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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 -
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 -
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 -
Open Access Macedonian Journal of... Jan 2018Acrocyanosis is an uncommon complaint belonging to the acro-syndromes. It typically presents with coolness and bluish discolourations of hands, feet, ears, nose, lips... (Review)
Review
Acrocyanosis is an uncommon complaint belonging to the acro-syndromes. It typically presents with coolness and bluish discolourations of hands, feet, ears, nose, lips and nipple. The most frequently affected parts of the body are the hands. This review discusses physical factors, vascular disorders, infectious diseases, haematological disorders, solid tumours genetic disorders, drugs, eating disorders, and spinal disease presenting as or leading to acrocyanosis.
PubMed: 29484025
DOI: 10.3889/oamjms.2018.035 -
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 -
Indian Journal of Dermatology 2017Approximately, 140 million people worldwide live permanently at high altitudes (HAs) and approximately another 40 million people travel to HA area (HAA) every year for...
Approximately, 140 million people worldwide live permanently at high altitudes (HAs) and approximately another 40 million people travel to HA area (HAA) every year for reasons of occupation, sports or recreation. In India, whole of Ladakh region, part of Northwest Kashmir, Northern part of Sikkim and Tenga valley of Arunachal are considered inhabited areas of HAA. The low quantity of oxygen, high exposure of ultraviolet (UV) light, very low humidity, extreme subzero temperature in winter, high wind velocity, make this region difficult for lowlanders as well as for tourists. Acute mountain sickness, HA pulmonary edema, HA cerebral edema, and thromboembolic conditions are known to occur in HA. However, enough knowledge has not been shared on dermatoses peculiar to this region. Xerosis, UV-related skin disorders (tanning, photomelanosis, acute and chronic sunburn, polymorphic light eruption, chronic actinic dermatitis, actinic cheilitis, etc.), cold injuries (frostbite, chilblains, acrocyanosis, erythrocyanosis, etc.) nail changes (koilonychias), airborne contact dermatitis, insect bite reaction, and skin carcinoma (basal cell carcinomas, squamous cell carcinomas, and also rarely malignant melanoma) are the dermatoses seen in HAAs. Early diagnosis and knowledge of HA dermatoses may prevent serious consequences of disease and improve the quality of life for the visitors as well as for native of the place.
PubMed: 28216727
DOI: 10.4103/0019-5154.198050 -
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 -
Journal of Vascular Surgery. Venous and... Oct 2016The spectrum of chronic venous disease (CVD) is well documented in adults; clinical guidelines standardize diagnosis and treatment. There is a paucity of data published...
BACKGROUND
The spectrum of chronic venous disease (CVD) is well documented in adults; clinical guidelines standardize diagnosis and treatment. There is a paucity of data published commenting on pediatric CVD exclusive of Klippel-Trénaunay syndrome (KTS) and post-thrombotic syndrome.
METHODS
This study aimed to define patterns of pediatric venous disease. All venous reflux studies performed on patients <18 years of age between January 2012 and June 2014 were reviewed. Study indication, patient history, clinical examination, and duplex ultrasound results were queried and described. Venous reflux parameters were compared using one-way analysis of variance.
RESULTS
Twenty patients were evaluated. All presented through the vascular surgery or multidisciplinary venous clinic at a tertiary academic medical center. Indications for referral included swelling (n = 10), varicose veins (n = 9), and rubor/acrocyanosis (n = 3); two patients carried a diagnosis of KTS. Mean age at study was 13 years (range, 5-17 years). Clinical examination revealed the following: dependent rubor (n = 3); edema (n = 9); and varicose veins or venous abnormality concerning for venous malformation (n = 9). There were no stigmata of chronic inflammation, hyperpigmentation, or ulceration; 90% of patients (n = 18) demonstrated venous reflux by duplex ultrasound interrogation. Mean right great saphenous vein (GSV) diameter was 0.49 cm (range, 0.31-0.66 cm); mean left GSV diameter was 0.55 cm (range, 0.24-0.93 cm). Adjunctive studies were often used (including magnetic resonance venography and lymphoscintigraphy). Despite the presence of venous reflux on imaging, an alternate diagnosis was made in 8 of 18 children (44%), including postural orthostatic hypotension syndrome (n = 2), vascular malformation (n = 2), lymphedema (n = 2), complex regional pain syndrome (n = 1), and acrocyanosis of disuse (n = 1). An additional case of KTS was identified. Three cases referred for varicose veins were diagnosed with venous malformation. Maximum GSV diameter and venous reflux time were compared across patients with isolated CVD, KTS, or an alternate diagnosis (as before). Whereas there was no significant difference in maximum GSV diameter, superficial venous reflux time was significantly increased in the patients with primary CVD and KTS (P = .0394).
CONCLUSIONS
The differential diagnosis for pediatric lower extremity edema and varicosities is broad; workup often requires adjunctive studies to secure the appropriate diagnosis. Often there is venous reflux present despite an alternative clinical diagnosis. Superficial venous reflux time may aid in the diagnosis of primary CVD. Whereas the clinical significance of pediatric venous reflux remains unclear, ongoing work to expand on venous parameters in healthy pediatric controls is warranted, as is additional follow-up to assess the natural history of pediatric venous disease.
Topics: Adolescent; Child; Child, Preschool; Diagnosis, Differential; Edema; Humans; Klippel-Trenaunay-Weber Syndrome; Phlebography; Saphenous Vein; Varicose Veins; Venous Insufficiency
PubMed: 27638996
DOI: 10.1016/j.jvsv.2016.06.004 -
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