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1.
Tocilizumab for coronavirus disease 2019 in pregnancy and lactation: a narrative review.
Jorgensen, SCJ, Lapinsky, SE
Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2022;(1):51-57
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Abstract
BACKGROUND Tocilizumab is a monoclonal antibody that interrupts interleukin-6 signalling, reducing downstream effects on inflammation and the innate immune response. It was shown to reduce mortality in patients with severe or critical coronavirus disease 2019 (COVID-19). Pregnant and breastfeeding people were largely excluded from clinical trials and hence, the extent to which results can be applied to these populations is not clear. OBJECTIVES To synthesize published data on tocilizumab in pregnancy and lactation, highlight important knowledge gaps, and help inform clinical decision-making about tocilizumab's use in these populations with COVID-19. SOURCES PubMed was searched for studies evaluating tocilizumab in pregnancy and lactation for COVID-19 and other indications. Literature on pharmacokinetics and reproductive/fetal safety of monoclonal antibodies in general was also sought. The US Food and Drug Administration and the European Medicines Agency guidance for the industry and regulatory approval documents were reviewed. CONTENT Published data on tocilizumab in pregnancy include 610 cases (n = 20 with COVID-19) together with seven mother-infant breastfeeding pairs. Higher rates of spontaneous abortion and premature birth have been reported compared with the general population, but multiple confounding variables limit interpretation. There is little data on tocilizumab exposure in the second and third trimesters when transplacental transport is highest. The effects of tocilizumab on the developing immune system are unclear. Pregnant patients with COVID-19 who received tocilizumab were often critically ill and corticosteroid use was uncommon. Neonatal follow up was limited. Tocilizumab appears to be compatible with breastfeeding. IMPLICATIONS Although the available data do not raise serious safety signals, they have significant limitations and are not sufficient to delineate the complete spectrum of potential adverse outcomes that may be associated with tocilizumab exposure during pregnancy and lactation. Diligent follow up and documentation of pregnancy outcomes will be important moving forward. A more effective regulatory framework to ensure equitable inclusion of pregnant people in research is clearly needed.
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COVID-19 and IL-6: Why vitamin D (probably) helps but tocilizumab might not.
Silberstein, M
European journal of pharmacology. 2021;:174031
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Abstract
Interleukin 6 (IL-6), which is involved in the cytokine storm phenomenon, is a therapeutic target in COVID-19, but monoclonal receptor antibody therapeutic agents such as tocilizumab have demonstrated mixed results. Could Vitamin D, which modulates IL-6, be more effective than currently deployed IL-6 antagonists, including tocilizumab, thereby presenting a useful therapeutic option in COVID-19? A narrative review of published trials examining the effect of Vitamin D administration in COVID-19 patients was conducted, and the theoretical basis for the use of tocilizumab as an IL-6 antagonist was compared with the immunomodulatory effect of Vitamin D on IL-6 production. Four of the six included studies reported a positive effect of Vitamin D on outcomes. While tocilizumab non-selectively blocks both anti-inflammatory and pro-inflammatory actions of IL-6, Vitamin D lowers immune cell IL-6 production, potentially reducing pro-inflammatory effects, but does not specifically target IL-6 receptors, avoiding any deleterious effect on the anti-inflammatory actions of IL-6. Vitamin D may have advantages over tocilizumab as an IL-6 immunomodulator, and, given that it is safe if administered under clinical supervision, there is a strong rationale for its use.
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X-Linked Hypophosphatemic Rickets: Multisystemic Disorder in Children Requiring Multidisciplinary Management.
Baroncelli, GI, Mora, S
Frontiers in endocrinology. 2021;:688309
Abstract
X-linked hypophosphatemic rickets (XLH) is the commonest inherited form of rickets. It is caused by an impaired regulation of fibroblast growth factor 23 (FGF23) due to a PHEX gene mutation, which leads to reduced tubular reabsorption of phosphate and renal 1α-hydroxylase activity and increased renal 24-hydroxylase activity. Hypophosphatemia associated with renal phosphate wasting, normal serum levels of calcium, parathyroid hormone, and 25-hydroxyvitamin D represents the main biochemical sign in affected patients. Patients with XLH show rickets and osteomalacia, severe deformities of the lower limbs, bone and muscular pain, stunted growth, and reduced quality of life. However, XLH is a multisystemic disorder requiring multidisciplinary approaches in specialized subdisciplines. Severe complications may occur in patients with XLH including craniosynostosis, hearing loss, progressive bone deformities, dental and periodontal recurrent lesions, and psychosocial distress. Moreover, long-term conventional treatment with active vitamin D metabolites and oral inorganic phosphate salts may cause endocrinological complications such as secondary or tertiary hyperparathyroidism, and adverse events in kidney as hypercalciuria, nephrocalcinosis, and nephrolithiasis. However, conventional treatment does not improve phosphate metabolism and it shows poor and slow effects in improving rickets lesions and linear growth. Recently, some trials of treatment with recombinant human IgG1 monoclonal antibody that targets FGF23 (burosumab) showed significant improvement of serum phosphate concentration and renal tubular reabsorption of phosphate that were associated with a rapid healing of radiologic signs of rickets, reduced muscular and osteoarticular pain, and improved physical function, being more effective for the treatment of patients with XLH in comparison with conventional therapy. Therefore, a global management of patients with XLH is strongly recommended and patients should be seen regularly by a multidisciplinary team of experts.
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Membranous nephropathy associated with multicentric Castleman's disease that was successfully treated with tocilizumab: a case report and review of the literature.
Saiki, R, Katayama, K, Hirabayashi, Y, Oda, K, Fujimoto, M, Murata, T, Nakajima, A, Dohi, K
BMC nephrology. 2021;(1):216
Abstract
BACKGROUND Multicentric Castleman's disease is a life-threatening disorder involving a systemic inflammatory response and multiple organ failure caused by the overproduction of interleukin-6. Although renal complications of Castleman's disease include AA amyloidosis, thrombotic microangiopathy, and membranoproliferative glomerulonephritis, membranous nephropathy is relatively rare. We experienced a case of secondary membranous nephropathy associated with Castleman's disease. CASE PRESENTATION The patient was a 43-year-old Japanese man who had shown a high zinc sulfate value in turbidity test, polyclonal hypergammaglobulinemia, anemia, and proteinuria. A physical examination revealed diffuse lymphadenopathy, an enlarged spleen and papulae of the body trunk. A skin biopsy of a papule on the patient's back showed plasma cells in the perivascular area and he was diagnosed with multicentric Castleman's disease, plasma cell variant. Kidney biopsy showed the appearance of bubbling in the glomerular basement membranes in Periodic acid methenamine silver stain and electron microscopy revealed electron dense deposits within and outside the glomerular basement membranes. Since immunofluorescence study showed predominant granular deposition of IgG1 and IgG2, he was diagnosed with secondary membranous nephropathy associated with Castleman's disease. He was initially treated with prednisolone alone, however his biochemical abnormalities did not improve. After intravenous tocilizumab (700 mg every 2 weeks) was started, his C-reactive protein elevation, anemia, and polyclonal gammopathy improved. Furthermore, his urinary protein level declined from 1.58 g/gCr to 0.13 g/gCr. The prednisolone dose was gradually tapered, then discontinued. He has been stable without a recurrence of proteinuria for more than 6 months. CONCLUSIONS Tocilizumab might be a treatment option for secondary membranous nephropathy associated with Castleman's disease.
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Coronavirus disease 2019 (COVID-19) in a patient with ankylosing spondylitis treated with secukinumab: a case-based review.
Coskun Benlidayi, I, Kurtaran, B, Tirasci, E, Guzel, R
Rheumatology international. 2020;(10):1707-1716
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Abstract
Severe acute respiratory syndrome coranovirus-2 (SARS-CoV-2) infection has become an important health-care issue worldwide. The coronavirus disease 2019 (COVID-19) has also raised concerns among patients with inflammatory rheumatic conditions and their treating physicians. There are emerging data regarding the potential risks of SARS-CoV-2 for this particular patient group. However, less is known with regard to the course of COVID-19 among patients receiving IL-17 inhibitors. The aim of the current article is to review the growing body of knowledge on the course/management of COVID-19 in patients with inflammatory rheumatic diseases by presenting a SARS-CoV-2 infected case with ankylosing spondylitis under secukinumab therapy. A 61-year old patient with ankylosing spondylitis who was on secukinumab therapy for 5 months admitted with newly onset fever and gastrointestinal complaints. After being hospitalized, she developed respiratory manifestations with focal pulmonary ground-glass opacities and multiple nodular densities in both lungs. The patient was tested positive for SARS-CoV-2 infection. Substantial clinical improvement was obtained following a management plan, which included tocilizumab, hydroxychloroquine, prednisolone and enoxaparin sodium. PubMed/MEDLINE and Scopus databases were searched by using relevant keywords and their combinations. The literature search revealed four articles reporting the clinical course of COVID-19 in seven rheumatic patients on secukinumab. The clinical course of SARS-CoV-2 infection was mild in most of these patients, while one of them experienced severe COVID-19. Interleukin-17 has been related to the hyperinflammatory state in COVID-19 and IL-17 inhibitors were presented as promising targets for the prevention of aberrant inflammation and acute respiratory distress in COVID-19. However, this hypothesis still remains to be proved. Further studies are warranted in order to test the benefits and risks of IL-inhibitors in SARS-CoV-2 infected individuals.
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Predictive role of vitamin A serum concentration in psoriatic patients treated with IL-17 inhibitors to prevent skin and systemic fungal infections.
Campione, E, Cosio, T, Lanna, C, Mazzilli, S, Ventura, A, Dika, E, Gaziano, R, Dattola, A, Candi, E, Bianchi, L
Journal of pharmacological sciences. 2020;(1):52-56
Abstract
The use of biological drugs in psoriasis is replacing traditional therapies due to their specific mechanism and limited side effects. However, the use of Interleukin 17 inhibitors and the modification of its cytokine pathway could favor the risk of fungal infections. All-trans retinoic acid is an active metabolite of vitamin A with anti-inflammatory and immunoregulatory properties through its capacity to stimulate both innate and adaptive immunity and to its effects on proliferation, differentiation and apoptosis in a variety of immune cells. Furthermore, it has been recently discovered that All-trans retinoic acid has a direct fungistatic effect against Candida and Aspergillus Fumigatus. On the basis of these new insights, in the current review, we suggest that the evaluation of serum level of All-trans retinoic acid or vitamin A should be considered as a predictive marker for the development of fungal infections among psoriatic patients treated with Interleukin 17 inhibitors. In clinical practice, vitamin A test could be added in the routine hospital diagnostic management for a better selection of psoriatic patients eligible to Interleukin 17 inhibitors.
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Bullous dermatoses secondary to anti-PD-L1 agents: a case report and review of the literature.
Kosche, C, Owen, JL, Sadowsky, LM, Choi, JN
Dermatology online journal. 2019;(10)
Abstract
Immune checkpoint inhibitors are used to treat numerous malignancies but may be associated with severe adverse events. Bullous dermatoses, chiefly bullous pemphigoid (BP), are potentially progressive adverse events that cause blistering skin lesions and may involve a significant body surface area. Herein, we report an 87-year-old man with urothelial cell carcinoma undergoing atezolizumab treatment who presented with an acute-onset blistering eruption. Biopsy revealed a subepidermal bulla, direct immunofluorescence revealed linear IgG and C3 deposits at the dermal-epidermal junction, and serum studies revealed elevated levels of antibodies to BP180 and BP230. Anti-PD-L1-induced BP was diagnosed, immunotherapy was withheld, and he was treated with oral doxycycline with niacinamide and clobetasol ointment. He restarted atezolizumab and has successfully received four cycles (every 3 weeks) while continuing this BP treatment regimen. A literature review revealed eight other cases of anti-PD-L1-induced bullous disorders. The incidence of bullous dermatoses with anti-PD-1/anti-PD-L1 agents combined is 1%, whereas the reported incidence for anti-PD-L1 agents alone ranges from 1.3-5%, raising concerns for a higher overall risk. In addition to our case, only one other case reported successful resumption of immunotherapy. Early control and management of immunotherapy-induced BP may reduce complications and prevent treatment discontinuation.
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Critical roles of inflammation in atherosclerosis.
Moriya, J
Journal of cardiology. 2019;(1):22-27
Abstract
There is accumulating evidence that vascular inflammation plays critical roles in pathophysiology of atherosclerosis. It is widely accepted that both innate and adaptive immune responses are important for initiation and progression of atherosclerosis, which mainly consist of monocytes, macrophages, neutrophils, T lymphocytes, and B lymphocytes. Moreover, inflammatory biomarkers such as high-sensitivity C-reactive protein and interleukin-6 are known to predict future cardiovascular events, as well as conventional low-density or high-density lipoprotein cholesterol. Thus, current understanding of the inflammatory mechanisms of atherosclerosis have led us to explore novel therapeutic approaches that reducing vascular inflammation itself could lower the rates of critical cardiovascular events. To address the inflammatory hypothesis of atherosclerosis, results of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) trial have been recently reported that anti-inflammatory therapy using canakinumab, a monoclonal antibody targeting interleukin-1β, significantly reduced recurrent cardiovascular events for secondary prevention of myocardial infarction at high inflammatory risk. In this review, we will first outline the mechanisms of atherosclerosis, especially focusing on their inflammatory aspects. Then we will introduce several critical inflammatory biomarkers that contribute to risk stratification of clinical cardiovascular events. Lastly, we will discuss potentiality and future perspectives of reducing inflammation as a novel therapeutic target for atherosclerotic cardiovascular diseases.
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Association of baseline LDL-C with total and cardiovascular mortality in patients using proprotein convertase subtilisin-kexin type 9 inhibitors: A systematic review and meta-analysis.
Khan, SU, Riaz, H, Rahman, H, Khan, MU, Khan, MS, Alkhouli, M, Kaluski, E, Leucker, TM, Blaha, MJ
Journal of clinical lipidology. 2019;(4):538-549
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Abstract
BACKGROUND The objective of this study was to investigate whether baseline low-density lipoprotein cholesterol (LDL-C) levels influence total and cardiovascular mortality reduction associated with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor therapy. METHODS In this meta-analysis, 9 randomized controlled trials were selected using Medline, Embase, and CENTRAL until November 2018. Analyses were stratified by mean baseline LDL-C (<100 mg/dL and ≥ 100 mg/dL). Stepwise prespecified sensitivity analyses were performed after excluding the SPIRE trials and by regrouping ODYSSEY OUTCOME mortality data according to the baseline LDL-C (< and ≥100 mg/dL). RESULTS In 83,321 patients, PCSK9 inhibitor therapy was not associated with a reduction in the risk of all-cause mortality (relative risk [RR], 0.94, 95% confidence interval [CI], 0.81-1.09, P = .41). These results remained consistent after excluding the SPIRE trials (RR, 0.89, 95% CI, 0.75-1.05, P = .18). However, the RR varied by baseline LDL-C, with significant RR reduction only in patients with LDL-C ≥ 100 mg/dL (RR, 0.39, 95% CI, 0.20-0.76) (P-interaction = .01). Meta-regression showed RR of 0.97 for all-cause mortality per 1 mg/dL higher baseline LDL-C (95% CI, 0.94-0.99). PCSK9 inhibitor therapy showed no significant effect on cardiovascular mortality, with no effect when excluding the SPIRE trials. However, after regrouping ODYSSEY OUTCOME estimates, there was a significant reduction in cardiovascular mortality restricted to patients with LDL-C ≥ 100 mg/dL (RR, 0.67, 95% CI, 0.51-0.87) (P-interaction = .006). CONCLUSION PCSK9 inhibitor therapy on a background statin treatment may reduce the risk of total and cardiovascular mortality in patients with baseline LDL-C ≥ 100 mg/dL. These results support current guidelines reserving PCSK9 inhibitors for high-risk patients with residually high LDL-C.
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Harnessing the Immune System in Pancreatic Cancer.
Das, S, Berlin, J, Cardin, D
Current treatment options in oncology. 2018;(10):48
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Abstract
Managing patients with metastatic pancreatic adenocarcinoma (mPDA) is a challenging proposition for any treating oncologist. Although the potency of first-line therapies has improved with the approvals of FOLFIRINOX and gemcitabine plus nab-paclitaxel, many patients are unable to derive significant benefit from later lines of therapy upon progression. Enrollment on clinical trials remains among the best options for patients with mPDA in all lines of therapy. At our institution, we routinely check for microsatellite instability (MSI-H) and perform next-generation sequencing (NGS) at the time of diagnosis in all good performance status mPDA patients. Although MSI-H status is only found in 1% of patients with mPDA, given pembrolizumab's tissue-agnostic approval for MSI-H tumors in later-line settings, it is a viable option when deciding on subsequent lines of therapy. Any use of immune therapy in mPDA is investigational outside the MSI-H setting. NGS can identify BRCA or other DNA damage response (DDR) defects in patients which can predict sensitivity to platinum-based therapies and influence choice of both initial and later lines of therapy. It can also identify rare actionable genomic alterations such as HER2 (2%) and TRK fusions (0.1%) and offer patients the option of enrollment on clinical trials with agents targeting these or other identified alterations. We believe enrolling mPDA patients on clinical trials with immune-modulating agents is critical to determine if there are other patient subsets, outside of the MSI-H setting, who would benefit from these approaches. Immunotherapy's general tolerability and potential to generate durable responses make it particularly appealing for mPDA patients. Although single-modality immunotherapy such as checkpoint inhibitors or vaccines have not demonstrated efficacy in this disease, combinatorial strategies targeting unique aspects of PDA including the tumor microenvironment and desmoplastic stroma have shown preclinical or early-phase success. Validating these treatments with later-phase prospective studies is essential to making immunotherapy a routine component of the treatment armamentarium for mPDA patients.