Dickkopf1 fuels inflammatory cytokine responses.

Many human diseases, including cancer, share an inflammatory component but the molecular underpinnings remain incompletely understood. We report that physiological and pathological Dickkopf1 (DKK1) activity fuels inflammatory cytokine responses in cell models, mice and humans. DKK1 maintains the elevated inflammatory tone of cancer cells and is required for mounting cytokine responses following ligation of toll-like and cytokine receptors. DKK1-controlled inflammation derives from cell-autonomous mechanisms, which involve SOCS3-restricted, nuclear RelA (p65) activity. We translate these findings to humans by showing that genetic DKK1 variants are linked to elevated cytokine production across healthy populations. Finally, we find that genetic deletion of DKK1 but not pharmacological neutralization of soluble DKK1 ameliorates inflammation and disease trajectories in a mouse model of endotoxemia. Collectively, our study identifies a cell-autonomous function of DKK1 in the control of the inflammatory response, which is conserved between malignant and non-malignant cells. Additional studies are required to mechanistically dissect cellular DKK1 trafficking and signaling pathways.

Effects of cyclophosphamide and rituximab in patients with connective tissue diseases with severe interstitial lung disease.

OBJECTIVES: We aimed to analyse the effects of real-life immunomodulatory therapy with cyclophosphamide and rituximab for interstitial lung disease (ILD) in patients with systemic sclerosis (SSc-ILD), anti-synthetase syndrome (ASS-ILD), or Sjögren's syndrome (SjS-ILD), in a single academic centre. METHODS: All inpatients with connective tissue diseases treated with intravenous bolus cyclophosphamide or rituximab were identified from the Medical Centre records. Information on patient characteristics, chest CT results, pulmonary function tests, therapies, and severe adverse events, were extracted from inpatient and outpatient records. RESULTS: Intravenous cyclophosphamide bolus therapy was used in 27 patients with SSc. Cyclophosphamide improved forced vital capacity (FVC) by more than 10% in 4 patients and stabilised it at -0.4% to +3.25% in 8. Rituximab constituted a rescue therapy in 14 SSc patients, and was used for treating 4 patients with ASS-ILD, 2 patients with SjS-ILD and one additional SSc-ILD patient. Rituximab led to FVC improvements of at least 5% in 8 patients and to stabilisation in another 6. 6 patients under cyclophosphamide and 8 patients under rituximab experienced severe adverse events. 8 of the 34 patients died, half of them from causes potentially related to therapy. CONCLUSIONS: In this subset of severely sick patients with connective tissue diseases, cyclophosphamide and/or rituximab led to improvement in 12 patients, and stabilisation was seen in 14. Despite the new options with nintedanib, immunomodulation remains a relevant therapeutic modality for ILD associated with connective tissue disease.

Dorsomorphin: A novel inhibitor of Dickkopf-1 in breast cancer.

Advanced stages of breast cancer are frequently complicated by bone metastases which cause substantial cancer-related morbidity and mortality. The Wnt-signaling antagonist Dickkopf-1 (DKK-1) has emerged as a crucial factor in the development and progression of osteolytic bone metastases. Although several signaling pathways have been implicated in promoting DKK-1 production in breast cancer cells, pharmacological interventions that interfere with tumor DKK-1 synthesis still remain scarce. In the current study, using an unbiased approach, we identified the small molecule Dorsomorphin as a potent suppressor of DKK-1 in several breast cancer cell lines (MDA-MB-231, MDA-Bone, MDA-MET and MCF7, respectively). Here, Dorsomorphin suppressed DKK-1 mRNA and protein production by 70 and 90%, respectively (p <0.001). Whereas bone morphogenic protein (BMP)- and AMP activated protein kinase (AMPK)-signaling are two well-established targets of Dorsomorphin, we show that neither pathway is essentially involved in facilitating its inhibitory effects on DKK-1. In summary, we identified Dorsomorphin as a potent pharmacological inhibitor of DKK-1 production in breast cancer cells. Whether Dorsomorphin reflects a valuable therapeutic agent in breast cancer warrants further investigations.

The association between lymphopenia and serious infection risk in rheumatoid arthritis.

OBJECTIVES: To investigate the relationship between occurrence of serious infection (SI) and lymphocyte counts in patients with RA using data from a single centre. METHODS: We used routinely captured data from a single tertiary rheumatology centre to explore the relationship between lymphopenia and SI risk. Adult RA patients were included over a 5-year follow-up period. Admissions due to confirmed SI were considered. SI rate with 95% confidence intervals was calculated. The association between SI with baseline lymphocyte counts, time-averaged lymphocyte counts throughout all follow-up, and a nadir lymphocyte count was assessed using Cox proportional hazards regression. The relationship between lymphopenia over time and SI was analysed using a mixed-effect model of lymphocyte counts prior to SI. RESULTS: This analysis included 1095 patients with 205 SIs during 2016 person-years of follow-up. The SI rate was 4.61/100 patient-years (95% CI: 3.76, 5.65). Compared with patients with nadir lymphocyte counts >1.5 × 109 cells/l, nadir lymphopenia <1 × 109 cells/l was significantly associated with higher SI risk (HR 3.28; 95% CI: 1.59, 6.76), increasing to HR 8.08 (95% CI: 3.74, 17.44) in patients with lymphopenia <0.5 × 109 cells/l. Lymphocyte counts were observed to be reduced in the 30-day period prior to SI. CONCLUSION: Lymphocyte counts below <1.0 × 109 cells/l were associated with higher SI risk in RA patients; the strongest association between lymphopenia and SI was observed when lymphocyte counts were below <0.5 × 109 cells/l. Lymphopenia may be used as a measure to stratify patients at risk of SI.

A population study of the reported incidence of native joint septic arthritis in the United Kingdom between 1998 and 2013.

OBJECTIVES: Septic arthritis is a life-threatening condition with mortality rates of 10-15%. Previous studies in other countries have shown the incidence of septic arthritis may be changing. Our aim was investigate the incidence and pattern of native joint septic arthritis in the UK. METHODS: We performed an analysis using Hospital Episode Statistics to investigate the reported incidence of septic arthritis in the UK between 1998 and 2013. RESULTS: A total of 54 532 cases of septic arthritis were reported via Hospital Episode Statistics during the timeframe studied. There has been a 43% increase in the reported incidence of septic arthritis, with rates rising from 5.5/100 000 in 1998 to 7.8/100 000 in 2013. The rate increased most rapidly in those >75 years of age (15/100 000 in 1998 and 31/100 000 in 2013). Staphylococcal species were the most frequently reported, followed by Streptococcus Pneumococcus rates were relatively stable, with the exception of a 7-fold spike in reported incidence in 2011. DISCUSSION: This large population-based study demonstrates that the incidence of septic arthritis is increasing in the UK. Rates are increasing most rapidly in the >75 years age group, which is likely the result of increasing co-morbidities. The clustering of pneumococcal cases has potential public health implications.

Parvovirus infection in early arthritis.

OBJECTIVES: To analyse the subgroup of early arthritis patients with new onset parvovirus infections for details that may help narrow the population tested. METHODS: From their routine patient charts, patient histories and clinical and serological data were obtained for all 130 patients of the Rheumatology division with parvovirus serology performed. 11 patients had acute parvovirus infections, defined by specific IgM antibodies. 95 patients had a previous infection, 16 were never infected, together forming the n=111 control group, and 8 patients had to be excluded. RESULTS: Most patients with acute parvovirus infection had an acute onset, highly symmetrical polyarthritis of small joints, which was preceded by prodromal symptoms. Positive ANA were frequently found, whereas C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were only mildly elevated. No frank synovitis was found longer than two weeks after disease onset. Most patients were free of symptoms within three months, and no patient in the parvovirus group developed rheumatoid arthritis or a connective tissue disease. CONCLUSIONS: Parvovirus serology may be helpful in patients with acute polyarthritis of very recent onset, and if they give a history of prodromal symptoms, in particular. In most instances, parvovirus arthritis is an acute disease, which is rapidly self-limiting.

Relevant incidence of cervical arthritis in patients with erosive seropositive rheumatoid arthritis even today.

OBJECTIVES: This paper aims to investigate adherence to, and outcome of, radiographic screening of patients with rheumatoid arthritis (RA) for cervical involvement, given the availability of state of the art disease-modifying anti-rheumatic drug (DMARD) and biological therapies. METHODS: Cervical screening results and clinical information were obtained from the charts of 395 consecutive patients with rheumatoid arthritis who attended an academic rheumatology outpatient clinic in a 3-month interval. This sample was combined with eight patients who underwent C1-C2 fusion at the Department of Orthopaedic Surgery. RESULTS: Reports on cervical spine x-ray films were not found in the charts of 67 patients (17 %), including 21 (8 %) of the 257 patients with a disease duration of ≥5 years. Nevertheless, 17 (7%) of these 257 patients had an increased atlantodental distance. An additional 4 RA patients of the Department of Orthopaedics were added for a total of 21 patients with cervical arthritis, 13 of whom had no cervical symptoms. All 21 patients with cervical arthritis had erosive peripheral arthritis with at least 10 years of disease duration, and were positive for rheumatoid factor. Almost half of these patients were not under adequate DMARD therapy when cervical instability was diagnosed, and none were on biological response modifiers. CONCLUSIONS: Screening for cervical arthritis is still of importance, especially in patients with erosive seropositive disease. In view of the documented incidence, adherence to screening protocols was disappointing.