower for c-TAK patients [c-TAK: 12 (50 %) vs. a-TAK: 94 (82%), p=0.001]. c-TAK patients had a PGA score of 6 (IQR 3-8), the PGA score in a-TAK patients was 1 (IQR 1-3), p&lt;0.001. Still, ITAS was similar for both groups [c-TAK: 1 (IQR 0-3) vs. a-TAK: 0 (IQR 0-2), p= 0.579]. 9 (38%) of c-TAK patients had at least one relapse, and the 43 (38%) of a-TAK patients had at least one relapse (p=0.960).TADS was similar [c-TAK: 8 (IQR 4-12), a-TAK: 8 (IQR 6-10), p=0.919]. However, VDI of the a-TAK patients was higher than the c-TAK patients [c-TAK: 4 (IQR 2-5), a-TAK: 5 (IQR 3-7), p=0.017]. Glucocorticoid related damage was higher in a-TAK patients (Diabetes: 8% vs. 4%, avascular necrosis: 6% vs. 0, and cataracts: 11% vs. 0)Conclusion:Aorta involvement, biologic agent use, and vascular interventions were more common in c-TAK patients. However, cumulative damage was not increased for c-TAK patients which may be partly explained by more common corticosteroid related side-effects in adults.Table 1.Baseline symptoms, physical examination findings*c-TAK (n= 24)a-TAK (n= 117)pSYMPTOMSStroke1 (4)8 (7)1Carotidynia019 (16)0.044Upper Extremity Claudication5 (21)72 (62)&lt;0.001Hypertension13 (54)22 (19)&lt;0.001Pulse loss (Radial)8/23 (35)62 (58)0.043BRUITSubclavian8 (35)62 (57)0.054Renal9 (39)15 (14)0.014Abdominal Aorta11 (48)9 (8)&lt;0.001*Values denote the number (%) of patientsFigure 1.Comparison of involved arteries* * Numbers in bars represent percentage of patients in each groupFigure 2.Angiographic classification types according to Hata* * Numbers in bars represent percentage of patients in each group. Type 2a and Type 2b are combined. a-TAK group had no patient with Type 3 diseaseTable 2.Medical treatment*First TreatmentTreated Everc-TAK (n=22)a-TAK (n=115)pc-TAK(n=24)a-TAK (n=114)pMethotrexate5 (23)69 (60)0.00112 (50)76 (67)0.123Azathioprine8 (36)38 (33)0.76321 (88)79 (69)0.070Leflunomide01 (1)13 (13)35 (31)0.070Cyclophosphamide†6 (27)6 (5)0.00412 (50)10 (9)&lt;0.001Biologics10 (42)16 (14)0.004Anti-TNF---4 (17)18 (16)-Tocilizumab---7 (29)4 (4)-*Values denote the number (%) of patients.Disclosure of Interests:None declared

FRI0220 EFFICACY OF ADJUNCTIVE METHOTREXATE IN PATIENTS WITH GIANT CELL ARTERITIS TREATED WITH TOCILIZUMAB PLUS PREDNISONE TAPERING: SUBANALYSIS OF THE GIACTA TRIAL

Background:There is conflicting evidence regarding the efficacy of methotrexate (MTX) in giant cell arteritis (GCA).1,2The benefit of adjunctive treatment with MTX remains to be determined in these patients. Data are presented from a subanalysis of the 52-week, double-blind, randomized controlled GiACTA trial in a subgroup of patients with GCA who received MTX in addition to tocilizumab (TCZ) or placebo (PBO) in combination with prednisone tapering.Objectives:Assess the efficacy of adjunctive MTX in patients with GCA.Methods:In part 1 of GiACTA, patients were randomly assigned to TCZ administered subcutaneously every week (QW) or every other week (Q2W) plus 26-week prednisone tapering or PBO plus 26-week (PBO+26) or 52-week (PBO+52) prednisone tapering.3MTX could be initiated at a stable dose during screening, continued during the double-blind period, and reduced or discontinued at the investigator’s discretion according to disease status. Efficacy was determined as the achievement of sustained remission (absence of GCA flare and C-reactive protein &lt;1 mg/dL from weeks 12 to 52 and adherence to the prednisone taper).3Results:During part 1 of GiACTA, 28 of 250 (11%) treated patients received adjunctive MTX for a median duration of 52.1 weeks: 14 of 149 (9%) TCZ-treated patients received MTX for a median of 52.1 weeks, and 14 of 101 (14%) PBO-treated patients received MTX for a median of 51.9 weeks. Baseline characteristics (Table 1) were balanced between patients who received and did not receive MTX, except for longer disease duration and a higher proportion of patients with relapsing GCA among those who received MTX. The MTX-treated patients tended to have lower prednisone doses at baseline. The median cumulative glucocorticoid dose received over 52 weeks was similar between PBO-treated patients who received MTX and those who did not (3033 mg and 3672 mg, respectively) and between TCZ-treated patients who received MTX and those who did not (1339 mg and 1862 mg, respectively). Sustained remission was achieved by 6 of 14 (43%) patients treated with TCZ + MTX and by 76 of 135 (56%) patients treated with TCZ without MTX (Figure 1). None of the 14 PBO + MTX-treated patients achieved sustained remission, whereas 16 of 87 (18%) patients who received PBO without MTX achieved sustained remission (among all patients in the primary analysis,382 of 149 [55%] in the TCZ groups and 16 of 101 [16%] in the PBO groups achieved sustained remission). The mean annualized relapse rate at 52 weeks was not different between the MTX-treated and MTX-untreated groups for the TCZ (0.76 with MTX vs 0.47 without MTX;p= 0.2549) or PBO (1.89 vs 1.46;p= 0.4611) groups (pvalues based onttests). Rates of adverse events per 100 patient-years were numerically higher in MTX-treated than MTX-untreated patients: 1267 and 858, respectively, in the TCZ groups and 1331 and 952, respectively, in the PBO groups.Conclusion:Preliminary data from a small subgroup of patients suggest that adjunctive MTX does not increase the likelihood of sustained remission, reduce disease relapse rate, or improve steroid sparing in patients with GCA. Response rates in TCZ-treated patients appear to be independent of treatment with MTX. The results from this post hoc analysis in a small sample of GCA patients treated with MTX should be confirmed in larger studies.

MON-168 Peri-Operative Glucocorticoids in Patients Having Total Joint Replacements: Help or Harm?

Introduction: There is limited evidence to guide peri-operative steroid regimen in patients receiving chronic glucocorticoid (GC) therapy. Many patients who undergo minor surgical procedures receive stress-dose steroids. While hemodynamic instability and hypotension are well-recognized risks of inadequate peri-operative GCs, there may be harms associated with using doses higher than necessary. Whether surgical outcomes differ according to peri-operative steroid dose is not known. We hypothesized that patients who had greater GC exposure have less hypotension, but higher rates of hyperglycemia and post-operative complications. Methods: This retrospective study investigated the relationships between peri-operative GC use and post-operative complications following total hip/knee joint replacement (arthroplasty) in patients with rheumatoid arthritis (RA). All GCs were converted to prednisone equivalents; GC exposure was assessed by number of doses and total cumulative dose during the hospitalization. Complications (infection, thromboembolism and cardiovascular events) were determined by chart review. Results: Of 432 patients with RA included, half (54%) underwent knee arthroplasty. Mean age was 64±12 years, 78% were women. Thirty percent of patients were on home GCs (mean dose 7±4mg/day). Median cumulative GC dose during hospitalization was 37mg [IQR 27, 57]. Compared to patients who only received one peri-operative dose of steroids, those who received multiple doses had a greater risk of post-operative complications (OR 3.319 (95% CI 1.03, 12.62; p<0.05] and hyperglycemia, glucose >180 mg/dl, [OR 1.812(0.99, 3.32; p<0.05]. They did not have an increase in hypotension or need for pressors. Among patients who received steroids while in the hospital (90%), there was a small but significant dose response relationship with hyperglycemia (r=0.16; p<0.01). Higher cumulative dose was also associated with higher risk of complications; for every 10 mg increase in cumulative dose, the risk of complications increased by 15% (p<0.01). Conclusions: Among RA patients undergoing arthroplasty, we did not find that lower doses of GCs were related to more hypotension. However, patients with higher GC exposure were more likely to have hyperglycemia and post-operative complications. Our results suggest that use of peri-operative GC is not without risk, and the lowest doses possible should be considered. Further studies are needed to confirm these findings and to define the optimal dosing strategies for patients receiving peri-operative GCs.

Oral glucocorticoids and incidence of hypertension in people with chronic inflammatory diseases: a population-based cohort study.

BACKGROUND:Only a few population-based studies have examined the association between glucocorticoids and hypertension, with inconsistent results. We aimed to investigate the effect of oral glucocorticoids on incidence of hypertension in adults with chronic inflammatory diseases.METHODS:We analyzed electronic health records from 389 practices in England during 1998–2017 of adults diagnosed with any of 6 chronic inflammatory diseases but with no previous diagnosis of hypertension. We used glucocorticoid prescription data to construct time-variant daily and cumulative variables of prednisolone-equivalent dose (cumulated from 1 year before the start of follow-up) and estimated incidence rates and adjusted hazard ratios (HRs) for hypertension using Cox regression analysis.RESULTS:Among 71 642 patients in the cohort, 24 896 (34.8%) developed hypertension during a median follow-up of 6.6 years. The incidence rate of hypertension was 46.7 (95% confidence interval [CI] 46.0–47.3) per 1000 person-years. Incidence rates increased with higher cumulative glucocorticoid prednisolone-equivalent dose, from 44.4 per 1000 person-years in periods of nonuse to 45.3 per 1000 person-years for periods with between > 0.0 and 959.9 mg (HR 1.14, 95% CI 1.09–1.19), to 49.3 per 1000 person-years for periods with 960–3054.9 mg (HR 1.20, 95% CI 1.14–1.27), and to 55.6 per 1000 person-years for periods with ≥ 3055 mg (HR 1.30, 95% CI 1.25–1.35). Cumulative effects were seen for the 6 diseases studied, but dose–response effects were not found for daily dose.INTERPRETATION:Cumulative dose of oral glucocorticoids was associated with increased incidence of hypertension, suggesting that blood pressure should be monitored closely in patients routinely treated with these drugs. Given that glucocorticoids are widely prescribed, the associated health burden could be high. Trial registration: ClinicalTrials. gov, no. NCT03760562.

Ten-year experience with rituximab for induction and maintenance therapy in patients with ANCA-associated systemic vasculitis

Rituximab (RTM), a monoclonal antibody against CD20+ receptors on the membrane of B-cells, is becoming increasingly important for the induction and maintenance treatment of antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis (ANCA-SV). The challenge facing us is to optimize its efficacy, while limiting adverse events (AEs).Objective: to evaluate the efficacy and safety of RTM used for the induction and maintenance of remission in ANCA-SV on the basis of 10-year single-center experience.Patients and methods. The paper presents the authors’ own 10-year experience with RTM used for the induction and maintenance of remission in 103 patients with ANCA-SV, including granulomatosis with polyangiitis (GPA) (n=58), microscopic polyangiitis (MPA) (n=35), ANCA-positive eosinophilic granulomatosis with polyangiitis (EGPA) (n=4), and ANCA-negative EGPA (n=6). The duration of a follow-up after initiation of RTM treatment was more than a year (with the exception of death cases) and averaged 25 to 58 months in different ANCA-SV groups. The patients were monitored every 3 months. The intervals between repeated cycles were dependent on the time course of changes in clinical and laboratory parameters. The mean cumulative RTM dose exceeded 3 g; 75% of patients received repeated cycles of RMT usually at a cumulative dose of 0.5–1.0 g at a 4–12-month interval.Results and discussion. Repeated RTM cycles for ANCA-SV were highly effective; the clinical response rate was 97%, while 90–93% of patients with different types of ANCA-SV achieved complete clinical response. Despite the fact that the examined population included a high proportion of patients with a severe or refractory course of the disease; ANCA-SV patients showed 10% mortality rates during the entire follow-up period. Anti-B-cell therapy with RTM is of great importance in obtaining long-term optimal results, making it possible to improve ANCA-SV control and to minimize the cumulative dose of glucocorticoids. Since in ANCA-SV, the use of repeated cycles of RTM, including that at a reduced dose of 0.5 g, contributes to the higher efficiency of treatment and to the lower risk of relapse, it is advisable to perform long-term (≥2 years) RTM therapy, by controlling the parameters of clinical and immunological activities and the levels of circulating CD20+ B cells and serum immunoglobulins, deficiency of which can potentially increase the risk of infectious AEs. When planning RTM therapy, it is necessary to consider the specific features of the safety profile for individual nosological entities and to make a careful appropriate monitoring of ANCA-SV patients receiving RTM. The risk of late-onset neutropenia was highest in patients with all types of ANCA-SV (3–10%). Infections in patients with GPA and MPA constitute a substantial proportion (10–11%) in serious AEs. Management of EGPA patients requires alertness to the risk of infusion-related reactions, primarily bronchospasm.Conclusion. There is a need for further investigation of an anti-B-cell therapy strategy, including the efficacy and safety of RTM in ANCA-SV and for clarification of indications and optimal RTM treatment regimens.

Giant Cell Arteritis: The Experience of Two Collaborative Referral Centers and an Overview of Disease Pathogenesis and Therapeutic Advancements.

PurposeGiant cell arteritis (GCA), a chronic vasculitis of the large and medium-sized arteries, affects people >50 years of age. This study assessed the prevalence of visual manifestations and other clinical features at presentation in an Italian cohort of GCA patients. Recent advances in the pathophysiology, diagnosis, and therapy of GCA are also reviewed.MethodsThis retrospective, single-center study conducted by the ophthalmology and internal medicine clinics of one university recruited 56 patients from 2005 to 2016 and followed them for 11–54 months.ResultsOcular involvement was diagnosed in 19 patients (33.9%), with permanent vision loss in 19.6% (7.1% of the cohort with bilateral vision loss). Arteritic anterior and posterior ischemic optic neuropathy were diagnosed in 11 patients (57.9%) and 1 patient (5.3%), respectively, cotton wool spots in 3 patients (15.8%), central retinal artery occlusion in 2 patients (10.5%), and anterior segment ischemia and multifocal choroidal ischemia in 1 patient each (5.3%). Polymyalgia rheumatica was associated with GCA in 44.6% of the patients. The most common extra-ocular manifestation was constitutional symptoms (82.1% of the patients). Large-vessel involvement, including of the ascending aorta, aortic arch, and left axillary artery, was diagnosed by magnetic resonance or computed tomography (CT) angiography and 18FDG positron emission/CT. Glucocorticoids (GCs) remain the standard-of-care worldwide, but methotrexate, provided as a steroid-sparing drug in 41% of the patients, resulted in earlier tapering, a lower cumulative dose of GCs, and a lower rate of relapse. Among the combinations of GCs and immunosuppressive drugs proposed to treat GCA, only tocilizumab has effectively induced and maintained disease remission.ConclusionAccording to our data and literature reports: a) GCA is a systemic disease; b) its diagnosis is expedited by the adjunct use of imaging techniques; c) insights into the pathogenesis of GCA may allow an improved, differentiated therapeutic approach.

Glucocorticoid use and complications following immune checkpoint inhibitor use in melanoma

Immune checkpoint inhibitors have demonstrated benefit in the treatment of cancer, but are associated with toxicities, which often require treatment with glucocorticoids. We aimed to determine the prevalence of glucocorticoid use in patients treated with immune checkpoint inhibitors for melanoma in a single centre. We performed a retrospective review of patients with advanced melanoma treated with an immune checkpoint inhibitor between September 2010 and January 2017. Patients treated with glucocorticoids had a cumulative dose and duration of glucocorticoid treatment calculated. New onset hyperglycaemia was also identified. Of 412 patients receiving immune checkpoint therapy, 157 (38%) required glucocorticoids to treat toxicities. The median cumulative glucocorticoid dose was 2,795 mg (prednisolone equivalent) with a median duration of 61 days. Twenty-seven patients receiving glucocorticoids were noted to develop new onset hyperglycaemia. Immune-related adverse events frequently occur in patients treated with immune checkpoint inhibitors. Consequently, patients receive prolonged courses of glucocorticoids. Awareness of glucocorticoid-induced side effects is required.

Metformin to reduce metabolic complications and inflammation in patients on systemic glucocorticoid therapy: a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial

An urgent need to reduce the metabolic side-effects of glucocorticoid overexposure has been recognised, as glucocorticoid excess can lead to Cushing's syndrome, which is associated with high morbidity. We aimed to evaluate the potential of metformin to reverse such effects while sparing the anti-inflammatory benefits of glucocorticoids. We did a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial involving four hospitals in the UK. Patients without diabetes were eligible if they were between the ages of 18 and 75 years with an inflammatory disease treated with continuous prednisolone (≥20 mg/day for ≥4 weeks and remaining on ≥10 mg/day for the subsequent 12 weeks, or its cumulative dose-equivalent). Eligible patients were randomly allocated (1:1) to either the metformin or placebo groups, using a computer-generated randomisation table stratified according to age and BMI. Metformin and placebo were administered orally for 12 weeks in escalating doses: 850 mg/day for the first 5 days, 850 mg twice a day for the next 5 days, and 850 mg three times a day subsequently. The primary outcome was the between-group difference in visceral-to-subcutaneous fat area ratio over 12 weeks, assessed by CT. Secondary outcomes included changes in metabolic, bone, cardiovascular, and inflammatory parameters over 12 weeks. Our analysis followed a modified intention-to-treat principle for the primary outcome. This study is registered with ClinicalTrials.gov, NCT01319994. Between July 17, 2012, and Jan 14, 2014, 849 patients were assessed for study eligibility, of which 53 were randomly assigned to receive either metformin (n=26) or placebo (n=27) for 12 weeks. 19 patients in the metformin group and 21 in the placebo group were eligible for the primary outcome analysis. Both groups received an equivalent cumulative dose of glucocorticoids (1860 mg prednisolone-equivalent [IQR 1060-2810] in the metformin group vs 1770 mg [1020-2356] in the placebo group); p=0·76). No change in the visceral-to-subcutaneous fat area ratio between the treatment groups was observed (0·11, 95% CI -0·02 to 0·24; p=0·09), but patients in the metformin group lost truncal subcutaneous fat compared with the placebo group (-3835 mm2, 95% CI -6781 to -888; p=0·01). Improvements in markers of carbohydrate, lipid, liver, and bone metabolism were observed in the metformin group compared with the placebo group. Additionally, those in the metformin group had improved fibrinolysis, carotid intima-media thickness, inflammatory parameters, and clinical markers of disease activity. The frequency of pneumonia (one event in the metformin group vs seven in the placebo group; p=0·01), overall rate of moderate-to-severe infections (two vs 11; p=0·001), and all-cause hospital admissions due to adverse events (one vs nine; p=0·001) were lower in the metformin group than in the placebo group. Patients in the metformin group had more events of diarrhoea than the placebo group (18 events vs eight; p=0·01). No significant changes in the visceral-to-subcutaneous fat area ratio between the treatment groups were observed; however, metformin administration did improve some of the metabolic profile and clinical outcomes for glucocorticoid-treated patients with inflammatory disease, which warrants further investigation. Barts Charity and Merck Serono.

Evaluation of the modified combined glucocorticoid toxicity index in rheumatoid arthritis: Preliminary data

Objective: to assess whether the modified combined glucocorticoid (GC) toxicity index (MCGTI) can be used to analyze adverse reactions (ARs) to GCs administered in the management of rheumatoid arthritis (RA). Subjects and methods . The investigation enrolled 71 RA patients (57 females, 14 males; mean age, 51.7+15.2 years). All the patients met the ACR/EULAR classification criteria and took GCs (the median duration of GC treatment duration was 7.1 [0.9; 12.0] years). In addition to the standard clinical, laboratory, and instrumental indicators, the daily and cumulative doses of GCs (in prednisolone equivalent) and MCGTI were analyzed. Results and discussion . The value of MCGTI statistically significantly correlated with treatment duration (r=0.411), age (r=0.384), and the cumulative dose of GCs (r=0.361), but did not correlate with their maximum dose (r=0.06). A ROC analysis showed that the critical level of the cumulative dose of GCs in relation to MCGTI was 17,337.5 mg. Conclusion. MCGTI correlates with cumulative dose (making it possible to establish its critical level), treatment duration, and age, which is the basis for further study of whether this can be applied in clinical practice to evaluate, predict, and prevent ARs.

Mathematical processing is affected by daily but not cumulative glucocorticoid dose in patients with systemic lupus erythematosus.

The impact of glucocorticoids on neurocognitive performance in patients with SLE is not fully addressed. We aimed to study the effect of daily and cumulative glucocorticoid dose on neurocognitive performance in SLE patients. Consecutive SLE patients and gender- and age-matched healthy controls (HCs) underwent the computer-based Automated Neuropsychological Assessment Matric (ANAM), which evaluates eight neurocognitive domains including learning, recall, visual perception, mental rotation, short-term memory, attention, sustained attention and working memory. The total and individual-domain throughput scores (TPSs) and the presence of cognitive dysfunction (total TPS <1.5 s.d. below the mean TPS of HCs) were compared between SLE patients and HCs. Within the SLE group, univariate and independent associations between prednisolone dose (daily and cumulative) and individual-domain TPS were studied by univariate and multivariable linear regression, respectively. A total of 96 SLE patients and 96 HCs were studied. SLE patients scored significantly worse across all the neurocognitive domains and had a significantly lower mean total TPS (P < 0.001) and a higher prevalence of cognitive dysfunction compared with HCs (25.0 vs 7.3%, P = 0.001). In SLE patients, daily prednisolone dose was significantly and negatively correlated with mathematical-processing TPS, which probes working memory (P = 0.018). No significant correlation between cumulative prednisolone dose and any of the individual-domain TPSs was found. In multivariable regression, higher daily prednisolone dose and doses >9 mg daily remained independently associated with lower mathematical-processing TPSs (P = 0.031). Daily prednisolone dose ≥9 mg, but not cumulative glucocorticoid dose, had an independent negative impact on mathematical processing in SLE patients.