Pulmonary hypertension in interstitial lung disease: an area of unmet clinical need.

Pulmonary hypertension (PH) is present in an important proportion of patients with interstitial lung diseases (ILDs), encompassing a large, heterogeneous group of diffuse parenchymal lung diseases. Development of ILD-related PH is associated with reduced exercise capacity, increased need for supplemental oxygen, decreased quality of life and earlier death. Diagnosis of ILD-related PH is important and requires a high index of suspicion. Noninvasive diagnostic assessment can suggest the presence of PH, although right heart catheterisation remains the gold standard to confirm the diagnosis and to assess its severity. A comprehensive assessment is needed to make sure reversible causes of PH have been ruled out, including thromboembolic events, untreated hypoxaemia and sleep disordered breathing. The results of trials concerning pulmonary vasodilators in this particular patient group have been disappointing and, in some cases, were even associated with an increased risk of harm. Newer strategies such as medications administered through inhalation and combinations with antifibrotic drugs show encouraging results. Moreover, unravelling the role of the vasculature in the pathophysiology of pulmonary fibrosis and ILD-related PH may potentially unlock new therapeutic opportunities.

An eye-opening case report of constrictive pericarditis.

Background: Constrictive pericarditis is characterized by the encasement of the heart by a stiff pericardium leading to impaired diastolic function, which ultimately leads to congestive heart failure. Case summary: We report a case of a young woman, who first presented to the ophthalmologist with the sudden appearance of floaters and vision reduction. Eventually, invasive haemodynamic assessment led to the diagnosis of constrictive pericarditis leading to venous congestion. Conclusion: Understanding the pathophysiology and integrating the results of invasive and non-invasive diagnostic work up is important in making this challenging diagnosis.

Malignant cardiac tamponade: safety and efficacy of intrapericardial bleomycin instillation.

BACKGROUND: Malignant cardiac tamponade is a life-threatening condition that requires prompt treatment and effective management to prevent recurrence. This paper describes safety and efficacy outcomes after intrapericardial instillation of bleomycin as well as possible predictors of survival. METHODS: We performed a 10-year retrospective, single-center study to evaluate the safety and efficacy of intrapericardial instillation of bleomycin in patients with suspected malignant cardiac tamponade. RESULTS: Intrapericardial instillation of bleomycin was performed in 31 cancer patients (9 men, 22 women) presenting with cardiac tamponade. Non-fatal complications occurred in 3 patients and relapse occurred in 1 patient. Overall survival was less than 10% at the end of the study. Median survival was 104 days (95% CI, 0-251 days). Survival was compared between different groups (defined by primary tumor, type of tumor, TNM stage and results of cytological analysis) with median survival being considerably higher when oncologic therapy was altered afterwards. CONCLUSIONS: The use of intrapericardial bleomycin instillation following pericardiocentesis for malignant cardiac tamponade is a safe procedure with a high success rate. Survival rates depend on further oncological treatment options available.

The use of point-of-care ultrasound in new-onset dyspnea: an unexpected diagnosis.

In this article, we report a patient with new-onset dyspnea and symptoms suggestive of heart failure, who had an unexpected diagnosis of a large left atrial myxoma with diastolic protrusion into the left ventricle. We further underline the role of cardiac Point-of-Care Ultrasound (POCUS) in the initial evaluation of patients with cardiac complaints in the emergency room setting. It can help to differentiate the patients' symptoms in order to achieve a more accurate diagnosis and thus increase the efficacy of the established therapy. In some cases, as with this patient, it can help to establish a diagnosis which needs prompt therapy.

Incidence, prevalence and long-term progression of Goh algorithm rated interstitial lung disease in systemic sclerosis in two independent cohorts in flanders: A retrospective cohort study.

OBJECTIVES: The epidemiology of interstitial lung disease (ILD) in systemic sclerosis (SSc) in Belgium is unknown. In literature, its prevalence varies between 19% and 52% in limited/diffuse cutaneous SSc (LcSSc/DcSSc). However, its prevalence in "early" SSc (pre-clinically overt SSc without [yet] skin involvement), nor its incidence rate in SSc (LcSSc/DcSSc/"early" SSc) has ever been described. Against this background, we aimed to determine the prevalence/incidence (rate) and progression of ILD in SSc. METHODS: 12-year follow-up data of consecutive SSc patients, included in two Flemish cohorts (University Hospitals Ghent and Leuven), were retrospectively analysed. ILD was classified according to the simplified Goh algorithm. Progression of ILD was defined as a relative decline of FVC ≥10%, a combined relative decline of FVC 5-10% and DLCO ≥15%, or as an increase in HRCT extent. RESULTS: 722 patients (60% LcSSc/ 20% DcSSc/ 20% "early" SSc, median (IQR) follow-up 39 [12-80] months) had baseline HRCT. 243 were rated to have ILD at baseline and 39 during follow-up (prevalence of 34%/ incidence rate of 20.3/1000PY, 95%CI:14.5-27.8). Amongst those with baseline ILD, 60% had lung functional progression at five years of follow-up. In the "early" SSc subgroup, eight patients were rated to have ILD at baseline and three during follow-up (prevalence of 6%/ incidence rate of 5.8/1000 PY, 95%CI:1.2-17.0). CONCLUSION: Both LcSSc and DcSSc patients should be monitored for ILD evolution. The low prevalence and incidence of ILD in the "early" SSc subgroup may instruct future decisions on the construction of uniform patient follow-up pathways in "early" SSc.

Pulmonary hypertension in connective tissue diseases, new evidence and challenges.

Pulmonary arterial hypertension is a lethal complication of different connective tissue diseases such as systemic sclerosis, mixed connective tissue disease and systemic lupus erythematosus. Although the treatment possibilities for patients with pulmonary arterial hypertension have increased in the last two decades and survival of patients with idiopathic pulmonary arterial hypertension has improved, the latter is not the case for patients with pulmonary arterial hypertension associated with connective tissue disease. In this narrative review, we review recent literature and describe the improvement of early diagnostic possibilities, screening modalities and treatment options. We also point out the pitfalls in diagnosis in this patient category and describe the unmet needs and what the focus of future research should be.

May capillaroscopy be a candidate tool in future algorithms for SSC-ILD: Are we looking for the holy grail? A systematic review.

OBJECTIVE: To investigate whether nailfold videocapillaroscopy (NVC), an increasingly worldwide used non-invasive tool to reliably evaluate the peripheral microcirculation, may be an outcome measure in future screening algorithms for systemic sclerosis related interstitial lung disease (SSc-ILD). METHODS: A systematic review to identify original research papers documenting an association between NVC and SSc-ILD was performed in 3 electronic databases according to the PRISMA guidelines. Subsequently, NVC parameters were subdivided according to the consented standardised capillaroscopic definitions of the EULAR Study Group on Microcirculation in Rheumatic Diseases / Scleroderma Clinical Trials Consortium on Capillaroscopy, into quantitative (capillary density, capillary dimension, capillary morphology and haemorrhages) and qualitative assessment (NVC pattern). RESULTS: The systematic search identified 310 unique search results, of which 2 cross-sectional and 1 longitudinal study were retained. In both cross-sectional studies, the presence of SSc-ILD was found to be inversely associated with capillary density (p = .008 and p = .005). The presence of a severe (active/late) NVC pattern was evaluated and associated with the presence of SSc-ILD in one of the cross-sectional studies. In the longitudinal study, incident SSc-ILD was associated with progressive capillary loss (p = .03) and the conversion to a worse (active/late) NVC pattern (p = .001/p = .003). CONCLUSIONS: This first systematic literature review investigating the role of NVC in SSc-ILD using standardised capillaroscopic definitions uncovered associations between NVC and (incident) SSc-ILD. If large prospective studies further corroborate and elucidate these findings, NVC might possibly be a candidate outcome measure to be integrated in screening algorithms for incident/progressive SSc-ILD.

Nailfold Videocapillaroscopy in Systemic Sclerosis-related Pulmonary Arterial Hypertension: A Systematic Literature Review.

OBJECTIVE: Pulmonary arterial hypertension (PAH) is one of the leading causes of death in systemic sclerosis (SSc). Current screening algorithms are hampered by low positive predictive values. Outcome measures that could add to performance characteristics would be welcome. We aim to evaluate the role of nailfold videocapillaroscopy (NVC) using standardized definitions, in SSc-related PAH (SSc-PAH). METHODS: A systematic review to identify original research papers documenting an association between NVC and right heart catheterization-defined SSc-PAH was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Subsequently, NVC characteristics were subdivided into quantitative (capillary density, dimension, morphology, and hemorrhages), semiquantitative, and qualitative assessment (NVC pattern), according to the definitions of the European League Against Rheumatism Study Group on Microcirculation in Rheumatic Diseases. RESULTS: The systematic search identified 316 unique search results, of which 5 were included in the final qualitative analysis. The occurrence of incident SSc-PAH unequivocally associated in 2 longitudinal studies with progressive capillary loss (p = 0.04 and p = 0.033) and the progression to a severe (active/late) NVC pattern (p = 0.05/0.01 and HR = 5.12, 95% CI 1.23-21.27). In 3 cross-sectional studies, SSc-PAH was found to be unequivocally inversely associated with capillary density (p = 0.001 and p < 0.05) and associated with the presence of a severe NVC pattern (p = 0.03 and p < 0.05). CONCLUSION: This is the first systematic literature review investigating the role of NVC in SSc-PAH using standardized description, to our knowledge. Unequivocal associations were found between (incident) SSc-PAH and capillary density and NVC pattern. Integration of NVC into current screening algorithms to boost their performance may be a future step.

Recurrent chest pain and dyspnoea in a patient with pulmonary arterial hypertension.

Background: Pulmonary arterial hypertension (PAH) is a devastating, life-threatening disease with poor prognosis when left untreated. The long-term prognosis is definitely influenced by the natural progression of PAH but late disease-specific complications may also contribute. Case summary: We present a patient with a long-standing idiopathic PAH in whom progressive dilatation of pulmonary trunk and pulmonary arteries leads to compression of the left main coronary artery and the left atrium with hemodynamic compromise. Conclusion: With the current treatment options, survival in PAH has improved. Guidelines focus on more aggressive treatment with initial combination therapy and earlier referral for transplantation.

Systemic sclerosis: state of the art on clinical practice guidelines.

Systemic sclerosis (SSc) is an orphan disease characterised by autoimmunity, fibrosis of the skin and internal organs, and vasculopathy. SSc may be associated with high morbidity and mortality. In this narrative review we summarise the results of a systematic literature research, which was performed as part of the European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases project, aimed at evaluating existing clinical practice guidelines or recommendations. Only in the domains 'Vascular & Ulcers' (ie, non-pharmacological approach to digital ulcer), 'PAH' (ie, screening and treatment), 'Treatment' and 'Juveniles' (ie, evaluation of juveniles with Raynaud's phenomenon) evidence-based and consensus-based guidelines could be included. Hence there is a preponderance of unmet needs in SSc referring to the diagnosis and (non-)pharmacological treatment of several SSc-specific complications. Patients with SSc experience significant uncertainty concerning SSc-related taxonomy, management (both pharmacological and non-pharmacological) and education. Day-to-day impact of the disease (loss of self-esteem, fatigue, sexual dysfunction, and occupational, nutritional and relational problems) is underestimated and needs evaluation.

A prospective, longitudinal study evaluating the baseline six-minute walk test as an individual reference value in systemic sclerosis patients.

OBJECTIVES: Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are the leading causes of death in systemic sclerosis (SSc). Although the six-minute walk test (6MWT) is used for evaluating ILD and PAH, no data are available on the evolution of the six-minute walk distance (6MWD) in SSc patients without ILD and PAH and whether the baseline 6MWD could serve as individual reference value for the management of those who will develop PAH or ILD. METHODS: Prospectively collected data of the first 6MWT (at baseline or 6-month follow-up) and the 6MWTs at 18-, 30-, 42-, 54-, and 66-month visit of 165 consecutive SSc patients without ILD and PAH, included in the Ghent University SSc Cohort between May 2006 and December 2016 were analysed. RESULTS: 96-100% of the included patients performed a 6MWT during the follow-up visits. The mean 6MWD during the baseline 6MWT of 165 SSc patients without ILD and PAH (35% limited, 56% limited cutaneous, 9% diffuse cutaneous SSc) was 484.20+/-92.65m with no significant difference in the 6MWD at different follow-up visits as compared to baseline. In 46 SSc patients without ILD and PAH who performed a 6MWT at baseline and at 66-month visit, the 6MWD walked at 66-month visit correlated with the baseline 6MWD (r=0.564, p<0.001). CONCLUSIONS: In SSc without ILD and PAH, the 6MWT is feasible and the 6MWD is clinically stable over a 66 months period. Hence, the individual 6MWD might be used as individual reference value in management of those who will develop PAH or ILD.

Reproducibility and Utility of the 6-minute Walk Test in Systemic Sclerosis.

OBJECTIVE: To assess the reproducibility and the utility of the 6-minute walk test (6MWT) in systemic sclerosis (SSc). METHODS: All patients with SSc who underwent at least two 6MWT within a minimum 3-month interval plus simultaneous routine clinical, biological, and functional evaluations were consecutively enrolled in this observational study over 6 years. Following American Thoracic Society guidelines, each 6MWT was repeated twice to assess the 6-minute walk distance (6MWD) reproducibility, with the highest value being reported for subsequent analysis. RESULTS: Among 56 (38 female) included patients aged 46 ± SD 12.7 years, with 17 ± 10 modified Rodnan skin score (mRSS) and 1 ± 0.8 Scleroderma Health Assessment Questionnaire (SHAQ) at first referral, 277 6MWT evaluations (5 ± 3.9 6MWT per patient) were performed over 23 ± 22.5 months followup. Meanwhile, 8 deaths (87.5% SSc-related) occurred. The mean 6MWD absolute value was 457 ± 117 m with a 4 ± 2.2 mean Borg dyspnea score. The 6MWD intraclass correlation coefficient was 0.996 (95% CI 0.995-0.999, p < 0.0001). In multivariate linear regression analysis, these factors were independently associated with a lower 6MWD: sex (R2 = 0.47, p < 0.0001), mRSS (R2 = 0.47, p = 0.008), tendon friction rub (R2 = 0.47, p = 0.003), SHAQ (R2 = 0.47, p = 0.02), muscle disability score (R2 = 0.47, p = 0.03), DLCO% (R2 = 0.47, p = 0.0008), and left ventricular ejection fraction (R2 = 0.47, p = 0.006). The 6MWD at first referral was an independent predictor for the overall mortality (HR 0.99, 95% CI 0.988-0.999) and the SSc-related mortality (HR 0.99, 95% CI 0.988-0.999). CONCLUSION: We show strong reproducibility for the 6MWD and confirm the 6MWT utility to assess the overall prognosis of patients with SSc.

Nailfold capillaroscopy in systemic lupus erythematosus: A systematic review and critical appraisal.

Nailfold capillaroscopy is an easy, non-invasive technique to assess microvascular involvement in rheumatic diseases. Multiple studies describe capillaroscopic changes in systemic lupus erythematosus (SLE), including a wide range of non-specific findings. On behalf of the European League Against Rheumatism (EULAR) study group on microcirculation in rheumatic diseases, a systematic review was done to obtain all original research studies (in English) in which SLE patients had capillaroscopy. Forty such studies are identified. This article firstly provides a résumé of the results of these studies according to capillaroscopic parameters (density, dimensions, morphology, haemorrhages), semi-quantitative assessment and qualitative assessment of capillaroscopy in SLE patients. Secondly, the correlations between capillaroscopic parameters in SLE patients and clinical and laboratory parameters (including auto-immune parameters) are outlined. The following capillaroscopic parameters are found to be significantly more prevalent in SLE patients compared to healthy controls: tortuous capillaries, abnormal morphology and haemorrhages. Hairpin-shaped capillaries are significantly less prevalent than in healthy persons. The semi-quantitatively determined nailfold capillaroscopic score (NFC score) in SLE patients is also higher than in healthy controls. Several correlations between clinical and laboratory parameters and capillaroscopic parameters are identified in the review. Disease activity is correlated with NFC score in seven studies, with abnormal morphology (i.e. "meandering") in one study and with haemorrhages in one study. Frequent attacks of Raynaud's phenomenon (RP) and gangrene are significantly correlated with dilated capillaries. In two studies a possible correlation between anti-SSA antibodies and lower density of capillaries is withheld. About other immune parameters conflicting results are found. In one study a significant negative correlation is found between 24-hour proteinuria and abnormal morphology (i.e. "meandering"). For the first time, an overview of the nailfold capillaroscopic changes that have been described in SLE and their correlations with clinical and laboratory findings is given. Further large-scale research on the identification of capillaroscopic changes in SLE and their correlations with standardised clinical and laboratory parameters, is ongoing at the EULAR study group on microcirculation in rheumatic diseases.

Two years follow-up of an open-label pilot study of treatment with rituximab in patients with early diffuse cutaneous systemic sclerosis.

OBJECTIVES: Following results in open-label studies of rituximab in patients with systemic sclerosis, a Belgian three-centre initiative was launched to explore safety and efficacy of rituximab in early, diffuse cutaneous systemic sclerosis (dcSSc). METHODS: Open-label study of 17 patients with early dcSSc, treated with two courses of rituximab, at month 0 and 6. Clinical examination, lung function testing, echocardiography, disease activity score (DAS) and functional status were performed at baseline and over 24 months of follow-up. RESULTS: Modified Rodnan skin score (MRSS) changed significantly over time, with a mean of 25.5 (standard deviation [SD] 6.0) at baseline to 12.6 (SD 5.1) at month 24 (Mixed Model Analysis [MMA] p < 0.0001), which is a decrease of 51% at month 24 vs. baseline. DAS showed significant decrease over the total study period, with a score of 4.1 (SD 1.7) at baseline to 1.5 (SD 1.8) at month 24 (MMA p < 0.0001). Additionally, this was significant at all time points vs. baseline, both for MRSS and DAS. Internal organ status remained clinically stable throughout the study period. No statistically significant differences compared to baseline were found at the follow-up time points. Seven serious adverse events took place, all except for one, considered unrelated to study medication. CONCLUSIONS: This is the first multicentre Belgian collaboration investigating potential efficacy of rituximab in early dcSSc. Rituximab appears to be safe and tolerable and it may have beneficial effects on skin involvement, on overall disease activity and on stabilization of internal organ status in early dcSSc.

An unexpected cause of liver cirrhosis and cardiomyopathy in a young man.

Introduction Juvenile hemochromatosis is a rare but severe form of hereditary hemochromatosis that typically presents early in life and can be fatal if left untreated. Case presentation We present the case of a 30-year-old man with a clear symptomatology of juvenile hemochromatosis, but in whom the diagnosis was initially mistaken for alcoholic liver disease because of known excessive use of alcohol, with the consequence that an adequate treatment was postponed. Discussion In this report, we discuss the diagnosis and treatment of juvenile hemochromatosis, focusing on the interaction between hemochromatosis and alcohol induced liver disease and how to differentiate both. We conclude that every young patient with suspected alcoholic liver disease and signs of iron overload should have a testing to rule out other iron overloading pathology, since early recognition and treatment with phlebotomy may prevent organ damage and improve life expectancy.

Screening for pulmonary arterial hypertension in an unselected prospective systemic sclerosis cohort.

Screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) improves outcomes. The DETECT screening algorithm is recommended in a high-risk SSc subgroup. This study aims to compare prospectively the positive predictive value of screening using the DETECT algorithm and the 2009 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines, and to compare their cost-effectiveness in an unselected, day-to-day SSc population. Post hoc, screening according to the 2015 ESC/ERS guidelines using echocardiographic parameters alone ("2015 echo screening") or combined with the DETECT algorithm ("2015 combined screening") in high-risk subjects was analysed.195 consecutive SSc patients included in the Ghent University Hospital SSc cohort were screened using different algorithms.The referral rate for right heart catheterisation was 32% (63 out of 195 patients) (46/4/13/34/40 patients using the DETECT algorithm/2009 guidelines/both/2015 echo screening/2015 combined screening). Right heart catheterisation was performed in 53 patients (84%) (36 (78%)/four (100%)/13 (100%)/28 (82%)/32 (80%) patients recommended by the DETECT algorithm/2009 guidelines/both/2015 echo screening/2015 combined screening). PAH was diagnosed in three patients (incidence 1.5%·year-1, 95% CI 0.5-4.4), in whom all algorithms recommended a right heart catheterisation. The positive predictive value was 6% (95% CI 2-17%; three out of 49 patients) for the DETECT algorithm, 18% (95% CI 6-41%; three out of 17 patients) for the 2009 guidelines, 23% (95% CI 8-50%; three out of 13 patients) for both, 11% (95% CI 4-27%; three out of 28 patients) for the 2015 echo screening and 9% (95% CI 3-24%; three out of 32 patients) for the 2015 combined screening. The cost was EUR224/80/90/112 per patient using the DETECT algorithm/2009 guidelines/2015 echo screening/2015 combined screening.Echocardiography may remain a candidate first step for PAH screening in SSc.

Six-minute walk test in or out in evaluation of systemic sclerosis patients?

OBJECTIVES: Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are the leading causes of death in systemic sclerosis (SSc) patients. Although the six-minute walk test (6MWT) is used for evaluating ILD and PAH in clinical practice, no data are available on six-minute walk distance (6MWD) and oxygen desaturation in SSc patients without ILD and PAH. METHODS: Prospectively collected data of the 6MWTs at baseline and 6-month follow-up of 300 consecutive SSc patients, included in the Ghent University Hospital Systemic Sclerosis Unit between May 2006 and April 2015 were analysed. RESULTS: The mean 6MWD of 165 SSc patients without ILD and PAH who performed a 6MWT at baseline or at the 6-month visit was 484±93m. Patients in the diffuse cutaneous (DcSSc) subgroup (435±94m) walked less than in the limited (LSSc) subgroup (499±91m, p=0.04) and tended to walk less than in the limited cutaneous (LcSSc) subgroup (483±92m, p=0.15). In 115 SSc patients without ILD and PAH who walked at both moments, there was no significant difference between the 6MWDs (mean difference -7.60m 95%CI [-19.93m; 4.73m], p=0.23) and the oxygen desaturation was not statistically different in 102 of them (mean difference 0.41% 95%CI [-0.49%; 1.31%], p=0.37). CONCLUSIONS: In SSc without ILD and PAH, the 6MWD and oxygen desaturation is clinically stable over a 6 months period. The DcSSc subgroup walks less than the LSSc and the LcSSc subgroup.

Stroke due to non-bacterial thrombotic endocarditis as initial presentation of breast invasive ductal carcinoma.

We present a case of a 71-year-old woman with recurrent stroke episodes due to non-bacterial thrombotic endocarditis (NBTE) leading to the diagnosis of an early-stage breast carcinoma. NBTE is associated with a variety of inflammatory states, including malignancy. NBTE presents itself with systemic embolization, mostly stroke. Treatment consists of treating the underlying condition and start of systemic anticoagulation therapy. Cardiac surgery is restricted to highly selected cases, since prognosis usually is limited by the neoplasm, which usually is in an advanced stage at time of diagnosis of NBTE. The malignancy usually is diagnosed prior to NBTE. Cases presenting with NBTE leading to the diagnosis of malignancy, however, are rarely reported. To our knowledge, we present the first case leading to the diagnosis of an early-stage breast carcinoma.