Johannes Nossent

Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci

Ankylosing spondylitis is a common, highly heritable inflammatory arthritis affecting primarily the spine and pelvis. In addition to HLA-B*27 alleles, 12 loci have previously been identified that are associated with ankylosing spondylitis in populations of European ancestry, and 2 associated loci have been identified in Asians. In this study, we used the Illumina Immunochip microarray to perform a case-control association study involving 10,619 individuals with ankylosing spondylitis (cases) and 15,145 controls. We identified 13 new risk loci and 12 additional ankylosing spondylitis–associated haplotypes at 11 loci. Two ankylosing spondylitis–associated regions have now been identified encoding four aminopeptidases that are involved in peptide processing before major histocompatibility complex (MHC) class I presentation. Protective variants at two of these loci are associated both with reduced aminopeptidase function and with MHC class I cell surface expression.

Disease activity and damage accrual during the early disease course in a multinational inception cohort of patients with systemic lupus erythematosus

An inception cohort of patients with systemic lupus erythematosus from 14 European centres was followed for up to 5 years in order to describe the current early disease course. At inclusion patients (n = 200, 89% female, mean age 35 years, 97% Caucasian, mean SLEDAI 12.2) fulfilled a mean of 6.5 ACR classification criteria. The most prevalent criteria were antinuclear Ab presence (97%) followed by anti-dsDNA Ab (74%), arthritis (69%), leukocytopenia (54%) and malar rash (53%), antiphospholipid Ab (48%) and anti-synovial membrane Ab (21.6%). Clinical signs of lupus nephritis (LN) were present in 39% with biopsy-confirmed LN seen in 25%. Frequent additional findings were hypocomplementaemia (54%), anti-SSA Ab (49%), alopecia (26%) and Raynaud’s phenomenon (31%). There were few regional differences in disease presentation and management. One and 5-year survival rates were 99% and 97% respectively. During the mean follow-up of 4.1 years 25% entered a state of early disease quiescence by global physician assessment, but the overall risk of subsequent flare was 60%. Maximum SLEDAI scores decreased over time, but 45% of patients accrued damage (SDI ≥1) for which baseline presence of proteinuria and persistent disease activity were independent predictors. The results indicate minor differences in SLE presentation and treatment within various regions of Europe and a high diagnostic reliance on anti-dsDNA Ab. Despite early reductions in disease activity and improved mortality, the risk for disease flare and damage development is, however, still substantial, especially in patients not entering an early remission.

Anti-dsDNA antibodies and disease classification in antinuclear antibody positive patients: the role of analytical diversity

Background: The presence of “anti-DNA antibodies in abnormal titres” is a well established criterion for SLE classification, but there is no agreement on the performance of this test. Objective: To study the correlation between clinical findings and five different solid and solution phase anti-DNA antibody assays. Methods: 158 consecutively collected ANA positive sera were studied in a double blind fashion. Anti-DNA antibodies were determined by different solid phase assays (ssDNA-, dsDNA- specific ELISA, EliA anti-dsDNA assay, Crithidia luciliae assay), and by an experimental solution phase anti-DNA assay using biotinylated pUC18 plasmid, human, calf thymus, and E coli DNA. Antibody affinity was determined by surface plasmon resonance. Clinical data were obtained independently of the laboratory analyses and later related to the anti-dsDNA findings. Results: Anti-dsDNA antibodies were most frequently detected by ELISA, but were not specific for SLE as they were present in up to 30% of other disease groups. Those detected by the Crithidia luciliae assay were predictive for SLE, while antibodies binding in solution phase ELISA using the pUC18 correlated strongly with the Crithidia luciliae assay. Surface plasmon resonance analysis showed that antibody binding to pUC18 was not due to higher relative affinity for dsDNA in general, but apparently to specificity for that plasmid DNA. Serum samples from three patients with lupus nephritis were positive in both pUC18 solution phase and Crithidia luciliae assays. Conclusions: Assay principle selection is decisive for the detection of clinically significant anti-DNA antibodies. Revision of the anti-DNA antibody criterion in the SLE classification may be needed.

Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1.

Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype.

Systemic lupus erythematosus. II. Observations on the occurrence of exacerbations in the disease course: Dutch experience with 110 patients studied prospectively

The incidence of exacerbations in the disease course was investigated in 110 patients with systemic lupus erythematosus (SLE) who were studied prospectively at our institute for lupus research. At the time of disease onset and diagnosis the male patients were much older than the female patients (about 10 years); exacerbation frequency during follow up was increased in the male patients. The follow up data showed that if a patient with SLE was prone to develop an exacerbation this mostly took place within the first five years of follow up. It could be calculated that after fulfilling the American Rheumatism Association criteria only 56% (62/110) of the patients developed a subsequent exacerbation. Features at the time of diagnosis, distinguishing those patients who developed a subsequent exacerbation from those who did not, were haemolytic anaemia, the presence of anti-Sm antibodies, and a falsely positive serological test for syphilis. At the time of diagnosis, however, the prevalences of these features were low; for haemolytic anaemia, anti-Sm antibodies, and a falsely positive serological test for syphilis they amounted to 40%, 5%, and 12% respectively.

Levels of Transforming Growth Factor-β Are Low in Systemic Lupus Erythematosus Patients with Active Disease

Objective. Cytokines are central regulators of the immune response but the workings of this complex network in systemic lupus erythematosus (SLE) are not fully understood. We investigated a range of inflammatory and immune-modulating cytokines to determine their value as biomarkers for disease subsets in SLE. Methods. This was a cross-sectional study in 102 patients with SLE (87% women, disease duration 10.6 yrs). Circulating concentrations of interleukin 1β (IL-1β), IL-4, IL-6, IL-10, IL-12, IL-17, monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1 (MIP-1α), MIP-1β, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and total transforming growth factor-β1 (TGF-β1) were related to disease activity (SLE Disease Activity Index; SLEDAI), lymphocyte subsets, autoantibody levels, accrued damage (Systemic Lupus International Collaborating Clinics/ACR Damage Index; SDI), and concomitant treatment. Results. Patients with SLE had lower levels of TGF-β1 (p = 0.01) and IL-1β (p = 0.0004) compared to controls. TGF-β1 levels were lower in patients with SLEDAI scores 1–10 and SDI > 3; and were correlated with CD4+, CD8+, and natural killer cell counts; and were independent of steroid or cytotoxic drug use. Treatment with cardiovascular drugs was associated with lower IL-12 levels. No consistent disease associations existed for the other cytokines investigated. Conclusion. Lower TGF-β1 was the most consistent cytokine abnormality in patients with SLE. The associations with disease activity, lymphocyte subsets, and damage suggest that TGF-β1 may be a therapeutic target of interest in SLE.

Epidemiological and clinical characteristics of psoriatic arthritis in northern Norway

Background: To determine the characteristics of psoriatic arthritis (PsA) in northern Norway, where the human leucocyte antigen HLA‐B27 is prevalent. Methods: An observational study of patients with ICD‐9 CR codes for psoriatic arthropathy (696.0 and 713.3) and spondylarthritis (720) seen during a 19‐year period at a single regional rheumatology department. In patients with confirmed PsA demographics, date of onset of arthritis and psoriasis, clinical presentation and subsequent disease course (including therapeutic measures) were recorded during a mean follow‐up of 11.1 years. Results: Arthritis was documented in 329/657 (50%) of patients with a diagnostic code for PsA. The mean annual incidence rate for PsA was 6.9/100 000 and the point prevalence was 130/100 000 (0.13%) adults. The male to female ratio was 1.4 and the mean age at onset of psoriasis was 27.8 years (SD 14.1), and 35 years (SD 11.8) at onset of arthritis. Arthritis preceded psoriasis in 13.8% of cases. Oligoarthritis was the most frequent subtype (48%), followed by polyarthritis (32%), spondylitis (9%), monoarthritis (7%), and classic distal interphalangeal (DIP) arthritis (2%). Erosive disease (56% of cases) occurred mainly with polyarthritis; arthritis mutilans occurred in six patients (2%). Surgical interventions were performed in 22% of patients. Disease activity fluctuated considerably over time. Mortality (4.3%) was increased in PsA patients with polyarthritis and secondary amyloidosis (n = 5). Conclusion: The prevalence of PsA and related spondylitis is not increased in northern Norway. PsA does, however, lead to a considerable burden of disease due to erosive disease development and surgical intervention.

SYSTEMIC LUPUS ERYTHEMATOSUS VII : FREQUENCY AND IMPACT OF SECONDARY SJOGREN'S SYNDROME

Background: The prognosis of patients with systemic lupus erythematosus (SLE) largely depends on the severity of cumulative organ damage during the course of the disease. While Sjùgrens syndrome (SS) predominantly affects exocrine glands, a considerable number of patients develop visceral organ damage. Thus, the occurrence of a secondary SS (2°SS) in SLE patients, may result in more extensive organ damage and thereby adversely affect prognosis. Patients/Methods: 138 patients meeting the 1982 American College of Rheumatology (ACR) classification criteria for SLE were prospectively studied over a mean period of ninety months. 2°SS was diagnosed according to the 1993 European Study Group criteria and complication rates and prognosis were compared between patients with and without SS. Results: 27 patients (19%) developed SS after a mean period of 48 months. There was a gradual increase in SS prevalence over time after SLE-onset. 2°SS patients were older (mean age 41 vs 35 years, P = 0.03), had less renal disease (19% vs 38%, P = 0.04), more thrombocytopenia (26% vs 9%, P = 0.05) and similar serological profiles (including anti-SSa) as patients without SS. Overall mortality was lower in patients with SS (4% vs 13.5%, P = 0.01), while lifetable analysis showed improved survival estimates for 2°SS patients with borderline statistical significance (P = 0.06). Conclusions:2SS develops in about one-fifth of SLE patients in a time-dependent fashion: these patients are older, have less renal involvement and their prognosis is at least as good as for those remaining free of SS.

Systemic lupus erythematosus. III. Observations on clinical renal involvement and follow up of renal function: Dutch experience with 110 patients studied prospectively.

A prospective study of 110 patients with systemic lupus erythematosus (SLE) was undertaken to evaluate the reliability of clinical signs of lupus nephritis, which developed in 39 (35%) patients. Those patients with SLE who showed no clinical signs of lupus nephritis had an excellent survival rate (10 year survival 93%) and retained normal renal function (serum creatinine less than 130 mumols/l); clinical lupus nephritis developed mainly in the first three years after diagnosis of SLE and was associated with a decreased survival rate (10 year survival 62%). Increased mortality was found in male patients with lupus nephritis over 25 years of age and in female patients with lupus nephritis under 25 years of age, while renal failure rates did not differ between these groups. Treatment of lupus nephritis with high dose prednisone alone or in combination with immunosuppressants did not result in differences in patient survival or renal function preservation. It was concluded that clinical variables are a reliable guide in the management of patients with SLE, and routine use of renal biopsy in these patients is rejected.

Prevalence, predictors and outcome of vascular damage in systemic lupus erythematosus.

Despite improved prognosis, patients with systemic lupus erythematosus (SLE) remain at increased risk for early death. Vascular events (VE) occur with increased frequency and contribute to premature death in SLE patients. As conventional cardiovascular risk factors do not fully explain this hazard, this study investigated the contribution of disease-specific features to VE development. Documented VE were classified as atherothrombotic, venous thrombotic, arterial thrombotic or tissue loss inducing vasculitis during a mean follow-up of nearly 12 years in the Tromsø Lupus cohort (n = 158). The impact of disease-specific factors (organ manifestations, laboratory findings, drug treatment, weighted average SLE Disease Activity Index (WAS) and cumulative Damage Index) was assessed by odds ratios for VE in multivariate analysis. A total of 41 patients (26%) developed VE, and atherothrombotic events were most common (73%). Overall, VE prevalence was 3.5/100 patient years, and VE risk increased linearly over time, reaching 35% after 20 years. WAS scores >3 increased, and use of hydroxychloroquine and antihypertensive medication reduced overall VE risk. Age >40 years was the main risk factor for atherothrombotic events. VE nearly quadrupled the risk of death. VE occurred in 26% of SLE patients, predominantly as atherothrombotic disease. VE prevalence increased linearly over time leading to a four-fold risk of mortality. Strategies for reducing disease activity, including treatment with antimalarials and antihypertensive drugs, are most likely to reduce the risk associated with VE in SLE.