Meta-analysis of effect of nintedanib on reducing FVC decline across interstitial lung diseases

INTRODUCTION: The effect of nintedanib on slowing the rate of decline in forced vital capacity (FVC) has been investigated in randomized placebo-controlled trials in subjects with idiopathic pulmonary fibrosis (IPF), other progressive fibrosing interstitial lung diseases (ILDs), and ILD associated with systemic sclerosis (SSc-ILD). We assessed the consistency of the effect of nintedanib on the rate of decline in FVC over 52 weeks across four placebo-controlled phase III trials. METHODS: We used data on FVC decline from the INPULSIS-1 and INPULSIS-2 trials in subjects with IPF, the INBUILD trial in subjects with progressing fibrosing ILDs other than IPF, and the SENSCIS trial in subjects with SSc-ILD. In each trial, the primary endpoint was the annual rate of decline in FVC (mL/year) assessed over 52 weeks. We performed fixed effect and random effects meta-analyses based on the relative treatment effect of nintedanib versus placebo on the rate of decline in FVC (mL/year) over 52 weeks. Heterogeneity of the relative treatment effect of nintedanib across populations was assessed using the I2 statistic, τ2 and corresponding p value from a Q test for heterogeneity. RESULTS: The combined analysis comprised 1257 subjects treated with nintedanib and 1042 subjects who received placebo. Nintedanib reduced the rate of decline in FVC (mL/year) over 52 weeks by 51.0% (95% CI 39.1, 63.0) compared with placebo. The relative effect (95% CI) was the same using the fixed effect and random effects models. There was no evidence of heterogeneity in the relative treatment effect of nintedanib across the populations studied (I2 = 0%, τ2 = 0, p = 0.93). CONCLUSIONS: A meta-analysis of data from four placebo-controlled trials demonstrated that nintedanib approximately halved the rate of decline in FVC over 52 weeks across subjects with different forms of pulmonary fibrosis, with no evidence of heterogeneity in its relative treatment effect across patient populations

Patient-reported outcomes and patient-reported outcome measures in interstitial lung disease: Where to go from here?

Patient-reported outcome measures (PROMs), tools to assess patient self-report of health status, are now increasingly used in research, care and policymaking. While there are two well-developed disease-specific PROMs for interstitial lung diseases (ILD) and idiopathic pulmonary fibrosis (IPF), many unmet and urgent needs remain. In December 2019, 64 international ILD experts convened in Erice, Italy to deliberate on many topics, including PROMs in ILD. This review summarises the history of PROMs in ILD, shortcomings of the existing tools, challenges of development, validation and implementation of their use in clinical trials, and the discussion held during the meeting. Development of disease-specific PROMs for ILD including IPF with robust methodology and validation in concordance with guidance from regulatory authorities have increased user confidence in PROMs. Minimal clinically important difference for bidirectional changes may need to be developed. Cross-cultural validation and linguistic adaptations are necessary in addition to robust psychometric properties for effective PROM use in multinational clinical trials. PROM burden of use should be reduced through appropriate use of digital technologies and computerised adaptive testing. Active patient engagement in all stages from development, testing, choosing and implementation of PROMs can help improve probability of success and further growth

Pharmacological Treatment of Idiopathic Pulmonary Fibrosis: Current Approaches, Unsolved Issues, and Future Perspectives

Idiopathic pulmonary fibrosis (IPF) is a devastating condition with a 5-year survival of approximately 20%. The disease primarily occurs in elderly patients. IPF is a highly heterogeneous disorder with a clinical course that varies from prolonged periods of stability to episodes of rapid deterioration. In the last decade, improved understanding of disease mechanisms along with a more precise disease definition has allowed the design and completion of a number of high-quality clinical trials. Yet, until recently, IPF was essentially an untreatable disease. Finally, pirfenidone and nintedanib, two compounds with antifibrotic properties, have consistently proven effective in reducing functional decline and disease progression in IPF. This is a major breakthrough for patients and physicians alike, but there is still a long way to go. In fact, neither pirfenidone nor nintedanib is a cure for IPF, and most patients continue to progress despite treatment. As such, comprehensive care of patients with IPF, including manag

The DIAMORFOSIS (DIAgnosis and Management Of lung canceR and FibrOSIS) survey: international survey and call for consensus.

Background Currently there is major lack of agreement on the diagnostic and therapeutic management of patients with idiopathic pulmonary fibrosis (IPF) and lung cancer. Our aim was to identify variations in diagnostic and management strategies across different institutions and provide rationale for a consensus statement on this issue. Methods This was a joint-survey by European Respiratory Society (ERS) Assemblies 8, 11 and 12. The survey consisted of 25 questions. Results Four hundred and ninety-four (n=494) physicians from 68 different countries and five continents responded to the survey. Ninety-four per cent of participants were pulmonologists, 1.8% thoracic surgeons and 1.9% oncologists; 97.7% were involved in multidisciplinary team approaches on diagnosis and management. Regular low-dose high-resolution computed tomography (HRCT) scan was used by 49.5% of the respondents to screen for lung cancer in IPF. Positron emission tomography (PET) scan and endobronchial ultrasound (EBUS) is performed by 60% and 88% to diagnose nodular lesions with mediastinal lymphadenopathy in patients with advanced and mild IPF, respectively. Eighty-three per cent of respondents continue anti-fibrotics following lung cancer diagnosis; safety precautions during surgical interventions including low tidal volume are applied by 67%. Stereotactic radiotherapy is used to treat patients with advanced IPF (diffusing capacity of the lung for carbon monoxide (DLCO) <35%) and otherwise operable nonsmall cell lung cancer (NSCLC) by 54% of respondents and doublet platinum regimens and immunotherapy for metastatic disease by 25% and 31.9%, respectively. Almost all participants (93%) replied that a consensus statement for the management of these patients is highly warranted. Conclusion The diagnosis and management of IPF-lung cancer (LC) is heterogeneous with most respondents calling for a consensus statement

Medical competence, anatomy and the polity in seventeenth-century Rome

At the centre of this article are two physicians active in Rome between 1600 and 1630 who combined medical practice with broader involvement in the dynamic cultural, economic and political scene of the centre of the Catholic world. The city's distinctive and very influential social landscape magnified issues of career-building and allows us to recapture physicians’ different strategies of self-fashioning at a time of major social and religious reorganization. At one level, reconstructing Johannes Faber and Giulio Mancini's medical education, arrival in Rome and overlapping but different career trajectories contributes to research on physicians’ identity in early modern Italian states. Most remarkable are their access to different segments of Roman society, including a dynamic art market, and their diplomatic and political role, claimed as well as real. But following these physicians from hospitals to courts, including that of the Pope, and from tribunals to the university and analysing the wide range of their writing – from medico-legal consilia to political essays and reports of anatomical investigations – also enriches our view of medical practice, which included, but went beyond, the bedside. Furthermore, their activities demand that we reassess the complex place of anatomical investigations in a courtly society, and start recovering the fundamental role played by hospitals – those quintessential Catholic institutions – as sites of routine dissections for both medical teaching and research. (pp. 551–567

Cardiovascular safety of nintedanib in subgroups by cardiovascular risk at baseline in the TOMORROW and INPULSIS trials

Nintedanib is a tyrosine kinase inhibitor used to treat idiopathic pulmonary fibrosis (IPF). We investigated the cardiovascular safety of nintedanib using pooled data from the TOMORROW and INPULSIS trials.Cardiovascular events were assessed post hoc in patients with a history of atherosclerotic cardiovascular disease (CVD) and/or one or more cardiovascular risk factors at baseline ("higher cardiovascular risk") and patients with no history of atherosclerotic CVD and no cardiovascular risk factors at baseline ("lower cardiovascular risk").Incidence rates were calculated for 1231 patients (n=723 nintedanib and n=508 placebo), of whom 89.9% had higher cardiovascular risk. Incidence rates of major adverse cardiovascular events were similar in the nintedanib and placebo groups in patients with higher cardiovascular risk (3.88 (95% CI 2.58-5.84) and 3.49 (95% CI 2.10-5.79) per 100 patient-years, respectively) and lower cardiovascular risk (4.78 (95% CI 1.54-14.82) and 5.37 (95% CI 1.73-16.65) per 100 patient-years, respectively). Incidence rates of myocardial infarction in the nintedanib and placebo groups, respectively, were 3.03 (95% CI 1.91-4.81) and 1.16 (95% CI 0.48-2.79) per 100 patient-years in patients with higher cardiovascular risk and 1.59 (95% CI 0.22-11.29) and 1.78 (95% CI 0.25-12.64) per 100 patient-years in patients with lower cardiovascular risk. Incidence rates of other ischaemic heart disease in the nintedanib and placebo groups, respectively, were 1.85 (95% CI 1.02-3.34) and 3.28 (95% CI 1.94-5.54) per 100 patient-years in patients with higher cardiovascular risk and 0 and 1.80 (95% CI 0.25-12.78) per 100 patient-years in patients with lower cardiovascular risk.These data help to establish the cardiovascular safety profile of nintedanib in IPF

Defining anti-synthetase syndrome: a systematic literature review

OBJECTIVES: Anti-synthetase syndrome (ASSD) is a heterogeneous autoimmune disease characterised by multi-system involvement with a wide variety of manifestations. Validated classification criteria are necessary to improve recognition and prevent misclassification, especially given the lack of reliable and standardised autoantibody testing. We systematically reviewed the literature to analyse proposed ASSD criteria, characteristics, and diagnostic performance. METHODS: We searched PubMed and Embase databases (01/01/1984 to 06/11/2018) and the ACR and EULAR meeting abstracts (2017-2018). Sensitivities, specificities, positive, negative likelihood ratios and risk of bias were calculated for ASSD criteria and key variables reported in the literature. We performed meta-analysis when appropriate. RESULTS: We retrieved 4,358 studies. We found 85 proposed ASSD criteria from a total of 82 studies. All but one study included anti-synthetase autoantibody (ARS) positivity in the ASSD criteria. Most studies required only one ASSD feature plus anti-ARS to define ASSD (n=64, 78%), whereas 16 studies required more than one ASSD variable plus anti-ARS. The only criteria not including anti-ARS positivity required 5 ASSD clinical features. We found limited data and wide variability in the diagnostic performance of each variable and definition proposed in the literature. Given these limitations we only meta-analysed the performance of individual muscle biopsy and clinical variables in diagnosing ASSD, which performed poorly. CONCLUSIONS: The current ASSD criteria include a variety of serological, clinical, and histological features with wide variability amongst proposed definitions and the performance of these definitions has not been tested. This systematic literature review suggests the need for additional data and consensus-driven classification criteria for ASSD