Frontometaphyseal dysplasia (FMD) is a progressive sclerosing skeletal dysplasia affecting the long bones and skull. The cause of FMD in some individuals is gain-of-function mutations in FLNA, although how these mutations result in a hyperostotic phenotype remains unknown. Approximately one half of individuals with FMD have no identified mutation in FLNA and are phenotypically very similar to individuals with FLNA mutations, except for an increased tendency to form keloid scars. Using whole-exome sequencing and targeted Sanger sequencing in 19 FMD-affected individuals with no identifiable FLNA mutation, we identified mutations in two genes-MAP3K7, encoding transforming growth factor β (TGF-β)-activated kinase (TAK1), and TAB2, encoding TAK1-associated binding protein 2 (TAB2). Four mutations were found in MAP3K7, including one highly recurrent (n = 15) de novo mutation (c.1454C>T [ p.Pro485Leu]) proximal to the coiled-coil domain of TAK1 and three missense mutations affecting the kinase domain (c.208G>C [p.Glu70Gln], c.299T>A [p.Val100Glu], and c.502G>C [p.Gly168Arg]). Notably, the subjects with the latter three mutations had a milder FMD phenotype. An additional de novo mutation was found in TAB2 (c.1705G>A, p.Glu569Lys). The recurrent mutation does not destabilize TAK1, or impair its ability to homodimerize or bind TAB2, but it does increase TAK1 autophosphorylation and alter the activity of more than one signaling pathway regulated by the TAK1 kinase complex. These findings show that dysregulation of the TAK1 complex produces a close phenocopy of FMD caused by FLNA mutations. Furthermore, they suggest that the pathogenesis of some of the filaminopathies caused by FLNA mutations might be mediated by misregulation of signaling coordinated through the TAK1 signaling complex.

Objective To evaluate rheumatoid arthritis (RA) disease activity and risk of RA‐associated interstitial lung disease (RA‐ILD). Methods We investigated disease activity and risk of RA‐ILD using the Brigham RA Sequential Study (BRASS, 2003–2016). All patients were diagnosed as having RA according to accepted criteria. Disease Activity Scores in 28 joints (DAS28) and covariate data were measured prospectively at annual study visits. Diagnosis of RA‐ILD was determined by review of images from clinically indicated chest computed tomography scans. We analyzed patients without RA‐ILD at baseline. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for RA‐ILD, using annually updated DAS28 data, with adjustment for known RA‐ILD risk factors (age, sex, smoking status, RA duration, and serologic status). We performed alternative analyses that did not censor at the time of missing DAS28 data and included adjustment for use of methotrexate, use of glucocorticoids, presence of bone erosions, and presence of rheumatoid nodules. Results Among 1,419 participants, the mean ± SD age was 55.8 ± 14.2 years, and 68.6% were seropositive for either cyclic citrullinated peptide or rheumatoid factor. We identified 85 incident cases of RA‐ILD during a mean ± SD follow‐up duration of 8.9 ± 4.2 years per patient. The moderate/high disease activity group had a multivariable HR of 2.22 (95% CI 1.28–3.82) for RA‐ILD compared to the remission/low disease activity group. Risk of RA‐ILD increased across disease activity categories: multivariable HR 1.00 (reference) for remission, 1.41 (95% CI 0.61–3.28) for low disease activity, 2.08 (95% CI 1.06–4.05) for moderate disease activity, and 3.48 (95% CI 1.64–7.38) for high disease activity (P for trend = 0.001). For each unit increase in the DAS28, the risk of RA‐ILD increased by 35% (95% CI 14–60%). Results were similar in analyses that included follow‐up for missing DAS28 data and with adjustment for use of methotrexate, use of glucocorticoids, presence of bone erosions, or presence of rheumatoid nodules. Conclusion Active articular RA was associated with an increased risk of developing RA‐ILD. These results suggest that decreasing systemic inflammation may alter the natural history of RA‐ILD development.

Stability or improvement in pulmonary function or severity of ILD on CT was seen in most patients. Use of RTX was well tolerated in the majority of patients. RTX may play a therapeutic role in patients with AS-ILD, and further clinical investigation is warranted.

Introduction:This paper reports on an ongoing primary care audit of cancer referrals undertaken in Scotland in 2006–2007 and 2007–2008.Methods:General practitioners (GPs) in Scotland were asked to review all new cancer diagnoses within their practice during the preceding year.Results:4181 patients were identified in year 1 and 12 294 in year 2. The pathway taken for patients to present to, and be referred from, their GP has been analysed for 7430 of the 12 294 patients identified within year 2 across five separate health boards. The time from first symptoms to presentation to a GP varied between tumour types, being the longest (median 30 days) for head and neck cancers and the shortest (median 2 days) for bladder cancer. In all, 25% of patients within the following tumour groups waited longer than 2 months to present to their GP following first symptoms: prostate, colorectal, melanoma and head and neck cancers. Once patients had presented to their GP, those with prostate and lung cancer were referred later (median time 11 days) than those with breast cancer (median time 2 days). The priority with which GPs referred patients varied considerably between tumour groups (breast cancer 77.5% ‘urgent' compared with prostate cancer 44.7% ‘urgent'). In one health board the proportion of cancer patients being referred urgently increased from 46% to 58% between the first and second audit.Conclusion:Our data show that there are very different patterns of presentation and referral for patients with cancer, with some tumour groups being more likely to be associated with a delayed diagnosis than others.