Gunter Assmann

Progranulin antibodies entertain a proinflammatory environment in a subgroup of patients with psoriatic arthritis

IntroductionPsoriatic arthritis (PsA) is a distinctive inflammatory arthritis which may typically develop in a subgroup of individuals suffering from psoriasis. We recently described progranulin autoantibodies (PGRN-Abs) in the sera of patients with different autoimmune diseases including seronegative polyarthritis. In the present study we investigated the occurrence of PGRN-Abs in PsA.MethodsPGRN-Abs were determined in 260 patients with PsA, 100 patients with psoriasis without arthritic manifestations (PsC) and 97 healthy controls using a recently described ELISA. PGRN plasma levels were determined from subgroups by a commercially available ELISA-kit. Possible functional effects of PGRN-antibodies were analysed in vitro by tumour necrosis factor (TNF)-α mediated cytotoxicity assays using WEHI-S and HT1080 cells.ResultsPGRN-Abs were detected with relevant titres in 50/260 (19.23%) patients with PsA, but in 0/100 patients with psoriasis without arthritic manifestations (P = 0.0001). All PGRN-Abs belonged to immunoglobulin G (IgG). PGRN-Abs were significantly more frequent in PsA patients with enthesitis or dactylitis. PGRN-Abs were also more frequent in PsA patients receiving treatment with TNF-α-blockers than in patients treated without TNF-α-blockers (20.8% versus 17.4%; P = 0.016). PGRN plasma levels were significantly lower in PGRN-Ab-positive patients with PsA than in healthy controls and patients with psoriasis without arthritic manifestations (P < 0.001), indicating a neutralizing effect of PGRN-Abs. Moreover cytotoxicity assays comparing PGRN-antibody positive with negative sera from matched patients with PsA, clearly showed a proinflammatory effect of PGRN antibodies.ConclusionNeutralizing PGRN-Abs occur with relevant titres in a subgroup of patients with PsA, but not in patients without arthritic manifestations (PsC). PGRN-Ab-positive patients had more frequent enthesitis or dactylitis. TNF-α-induced cytotoxicity assays demonstrated that the protective effects of progranulin were inhibited by serum containing PGRN-Abs. This suggests that PGRN-Ab might not only be useful as a diagnostic and prognostic marker, but may provide a proinflammatory environment in a subgroup of patients with PsA.

Genetic variations in genes encoding RANK, RANKL, and OPG in rheumatoid arthritis: a case-control study.

Objective. Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the joints, which may lead to structural damage of the cartilage and bone. The receptor activator of nuclear factor-κB (RANK) and the osteoprotegerin (OPG) cascade system have been reported to be essential in osteoclastogenesis. Genetic variations in the genes coding for RANK, RANK ligand (RANKL), and OPG are thought to play roles in the susceptibility to RA. Methods. In our case-control study, genomic DNA was obtained from 534 patients with RA who fulfilled the American College of Rheumatology 1987 criteria and 516 healthy control blood donors (HC). We studied 7 single-nucleotide polymorphisms (SNP) in the genes of RANK (2 SNP: rs1805034, rs35211496), OPG (2 SNP: rs3102735, rs2073618), and RANKL (3 SNP: rs9533156, rs2277438, rs1054016) using TaqMan assay-guided polymerase chain reaction. Genotype and allelic frequencies comparing RA patients with HC were analyzed by chi-square test for 2 × 3 and 2 × 2 tables, respectively. Results. Genotype distributions of the SNP rs35211496 in the RANK gene as well as the SNP rs2277438 in the RANKL gene differed significantly between patients with RA and HC. The frequency of the minor allele of rs9533156 of RANKL was significantly higher in patients with RA than in HC (OR 0.84, 95% CI 0.71–0.99, p = 0.047). Multivariate analysis adjusted to sex and investigating SNP demonstrated a significantly elevated risk for RA associated with the major allele in the RANK SNP rs35211496 (p = 0.0231) and with the minor allele in the RANKL SNP rs2277438 (p = 0.0092). No significantly increased risk was detected in the other SNP. Conclusion. The minor allele of the RANK SNP rs35211496 may be protective against RA, while the minor alleles of the RANKL SNP rs2277438 may increase susceptibility to RA.

Intra-Articular Glucocorticosteroid Injection into Sternocostoclavicular Joints in Patients with SAPHO Syndrome

OBJECTIVE Painful swelling of the anterior chest wall caused by osteitis and hyperostosis in the sternocostoclavicular region are characteristically observed in patients suffering from SAPHO syndrome. Autoimmune triggering of inflammation and bacterial infection is hypothesized to be involved in the pathogenesis. Promising treatment modalities include antirheumatic and antibiotic medications. METHODS Ten patients with SAPHO syndrome and symptomatic osteitis in the sternocostoclavicular region were treated by a single instillation of glucocorticosteroids (20 mg triamcinolone) into the sternocostoclavicular joints. The disease activity was evaluated on the basis of a questionnaire asking for osteitis activity (quantified for complains on a scale of 0-6), by Health Assessment Questionnaire (HAQ) score, erythrocyte sedimentation rate, C-reactive protein, and magnet resonance imaging (MRI) scanning of the sternocostoclavicular region (osteitis scores quantified for inflammation on a scale of 0-2 by the radiologist) prior to injection and after 12 weeks. No changes of the preexisting antirheumatic therapy were allowed during the observation interval. RESULTS All patients continued the study during the follow-up. The osteitis score changed from 4.2 (mean; standard error (SE) ±0.3) to 3.2 (±0.4), [P = 0.062], the erythrocyte sedimentation rate from 19.0 (range from 12 to 30) to 19.9 (from 12 to 27), [P = 0.430], and the MRI score from 1.6 (±0.2) to 1.5 (±0.2) [P = 1.0]. One patient developed an increase of the clinical osteitis activity from 3 to 5 according the scoring system; only 2 patients showed a reduction of the MRI activity score from 2 to 1. CONCLUSIONS Intra-articular glucocorticosteroid instillation does not appear to reduce osteitis in the sternocostoclavicular region in patients with SAPHO syndrome.

Contrasting association of a non-synonymous leptin receptor gene polymorphism with Wegener’s granulomatosis and Churg–Strauss syndrome

OBJECTIVE There is evidence that the leptin/ghrelin system is involved in T-cell regulation and plays a role in (auto)immune disorders such as SLE, RA and ANCA-associated vasculitides (AAVs). Here, we evaluate the genetic background of this system in WG. METHODS We screened variations in the genes encoding leptin, ghrelin and their receptors, the leptin receptor (LEPR) and the growth hormone secretagogue receptor (GHSR). Three single nucleotide polymorphisms (SNPs) in each gene region were analysed in 460 German WG cases and 878 ethnically matched healthy controls. RESULTS A three-SNP haplotype of GHSR was significantly associated with WG [P = 0.0067; corrected P-value (P(c)) = 0.026; odds ratio (OR) = 1.30; 95% CI 1.08, 1.57], as was one non-synonymous SNP in LEPR (Lys656Asn, P = 0.0034; P(c) = 0.013; OR = 0.72; 95% CI 0.58, 0.90). These four SNPs were re-analysed in independent cohorts of 226 German WG cases and 519 controls. While the GHSR association was not confirmed, allele frequencies of the LEPR SNP were virtually identical to those from the initial cohorts. Analysis of this SNP in the combined WG and control panels revealed a significant association of the LEPR 656Lys allele with WG (P = 0.00032; P(c) = 0.0013; OR = 0.72; 95% CI 0.60, 0.86). Remarkably, the Lys656Asn SNP showed contrasting allele distribution in two cohorts of 108 and 88 German cases diagnosed with Churg-Strauss syndrome (CSS, combined P = 0.0067; OR = 1.41; 95% CI 1.10, 1.81), whereas identical allele frequencies were revealed when comparing British WG and microscopic polyangiitis cases. CONCLUSIONS While GHSR has to be further evaluated, these data provide profound evidence for an association of the LEPR Lys656Asn SNP with AAV, resulting in opposing effects in WG and CSS.

Genetic polymorphism of the OPG gene associated with breast cancer

BackgroundThe receptor activator of NF-κB (RANK), its ligand (RANKL) and osteoprotegerin (OPG) have been reported to play a role in the pathophysiological bone turnover and in the pathogenesis of breast cancer. Based on this we investigated the role of single nucleotide polymorphisms (SNPs) within RANK, RANKL and OPG and their possible association to breast cancer risk.MethodsGenomic DNA was obtained from Caucasian participants consisting of 307 female breast cancer patients and 396 gender-matched healthy controls. We studied seven SNPs in the genes of OPG (rs3102735, rs2073618), RANK (rs1805034, rs35211496) and RANKL (rs9533156, rs2277438, rs1054016) using TaqMan genotyping assays. Statistical analyses were performed using the χ2-tests for 2 x 2 and 2 x 3 tables.ResultsThe allelic frequencies (OR: 1.508 CI: 1.127-2.018, p=0.006) and the genotype distribution (p=0.019) of the OPG SNP rs3102735 differed significantly between breast cancer patients and healthy controls. The minor allele C and the corresponding homo- and heterozygous genotypes are more common in breast cancer patients (minor allele C: 18.4% vs. 13.0%; genotype CC: 3.3% vs. 1.3%; genotype CT: 30.3% vs. 23.5%). No significantly changed risk was detected in the other investigated SNPs. Additional analysis showed significant differences when comparing patients with invasive vs. non-invasive tumors (OPG rs2073618) as well as in terms of tumor localization (RANK rs35211496) and body mass index (RANKL rs9533156 and rs1054016).ConclusionsThis is the first study reporting a significant association of the SNP rs3102735 (OPG) with the susceptibility to develop breast cancer in the Caucasian population.

Prevalence of anti-citrullinated protein antibodies (ACPA) in patients with diffuse large B-cell lymphoma (DLBCL): a case-control study.

Background Antibodies against citrullinated proteins (ACPA) have been recognised as the most specific serum marker for rheumatoid arthritis. However, serum autoantibodies such as anti-nuclear antibodies have also been detected in the sera of different lymphatic malignancies without accompanying rheumatologic disease. Therefore, we conducted a study to evaluate the prevalence of ACPA in diffuse large B-cell non-Hodgkin lymphoma (DLBCL). Methods Sera of 395 DLBCL patients and 258 age-matched healthy controls were investigated to evaluate the prevalence of ACPA and RF. ACPA-positive data were stratified into subgroups of RF positivity and established prognostic parameters for DLBCL, including overall survival. In addition, the ACPA serum concentrations levels were compared to an ACPA-positive RA cohort (n = 175). The statistics were performed with χ2 test and Mann- Whitney-U test; Kaplan-Meyer curves (log rank test) were used to analyse the overall survival. P-value <0.05 was statistically significant. Results ACPA, but not RF, occurred significantly more frequently in the sera of DLBCL patients than in healthy controls (3.5% versus 0.8%, p = 0.030). However, the ACPA serum concentration levels were significantly lower than in RA patients (median 10.4 versus 124.1 U/ml, p = 0.0001). After subgroup stratification, ACPA positivity in DLBCL was significantly associated with male gender (4.4% versus 0%, p = 0.022; odds ratio 1.046, CI 1.014–1.079) and with RF-IgM seropositivity (1.77% versus 0%, p = 0.043), but not with prognostic parameters for DLBCL. Conclusions DLBCL is associated with a significantly higher prevalence of ACPA, with an increased prevalence in male patients, and simultaneous RF-IgM positivity. However, ACPA is not prognostic for DLBCL. The prevalence of RF-IgM, -IgA, or -IgG did not differ from healthy controls.

Genetic variations in the genes encoding receptor activator nuclear factor κ B (RANK), receptor activator nuclear factor κ B ligand (RANKL) and osteoprotegerin (OPG) in patients with psoriasis and psoriatic arthritis: A case–control study

Psoriasis (Ps) and psoriatic arthritis (PsA) are diseases of unknown origin. However, the receptor activator nuclear factor κ B ligand (RANKL) might play a key role in the pathomechanisms of the disease. Our aim was to study seven single nucleotide polymorphisms (SNP) in the genes encoding for receptor activator nuclear factor κ B (RANK, two SNP), osteoprotegerin (OPG, two SNP) and RANKL (three SNP in patients with Ps and PsA). A case–control study with 156 Ps patients (45 with PsA) and 516 healthy blood donors was conducted to evaluate an association of the SNP with Ps and PsA by genotyping of DNA by polymerase chain reaction. None of the seven SNP showed any differences in the allelic or genotype frequencies between Ps patients and controls. Our study showed no significant association between the SNP in the genes encoding for RANK, OPG and RANKL with susceptibility of disease in Ps and PsA patients.