The KRN mouse model of inflammatory arthritis

Abstract.: In 1996 a new murine model of spontaneous arthritis was described by the group of Benoist and Mathis. Mice transgenic for a T cell receptor recognizing an epitope of bovine RNase and bred onto a NOD background developed severe destructive arthritis, which resembles human rheumatoid arthritis in many respects. The development of disease requires the presence of T and B lymphocytes and is dependent on the MHC class II molecule I-Ag7. B cell activation by antigen and an additional CD40-CD40 ligand interaction was found to give rise to the production of autoantibodies. Glucose-6-phosphate isomerase was identified as the target of the autoantibodies; moreover, the transgenic T cells were demonstrated to exhibit a dual specificity for both bovine RNase and glucose-6-phosphate isomerase. Importantly, the arthritis is serum transferable to normal recipients, enabling the examination of the pathogenic mechanisms of joint inflammation and destruction. Recent studies suggest the crucial involvement of the innate immune system in the development of antibody-induced arthritis. Complement components, Fc receptors and neutrophils are indispensable for disease induction. An overview of the existing data is given and the emerging concepts of the pathogenesis of the K/BxN arthritis are discussed with respect to their relevance for human rheumatoid arthritis. Because of the reliable and robust induction of joint inflammation by serum transfer this new disease model has been and will be a valuable means to address the as-yet-unanswered key questions related to the development of arthriti

The KRN mouse model of inflammatory arthritis

In 1996 a new murine model of spontaneous arthritis was described by the group of Benoist and Mathis. Mice transgenic for a T cell receptor recognizing an epitope of bovine RNase and bred onto a NOD background developed severe destructive arthritis, which resembles human rheumatoid arthritis in many respects. The development of disease requires the presence of T and B lymphocytes and is dependent on the MHC class II molecule I-Ag7. B cell activation by antigen and an additional CD40-CD40 ligand interaction was found to give rise to the production of autoantibodies. Glucose-6-phosphate isomerase was identified as the target of the autoantibodies; moreover, the transgenic T cells were demonstrated to exhibit a dual specificity for both bovine RNase and glucose-6-phosphate isomerase. Importantly, the arthritis is serum transferable to normal recipients, enabling the examination of the pathogenic mechanisms of joint inflammation and destruction. Recent studies suggest the crucial involvement of the innate immune system in the development of antibody-induced arthritis. Complement components, Fc receptors and neutrophils are indispensable for disease induction. An overview of the existing data is given and the emerging concepts of the pathogenesis of the K/BxN arthritis are discussed with respect to their relevance for human rheumatoid arthritis. Because of the reliable and robust induction of joint inflammation by serum transfer this new disease model has been and will be a valuable means to address the as-yet-unanswered key questions related to the development of arthriti

The long-term impact of early treatment of rheumatoid arthritis on radiographic progression: a population-based cohort study

Objective. To measure the long-term rate of radiographic progression in a cohort of patients treated early vs late with conventional DMARDs. Methods. The long-term rate of radiographic progression in patients included in the Swiss clinical quality management in rheumatoid arthritis (SCQM-RA) registry who initiated treatment with conventional DMARDs within the first year of symptom onset (early DMARD) vs patients who initiated treatment 1-5 years after symptom onset (late DMARD). Radiographic progression was assessed in 38 joints using a validated score (Ratingen Score). The rate of progression was calculated using a multivariate regression model for longitudinal data, adjusting for potential confounders. Results. A total of 970 RA patients were included. The 368 patients in the early DMARD group started therapy after a median symptom duration of 6 months, whereas the 602 patients in the late DMARD group initiated therapy after median 2.5 years. RF, MTX use and other risk factors for erosive disease progression were similar between the two groups. However, the estimated rate of radiographic progression at baseline was higher in the early DMARD vs the late DMARD group (1.8 vs 0.6, P < 0.01). In spite of this, the long-term rate of radiographic progression was significantly lower in the early DMARD group after adjustment for confounding factors (−0.35 at 5 years, P = 0.012). Conclusion. This result supports the concept of a therapeutic window of opportunity early in the disease course and suggests that early initiation of DMARD therapy results in a long-lasting reduction of radiographic damag

Chondrocalcinosis and osteoporosis in a patient with renal tubular disorder

We report the case of a 50-year old male patient presenting with a combination of chondrocalcinosis and osteoporosis related to a renal tubular disorder. Laboratory studies revealed hypokalemia, hypomagnesemia, hypocalcemia with renal wastage and metabolic alkalosis, compatible with a renal tubular transport disorder with similarities to Bartter's and Gitelman's syndrome. Calcifications of the menisci and cartilage on X-rays of knee joints suggested chondrocalcinosis, which has been associated with Gitelman's syndrome. Radiologically suspected osteopenia was confirmed by a bone density scan that revealed osteoporosis of the vertebral column. An association of osteoporosis with hypercalciuria, which commonly occurs in Bartter's syndrome patients, has been reported. Upon treatment of the renal tubular disorder with spironolactone and a thiazide diuretic in combination with calcium and magnesium supplementation, the electrolyte abnormalities resolved and arthralgias disappeared. Our case demonstrates a renal tubular dysfunction with features of both Bartter's and Gitelman's syndrome along with concurrent chondrocalcinosis and osteoporosis. Furthermore, the occurrence of osteoporosis in this relatively young patient, in the absence of other risk factors, demonstrates that renal tubular disorders should be suspected in presenile osteoporosis. Vice versa, since osteoporosis usually is asymptomatic before fracturing, patients with renal tubular disorders should be examined for osteoporosis

CHONDROCALCINOSIS AND OSTEOPOROSIS IN A PATIENT WITH RENAL TUBULAR DISORDER

ABSTRACT We report the case of a 50-year old male patient presenting with a combination of chondrocalcinosis and osteoporosis related to a renal tubular disorder. Laboratory studies revealed hypokalemia, hypomagnesemia, hypocalcemia with renal wastage and metabolic alkalosis, compatible with a renal tubular transport disorder with similarities to Bartter&apos;s and Gitelman&apos;s syndrome. Calcifications of the menisci and cartilage on X-rays of knee joints suggested chondrocalcinosis, which has been associated with Gitelman&apos;s syndrome. Radiologically suspected osteopenia was confirmed by a bone density scan that revealed osteoporosis of the vertebral column. An association of osteoporosis with hypercalciuria, which commonly occurs in Bartter&apos;s syndrome patients, has been reported. Upon treatment of the renal tubular disorder with spironolactone and a thiazide diuretic in combination with calcium and magnesium supplementation, the electrolyte abnormalities resolved and arthralgias disappeared. Our case demonstrates a renal tubular dysfunction with features of both Bartter&apos;s and Gitelman&apos;s syndrome along with concurrent chondrocalcinosis and osteoporosis. Furthermore, the occurrence of osteoporosis in this relatively young patient, in the absence of other risk factors, demonstrates that renal tubular disorders should be suspected in presenile osteoporosis. Vice versa, since osteoporosis usually is asymptomatic before fracturing, patients with renal tubular disorders should be examined for osteoporosis

18F-Fluoride PET/CT for detection of sacroiliitis in ankylosing spondylitis

Purpose: The aim of this study was to evaluate the performance of 18F-fluoride-PET/CT (PET/CT) for the diagnosis of sacroiliac joint (SIJ) arthritis in patients with active ankylosing spondylitis (AS). Methods: Included in the study were 15 patients with AS according to the modified New York criteria (AS group) and with active disease and 13 patients with mechanical low back pain (MLBP; control group) who were investigated with whole-body 18F-fluoride PET/CT. The ratio of the uptake in the SIJ and that in the sacrum (SIJ/S) was calculated for every joint. Results: The mean SIJ/S ratio of 30 quantified joints in the AS group was 1.66 (range 1.10-3.07) with PET/CT, and the mean SIJ/S ratio of 26 quantified joints in the MLBP group was 1.12 (range 0.71-1.52). The area under the receiver operating characteristic curve for SIJ arthritis was 0.84. With plain radiography as a the gold standard and taking an SIJ/S ratio of >1.3 as the threshold, the sensitivity, specificity and accuracy on a per patient basis were 80%, 77% and 79%, respectively. On a per SIJ basis, the greatest sensitivity (94%) was found in grade 3 sacroiliitis (n = 16). Conclusion: Our results suggest that quantitative 18F-fluoride PET/CT may play a role in the diagnosis of sacroiliitis in active AS and is an alternative to conventional bone scintigraphy in times of molybdenum shortag

Targeted delivery to inflammatory monocytes for efficient RNAi-mediated immuno-intervention in auto-immune arthritis

Poster presentationInternational audienc

HLA-B27 as a predictor of effectiveness of treatment with TNF inhibitors in axial spondyloarthritis: data from the Swiss Clinical Quality Management Registry

OBJECTIVE: To explore the impact of the human leucocyte antigen (HLA)-B27 on the effectiveness of tumor necrosis factor inhibitors (TNFi) in patients with axial spondyloarthritis (axSpA). METHODS: A total of 1109 patients with available HLA-B27 status (831 B27+ patients and 278 B27- patients) fulfilling the Assessment of Spondyloarthritis international Society classification criteria for axSpA from the prospective Swiss Clinical Quality Management Registry initiating a first TNFi were included. Drug retention was investigated with multiple adjusted Cox proportional hazard models with imputation of missing values. Multiple-adjusted logistic regression analyses were used to assess the proportion of patients reaching 50% reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50) at 1 year. RESULTS: B27+ and B27- patients differed with regard to age, sex, BASDAI, C-reactive protein (CRP), body mass index, enthesitis, uveitis, and classification status. After adjustment for potential confounders for the relationship between HLA-B27 and drug effectiveness (sex and family history of spondyloarthritis), a higher risk of drug discontinuation was found in B27- patients (HR 1.53, 95% CI 1.27-1.83). This difference decreased after additional adjustment for parameters which may act as mediators (HR 1.30, 95% CI 1.30-1.55). Male sex and elevated C-reactive protein (CRP) levels were consistently associated with longer retention. Comparable results were obtained for BASDAI50 responses. CONCLUSION: The HLA-B27 genotype is an important predictor of treatment effectiveness. Male sex and CRP seem, however, to better describe variability of response in individual patients. This data may help avoiding potential discrimination of B27- individuals with regard to TNFi initiation. Key Points • HLA-B27 is a predictor of effectiveness of TNF inhibitors in axial spondyloarthritis. • Variability of response in individual patients is better defined by sex and objective markers of disease activity, such as C-reactive protein

HLA-B27 as a predictor of effectiveness of treatment with TNF inhibitors in axial spondyloarthritis: data from the Swiss Clinical Quality Management Registry.

OBJECTIVE To explore the impact of the human leucocyte antigen (HLA)-B27 on the effectiveness of tumor necrosis factor inhibitors (TNFi) in patients with axial spondyloarthritis (axSpA). METHODS A total of 1109 patients with available HLA-B27 status (831 B27+ patients and 278 B27- patients) fulfilling the Assessment of Spondyloarthritis international Society classification criteria for axSpA from the prospective Swiss Clinical Quality Management Registry initiating a first TNFi were included. Drug retention was investigated with multiple adjusted Cox proportional hazard models with imputation of missing values. Multiple-adjusted logistic regression analyses were used to assess the proportion of patients reaching 50% reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50) at 1 year. RESULTS B27+ and B27- patients differed with regard to age, sex, BASDAI, C-reactive protein (CRP), body mass index, enthesitis, uveitis, and classification status. After adjustment for potential confounders for the relationship between HLA-B27 and drug effectiveness (sex and family history of spondyloarthritis), a higher risk of drug discontinuation was found in B27- patients (HR 1.53, 95% CI 1.27-1.83). This difference decreased after additional adjustment for parameters which may act as mediators (HR 1.30, 95% CI 1.30-1.55). Male sex and elevated C-reactive protein (CRP) levels were consistently associated with longer retention. Comparable results were obtained for BASDAI50 responses. CONCLUSION The HLA-B27 genotype is an important predictor of treatment effectiveness. Male sex and CRP seem, however, to better describe variability of response in individual patients. This data may help avoiding potential discrimination of B27- individuals with regard to TNFi initiation. Key Points • HLA-B27 is a predictor of effectiveness of TNF inhibitors in axial spondyloarthritis. • Variability of response in individual patients is better defined by sex and objective markers of disease activity, such as C-reactive protein