Non-infectious comorbidity in patients with multiple sclerosis: A national cohort study in Sweden.

BACKGROUND: Comorbidity is of significant concern in multiple sclerosis (MS). Few population-based studies have reported conditions occurring in MS after diagnosis, especially in contemporary cohorts. OBJECTIVE: To explore incident comorbidity, mortality and hospitalizations in MS, stratified by age and sex. METHODS: In a Swedish population-based cohort study 6602 incident MS patients (aged ≥18 years) and 61,828 matched MS-free individuals were identified between 1 January 2008 and 31 December 2016, using national registers. Incidence rates (IRs) and incidence rate ratios (IRRs) with 95% CI were calculated for each outcome. RESULTS: IRs of cardiovascular disease (CVD) were higher among MS patients than MS-free individuals, (major adverse CVD: IRR 1.42; 95% CI 1.12-1.82; hemorrhagic/ischemic stroke: 1.46; 1.05-2.02; transient ischemic attack: 1.65; 1.09-2.50; heart failure: 1.55; 1.15-2.10); venous thromboembolism: 1.42; 1.14-1.77). MS patients also had higher risks of several non-CVDs such as autoimmune conditions (IRR 3.83; 3.01-4.87), bowel dysfunction (2.16; 1.86-2.50), depression (2.38; 2.11-2.68), and fractures (1.32; 1.19-1.47), as well as being hospitalized and to suffer from CVD-related deaths ((1.91; 1.00-3.65), particularly in females (3.57; 1.58-8.06)). CONCLUSION: MS-patients experience a notable comorbidity burden which emphasizes the need for integrated disease management in order to improve patient care and long-term outcomes of MS.

Infections in patients with multiple sclerosis: A national cohort study in Sweden.

BACKGROUND: Multiple sclerosis (MS) patients have an increased risk of infections, but few population-based studies have reported infections occurring in MS in the years immediately after diagnosis. OBJECTIVE: To explore incident infections in MS, stratified by age and sex. METHODS: In a Swedish population-based cohort study 6602 incident MS patients (aged ≥18 years), matched at diagnosis with 61,828 matched MS-free individuals were identified between 1st January 2008 and 31st December 2016, using national registers. Incidence rates (IR) and incidence rate ratios (IRR) with 95% CI were calculated for each outcome. RESULTS: The IRRs were 2.54 (95% CI 2.28-2.83) for first serious infection and 1.61 (1.52-1.71) for first non-serious infection. Compared with MS-free individuals, MS patients had higher IRs for skin, respiratory/throat infections, pneumonia/influenza, bacterial, viral, and fungal infections, with the highest IRR observed for urinary tract/kidney infections (2.44; 2.24-2.66). The cumulative incidence for most of these infections was higher among MS patients than MS-free individuals, both 0 to <5 and 5 to <9 years after index date. CONCLUSION: The burden of infections around the time of MS diagnosis and subsequent infection risk, underscore the need for careful considerations regarding the risk-benefit across different disease-modifying therapies.

Incident cardiovascular disease in patients diagnosed with multiple sclerosis: A multi-database study.

BACKGROUND: Recent data on rates of cardiovascular disease (CVD) in patients after MS diagnosis are sparse. OBJECTIVE: To describe incident CVD in MS patients after diagnosis compared with a matched non-MS population. METHODS: We conducted a matched cohort study in two separate electronic medical databases, the United States Department of Defense military health care system and the United Kingdom's Clinical Practice Research Datalink GOLD. The study population included all patients with a first recorded diagnosis of MS and no history of CVD or selected measurable comorbidities associated with CVD and matched non-MS patients who were also free of CVD and the CVD associated comorbidities. We identified incident CVD outcomes first recorded after the MS diagnosis / matched date and calculated incidence rates and incidence rate ratios by type of CVD. RESULTS: Rates of venous thromboembolism and peripheral vascular disease were 2-fold higher among MS than non-MS patients in both databases and the risk of myocardial infarction was 2.5 times higher among female MS patients compared with non-MS females in both databases. Other CVD outcomes were not consistent between databases. CONCLUSION: MS patients in the UK and the US have increased risk of venous thromboembolism and peripheral vascular disease. The risk of myocardial infarction is increased among female MS patients.

Herpes Zoster, Hepatitis C, and Tuberculosis Risk with Apremilast Compared to Biologics, DMARDs and Corticosteroids to Treat Psoriasis and Psoriatic Arthritis.

PURPOSE: Psoriasis and psoriatic arthritis (PsA) are associated with an increased infection risk. In this cohort study of patients with treated psoriasis or PsA, we used MarketScan (2014-2018) to estimate rates of herpes zoster, hepatitis C (HepC) and tuberculosis (TB) with apremilast compared to other systemic treatments. MATERIALS AND METHODS: Patients were exposed from first apremilast [APR], DMARD, TNF-inhibitor [TNF], IL-inhibitor [IL], or corticosteroids [CS] prescription after March 21, 2014. Study exposures were APR, DMARDs only, TNF-only, IL-only, CS-only, DMARDs+CS, TNF+DMARDs and/or CS, IL+DMARDs and/or CS. Cases had treated herpes zoster, HepC, or TB event. We calculated incidence rates (IRs) [95% confidence intervals] per 1000 patient-years. RESULTS: The study population included 131,604 patients. For herpes zoster (N=2271), IRs were highest for users of DMARDs+CS (12.5 [9.8-15.7]), CS-only (12.5 [10.4-14.1]), and TNF+DMARDs and/or CS (11.9 [10.6-13.4]), compared with DMARDs only (9.9 [8.7-11.2]). IRs were lowest for users of IL-only (6.7 [5.8-7.8]) and APR (7.0 [5.8-8.4]). IRs of HepC (N=150) and TB (N=81) were low and between-treatment differences were not significant. CONCLUSION: Rates of herpes zoster varied by treatment: highest among those who received polytherapy, lowest in users of apremilast only. IRs for HepC and TB were low for all exposures.

Multi-database study of multiple sclerosis: identification, validation and description of MS patients in two countries.

OBJECTIVE: To describe the resources and methods used to identify and validate multiple sclerosis (MS) and match non-MS patients in each of the two databases, and to characterize their demographics, comorbidities and concomitant medications. METHODS: This study was conducted in two separate electronic medical databases, the United States Department of Defense (DOD) military health care system and the United Kingdom's Clinical Practice Research Datalink (CPRD) GOLD. We identified patients with a first recorded diagnosis of MS in 2001-2016 (CPRD) or 2004-2017 (DOD) and matched non-MS patients using algorithms appropriate to each database. We describe patient symptoms, comorbidities, and medication use at the time of the MS diagnosis and compared them to the non-MS cohort. RESULTS: We identified 8695 patients with MS and 86,934 matched non-MS patients in the DOD database and 6932 patients with MS and 68,526 matched non-MS patients in CPRD GOLD. Most MS patients were female (around 70%) and were diagnosed before age 60 (88%). MS patients had higher prevalence of depression and other psychiatric conditions at MS diagnosis compared to non-MS patients. Epilepsy, fractures and infections were also more common. MS patients had many expected symptoms and treatments documented in their records prior to the MS diagnosis. CONCLUSION: These results are consistent between the two databases, as well as with previous studies of MS. Future analyses of these patients' experience after MS diagnosis will provide valuable insights into disease and treatment patterns in relation to risk of chronic diseases and mortality.

Case histories in pharmaceutical risk management.

The development and implementation of programs in the U.S. to minimize risks and assess unintended consequences of new medications has been increasingly required by the Food and Drug Administration (FDA) since the mid 1990s. This paper provides four case histories of risk management and post-marketing surveillance programs utilized recently to address problems associated with possible abuse, dependence and diversion. The pharmaceutical sponsors of each of these drugs were invited to present their programs and followed a similar template for their summaries that are included in this article. The drugs and presenting companies were OxyContin, an analgesic marketed by Purdue Pharma L.P., Daytrana and Vyvanse, ADHD medications marketed by Shire Pharmaceuticals, Xyrem for narcolepsy marketed by Jazz Pharmaceuticals, and Subutex and Suboxone for opioid dependence marketed by Reckitt Benckiser Pharmaceuticals Inc. These case histories and subsequent discussions provide invaluable real-world examples and illustrate both the promise of risk management programs in providing a path to market and/or for keeping on the market drugs with serious potential risks. They also illustrate the limitations of such programs in actually controlling unintended consequences, as well as the challenge of finding the right balance of reducing risks without posing undue barriers to patient access. These experiences are highly relevant as the FDA increasingly requires pharmaceutical sponsors to develop and implement the more formalized and enforceable versions of the risk management term Risk Evaluation and Mitigation Strategies (REMS).

Case-control study of the association between select HLA genes and anti-erythropoietin antibody-positive pure red-cell aplasia.

AIMS: Antibody (Ab)-positive pure red-cell aplasia (PRCA) is a very rare but serious adverse event associated with recombinant human erythropoietin treatment (4.1 reports per 100,000 patient-years) in which patients produce antibodies to recombinant and endogenous erythropoietin, halting red blood cell production. In a previous case series, four Thai subjects with chronic kidney disease and Ab-positive PRCA were reported to have the HLA-DRB1*9 allele. To confirm a possible association of HLA-DRB1*9 and Ab-positive PRCA, we performed a pharmacogenomic analysis using subjects from an earlier case-control study of risk factors associated with Ab-positive PRCA, which had been performed using subjects from Europe or Canada. The primary goal of the analysis was to test the association between HLA-DRB1*9 and Ab-positive PRCA. A secondary goal was to perform an exploratory analysis in order to identify additional HLA alleles potentially associated with Ab-positive PRCA. PATIENTS & METHODS: Subjects were taken from a case-control study of Ab-positive PRCA in chronic kidney disease patients treated in Europe or Canada. Ab-positive PRCA cases (n=24) were matched to controls (n=81) by timing of treatment exposure and, when possible, by location. RESULTS: The allele frequency of HLA-DRB1*9 was 12.5% in cases vs 1.2% in controls (p=0.002). The frequency of the HLA-DRB1*9/other genotype was 25.0% in cases vs 2.5% in controls (p=0.004; OR: 10.8 [95% CI: 2.2-53.7]). Within the exploratory analysis, six additional HLA alleles (HLA-A*25, HLA-B*53, HLA-C*12, HLA-DQB1*3, HLA-DQB1*6 and HLA-DRB1*4) were also found to be associated with Ab-positive PRCA. CONCLUSION: This study confirmed that HLA-DRB1*9 occurs at a significantly higher frequency in Ab-positive PRCA cases than in controls; however, within this sample set, carrying the *9 allele was neither necessary nor sufficient to cause Ab-positive PRCA.

Comparative effect of human soluble insulin and insulin aspart upon hypoglycaemia-induced alterations in cardiac repolarization.

AIMS: Sudden death in young diabetic patients has been associated with nocturnal hypoglycaemia perhaps as a result of cardiac dysrhythmias following abnormal cardiac repolarization during hypoglycaemia. It was therefore important to compare the effect of soluble human insulin (HI) and a rapid-acting insulin analogue, insulin aspart (IAsp), on these aspects of cardiac function. METHODS: A total of 17 healthy males underwent identical hyperinsulinaemic hypoglycaemic clamps with blood glucose maintained at 5 mm for 30 min and reduced to 2.5 mm after an additional 30 min. Subjects received either HI or IAsp on two different occasions separated by 4-6 weeks. Regular measurements were made of two measures of cardiac repolarization, QT dispersion and QTc as well as of counter-regulatory hormones. RESULTS: The blood glucose lowering effect did not differ between IAsp and HI and the clearance rates were similar (HI mean +/- SD 1.24 +/- 0.12 l h(-1) kg(-1), IAsp mean +/- s.d. 1.22 +/- 0.32 l h(-1) kg(-1)). There were similar significant increases but no difference between treatments in QTc after hypoglycaemia induced by either IAsp or HI (480 +/- 37 ms vs 480 +/- 25 ms; NS). However, QT dispersion during hypoglycaemia was less pronounced with IAsp than with HI (92 +/- 36 ms vs 107 +/- 42 ms; P < 0.05). Plasma adrenaline increased significantly and similarly after both insulins (initial and final concentration, HI, 0.23 +/- 0.01 to 4.87 +/- 0.48 nm, P < 0.001, IAsp, 0.24 +/- 0.01 to 4.99 +/- 0.48 nm, P < 0.001). Serum potassium decreased significantly but by a similar amount between the groups (initial and final concentration, HI, 4.18 +/- 0.3 to 4.2 +/- 0.2 mm, P < 0.001, IAsp, 4.2 +/- 0.3 to 4.2 +/- 0.3 mm, P < 0.001). CONCLUSIONS: Soluble human insulin and insulin aspart had similar effects upon hypoglycaemia-induced alterations in cardiac repolarization, presumably because the effects of both regular insulin and insulin aspart on the sympathoadrenal response and potassium concentration were the same.

New insulins in the treatment of diabetes mellitus.

Landmark studies have confirmed the importance of intensified insulin treatment for minimizing long-term diabetic complications. Human insulin is still first-line treatment. However, even the most intensive of human insulin-based regimens can only poorly reproduce physiologically desirable insulin release, which includes rapid outbursts of insulin at mealtimes coupled with relatively low and stable basal levels between meals. Encouragingly, there are now four available or soon-to-be-available insulin analogues that offer the potential for more physiological insulin profiles. Insulin lispro and insulin aspart are rapid-acting insulin analogues intended for immediate pre-meal administration in type 1 or type 2 diabetes. Compared with injected human insulin, they improve post-prandial glucose control and reduce late post-meal and night-time hypoglycaemic episodes. Two basal insulin analogues, insulin glargine and insulin detemir, have also shown beneficial profiles with regard to night-time hypoglycaemia.Some, but not all, studies with the two rapid-acting insulins have shown improvement in overall glucose control, as assessed by HbA(1c), in comparison to human insulin. These results are encouraging and provide hope that entirely analogue-based regimens may improve overall glycaemic control and ease of use of insulin.

Twice-daily biphasic insulin aspart 30 versus biphasic human insulin 30: a double-blind crossover study in adults with type 2 diabetes mellitus.

OBJECTIVE: The purpose of this study was to compare the pharmacokinetics and pharmacodynamics of the premixed insulin analogue biphasic insulin aspart (BIAsp 30) with the equivalent premixed biphasic human insulin (BHI 30), administered twice daily, in patients with type 2 diabetes mellitus. METHODS: In this randomized, double-blind, crossover trial, 13 patients (mean age, 64 years; baseline mean glycosylated hemoglobin, 7.7%; mean body mass index, 28.1 kg/m2) received 2 weeks of treatment with BIAsp 30 and 2 weeks of BHI 30 administered immediately before dinner and breakfast. At the end of each 2-week treatment period, 24-hour serum insulin and glucose profiles were determined using specific 2-sided enzyme-linked immunosorbent assays. All pharmacodynamic and pharmacokinetic end points were analyzed using analysis of variance. RESULTS: Total daily insulin exposure was similar between treatment periods. Mean area under the total insulin concentration-time profile during the 2 hours following administration of BIAsp 30 was 17% greater than that of BHI 30 after dinner and 44% greater after breakfast; both differences were statistically significant. The maximum serum insulin aspart concentrations following BIAsp 30 were significantly higher after dinner (18%) and breakfast (35%). Peak serum insulin concentration was reached 1 hour earlier after breakfast and 45 minutes earlier after dinner in the BIAsp 30 group; differences were significant only after breakfast. The mean daily prandial glucose excursion was significantly lower for BIAsp 30 (16.2 mmol x h x L(-1)) than BHI 30 (17.9 mmol x h x L(-1)). Postprandial 4-hour glucose excursions were significantly lower with BIAsp 30 than with BHI 30 after dinner and breakfast, but were significantly greater after lunch. Mean 24-hour and nocturnal serum glucose concentrations were similar, and both insulins were associated with < or = 7 minor and no major hypoglycemic events. CONCLUSIONS: Premeal injection of BIAsp 30 in a twice-daily regimen significantly reduced overall postprandial glucose excursions. This effect may be of importance when improvement in postprandial glucose control is desired.

Immune responses to insulin aspart and biphasic insulin aspart in people with type 1 and type 2 diabetes.

OBJECTIVE: The antibody responses to a novel rapid-acting insulin analog, insulin aspart (IAsp), and their potential clinical correlates were studied with a specifically developed method in 2,420 people with diabetes treated for up to 1 year with preprandial subcutaneous injections of IAsp. RESEARCH DESIGN AND METHODS: Circulating insulin antibodies were analyzed by radioimmunoassay with (125)I insulin or IAsp tracers and polyethylene glycol precipitation. Four multinational, open, parallel group studies were conducted in Europe and North America, with a total of 1,534 people with diabetes exposed to IAsp and 886 people exposed to human insulin (HI) as meal-related insulin for 6-12 months. RESULTS: Insulin antibodies specific to HI or IAsp were absent in a majority of patients throughout the 6- to 12-month study periods. A majority of the patients (64-68%) had antibodies cross-reacting between HI and IAsp when entering the studies, with baseline levels (means +/- SD of percent bound/total) of 16.6 +/- 16.3% in study 1 and 10.3 +/- 14.0% in study 4. In all four studies, cross-reactive antibodies increased in patients exposed to IAsp, with a maximum at 3 months, and thereafter there was a decline toward baseline levels at 9-12 months (levels at 3 and 12 months: 22.3 +/- 19.7 and 16.8 +/- 16.5% in study 1 and 21.5 +/- 21.9 and 16.9 +/- 17.4% in study 4). Antibody levels showed similar changes in people with type 1 and type 2 diabetes, and there was no consistent relationship between antibody formation and glycemic control or between antibody formation and safety in terms of adverse events. CONCLUSIONS: Treatment with IAsp is associated with an increase in cross-reactive insulin antibodies, with a subsequent fall toward baseline values, without any indication of clinical relevance because no effect on efficacy or safety could be identified.

Insulin aspart: promising early results borne out in clinical practice.

The novel, rapid-acting insulin analogue insulin aspart (IAsp; Novo Nordisk) has been shown in preclinical studies to be more rapidly absorbed than human insulin (HI) when administered subcutaneously. IAsp reaches higher peak serum concentrations in a shorter time than HI, whilst maintaining a similar receptor binding and safety profile. The physiological pharmacokinetic profile of IAsp compared to that of HI has been demonstrated in both adult and paediatric populations and was accompanied by small but statistically significant reductions in HbA(1c), lower postprandial glucose excursions and a reduced risk of late postprandial and major nocturnal hypoglycaemia. Benefits may be maximised by dose optimisation, using bolus doses that result in effective postprandial glucose reduction, as well as higher and multiple basal insulin doses. The safety profile, including cardiovascular risk, is equivalent to HI.