Cystic Fibrosis
The Contribution of Transcriptomics to Biomarker Development in Systemic Vasculitis and SLE.
The Contribution of Transcriptomics to Biomarker Development in Systemic Vasculitis and SLE.
Curr Pharm Des. 2015;21(17):2225-35
Authors: Flint SM, McKinney EF, Lyons PA, Smith KG
Abstract
A small but increasing number of gene expression based biomarkers are becoming available for routine clinical use, principally in oncology and transplantation. These underscore the potential of gene expression arrays and RNA sequencing for biomarker development, but this potential has not yet been fully realized and most candidates do not progress beyond the initial report. The first part of this review examines the process of gene expression- based biomarker development, highlighting how systematic biases and confounding can significantly skew study outcomes. Adequate validation in an independent cohort remains the single best means of protecting against these concerns. The second part considers gene-expression based biomarkers in Systemic Lupus Erythematosus (SLE) and systemic vasculitis. The type 1 interferon inducible gene signature remains by far the most studied in autoimmune rheumatic disease. While initially presented as an objective, blood-based biomarker of active SLE, subsequent research has shown that it is not specific to SLE and that its association with disease activity is considerably more nuanced than first thought. Nonetheless, it is currently under evaluation in ongoing trials of anti-interferon therapy. Other candidate markers of note include a prognostic CD8+ T-cell gene signature validated in SLE and ANCA-associated vasculitis, and a disease activity biomarker for SLE derived from modules of tightly correlated genes.
PMID: 25771200 [PubMed - indexed for MEDLINE]
Vanzacaftor, Tezacaftor and Deutivacaftor
2025 Jan 15. Drugs and Lactation Database (LactMed®) [Internet]. Bethesda (MD): National Institute of Child Health and Human Development; 2006–.
ABSTRACT
No information is available on milk or infant serum levels of vanzacaftor or deutivacaftor. Information from mother-infant pairs with elexacaftor, ivacaftor and tezacaftor indicates that tezacaftor has low levels in milk and infant serum. Deutivacaftor is a deuterated form of ivacaftor that has slower clearance, a longer half-life and greater maternal exposure. Transient mild elevations in bilirubin and liver enzymes during maternal therapy have been reported in breastfed infants whose mothers were taking another combination product containing tezacaftor and ivacaftor. Enzyme levels tended to normalize during continued breastfeeding. Until more data are available, monitoring of infant bilirubin and liver enzymes might be advisable during breastfeeding with maternal vanzacaftor, tezacaftor and deutivacaftor therapy.[1] Congenital cataracts in breastfed infants has been reported in the infants of mothers who took drugs of this class during pregnancy. Examination of breastfed infants for cataracts has been recommended.[2] Anecdotal evidence indicates that these types of drugs in breastmilk may moderate cystic fibrosis in breastfed infants.
Ivacaftor
2021 Apr 19. Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006–.
ABSTRACT
Information from one maternal-infant pair with ivacaftor and lumacaftor indicates that maternal ivacaftor therapy produce low levels in milk. An international survey of cystic fibrosis centers found no adverse effects in breastfed infants of mothers taking these drugs. A task force respiratory experts from Europe, Australia and New Zealand found that these drugs are probably safe during breastfeeding.[1] One breastfed infant had transient elevations in bilirubin and liver enzymes during maternal therapy that could not definitively be attributed to the drugs in breastmilk. Until more data are available, monitoring of infant bilirubin and liver enzymes might be advisable during breastfeeding with maternal ivacaftor therapy. Examination of breastfed infants for cataracts has also been recommended.[2]
Tezacaftor and Ivacaftor
2021 Apr 19. Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006–.
ABSTRACT
Information from one maternal-infant pair with ivacaftor and lumacaftor indicates that maternal ivacaftor therapy produce low levels in milk. An international survey of cystic fibrosis centers found no adverse effects in breastfed infants of mothers taking these drugs. A task force respiratory experts from Europe, Australia and New Zealand found that these drugs are probably safe during breastfeeding.[1] One breastfed infant had transient elevations in bilirubin and liver enzymes during maternal therapy that could not definitively be attributed to the drugs in breastmilk. Until more data are available, monitoring of infant bilirubin and liver enzymes might be advisable during breastfeeding with maternal tezacaftor and ivacaftor therapy. Examination of breastfed infants for cataracts has also been recommended.[2]
Lumacaftor and Ivacaftor
2021 Apr 19. Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006–.
ABSTRACT
Information from one maternal-infant pair with ivacaftor and lumacaftor indicates that maternal ivacaftor therapy produce low levels in milk. An international survey of cystic fibrosis centers found no adverse effects in breastfed infants of mothers taking these drugs. A task force respiratory experts from Europe, Australia and New Zealand found that these drugs are probably safe during breastfeeding.[1] One breastfed infant had transient elevations in bilirubin and liver enzymes during maternal therapy that could not definitively be attributed to the drugs in breastmilk. Until more data are available, monitoring of infant bilirubin and liver enzymes might be advisable during breastfeeding with maternal lumacaftor and ivacaftor therapy. Examination of breastfed infants for cataracts has also been recommended.[2]
Diagnostic Tests for Diabetes Mellitus
2025 Feb 7. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000–.
ABSTRACT
In this chapter, indications for screening for diabetes mellitus are reviewed. Criteria for diagnosis are fasting plasma glucose ≥ 126 mg/dl (7.0 mmol/l) or random glucose ≥200 mg/dl (11.1 mmol/l) with hyperglycemic symptoms, hemoglobin A1c (HbA1c) ≥6.5%, and oral glucose tolerance testing (OGTT) 2-h glucose ≥200 mg/dl (11.1 mmol/l) after 75 g of glucose. One-step and two-step strategies for diagnosing gestational diabetes using pregnancy-specific criteria as well as use of the 2-h 75-g OGTT for the postpartum testing of women with gestational diabetes (4-12 weeks after delivery) are described. Testing for other forms of diabetes with unique features are reviewed, including the recommendation to use the 2-h 75 g OGTT to screen for cystic fibrosis-related diabetes and post-transplantation diabetes, fasting glucose test for HIV positive individuals, and genetic testing for monogenic diabetes syndromes including neonatal diabetes and maturity-onset diabetes of the young (MODY). Elevated measurements of pancreatic islet autoantibodies (e.g., to the 65-KDa isoform of glutamic acid decarboxylase (GAD65), tyrosine phosphatase related islet antigen 2 (IA-2), insulin (IAA), and zinc transporter (ZnT8)) suggest autoimmune type 1 diabetes (vs type 2 diabetes). IAA is primarily measured in youth. The use of autoantibody testing in diabetes screening programs is recommended in first degree relatives of an individual with type 1 diabetes or in research protocols. C-peptide measurements can be helpful in identifying those who have type 1 diabetes (low or undetectable c-peptide) from those who may have type 2 or monogenic diabetes. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.
Cystic Fibrosis
2001 Mar 26 [updated 2022 Nov 10]. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022.
ABSTRACT
CLINICAL CHARACTERISTICS: Cystic fibrosis (CF) is a multisystem disease affecting epithelia of the respiratory tract, exocrine pancreas, intestine, hepatobiliary system, and exocrine sweat glands. Morbidities include recurrent sinusitis and bronchitis, progressive obstructive pulmonary disease with bronchiectasis, exocrine pancreatic deficiency and malnutrition, pancreatitis, gastrointestinal manifestations (meconium ileus, rectal prolapse, distal intestinal obstructive syndrome), liver disease, diabetes, male infertility due to hypoplasia or aplasia of the vas deferens, and reduced fertility or infertility in some women. Pulmonary disease is the major cause of morbidity and mortality in CF.
DIAGNOSIS/TESTING: The diagnosis of CF is established in a proband with:
Elevated immunoreactive trypsinogen on newborn screen, signs and/or symptoms suggestive of CF, or family history of CF; AND
Evidence of an abnormality in cystic fibrosis transmembrane conductance regulator (CFTR) function: sweat chloride ≥60 mmol/L on sweat chloride testing, biallelic CFTR CF-causing pathogenic variants, or nasal transmembrane epithelial potential difference measurement consistent with CF.
MANAGEMENT: Treatment of manifestations – targeted therapy: CFTR modulator therapy is available for individuals with responsive CFTR variants.
Supportive care: Newborns: management by a CF specialist or CF care center; airway clearance instruction; encouraging feeding with breast milk; routine vaccinations; contact precautions with every encounter; antibiotics for bacterial suppression and treatment; nutrition management; pancreatic enzyme replacement; nutrient-dense food and supplements; fat-soluble vitamin supplements; laxative treatment as needed with surgical management for bowel obstruction; and salt and water supplementation.
After the newborn period: airway clearance; pulmonary treatment (bronchodilator, hypertonic saline, dornase alfa, airway clearance, inhaled corticosteroids and/or long-acting beta agonist, and aerosolized antibiotic); standard treatments for pneumothorax or hemoptysis; double lung transplant for those with advanced lung disease; routine vaccinations including influenza; contact precautions; antibiotics for bacterial suppression and treatment; antibiotics and/or surgical intervention for nasal/sinus symptoms; nutrition management; pancreatic enzyme replacement; nutrient-dense food and supplements; fat-soluble vitamin supplements; laxative treatment as needed with surgical management for bowel obstruction; standard treatments for gastroesophageal reflux disease; oral ursodiol for biliary sludging/obstruction; liver transplant when indicated; management of CF-related diabetes mellitus by an endocrinologist; assisted reproductive technologies (ART) for infertility; salt and water supplementation; standard treatments for associated mental health issues.
Surveillance: Frequent assessment by a CF specialist to monitor for new or worsening manifestations; pulmonary function testing frequently after age five years; chest x-ray or chest CT examination to assess for bronchiectasis every two years or as needed; cultures of respiratory tract secretions at least every three months; non-tuberculosis mycobacterium culture and serum IgE annually or as indicated; annual CBC with differential; annual ENT assessment; monitoring growth and GI manifestations at each visit; fecal elastase as needed; annual serum vitamin A, D, E, and PT (as a marker of vitamin K); annual liver function tests; annual random glucose, annual two-hour glucose tolerance test beginning at age ten years; DXA scan as needed in adolescence; infertility assessment as needed; annual electrolytes, BUN, and creatinine; annual assessment of depression and anxiety.
Agents/circumstances to avoid: Environmental smoke, exposure to respiratory infections, dehydration.
Evaluation of relatives at risk: Molecular genetic testing of at-risk sibs (if the pathogenic variants in the family are known) or sweat chloride testing of at-risk sibs (if the pathogenic variants in the family are not known) to identify as early as possible those who should be referred to a CF center for initiation of early treatment.
GENETIC COUNSELING: CF is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a CFTR pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the CFTR pathogenic variants have been identified in an affected family member, targeted heterozygote testing for at-risk relatives and prenatal/preimplantation genetic testing for CF are possible.