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Blood Sep 2022Sutimlimab, a first-in-class humanized immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits the classical complement pathway at C1s, rapidly halted... (Randomized Controlled Trial)
Randomized Controlled Trial
Sutimlimab, a first-in-class humanized immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits the classical complement pathway at C1s, rapidly halted hemolysis in the single-arm CARDINAL study in recently transfused patients with cold agglutinin disease (CAD). CADENZA was a 26-week randomized, placebo-controlled phase 3 study to assess safety and efficacy of sutimlimab in patients with CAD without recent (within 6 months prior to enrollment) transfusion history. Forty-two patients with screening hemoglobin ≤10 g/dL, elevated bilirubin, and ≥1 CAD symptom received sutimlimab (n = 22) or placebo (n = 20) on days 0 and 7 and then biweekly. Composite primary endpoint criteria (hemoglobin increase ≥1.5 g/dL at treatment assessment timepoint [mean of weeks 23, 25, 26], avoidance of transfusion, and study-prohibited CAD therapy [weeks 5-26]) were met by 16 patients (73%) on sutimlimab, and 3 patients (15%) on placebo (odds ratio, 15.9 [95% confidence interval, 2.9, 88.0; P < .001]). Sutimlimab, but not placebo, significantly increased mean hemoglobin and FACIT-Fatigue scores at treatment assessment timepoint. Sutimlimab normalized mean bilirubin by week 1. Improvements correlated with near-complete inhibition of the classical complement pathway (2.3% mean activity at week 1) and C4 normalization. Twenty-one (96%) sutimlimab patients and 20 (100%) placebo patients experienced ≥1 treatment-emergent adverse event. Headache, hypertension, rhinitis, Raynaud phenomenon, and acrocyanosis were more frequent with sutimlimab vs placebo, with a difference of ≥3 patients between groups. Three sutimlimab patients discontinued owing to adverse events; no placebo patients discontinued. These data demonstrate that sutimlimab has potential to be an important advancement in the treatment of CAD. This trial was registered at www.clinicaltrials.gov as #NCT03347422.
Topics: Anemia, Hemolytic, Autoimmune; Antibodies, Monoclonal, Humanized; Bilirubin; Double-Blind Method; Hemoglobins; Humans; Treatment Outcome
PubMed: 35687757
DOI: 10.1182/blood.2021014955 -
Journal of General and Family Medicine May 2021Primary acrocyanosis is a benign condition characterized by persistent blue discoloration of the peripheral extremities caused by vasospasm.
Primary acrocyanosis is a benign condition characterized by persistent blue discoloration of the peripheral extremities caused by vasospasm.
PubMed: 33977015
DOI: 10.1002/jgf2.416 -
Open Access Macedonian Journal of... Sep 2019Understanding the mechanisms of cancer immune-tolerance is one of the most important challenges. Several studies have demonstrated the potential anticarcinogenic effects... (Review)
Review
Understanding the mechanisms of cancer immune-tolerance is one of the most important challenges. Several studies have demonstrated the potential anticarcinogenic effects of beta-blockers, in patients with prostate cancer, breast cancer, and melanoma. At the other side variety of dermatoses may be caused or aggravated by β-blockers-psoriasis, lichen planus-like drug eruptions (LDE), acrocyanosis, alopecia etc. Beta-blockers have been shown to improve the prognosis of melanoma patients significantly. Propranolol inhibits melanoma by downregulating the tumour angiogenesis but also tumour cell proliferation, invasiveness and local immune suppression. Studies showed that only β3-but, not β2-adrenoceptors, were up-regulated under hypoxia in peripheral blood mononuclear cells and selectively expressed in immune cell sub-populations including Treg, MDSC, and NK. They increased NK and CD8 number and cytotoxicity. Catecholamines may retard melanoma progression and that β-blockers may have unrecognised potential as a therapeutic intervention for melanoma, in the prevention of the growth of melanoma in all stages and as adjuvant therapy with other targeted and immune therapies for melanoma.
PubMed: 31850134
DOI: 10.3889/oamjms.2019.781 -
Cold Spring Harbor Molecular Case... Feb 2022Ethylmalonic encephalopathy (MIM #602473) is a rare autosomal recessive metabolic condition caused by biallelic variants in (MIM #608451), characterized by global...
Ethylmalonic encephalopathy (MIM #602473) is a rare autosomal recessive metabolic condition caused by biallelic variants in (MIM #608451), characterized by global developmental delay, infantile hypotonia, seizures, and microvascular damage. The microvascular changes result in a pattern of relapsing spontaneous diffuse petechiae and purpura, positional acrocyanosis, and pedal edema, hemorrhagic suffusions of mucous membranes, and chronic diarrhea. Here, we describe an instructive case in which ethylmalonic encephalopathy masqueraded as meningococcal septicemia and shock. Ultrarapid whole-genome testing (time to result 60 h) and prompt biochemical analysis facilitated accurate diagnosis and counseling with rapid implementation of precision treatment for the metabolic crisis related to this condition. This case provides a timely reminder to consider rare genetic diagnoses when atypical features of more common conditions are present, with an early referral to ensure prompt biochemical and genomic diagnosis.
Topics: Brain Diseases, Metabolic, Inborn; Humans; Mitochondrial Proteins; Nucleocytoplasmic Transport Proteins; Purpura; Sepsis
PubMed: 35165146
DOI: 10.1101/mcs.a006193 -
Journal of Primary Care & Community... 2023Acrocyanosis and erythema pernio are 2 dermatologic manifestations of vasospastic changes. Primary care providers should consider that these conditions can occur as...
INTRODUCTION
Acrocyanosis and erythema pernio are 2 dermatologic manifestations of vasospastic changes. Primary care providers should consider that these conditions can occur as primary or idiopathic conditions and as secondary conditions related to another disease or medication. Herein we describe a case of acrocyanosis and erythema pernio attributed to vincristine therapy.
CASE DESCRIPTION
A 22-year-old man was evaluated for discomfort and red lesions involving the toes of both feet for several weeks. He had completed chemotherapy 1 month earlier for Ewing sarcoma in the right femur. Local control for the primary tumor included wide local excision and reconstruction with a vascularized fibular allograft from the right fibula. On examination, his right foot was dark blue and cool. Toes on both feet had nonpainful erythematous papules. After the case was discussed with the patient's oncology team, the diagnosis was medication-induced acrocyanosis of the right foot and bilateral erythema pernio. Treatment consisted of supportive care to keep the feet warm and promote circulation to the feet. At 2-week follow-up, the patient's symptoms and the appearance of his feet had markedly improved.
DISCUSSION
Primary care clinicians should be able to recognize dermatologic manifestations of vasospastic changes, including acrocyanosis and erythema pernio, and rule out possible secondary causes, such as pharmacologic agents. This patient's history of therapy for Ewing sarcoma prompted consideration of medication-induced vasospastic changes most likely related to the adverse vasospastic effects of vincristine. Symptoms should improve with cessation of the offending medication.
Topics: Male; Humans; Young Adult; Adult; Chilblains; Vincristine; Sarcoma, Ewing; Erythema
PubMed: 37335086
DOI: 10.1177/21501319231181879 -
Experimental and Therapeutic Medicine Aug 2019β-Blockers are a widely utilised class of medication. They have been in use for a variety of systemic disorders including hypertension, heart failure and intention... (Review)
Review
β-Blockers are a widely utilised class of medication. They have been in use for a variety of systemic disorders including hypertension, heart failure and intention tremors. Their use in dermatology has garnered growing interest with the discovery of their therapeutic effects in the treatment of haemangiomas, their potential positive effects in wound healing, Kaposi sarcoma, melanoma and pyogenic granuloma, and, more recently, pemphigus. Since β-blockers are deployed in a variety of disorders, which have cutaneous co-morbidities such as psoriasis, their pertinence to dermatologists cannot be overstated. Likewise, β-blockers, like any other drug category, carry risks of side effects, some of which are dermatologic. These include triggering and exacerbation of psoriasis, psoriatic and rheumatoid arthritis, anaphylaxis, contact dermatitis, occupational contact dermatitis, Raynaud's disease, alopecia, lichen planus-like drug eruption, hyperhydrosis and vitiligo. While recent articles have focussed on the positive uses of β-blockers, it may also be wise to call our attention to the potential dermatologic adverse effects that may follow β-blocker use, as well as possible therapeutic approaches to these. This short review will focus on those dermatoses resulting from β-blocker use, which have an immunologic basis.
PubMed: 31384329
DOI: 10.3892/etm.2019.7504 -
Hematology. American Society of... Dec 2022Cold-reactive autoimmune hemolytic anemia (AIHA) is rare among the hemolytic anemias. It results when 1 of a variety of processes causes the generation of immunoglobulin...
Cold-reactive autoimmune hemolytic anemia (AIHA) is rare among the hemolytic anemias. It results when 1 of a variety of processes causes the generation of immunoglobulin M (IgM) autoantibodies against endogenous erythrocytes, resulting in complement activation and predominantly intravascular hemolysis. Cold AIHA is typically a primary lymphoproliferative disorder with marrow B-cell clones producing pathogenic IgM. More rarely, secondary cold AIHA (cAIHA) can develop from malignancy, infection, or other autoimmune disorders. However, in children cAIHA is typically post infection, mild, and self-limited. Symptoms include a sequelae of anemia, fatigue, and acrocyanosis. The severity of disease is variable and highly dependent on the thermal binding range of the autoantibody. In adults, treatment has most commonly focused on reducing antibody production with rituximab-based regimens. The addition of cytotoxic agents to rituximab improves response rates, but at the expense of tolerability. Recent insights into the cause of cold agglutinin disease as a clonal disorder driven by complement form the basis of newer therapeutic options. While rituximab-based regimens are still the mainstay of therapy, options have now expanded to include complement-directed treatments and other B-cell-directed or plasma-cell-directed therapies.
Topics: Child; Adult; Humans; Anemia, Hemolytic, Autoimmune; Hemolysis; Rituximab; Autoantibodies; Erythrocytes; Immunoglobulin M; Complement System Proteins
PubMed: 36485161
DOI: 10.1182/hematology.2022000369 -
Dermatologic Therapy Nov 2020Disseminated intravascular coagulation (DIC) is linked with severe COVID-19, prompting considerable concern. DIC can be a devastating systemic disorder. It is often... (Review)
Review
Disseminated intravascular coagulation (DIC) is linked with severe COVID-19, prompting considerable concern. DIC can be a devastating systemic disorder. It is often markedly manifest on the skin as acrocyanosis or as petechiae and purpura with progression to hemorrhagic bullae. Subcutaneous hematomas may occur, as may thrombotic findings including necrosis and gangrene. The most common cause is infection, with special emphasis now on COVID-19. We have reviewed the medical literature under the search terms "Disseminated intravascular coagulation" and "consumption coagulopathy" for the past two decades in the English language using Medline and Google Scholar to update special concerns and considerations, focusing on those with COVID-19. Skin findings with DIC may be prominent. The severity of cutaneous lesions often correlates with the gravity of systemic disease. DIC is most effectively treated by addressing the underlying cause and resuscitating the patient using supportive measures. It is pivotal to recognize and treat DIC early, before deadly complications, such as multiple organ failure, arise.
Topics: Blood Coagulation; COVID-19; Disseminated Intravascular Coagulation; Early Diagnosis; Host-Pathogen Interactions; Humans; Predictive Value of Tests; Prognosis; Risk Assessment; Risk Factors; SARS-CoV-2
PubMed: 32700813
DOI: 10.1111/dth.14053 -
Acta Dermato-venereologica Dec 2021Numerous cases of chilblains have been observed in the course if the COVID-19 pandemic. The aims of this study were to provide comprehensive follow-up data for patients...
Numerous cases of chilblains have been observed in the course if the COVID-19 pandemic. The aims of this study were to provide comprehensive follow-up data for patients reporting chilblains, and to determine the risk factors for incomplete recovery. Patients referred to 5 hospitals in France between March and May 2020 for chilblains were surveyed on December 2020. A teleconsultation was offered. Among 82 patients reporting chilblains, 27 (33%) reported complete recovery, 33 (40%) had recurrences of chilblains after their hands and feet had returned to normal, and 22 (27%) developed persistent acral manifestations, mostly acrocyanosis, with or without further recurrences of chilblains. Most recurrences of chilblains occurred during the following autumn and winter. A past history of chilblains was not associated with recurrences or persistent acral manifestations. Women had a significantly higher risk of developing recurrences or persistent acral manifestations (odds ratio 1.30; 95% confidence interval 1.06-1.59). In conclusion, two-thirds of patients reporting chilblains at the start of the COVID-19 pandemic experienced persistent or recurrent acral manifestations after a 10-month follow-up.
Topics: Biopsy; COVID-19; Chilblains; Female; Humans; Pandemics; SARS-CoV-2
PubMed: 34515805
DOI: 10.2340/00015555-3930 -
Sao Paulo Medical Journal = Revista... 2022Although an association has been made between coronavirus disease 2019 (COVID-19) and microvascular disease, data on vascular complications (other than venous...
BACKGROUND
Although an association has been made between coronavirus disease 2019 (COVID-19) and microvascular disease, data on vascular complications (other than venous thromboembolism) are sparse.
OBJECTIVE
To investigate the vascular complications in severely ill patients hospitalized with COVID-19 and their association with all-cause mortality.
DESIGN AND SETTING
This cohort study was conducted at the Universidade Federal de São Paulo, Brazil.
METHODS
All 305 consecutive patients diagnosed with COVID-19 and hospitalized in the intensive care unit (ICU) of a tertiary university hospital from April 2 to July 17, 2021, were included and followed up for 30 days.
RESULTS
Of these, 193 (63.3%) were male, and the mean age was 59.9 years (standard deviation = 14.34). The mortality rate was 56.3% (172 patients), and 72 (23.6%) patients developed at least one vascular complication during the follow-up period. Vascular complications were more prevalent in the non-survivors (28.5%) than in the survivors (17.3%) group and included disseminated intravascular coagulation (DIC, 10.8%), deep vein thrombosis (8.2%), acrocyanosis (7.5%), and necrosis of the extremities (2%). DIC (adjusted odds ratio (aOR) 2.30, 95% confidence interval (CI) 1.01-5.24, P = 0.046) and acrocyanosis (aOR 5.21, 95% CI 1.48-18.27, P = 0.009) were significantly more prevalent in the non-survivors than in the survivors group.
CONCLUSION
Vascular complications in critically ill COVID-19 patients are common (23.6%) and can be closely related to the mortality rate (56.3%) until 30 days after ICU admission. Macrovascular complications have direct implications for mortality, which is the main outcome of the management of COVID-19.
REGISTRATION
RBR-4qjzh7 (https://ensaiosclinicos.gov.br/rg/RBR-4qjzh7).
Topics: Humans; Male; Middle Aged; Female; COVID-19; Cohort Studies; Brazil; Hospitalization; Intensive Care Units; Critical Illness; Retrospective Studies
PubMed: 36541953
DOI: 10.1590/1516-3180.2022.0171.R2.17102022