Gerdur Gröndal

A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans

Systemic lupus erythematosus (SLE, OMIM 152700) is a complex autoimmune disease that affects 0.05% of the Western population, predominantly women. A number of susceptibility loci for SLE have been suggested in different populations, but the nature of the susceptibility genes and mutations is yet to be identified. We previously reported a susceptibility locus (SLEB2) for Nordic multi-case families. Within this locus, the programmed cell death 1 gene (PDCD1, also called PD-1) was considered the strongest candidate for association with the disease. Here, we analyzed 2,510 individuals, including members of five independent sets of families as well as unrelated individuals affected with SLE, for single-nucleotide polymorphisms (SNPs) that we identified in PDCD1. We show that one intronic SNP in PDCD1 is associated with development of SLE in Europeans (found in 12% of affected individuals versus 5% of controls; P = 0.00001, r.r. (relative risk) = 2.6) and Mexicans (found in 7% of affected individuals versus 2% of controls; P = 0.0009, r.r. = 3.5). The associated allele of this SNP alters a binding site for the runt-related transcription factor 1 (RUNX1, also called AML1) located in an intronic enhancer, suggesting a mechanism through which it can contribute to the development of SLE in humans.

Increased number of interleukin-10-producing cells in systemic lupus erythematosus patients and their first-degree relatives and spouses in Icelandic multicase families

OBJECTIVE To evaluate the production of interleukin-10 (IL-10) as well as levels of IgG and antinuclear antibodies (ANA) in systemic lupus erythematosus (SLE) patients and their first-degree relatives and spouses in Icelandic SLE multicase families. METHODS IL-10 production was studied by enzyme-linked immunospot assay of freshly isolated peripheral blood mononuclear cells. Total IgG and ANA were also investigated. Subjects consisted of 23 SLE patients and 47 of their first-degree relatives in 9 Icelandic multicase families. Subjects were ethnically matched by a group of healthy controls. A separate study investigated 12 SLE patients (also from SLE multicase families) and their spouses and a matched group of healthy controls. A predefined protocol was used to obtain both clinical and laboratory data, including information about SLE and other autoimmune disorders. RESULTS The SLE patients had a significantly higher number of IL-10-producing cells compared with both first-degree relatives and healthy controls (P = 0.0005 and P < 0.0001, respectively). First-degree relatives also had a significantly higher number of IL-10-producing cells compared with healthy controls (P = 0.01). This was also true for the spouses of SLE patients, who had a higher number of IL-10-producing cells compared with matched healthy controls (P = 0.02). CONCLUSION SLE patients and their first-degree relatives, as well as a limited number of healthy spouses of SLE patients, had increased numbers of spontaneous IL-10-producing cells. These data support the hypothesis that IL-10 production may be genetically determined, and may predispose one toward development of SLE. This has previously been suggested by studies of SLE patients and their relatives in another ethnic population, using another method for measuring IL-10 production. Although these data are based on a small number of observations, they suggest that not only genetic but also environmental factors may be of importance in determining IL-10 production, since the spouses of SLE patients also had an increased number of IL-10-producing cells.

Mannan-binding lectin and complement C4A in Icelandic multicase families with systemic lupus erythematosus.

Objective: To determine whether low mannan-binding lectin (MBL) and C4A null alleles (C4AQ0) are associated with systemic lupus erythematosus (SLE) in multicase families with SLE. Methods: Low MBL level was determined by measuring serum levels and by genotyping for mutant structural (B/C/D, designated as 0) and promoter (LX) alleles (by real-time polymerase chain reaction). C4AQ0 was detected by protein electrophoresis and corroborated with haplotype and genotype analysis. In nine Icelandic families, 24 patients with SLE were compared with 83 first-degree and 23 second-degree relatives without SLE. Twenty four unrelated family members and a population group of 330 Icelanders served as controls. Results: Overall, the frequency of low MBL genotypes (0/0, LX/0 and wild-type/0) tended to be higher in patients with SLE than in their first-degree and second-degree relatives (p = 0.06), but the frequency was similar in the families and in the controls (p = 0.6). The frequency of C4AQ0 was, however, increased in patients and their relatives compared with that in the controls (p = 0.04). The combination of low MBL genotypes and C4AQ0 was found more often in the patients than in their relatives (p = 0.03) and controls (p = 0.02). However, low MBL level was observed only in patients and first-degree relatives in five of the nine multicase families. In these five families, patients with SLE had low MBL genotypes more often (64%) than their first-degree (38%) and second-degree (0%) relatives (p = 0.001), and the patients with SLE also had, accordingly, lower MBL levels than their relatives (p = 0.001). Conclusions: These findings indicate that low MBL levels can predispose people to SLE and highlight the genetic heterogeneity of this disease.

Impact of different infliximab dose regimens on treatment response and drug survival in 462 patients with psoriatic arthritis: results from the nationwide registries DANBIO and ICEBIO

OBJECTIVE The aim of this study was to describe dose regimens, dose escalation and clinical outcomes in TNF-α inhibitor (TNFi)-naive patients with PsA treated with infliximab in routine rheumatology care. METHODS We conducted an observational cohort study based on the nationwide Danish Rheumatologic Database (DANBIO) and Center for Rheumatology Research (ICEBIO) registries. Stratified by country, characteristics of patients treated with ≤3 mg infliximab/kg body weight, 3-5 mg/kg or ≥5 mg/kg every 8 weeks were described. Outcomes were evaluated by ACR 20%, 50% and 70% (ACR20/50/70) responses and European League Against Rheumatism good response after 6 months, disease activity after 12 months, Kaplan-Meier plots and regression analyses. RESULTS Four hundred and sixty-two patients (376 Danish, 86 Icelandic) received treatment with infliximab. In Danish patients, the starting dose was ≤3 mg/kg in 110 patients (29%), 3-5 mg/kg in 157 (42%), ≥5 mg/kg in 38 (10%) and unregistered in 71 (19%). In Icelandic patients, corresponding numbers were 64 (74%), 17 (27%), 0 (0%) and 5 (6%). Patients with a higher body weight received lower doses per kilogram. Danish patients received higher doses than Icelandic patients at baseline [median 3.1 (interquartile range 3.0-3.8) vs 2.3 (2.1-2.9) mg/kg, P < 0.05] and after 12 months [3.3 (3.0-4.5) vs 2.9 (2.2-3.5) mg/kg, P < 0.0001]. After 12 months, 58% of Danish and 66% of Icelandic patients maintained treatment. Danish patients had shorter drug survival than Icelandic patients (1183 vs 483 days). In univariate analyses stratified by country, time until dose escalation, response rates, drug survival and 1-years disease activity were independent of starting dose. Drug survival was shorter among patients not receiving concomitant MTX. CONCLUSION In clinical practice, > 70% of Icelandic and Danish PsA patients treated with infliximab received sustained doses below the 5 mg/kg every 8 weeks recommended in international guidelines. Lower starting doses did not affect drug survival or response.

Association of three systemic lupus erythematosus susceptibility factors, PD-1.3A, C4AQ0, and low levels of mannan-binding lectin, with autoimmune manifestations in icelandic multicase systemic lupus erythematosus families

OBJECTIVE To study autoimmune diseases and autoantibodies in Icelandic multicase systemic lupus erythematosus (SLE) families and to determine the association of 3 SLE susceptibility factors, PD-1.3A, C4AQ0, and low levels of mannan-binding lectin (MBL), with autoimmune disease in this population. METHODS Eight SLE multicase families were studied, comprising a total of 124 family members (23 patients with SLE and 101 relatives). The diagnosis of an autoimmune disease was established and autoantibodies were measured in each family. In addition, PD-1.3A alleles were genotyped, and C4AQ0 allotypes were established by electrophoresis and haplotype analysis. Low levels of MBL were determined using enzyme-linked immunosorbent assay and variant-allele genotyping. RESULTS In the SLE multicase families there was a high frequency of other autoimmune diseases (32.2%) and a high frequency of autoantibodies (53.2%). Of all family members, 59.7% were determined to have SLE, other autoimmune diseases, antinuclear antibodies, and/or other autoantibodies. The families showed genetic heterogeneity for PD-1.3A, C4AQ0, and low MBL levels; the frequency of each factor ranged from 0% to 85%. The frequencies of PD-1.3A and C4AQ0 were significantly increased in patients with SLE, relatives with other autoimmune diseases, and non-autoimmune disease relatives compared with controls. In the 7 families whose members had low levels of MBL, this factor was significantly associated with SLE, but the frequency of low MBL was decreased in relatives with other autoimmune diseases as compared with non-autoimmune disease relatives and controls. There were indications of an additive effect, and 91% of patients with SLE, 78% of relatives with other autoimmune diseases, and 75% of non-autoimmune disease relatives carried at least 1 of the 3 factors. CONCLUSION These results demonstrate a high frequency of autoimmune diseases and autoantibodies in SLE multicase families. PD-1.3A and C4AQ0 are part of a predisposing genetic background. Other genetic and/or environmental factors are necessary for disease expression, demonstrated by a high frequency of PD-1.3A and C4AQ0 in non-autoimmune disease relatives. Low MBL levels may be one such contributing factor. The results of this study provide an example of epistatic genetic effects and overlapping genetics in autoimmune diseases.

Drug-Induced Autoimmune Hepatitis: Response to Corticosteroids and Lack of Relapse After Cessation of Steroids

Most patients had been prior participants in previous studies. Inclusion criteria were a drug reaction with well-documented cause of DIAIH, with positive antinuclear antibodies and/or smooth muscle antibodies and/ or elevated IgG; 10 times above the upper limit of normal elevation in alanine aminotransferase with a hepatocellular or mixed pattern; or requirement of corticosteroids in patients with hepatocellular type of injury, the latter defined as no improvement in alanine aminotransferase and aspartate aminotransferase after discontinuation of the implicated agent. Roussel Uclaf Causality Assessment Method was used for causality assessment of suspected DILI. The new simplified criteria for autoimmune hepatitis (AIH) were calculated.

Doubling the single-dose infusion rate of tocilizumab in rheumatoid arthritis is safe and efficacious

Objectives: To investigate the impact of enhanced infusion rate of tocilizumab on the occurrence of infusion reactions, overall safety, and efficacy in rheumatoid arthritis (RA). Method: We conducted a 24-week multicentre, open-label, randomized parallel group study comparing adverse event (AE) and effect profiles following tocilizumab IV 8 mg/kg every 4 weeks over 31 min vs. standard 60-min infusions in patients with RA and an inadequate clinical response to disease-modifying anti-rheumatic drugs (DMARDs) and/or tumour necrosis factor (TNF)-α inhibitors. Results: A total of 47 patients were enrolled in the study and randomized to fast infusions (n = 25) and controls (n = 22). Incidences of infusion reactions were similar between the two groups, neither of them leading to withdrawal. Likewise, the incidence of additional AEs did not differ between the treatment arms. Two serious adverse events (SAEs) were reported, in the control group. Four patients withdrew due to AEs, two from each arm. Efficacy at week 24 was comparable between groups. Conclusions: In RA, monthly tocilizumab infusions of 8 mg/kg provided over 31 or 60 min during 24 weeks did not differ concerning safety or efficacy.

Drivers of costly treatment strategies in rheumatoid arthritis

www.thelancet.com Published online May 16, 2016 http://dx.doi.org/10.1016/S0140-6736(16)30548-7 1 Diff erent countries have taken diff erent roadmaps to guide the prescription of expensive drugs. In the UK, a non-departmental public body called the National Institute for Health and Care Excellence; in the Netherlands, a similar public body called the Dutch National Health Care Institute; and in Iceland, a specialised committee recommend when expensive biological drugs will be reimbursed. These committees base their recommendations on the available clinical and economic evidence. In view of the scarcity of evidence on treatment strategies using expensive drugs in rheumatoid arthritis, some friction often occurs between the wish of doctors and the decisions made by offi cial bodies. Ideally, such frictions can be prevented by the availability of evidence. Therefore the eff orts of Porter and colleagues are important. They report that a treatment strategy with an anti-CD20 antibody is non-inferior to the prescription of a tumour necrosis factor (TNF) inhibitor in patients with active rheumatoid arthritis that need biological treatment. Relevant for society is that the treatment strategy that starts with anti-CD20 is cheaper. But how valid is the conclusion of this Article? Porter and colleagues’ study has an open-label design, which means that—although the data on patient characteristics seem to be similar to other studies—huge patient selection has potentially occurred. This potential for bias is emphasised by the fact that despite recruiting for a very common disease (active rheumatoid arthritis) and a very common disease state (not treated with biologicals before), the study needed 35 centres and 4 years to recruit 340 patients, translating to 2–3 patients per centre per year. How relevant such patient selection can be is shown by a randomised controlled trial of methotrexate versus placebo in active psoriatic arthritis, which showed no evidence for methotrexate improving synovitis. This trial also struggled to recruit for a very common disease, active psoriatic arthritis, needing 22 centres and 7 years, making the representativeness of the patients and the relevancy of the results for daily practice questionable. Additionally, information about the baseline characteristics of the patients recruited in the trial was limited (such as the number of previous disease modifying anti-rheumatic drugs), which also makes their representativeness for patients in daily practice diffi cult to assess. In the baseline characteristics, Porter and colleagues state that about 25% of both groups were methotrexate intolerant, which has greater consequences for the patients given TNF inhibitor than for the rituximab group because TNF inhibitors are less eff ective as a monotherapy than in combination with methotrexate whereas data from observational studies suggest that the eff ectiveness of rituximab in addition to methotrexate is not clearly more eff ective than rituximab monotherapy. How relevant is the study by Porter and colleagues for clinical practice? The side-eff ect profi le of rituximab is diff erent from a TNF inhibitor, especially because rituximab is reported to be associated with the very rare but deadly complication of progressive multifocal leukoencephalopathy. As discussed by Porter and colleagues, because of this complication, the European Medicines Agency (EMA) rejected the application to extend the licence of rituximab to patients with rheumatoid arthritis who had not been given biologicals before. Therefore, formally, rituximab as a fi rst option is a non-approved indication. A non-approved indication is legally diff erent from off -label use and what the consequences are for prescribing a drug for which the indication was rejected by the EMA is unclear. Porter and colleagues conclude that starting with rituximab is cost-saving. But the costs are the offi cial UK prices. Offi cial prices are rarely paid. In most countries tender systems exist that lead to totally diff erent prices. Norway’s drug procurement cooperation recently published the Norwegian national hospital tender for biologicals. The tender showed that Orion Pharma proposed in 2015 a 72% price reduction for the infl iximab biosimilar, Remsima, an off er that gives a 69% lower cost than the price off ered by Merck for their originator product, Remicade (infl iximab). These diff erences are magnitudes higher than the calculated £2000 diff erence in the ORBIT study. In our view, the main message for clinical practice of the ORBIT Article is that starting anti-CD20 as a fi rstline biological seems to be as eff ective as starting with a TNF inhibitor in patients with seropositive active rheumatoid arthritis who have given informed consent after being made aware that the EMA rejected this strategy on the basis of safety. Drivers of costly treatment strategies in rheumatoid arthritis

Characterization of a susceptibility locus for SLE, SLEB5, on chromosome 4p14-13.

Systemic lupus erythematosus is a systemic autoimmune disorder of unknown aetiology but is most likely caused by an interaction between several genetic factors and the environment. In a previously published genome scan we presented linkage to a marker on chromosome 4p13 in Icelandic families. Fine mapping of the region has been performed using 10 multicase families from Iceland and the maximum two‐point LOD score was given by marker D4S2974 (Z = 3.57, α = 1). Multipoint analyses of the markers in the region suggest a putative disease gene to be located between markers D4S405 and D4S2381. The maximum multipoint LOD score (Z = 3.76) was given for marker D4S2974 in combination with the novel repeat GT4C2. A family‐specific haplotype was segregating with the disease in each of eight families although a founder haplotype could not be identified. Analysis of recombination events in the patients delimited the susceptibility locus to approximately 3 cM. The susceptibility locus identified probably contains a mutation that has been enriched in the Icelandic population but is less common in other populations. We also show that this region is not identical to a susceptibility locus for SLE located on 4p16 where we detect no linkage.

Biological treatment in ankylosing spondylitis in the Nordic countries during 2010–2016: a collaboration between five biological registries

Objectives: Large-scale observational cohorts may be used to study the effectiveness and rare side effects of biological disease-modifying anti-rheumatic drugs (bDMARDs) in ankylosing spondylitis (AS), but may be hampered by differences in baseline characteristics and disease activity across countries. We aimed to explore the research infrastructure in the five Nordic countries regarding bDMARD treatment in AS. Method: This observational cohort study was based on data from biological registries in Denmark (DANBIO), Sweden (SRQ/ARTIS), Finland (ROB-FIN), Norway (NOR-DMARD), and Iceland (ICEBIO). Data were collected for the years 2010–2016. Registry coverage, registry inventory (patient characteristics, disease activity measures), and national guidelines for bDMARD prescription in AS were described per country. Incident (first line) and prevalent bDMARD use per capita, country, and year were calculated. In AS patients who started first line bDMARDs during 2010–2016 (n = 4392), baseline characteristics and disease activity measures were retrieved. Results: Registry coverage of bDMARD-treated patients ranged from 60% to 95%. All registries included extensive prospectively collected data at patient level. Guidelines regarding choice of first line drug and prescription patterns varied across countries. During the period 2010–2016 prevalent bDMARD use increased (p < 0.001), whereas incident use tended to decrease (p for trend < 0.004), with large national variations (e.g. 2016 incidence: Iceland 10.7/100 000, Finland 1.7/100 000). Baseline characteristics were similar regarding C-reactive protein, but differed for other variables, including the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (range 3.5–6.3) and Ankylosing Spondylitis Disease Activity Score (ASDAS) (2.7–3.8) (both p < 0.0001). Conclusion: Collaboration across the five Nordic biological registries regarding bDMARD use in AS is feasible but national differences in coverage, prescription patterns, and patient characteristics must be taken into account depending on the scientific question.