ABSTRACT
Background: Graft-versus-host disease (GVHD) is a potentially fatal complication of allogeneic hematopoietic stem cell transplant. The mainstay of treatment is corticosteroids, which are ineffective in 30-50% of cases. Steroid-refractory GVHD (SR-GVHD) confers a poor prognosis, with high mortality rates despite appropriate therapy. While there is no reliable treatment for SR-GVHD, a variety of novel therapeutic options are slowly emerging and have yet to be examined simultaneously. Objectives: This review evaluates the potential of novel therapeutic options, as well as their efficacy and safety, for the treatment of SR-GVHD. Study Design. The literature search was conducted in PubMed, Cochrane, and Embase, employing MeSH terms and keywords. The studies had to be prospective phases 1, 2, or 3. We excluded retrospective and nonoriginal studies. Results: While the only approved drug for acute GVHD is ruxolitinib with an impressive overall response rate of 73.2% and a complete response of 56.3%, several monoclonal antibodies and other agents are currently under investigation, offering promising results. These include anti-CD2, anti-CD147, IL-2 antagonist, a mixture of anti-CD3 and anti-CD7 antibodies, anti-CD25, monoclonal antibody to a4b7 on T-cells, anti-CD26, pentostatin, sirolimus, denileukin diftitox, infliximab, itacitinib, and alpha-1 antitripsin. However, the toxicities associated with these novel drugs need further investigation. For chronic GVHD, approved options include ruxolitinib with an ORR of up to 62%, ibrutinib with an ORR of up to 77%, and belumosudil with an ORR of up to 77%. Meanwhile, emerging treatments include tyrosine kinase inhibitors such as nilotinib, rituximab, and low-dose IL-2, as well as axatilimab and pomalidomide. Conclusion: While their efficacy needs to be better evaluated through large-scale, multicenter, randomized clinical trials, these novel agents show potential and could provide a better alternative for SR-GVHD treatment in the future.
ABSTRACT
OBJECTIVE: Previous basic and cross-sectional studies obtained conflicting results regarding the association of pathogens with coronary artery calcium (CAC). The aim of this study is to prospectively evaluate this association in a population-based cohort. METHODS: We examined 5744 individuals aged 45-84 years at baseline (2000-02) who underwent repeated CAC assessment on average 2.4 years later (a half at visit 2 [2002-04] and the other half at visit 3 [2004-05]). CAC incidence was defined as newly detectable CAC at follow-up (475 cases of 2942 participants). CAC progression was defined as annualized change in CAC Agatston score ≥10 units/year if baseline CAC score >0 to <100 or ≥10%/year if baseline score ≥ 100 (1537 cases of 2802 participants). Seropositivity was assessed in the entire cohort for Chlamydia pneumoniae and in a random sample (n = 873) for Helicobacter pylori, cytomegalovirus, herpes simplex virus, and hepatitis A virus. RESULTS: Seropositivity to C. pneumoniae was not significantly associated with CAC incidence (odds ratio [OR] 1.11 [95% CI, 0.88-1.39], P = 0.371) or progression (1.14 [0.96-1.36], P = 0.135) even in unadjusted models. When CAC incidence and progression were combined, we observed significant association with C. pneumoniae seropositivity before adjustment (OR 1.17 [1.03-1.33], P = 0.016) but not in a model adjusting for traditional risk factors (1.04 [0.90-1.19], P = 0.611). The results were consistent across subgroups according to age, sex, and race/ethnicity. None of five pathogens or their accrual was associated with CAC incidence and progression in the subsample. CONCLUSION: Our prospective study does not support the pathophysiological involvement of these pathogens in CAC development.
