Angiotensin-converting enzyme 1 gene polymorphisms in patients with systemic sclerosis-associated interstitial lung disease: a single centre retrospective observational study.

Angiotensin-converting enzyme (ACE) 1 gene polymorphisms have been associated with vascular permeability, alveolar endothelial dysfunction and fibroblast proliferation and have been studied in pulmonary diseases such as COPD and idiopathic pulmonary fibrosis. Similar mechanisms of ACE 1 polymorphisms have been seen in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD). We are presenting a retrospective observational study in patients with SSc-ILD and analysing the association of ACE 1 gene polymorphisms (DD, II and ID) with the features of SSc, changes in pulmonary function tests (PFTs) and lung HRCT over three different periods of time (at the time of the diagnosis, 5 and 10 years after the diagnosis). The aim of the study was to determine whether ACE 1 gene polymorphisms have an effect on the severity of SSc-ILD. We found no statistically significant differences in the development and severity of SSc-ILD and changes in PFTs between subgroups of ACE 1 gene polymorphism over the analysed periods (at the time of diagnosis HRCT changes p = 0.270, FEV1 p = 0.483, FVC p = 0.497, DLco p = 0.807, after 5 years HRCT changes p = 0.163, FEV1 p = 0.551, FVC p = 0.362, DLco p = 0.620 and 10 years of follow-up HRCT changes p = 0.853, FEV1 p = 0.589, FVC p = 0.328, DLco p = 0.992). However, patients with the ID genotype showed a significant reduction in FEV1 after 10 years of follow-up in comparison to baseline levels (91.0 (IR 80.0-105.0) at the time of diagnosis and 84.0 (IR 69.0-99.0) after 10 years, p = 0.014). Our study suggests that ACE 1 gene polymorphisms do not have a role in the severity of SSc-ILD. Further studies are needed to explain the exact role of ACE 1 gene polymorphisms in SSc-ILD and SSc in general.

Secondary antibody deficiency is associated with development of infection in kidney transplantation: Results of a multicenter study.

BACKGROUND: We performed a multicenter study to assess the association between secondary antibody deficiency (immunoglobulin G [IgG] hypogammaglobulinemia combined with low levels of specific antibodies) and development of infection in kidney transplantation. METHODS: We prospectively analyzed 250 adult kidney recipients at four centers. The assessment points were before transplantation and 7 and 30 days after transplantation. The immune parameters were as follows: IgG, IgA, and IgM and complement factors C3 and C4 tested by nephelometry; specific IgG antibodies to cytomegalovirus (CMV) and IgG and IgG2 antibodies to pneumococcal polysaccharide (anti-PPS) determined using enzyme-linked immunosorbent assay. The clinical follow-up period lasted 6 months. The clinical outcomes were CMV disease and recurrent bacterial infections requiring antimicrobial therapy. STATISTICS: Multivariate logistic regression. RESULTS: At day 7, IgG hypogammaglobulinemia (IgG levels < 700 mg/dL) combined with low IgG anti-CMV antibody titers (defined as levels < 10 000 units) was present in 12% of kidney recipients. IgG hypogammaglobulinemia combined with low IgG anti-PPS antibody titers (defined as levels < 10 mg/dL) at 1 month after kidney transplantation were recorded in 16% of patients. At day 7 the combination of IgG hypogammaglobulinemia and low anti-CMV titers was independently associated with the development of CMV disease (odds ratio [OR], 6.95; 95% confidence interval [CI], 1.17-41.31; P = .033). At day 30 after transplantation, the combination of IgG < 700 mg/dL and IgG anti-PPS < 10 mg/dL, was independently associated with recurrent bacterial infection (OR, 5.942; 95% CI, 1.943-18.172; P = .002). CONCLUSION: In a prospective multicenter study, early immunologic monitoring of secondary antibody deficiency proved useful for the identification of kidney recipients who developed severe infection.

[Guidelines for the diagnosis and treatment of hereditary angioedema]. / Smjernice za dijagnostiku i lijecenje hereditarnog angioedema.

Hereditary angioedema (HAE) is a rare but potentially fatal genetic disorder with nonpitting, nonerythematous, and not pruritic swelling which can affect the hands, feet, face, genitals and visceral mucosa. The type, frequency, and severity of the attacks vary between patients, and over the lifetime of an individual patient. Efforts in Croatian counties have identified approximately 100 patients (but there must be more undiagnosed patients). The first global guideline for the management of HAE was developed by the World Allergy Organization HAE International Alliance and published in 2012. Based on that document the Working group of Croatian experts was assigned to propose guideline for HAE management in Croatia. HAE is is most often related to decreased or dysfunctional C1 inh with autoactivation of C1 and bradykinin accumulation leading to localized dilatation and increased permeability of blood vessels resulting in tissue swelling. A diagnosis of HAE can be confirmed by measuring complement and C1 inh quantitative and functional levels.Three HAE types could be differentiated: HAE type 1 (C1 inh level is low), HAE type 2 (C1 inh level is normal but dysfunctional), and HAE type 3 (normal level and function of C1 inh). All patients suspected to have HAE-1/2 should be assessed for blood levels of C4, C1 inh protein, and C1 inh function. All attacks that result in debilitation/dysfunction and/or involve the face, the neck, or the abdomen should be considered for on-demand treatment. It is recommended that attacks are treated as early as possible. HAE attacks are treated with C1 inh, ecallantide, or icatibant.If these drugs are not available, attacks should be treated with solvent detergent-treated plasma (SDP). If SDP is not available, then attacks should be treated with frozen plasma.Intubation or tracheotomy should be considered early in progressive upper airway edema. Patients with attacks could receive adjuvant therapy when indicated (pain management, intravenous fluids). All patients should have on-demand treatment for two attacks and carry their on-demand treatment at all times. The administration of short-term prophylaxis should be considered before surgeries (dental/intraoral surgery, where endotracheal intubation is required), where upper airway or pharynx is manipulated, and before bronchoscopy or endoscopy. Long-term prophylaxis should be considered in all severely symptomatic HAE-1/2 patients. C1 inh concentrate or androgens can be used. Screening children for HAE-1/2 should be deferred until the age of 12 months, and all offspring of an affected parent should be tested.

Real world experience with nintedanib in connective tissue disease-related interstitial lung disease: a retrospective cohort study.

Various connective tissue diseases tend to affect specific organs, lungs being the organ with the most serious repercussions and consequences. The diagnosis of interstitial lung disease makes the treatment more difficult and worsens long-term prognosis and overall survival. Positive results from the registration studies of nintedanib led to approval of the drug for the treatment of idiopathic pulmonary fibrosis and chronic fibrosing interstitial lung diseases in connective tissue diseases. After registration, real-world data on the use of nintedanib are being collected in everyday clinical practise. The objective of the study was to collect and analyse real world experience gathered after the registration of nintedanib for the treatment of CTD-ILD and to show if the positive results collected from a homogeneous and "representative" study population can be applied to everyday clinical practice. We are presenting a retrospective observational case-series study of patients treated with nintedanib from the three largest Croatian centers specialised in the treatment of connective tissue diseases with interstitial lung diseases. Stabilisation or improved of lung function tests was reported in 68% of patients when changes in predicted FVC were observed and in 72% of patients when changes in DLco were analysed. Almost all of the reported patients (98%) were treated with nintedanib as an add-on drug to immunosuppressants. The most common side-effects were gastrointestinal symptoms and abnormal liver function tests in less extent. Our real-world data confirm the tolerability, efficacy and similar side-effects of nintedanib as reported in pivotal trials. Key Points • Interstitial lung disease is a common manifestation of several connective tissue diseases and its progressive fibrosing phenotype contributes to high mortality rate and many unmet needs regarding the treatment remain. • Registration studies of nintedanib obtained sufficient data and positive results to support approval of the drug. • Real-world evidence from our CTD-ILD centres confirm the clinical trial data regarding efficacy, tolerability and safety of nintedanib.

Ultrasonic Evaluation of Diaphragm in Patients with Systemic Sclerosis.

The diaphragm is the most important muscle in respiration. Nevertheless, its function is rarely evaluated. Patients with systemic sclerosis (SSc) could be at risk of diaphragmatic dysfunction because of multiple factors. These patients often develop interstitial lung disease (SSc-ILD) and earlier studies have indicated that patients with different ILDs have decreased diaphragmatic mobility on ultrasound (US). This study aimed to evaluate diaphragmatic function in SSc patients using US with regard to the ILD, evaluated with the Warrick score on high-resolution computed tomography (HRCT), and to investigate associations between ultrasonic parameters and dyspnea, lung function, and other important clinical parameters. In this cross-sectional study, we analyzed diaphragm mobility, thickness, lung function, HRCT findings, Modified Medical Research Council (mMRC) dyspnea scale, modified Rodnan skin score (mRSS), autoantibodies, and esophageal diameters on HRCT in patients with SSc. Fifty patients were enrolled in the study. Patients with SSc-ILD had lower diaphragmatic mobility in deep breathing than patients without ILD. The results demonstrated negative correlations between diaphragmatic mobility and mMRC, mRSS, anti-Scl-70 antibodies, esophageal diameters on HRCT, and a positive correlation with lung function. Patients with SSc who experience dyspnea should be evaluated for diaphragmatic dysfunction for accurate symptom phenotyping and personalized pulmonary rehabilitation treatment.

Misleading symptoms of hereditary angioedema type II mimicking familial mediterranean fever.

Hereditary angioedema (HAE) is a rare, debilitating and potentially life-threatening disease characterized by recurrent attacks of oedema. With the development of new therapies and better availability of diagnostic tools, important advances have been made. However, the disease still remains frequently misdiagnosed and inadequately treated. Familial Mediterranean fever (FMF) is an autoinflammatory syndrome comprised of serositis, fever, arthritis and skin involvement. Both diseases can cause severe abdominal pain resembling that of acute abdomen. We report a case of three family members that presented with various symptoms that could fit in a clinical picture of both diseases, only to confirm a diagnosis of HAE type II after a diagnostic delay of many years.