Negative association of the chemokine receptor CCR5 d32 polymorphism with systemic inflammatory response, extra-articular symptoms and joint erosion in rheumatoid arthritis

Introduction Chemokines and their receptors control immune cell migration during infections as well as in autoimmune responses. A 32 bp deletion in the gene of the chemokine receptor CCR5 confers protection against HIV infection, but has also been reported to decrease susceptibility to rheumatoid arthritis (RA). The influence of this deletion variant on the clinical course of this autoimmune disease was investigated. Methods Genotyping for CCR5d32 was performed by PCR and subsequent electrophoretic fragment length determination. For the clinical analysis, the following extra-articular manifestations of RA were documented by the rheumatologist following the patient: presence of rheumatoid nodules, major organ vasculitis, pulmonary fibrosis, serositis or a Raynaud's syndrome. All documented CRP levels were analyzed retrospectively, and the last available hand and feet radiographs were analyzed with regards to the presence or absence of erosive disease. Results Analysis of the CCR5 polymorphism in 503 RA patients and in 459 age-matched healthy controls revealed a significantly decreased disease susceptibility for carriers of the CCR5d32 deletion (Odds ratio 0.67, P = 0.0437). Within the RA patient cohort, CCR5d32 was significantly less frequent in patients with extra-articular manifestations compared with those with limited, articular disease (13.2% versus 22.8%, P = 0.0374). In addition, the deletion was associated with significantly lower average CRP levels over time (median 8.85 vs. median 14.1, P = 0.0041) and had a protective effect against the development of erosive disease (OR = 0.40, P = 0.0047). Intriguingly, homozygosity for the RA associated DNASE2 -1066 G allele had an additive effect on the disease susceptibility conferred by the wt allele of CCR5 (OR = 2.24, P = 0.0051 for carrier of both RA associated alleles) Conclusions The presence of CCR5d32 significantly influenced disease susceptibility to and clinical course of RA in a German study population. The protective effect of this deletion, which has been described to lead to a decreased receptor expression in heterozygous patients, underlines the importance of chemokines in the pathogenesis of RA

Generalised musculoskeletal problems

The last decades have witnessed enormous progress in understanding the pathogenic mechanisms of rheumatic diseases. Based on these findings new paradigms in the treatment of many rheumatic diseases could be established leading to an improvement in the outcome of rheumatic diseases that was not conceivable at the end of the last century. However, in recent years many studies revealed a gap between the perceived (and measured) disease activity and various other parameters best summarized as patient reported outcomes (PRO). The PRO such as pain, fatigue, sleep quality and quality of life are getting more attention since regulatory agencies, e.g. FDA as well as EMA, require PRO to be included in clinical studies for approval of new treatments

Praxisorientiert auf Erfolgskurs: problemorientiertes Lernen in der Leipziger Medizin

Mit Inkrafttreten der neuen Approbationsordnung für Ärzte hat die Medizinische Fakultät der Universität Leipzig zum Wintersemester 2003/04 ihr Curriculum umgestellt. Der Studiengang wurde komplett neu konzipiert und es wurden erstmalig für Leipzig auch 3 Kurse mit problemorientiertem Lernen (POL) eingeführt

Humoral Immunity to Varicella Zoster Virus in Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis Compared to Healthy Controls

Background: The prevalence of herpes zoster (HZ) is high in patients with rheumatic diseases. Systemic lupus erythematosus (SLE) doubles the risk for developing HZ. However, little is known about natural humoral immunity against varicella zoster virus (VZV) in patients with SLE. Hence, we compared VZV IgG antibody concentrations in a group of SLE patients with healthy controls and patients with rheumatoid arthritis (RA). Methods: n = 56 patients with SLE, n = 54 patients with RA, and n = 56 healthy controls were included in this study. The VZV IgG antibody concentration was measured using an enzyme-linked immunosorbent assay (ELISA). The antibody concentrations were compared between the groups. Results: Overall IgG antibody titers for VZV in SLE patients were comparable to healthy controls but higher when compared to patients with rheumatoid arthritis (p = 0.0012). In consequence, antibody levels in controls were higher than in RA patients (p = 0.0097). Stratification by age revealed highest titers among SLE patients in the fourth life decade (p = 0.03 for controls, p = 0.0008 for RA patients) whereas RA patients in their sixth decade had the lowest antibody concentration (p = 0.03 for controls, p = 0.04 for SLE patients). Regarding the individual HZ history, antibody levels of SLE patients with a positive history exceeded all other groups. Conclusions: Although humoral VZV immunity in SLE patients is comparable to healthy controls it seems to be pronounced in young SLE patients between 30 and 39. The lowest VZV IgG levels were found in RA patients. HZ seems to induce antibody production, particularly in patients with SLE. Immunological processes might contribute to VZV antibody levels in SLE patients, but further investigations are needed to substantiate this hypothesis. Even though the increased HZ prevalence seems to be independent of humoral immunity in SLE patients, reduced humoral immunity might contribute to HZ in RA patients. The available HZ subunit vaccination might be an appropriate way to reduce the HZ risk in patients with rheumatic diseases

IL-10 Induced by mTNF Crosslinking-Mediated Reverse Signaling in a Whole Blood Assay Is Predictive of Response to TNFi Therapy in Rheumatoid Arthritis

(1) Background: To date, the response of patients with rheumatoid arthritis (RA) to the various biologic DMARD available cannot be predicted due to a lack of reliable biomarkers. Based on our preliminary work on tmTNF reverse signaling, we developed a whole-blood assay measuring tmTNF crosslinking-induced IL-10 production to predict the response to TNF inhibitor (TNFi) therapy. (2) Methods: This prospective study included patients with active RA. Depending on the clinical judgment of the attending rheumatologist, either therapy with a TNF or JAK inhibitor was initiated. Clinical parameters and blood samples were obtained at baseline and after 8 weeks of therapy. The blood samples were collected using a newly developed whole-blood assay based on the principle of tmTNF reverse signalling. Subsequently, IL-10 was measured via enzyme-linked immunosorbent assay (ELISA) technique. (3) Results: 63 patients with RA were enrolled. In fifteen patients, TNFi therapy was initiated, while eight patients started a JAKi treatment. The cross-sectional analysis of all patients showed a positive correlation between tmTNF crosslinking-induced IL-10 and parameters of disease activity (CRP [r = 0.4091, p = 0.0009], DAS28 [r = 0.3303, p = 0.0082]) at baseline. In the TNFi treatment study, IL-10 was found to be significantly higher in EULAR responders than in non-responders (p = 0.0033). After initiation of JAKi treatment, in contrast, IL-10 induction was not linked to response. Longitudinal analysis of the TNFi-treated patients revealed IL-10 to decrease in responders (p = 0.04), but not in non-responders after 8 weeks of therapy. Of importance, the IL-10 production at baseline correlated inversely with TNFi response determined by DDAS28 in patients with TNFi treatment (r = 0.5299, p = 0.0422) while no such link was observed under JAKi therapy (p = 0.22). Receiver operation characteristics (ROC) analysis demonstrated a high performance of tmTNF/crosslinking-induced IL-10 in predicting a TNFi therapy response according to the EULAR criteria (AUC = 0.9286, 95% Confidence interval 0.7825–1.000, p = 0.0055). (4) Conclusions: In this pilot investigation, we demonstrated the feasibility of a whole-blood assay measuring tmTNFinduced IL-10 to predict clinical response to TNF inhibitor treatment. This approach might support rheumatologists in their decision for an individually tailored RA therapy

Association of PTPN22 1858 single-nucleotide polymorphism with rheumatoid arthritis in a German cohort: higher frequency of the risk allele in male compared to female patients

The functional single-nucleotide polymorphism (SNP) of the gene PTPN22 is a susceptibility locus for rheumatoid arthritis (RA). The study presented here describes the association of the PTPN22 1858T allele with RA in a German patient cohort; 390 patients with RA and 349 controls were enrolled in the study. For 123 patients, clinical and radiographic documentation over 6 years was available from the onset of disease. Genotyping of the PTPN22 1858 SNP was performed using an restriction fragment length polymorphism PCR-based genotyping assay. The odds ratio to develop RA was 2.57 for carriers of the PTPN22 1858T allele (95% confidence interval (CI) 1.85–3.58, p < 0.001), and 5.58 for homozygotes (95% CI 1.85–16.79). The PTPN22 1858T allele was significantly associated not only with rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) positive RA, but also with RF and anti-CCP negative disease. The frequency of the PTPN22 1858T allele was increased disproportionately in male patients (53.8% compared to 33.0% in female patients, p < 0.001), and the resulting odds ratio for male carriers was increased to 4.47 (95% CI 2.5–8.0, p < 0.001). Moreover, within the male patient population, the rare allele was significantly associated with the HLA-DRB1 shared epitope (p = 0.01). No significant differences in disease activity or Larsen scores were detected. The results provide further evidence that the PTPN22 1858T allele is associated with RA irrespective of autoantibody production. The increased frequency of the risk allele in male patients and its association with the shared epitope indicate that the genetic contribution to disease pathogenesis might be more prominent in men

Dualitatea relaţiei dintre osteoartroza genunchiului şi maladiile cardiovasculare

Osteoartroza și bolile cardiovasculare (BCV) sunt două condiții patologii predominante în populația în vârstă de peste 70 de ani. Datele de literatură prezintă rezultate controversate cu privire la interrelația dintre osteoartroza și maladiile cardiovasculare, evidențiindu-se o serie de factori de risc comuni (așa ca obezitatea, sedentarismul etc.), precum și verigi patogenetice intercalate. Osteoartroza și BCV se asociază la un număr mare de pacienți din multe motive: factori de risc comuni (îmbătrânirea și obezitatea), etiologia comună (de exemplu, inflamația cronică) și indirect, prin pierderea funcționalității articulare și dizabilitate, precum și utilizarea de analgezice care conduc la creșterea riscului cardiovascular. Complexitatea interacțiunilor dintre aceste patologii rămâne incomplet elucidată și necesită cercetări suplimentare

Двойственность отношений между артрозом коленного сустава и сердечно-сосудистыми забо- леваниями

IP USMF ,,Nicolae Testemițanu”, Medizin Leipzig University, Faculty of MedicineRezumat Osteoartroza și bolile cardiovasculare (BCV) sunt două condiții patologii predominante în populația în vârstă de peste 70 de ani. Datele de literatură prezintă rezultate controversate cu privire la interrelația dintre osteoartroza și maladiile cardiovasculare, evidențiindu-se o serie de factori de risc comuni (așa ca obezitatea, sedentarismul etc.), precum și verigi patogenetice intercalate. Osteoartroza și BCV se asociază la un număr mare de pacienți din multe motive: factori de risc comuni (îmbătrânirea și obezitatea), etiologia comună (de exemplu, inflamația cronică) și indirect, prin pierderea funcționalității articulare și dizabilitate, precum și utilizarea de analgezice care conduc la creșterea riscului cardiovascular. Complexitatea interacțiunilor dintre aceste patologii rămâne incomplet elucidată și necesită cercetări suplimentare.Остеоартроз и сердечнососудистые заболевания являются два из самых распространенных патологий среди населения в возрасте старше 70 лет. Данные литературы показывают противоречивые результаты, касающиеся взаимосвязи между остеоартрозом и сердечнососудистыми заболеваниями, выделив ряд общих факторов риска (таких как ожирение, отсутствие физической активности и т.д.) и общие патогенические звенья. Остеоартроз и сердечнососудистые заболевания ассоциируются у большинства пациентов, по многим причинам: факторы риска (старение и ожирение) общая этиология (например, хроническое воспаление), как и утерянная физическая функция и инвалидность, а также использование обезболивающих, что приводит к увеличению сердечнососудистого риска. Сложность взаимодействий между этими патологиями остается не полностью изученной и требует дальнейших исследований.Osteoarthritis and cardiovascular diseases (CVD) are the two most prevalent conditions in the population aged over 70. Literature data show controversial results regarding the interrelationship between osteoarthritis and cardiovascular diseases, highlighting a number of common risk factors (such as obesity, physical inactivity etc.) and pathogenesis links interposed. Osteoarthritis and CVD are associated to a large number of patients for many reasons: risk factors (aging and obesity), common etiology (eg, chronic inflammation) and indirectly through loss of physical function and disability, and the use of analgesic medication leading to increased cardiovascular risk. The complexity of the interactions between these diseases remains incompletely elucidated and requires further research