Personal and family history of immune-related conditions increase the risk of plasma cell disorders: a population-based study

The associations between immune-related conditions and multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) have previously been investigated with inconsistent results. In a large population-based study, we identified 19 112 patients with MM, 5403 patients with MGUS, 96 617 matched control subjects, and 262 931 first-degree relatives. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for the association of MM and MGUS with immune-related conditions by use of logistic regression. A personal history of all infections combined was associated with a significantly increased risk of MM (OR = 1.2; 95% CI, 1.1-1.3), and a personal history of all conditions in the categories infections (OR = 1.6; 95% CI, 1.5-1.7), inflammatory conditions (OR = 1.4; 95% CI, 1.2-1.5), and autoimmune diseases (OR = 2.1; 95% CI, 1.9-2.4) was associated with a significantly increased risk of MGUS. Several specific immune-related conditions elevated the risk of MM and/or MGUS. A family history of autoimmune disease was associated with a significantly increased risk of MGUS (OR = 1.1; 95% CI, 1.00-1.2), but not MM. Our findings suggest that immune-related conditions and/or their treatment are of importance in the etiology of MGUS and possibly MM. The association of both personal and family history of autoimmune disease with MGUS indicates the potential for shared susceptibility for these conditions.     

Nateglinide improves postprandial hyperglycemia and insulin secretion in renal transplant recipients

BACKGROUND: Postprandial hyperglycemia (PPHG) frequently occurs among renal transplant recipients (RTR). Reduced early insulin response (EIR) after a meal leads to impaired suppression of endogenous glucose production and subsequently PPHG, which is a risk factor for cardiovascular disease. Nateglinide is a rapid acting insulin secretagogue inducing an EIR after a meal. Our main objective was to investigate the safety and effect of nateglinide treatment on postprandial plasma glucose excursions and insulin secretion in RTR with PPHG. PATIENTS AND METHODS: A total of 14 Caucasian RTR with new-onset diabetes mellitus (NODM; n = 6) or impaired glucose tolerance (IGT; n = 8) were included. The insulin response and glucose excursions were measured for 240 min after a standardized liquid meal at baseline and after two-wk treatment with nateglinide. RESULTS: Treatment with nateglinide was followed by a significant decrease in mean two-h plasma glucose from 10.5 mmol/L (3.1) to 7.6 mmol/L (2.1; p < 0.001) and a decline in total postprandial area under the curve (AUC) of glucose concentration (p < 0.001). Both estimated EIR and the late insulin response increased significantly (p = 0.008 and p = 0.003, respectively). No serious adverse event was observed during the study period. CONCLUSIONS: Treating RTR with nateglinide for two-wk significantly improved PPHG, increased the insulin response following a standardized meal and was well tolerated.     

Antiepileptic drug interactions - principles and clinical implications

Antiepileptic drugs (AEDs) are widely used as long-term adjunctive therapy or as monotherapy in epilepsy and other indications and consist of a group of drugs that are highly susceptible to drug interactions. The purpose of the present review is to focus upon clinically relevant interactions where AEDs are involved and especially on pharmacokinetic interactions. The older AEDs are susceptible to cause induction (carbamazepine, phenobarbital, phenytoin, primidone) or inhibition (valproic acid), resulting in a decrease or increase, respectively, in the serum concentration of other AEDs, as well as other drug classes (anticoagulants, oral contraceptives, antidepressants, antipsychotics, antimicrobal drugs, antineoplastic drugs, and immunosupressants). Conversely, the serum concentrations of AEDs may be increased by enzyme inhibitors among antidepressants and antipsychotics, antimicrobal drugs (as macrolides or isoniazid) and decreased by other mechanisms as induction, reduced absorption or excretion (as oral contraceptives, cimetidine, probenicid and antacides). Pharmacokinetic interactions involving newer AEDs include the enzyme inhibitors felbamate, rufinamide, and stiripentol and the inducers oxcarbazepine and topiramate. Lamotrigine is affected by these drugs, older AEDs and other drug classes as oral contraceptives. Individual AED interactions may be divided into three levels depending on the clinical consequences of alterations in serum concentrations. This approach may point to interactions of specific importance, although it should be implemented with caution, as it is not meant to oversimplify fact matters. Level 1 involves serious clinical consequences, and the combination should be avoided. Level 2 usually implies cautiousness and possible dosage adjustments, as the combination may not be possible to avoid. Level 3 refers to interactions where dosage adjustments are usually not necessary. Updated knowledge regarding drug interactions is important to predict the potential for harmful or lacking effects involving AEDs.     

Do asthma and allergy influence subsequent pet keeping? An analysis of childhood and adulthood

BACKGROUND: Asthma and allergy might influence the choice of keeping pets, leading to apparent protective effects of pets on allergic disease. OBJECTIVE: We investigated the effects of asthma and allergy on subsequent pet keeping in childhood and adulthood. METHODS: Information about asthma and pet keeping at ages 0 to 4, 5 to 15, 20 to 44, and 26 to 56 years was provided by 9812 subjects participating in the 9-year follow-up of the European Community Respiratory Health Survey. RESULTS: In childhood asthma debut at younger than 5 years was associated with less cat keeping at 5 to 15 years (odds ratio [OR], 0.60; 95% CI, 0.44-0.82), an effect only observed when the parents did not have asthma or allergy (P(interaction) = .045). Childhood asthma did not influence adult pet ownership, unless there were adult symptoms. Adults less often acquired cats at follow-up if they had 3 or more asthma symptoms (OR, 0.78; 95% CI, 0.64-0.95), were taking asthma medication (OR, 0.48; 95% CI, 0.31-0.74), had hay fever (OR, 0.75; 95% CI, 0.62-0.91), had atopy (OR, 0.75; 95% CI, 0.61-0.91), or had specific IgE to cat (OR, 0.57; 95% CI, 0.39-0.82) at baseline. Adults who already had pets usually continued keeping the same type of pet, except that the presence of 3 or more asthma symptoms was associated with less subsequent dog keeping (OR, 0.69; 95% CI, 0.53-0.89). Pet removal between surveys to reduce allergen was reported by 4.7%. CONCLUSION: Selective avoidance subsequent to asthma or allergy was observed for childhood cat keeping and adult cat acquisition. Avoidance would produce an apparent protective effect of cats on childhood asthma (large OR, 0.83). Avoidance was generally not observed for dogs or birds. CLINICAL IMPLICATIONS: A part of the protective effects of childhood cats on asthma and allergy can be attributed to selective avoidance.     

Predicting risk for radiographic damage in rheumatoid arthritis: comparative analysis of the multi-biomarker disease activity score and conventional measures of disease activity in multiple studies

Objective: To compare the multi-biomarker disease activity (MBDA) score with the DAS28-CRP and CRP for predicting risk of radiographic progression in patients with rheumatoid arthritis.

Methods: Published studies of the MBDA score and radiographic progression with ≥100 patients per cohort were evaluated. Rates of radiographic progression over 1?year were determined across the low/moderate/high categories for MBDA score (low/moderate/high: <30, 30–44, >44), DAS28-CRP (low/moderate/high: ≤2.67, >2.67–4.09, >4.09) and CRP (low/moderate/high: ≤10, >10–30, >30?mg/L), with positive and negative predictive value (PPV, NPV) and relative risk (RR) determined for high vs. not-high (i.e. low and moderate combined) categories. Patient-level data from studies having all three measures was pooled to: (1) determine a combined RR for radiographic progression in the high vs. not-high categories for each measure; and (2) compare the predictive ability of MBDA score vs. DAS28-CRP by comparing the rates of radiographic progression observed in subgroups created by cross-classifying the high and not-high categories of each measure.

Results: Five cohorts were identified for inclusion (total N=929). In each, radiographic progression was more frequent with increasing MBDA scores. Among the three cohorts with requisite data, PPVs were generally similar using categories of MBDA score, DAS28-CRP or CRP but NPVs were greater for MBDA score (93–97%) than DAS28-CRP or CRP (77–87%). RRs for radiographic progression were greater when based on categories of MBDA score than DAS28-CRP or CRP and the combined RR was greater for MBDA score (4.6, p?<?.0001) than DAS28-CRP (1.7, p?=?.02) or CRP (1.7, p?=?.002). For patients cross-classified by MBDA score and DAS28-CRP, high vs. not-high MBDA score significantly predicted radiographic progression independently of DAS28-CRP.

Conclusions: High and not-high MBDA scores were associated with increased and low risk, respectively, for radiographic progression over one year. MBDA score was a better predictor of radiographic progression than DAS28-CRP or CRP.     

A novel heterozygous nonsense mutation of the OPTN gene segregating in a Danish family with ALS

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. About 10% of ALS cases are familial (FALS) and the genetic defect is known only in approximately 20%-30% of these cases. The most common genetic cause of ALS is SOD1 (superoxide dismutase 1) mutation. Very recently, mutations of the optineurin gene (OPTN), which is involved in open-angle glaucoma, were identified in 3 Japanese patients/families with ALS, and subsequently in a few FALS patients of European descent. We found a heterozygous nonsense mutation (c.493C>T, p.Gln165X, exon 6) in the OPTN gene in a Danish patient with ALS, and the mutation segregated from his affected father. The p.Gln165X mutation could not be detected in 1070 healthy Danish controls, in 1000 Danish individuals with metabolic phenotypes or in 64 sporadic ALS (SALS) cases. The p.Gln165X mutation described in this study is the first mutation reported in a Danish family and is likely involved in disease pathogenesis. Until now, only few OPTN mutations have been associated with ALS. As the underlying genetic defect is known only in approximately 20%-30% of FALS families, further screening of these cases is necessary for establishing the contribution of OPTN mutations in disease pathogenesis.     

Novel heterozygous nonsense mutation of the OPTN gene segregating in a Danish family with ALS

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. About 10% of ALS cases are familial (FALS) and the genetic defect is known only in approximately 20%-30% of these cases. The most common genetic cause of ALS is SOD1 (superoxide dismutase 1) mutation. Very recently, mutations of the optineurin gene (OPTN), which is involved in open-angle glaucoma, were identified in 3 Japanese patients/families with ALS, and subsequently in a few FALS patients of European descent. We found a heterozygous nonsense mutation (c.493C>T, p.Gln165X, exon 6) in the OPTN gene in a Danish patient with ALS, and the mutation segregated from his affected father. The p.Gln165X mutation could not be detected in 1070 healthy Danish controls, in 1000 Danish individuals with metabolic phenotypes or in 64 sporadic ALS (SALS) cases. The p.Gln165X mutation described in this study is the first mutation reported in a Danish family and is likely involved in disease pathogenesis. Until now, only few OPTN mutations have been associated with ALS. As the underlying genetic defect is known only in approximately 20%-30% of FALS families, further screening of these cases is necessary for establishing the contribution of OPTN mutations in disease pathogenesis.