PKK deficiency in B cells prevents lupus development in Sle lupus mice.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies that can result in damage to multiple organs. It is well documented that B cells play a critical role in the development of the disease. We previously showed that protein kinase C associated kinase (PKK) is required for B1 cell development as well as for the survival of recirculating mature B cells and B-lymphoma cells. Here, we investigated the role of PKK in lupus development in a lupus mouse model. We demonstrate that the conditional deletion of PKK in B cells prevents lupus development in Sle1Sle3 mice. The loss of PKK in Sle mice resulted in the amelioration of multiple classical lupus-associated phenotypes and histologic features of lupus nephritis, including marked reduction in the levels of serum autoantibodies, proteinuria, spleen size, peritoneal B-1 cell population and the number of activated CD4 T cells. In addition, the abundance of autoreactive plasma cells normally seen in Sle lupus mice was also significantly decreased in the PKK-deficient Sle mice. Sle B cells deficient in PKK display defective proliferation responses to BCR and LPS stimulation. Consistently, B cell receptor-mediated NF-κB activation, which is required for the survival of activated B cells, was impaired in the PKK-deficient B cells. Taken together, our work uncovers a critical role of PKK in lupus development and suggests that targeting the PKK-mediated pathway may represent a promising therapeutic strategy for lupus treatment.

The Relationship Between Focal and Generalized Bone Loss in Rheumatoid Arthritis.

OBJECTIVE: To determine if there is an association between focal and systemic bone loss in patients with RA. METHODS: Bone loss is a hallmark finding in rheumatoid arthritis (RA) and manifests as localized, periarticular and systemic bone loss. RA patients were selected from the Consortium of Rheumatology Researchers of North America (CORRONA) database. Multiple logistic regression models were constructed to assess the association between the presence or absence of erosions and T-scores at the lumbar spine (LS) and total hips and adjusted for age, gender, body mass index (BMI), medications and disease activity indices. RESULTS: Data on erosions and T-scores were available in 3,898 and 5,099 subjects, respectively. Patients with erosions had a significantly lower LS T-scores (-0.9) compared to RA patients without erosions (p=0.0002). Similarly, the mean total hip T-scores were significantly lower in patients with (-1.4) compared to subjects without erosions (-1.0) (p<0.01). The odds of having no erosion increased by 21% for each 1-unit increase in LS T-score and 46% for each 1 unit increase in hip Tscore. Patients with erosions were significantly younger (p<0.01) had a lower BMI (p<0.01) and higher DAS28 scores than those without erosions. More patients with erosions were on anti-TNF therapy, disease modifying drugs and osteoporosis medications than patients without erosions (p<0.01, 0.003 and 0.0003). CONCLUSION: RA patients with bone erosions have significantly lower T-scores at the LS and hips compared with RA patients without erosions. These data suggest a relationship between localized and generalized bone loss in RA.

Hospitalization of patients with systemic lupus erythematosus is a major cause of direct and indirect healthcare costs.

Objectives The objective of this study was to calculate the direct and indirect costs of admission for systemic lupus erythematosus (SLE) patients, identify the population at risk and investigate potential reasons for admission. Methods We conducted a financial analysis of all admissions for SLE to Strong Memorial Hospital between 1 July 2013 and 30 June 2015. Patient and financial records for admissions with a SLE diagnosis for the above period were retrieved. The total cost of admissions was used as a measure of direct costs and the length of stay used to assess indirect costs. Additionally, we analyzed the demographics of the hospitalized population. Results The average, annual cost of confirmed admissions to Strong Memorial Hospital for SLE was US$3.9-6.4 m. The mean annual cost per patient for hospitalization was US$51,808.41. The length of stay for all SLE patients was 1564-2507 days with an average of 8.5 days per admission. The majority of patients admitted were young women from the city of Rochester. Infections were the most common reason for admissions. Conclusion We demonstrated that admissions are a source of high direct and indirect costs to the hospital and a significant financial burden to the patient. Implementing measures to improve the quality of care for SLE patients will help decrease the morbidity and lower the economic costs to hospitals.

Effect of adalimumab on joint disease: features of patients with psoriatic arthritis detected by magnetic resonance imaging.

BACKGROUND: Bone marrow oedema (BMO), synovitis, effusion and joint erosion on magnetic resonance imaging (MRI) may be used as outcome measures in psoriatic arthritis (PsA). OBJECTIVE: To assess the impact of adalimumab on BMO, synovitis, effusion and erosions in PsA, as measured by MRI. METHODS: Fifteen patients with active PsA (> or =3 tender and > or =3 swollen joints) were enrolled in an open-label pilot study. Each received adalimumab subcutaneously every other week for 24 weeks. MRI was obtained at baseline and 24 weeks. RESULTS: MRI was available for 11 patients, pre and post-therapy. BMO and effusion scores improved markedly after 24 weeks of adalimumab, while no significant change was noted in erosion score. An unanticipated finding, however, was the lack of improvement in the MRI synovitis score. CONCLUSIONS: Improvement in BMO and unchanged erosion scores may explain the "anti-erosive" effects of adalimumab in PsA. Persistence of BMO and synovitis on MRI suggests ongoing disease activity and supports the continuation of long-term anti-TNF therapy.

The effect of etanercept on osteoclast precursor frequency and enhancing bone marrow oedema in patients with psoriatic arthritis.

OBJECTIVE: The frequency of osteoclast precursors (OCPF) and the presence of bone marrow oedema (BMO) are potential response biomarkers in psoriatic arthritis (PsA). Previous studies suggest a central role for tumour necrosis factor (TNF) in the formation of osteoclast precursors. To better understand this association, the effect of etanercept on OCPF and BMO was analysed in PsA patients with erosive arthritis. METHODS: A total of 20 PsA patients with active erosive PsA were enrolled. Etanercept was administered twice weekly for 24 weeks. OCPF was measured and clinical assessments were performed at baseline, 2, 12 and 24 weeks. Gadolinium enhanced MR images were obtained at baseline and 24 weeks. RESULTS: Significant improvements in joint score (p<0.001), HAQ scores (p<0.001) and SF-36 parameters were observed after 6 months of therapy with etanercept compared to baseline. The median OCPF decreased from 24.5 to 9 (p = 0.04) and to 7 (p = 0.006) after 3 months and 6 months of treatment, respectively. MR images were available for 13 patients. The BMO volume decreased in 47 and increased in 31 sites at 6 months. No correlation was noted between OCPF, BMO and clinical parameters. CONCLUSION: The rapid decline in OCPF and overall improvement in BMO after anti-TNFalpha therapy provides one mechanism to explain the anti-erosive effects of TNF blockade in PsA. Persistence of BMO after etanercept treatment, despite a marked clinical response, was unexpected, and suggests ongoing subchondral inflammation or altered remodelling in PsA bone.