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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 -
VASA. Zeitschrift Fur Gefasskrankheiten Feb 2018Erythromelalgia is a rare syndrome characterized by the intermittent or, less commonly, by the permanent occurrence of extremely painful hyperperfused skin areas mainly... (Review)
Review
Erythromelalgia is a rare syndrome characterized by the intermittent or, less commonly, by the permanent occurrence of extremely painful hyperperfused skin areas mainly located in the distal extremities. Primary erythromelalgia is nowadays considered to be a genetically determined neuropathic disorder affecting SCN9A, SCN10A, and SCN11A coding for NaV1.7, NaV1.8, and NaV1.9 neuronal sodium channels. Secondary forms might be associated with myeloproliferative disorders, connective tissue disease, cancer, infections, and poisoning. Between the pain episodes, the affected skin areas are usually asymptomatic, but there are patients with typical features of acrocyanosis and/or Raynaud's phenomenon preceding or occurring in between the episodes of erythromelalgia. Diagnosis is made by ascertaining the typical clinical features. Thereafter, the differentiation between primary and secondary forms should be made. Genetic testing is recommended, especially in premature cases and in cases of family clustering in specialized genetic institutions after genetic counselling. Multimodal therapeutic intervention aims toward attenuation of pain and improvement of the patient's quality of life. For this purpose, a wide variety of nonpharmacological approaches and pharmacological substances for topical and systemic use have been proposed, which are usually applied individually in a step-by-step approach. Prognosis mainly depends on the underlying condition and the ability of the patients and their relatives to cope with the disease.
Topics: Erythromelalgia; Genetic Predisposition to Disease; Humans; Molecular Diagnostic Techniques; Pain Measurement; Phenotype; Predictive Value of Tests; Risk Factors; Treatment Outcome
PubMed: 29299961
DOI: 10.1024/0301-1526/a000675 -
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 -
Innere Medizin (Heidelberg, Germany) Jun 2022Vascular acrosyndromes are characterized by sparse, uniform clinical manifestations and a variety of possible pathomechanisms. The present article focuses on the... (Review)
Review
Vascular acrosyndromes are characterized by sparse, uniform clinical manifestations and a variety of possible pathomechanisms. The present article focuses on the functional entities. Raynaud phenomenon is based on cold- or stress-induced vasospasms of acral arteries. It is defined by the color changes of the skin, in the typical case white-blue-red (tricolore). The long fingers are most commonly affected. The etiology is unknown, and the pathophysiology is poorly understood. A distinction is made between primary and a secondary Raynaud phenomenon. The most important underlying diseases include collagenosis, primarily systemic sclerosis, and malignancies; furthermore, medications and drugs may promote vasospasm. Treatment is aimed at preventing or breaking the vasospasm, but has been only partially effective in doing so. Acrocyanosis is a vasospastic dystonic acral disorder that results in permanent reddish-livid discoloration, especially of the hands and feet. Secondary forms occur in collagenosis, malignancies, and myelodysplastic syndromes. The etiology and pathophysiology are virtually unknown. Targeted pharmacological intervention is not possible. Unlike all other vascular acrosyndromes, erythromelalgia is characterized by hyperemia. The primary form is a genetic sodium channelopathy, while secondary forms include malignancies, connective tissue diseases, and myelodysplastic syndromes. The symptoms are often distressing and disabling. Therapy requires a multimodal approach that includes both nonpharmacological and pharmacological strategies. Close interdisciplinary collaboration is essential for the management of this disease.
Topics: Cyanosis; Erythromelalgia; Humans; Myelodysplastic Syndromes; Raynaud Disease; Vascular Diseases
PubMed: 35925129
DOI: 10.1007/s00108-022-01340-w -
Best Practice & Research. Clinical... May 2024Raynaud's syndrome is a common finding in many autoimmune conditions. Accurately diagnosing Raynaud's, and differentiating it from mimicking conditions, is imperative in... (Review)
Review
Raynaud's syndrome is a common finding in many autoimmune conditions. Accurately diagnosing Raynaud's, and differentiating it from mimicking conditions, is imperative in rheumatologic diseases. Raynaud's syndrome and Raynaud's mimickers, especially painful Raynaud's mimickers, can prove a diagnostic challenge for the practicing rheumatologist. Painful Raynaud's mimickers can lead to increased patient stress and unnecessary medical work up; Healthcare providers need to be aware of Raynaud's mimickers when evaluating patient concerns of skin color changes and pain. The present narrative review aims to highlight Raynaud's syndrome, important painful mimickers that may be seen, diagnosis, and updated management recommendations.
PubMed: 38704280
DOI: 10.1016/j.berh.2024.101948 -
Cardiology Clinics Nov 2021Vasospastic disorders are prevalent in the general population and can affect individuals of any age. Primary (or idiopathic) vasospastic disorders often have a benign... (Review)
Review
Vasospastic disorders are prevalent in the general population and can affect individuals of any age. Primary (or idiopathic) vasospastic disorders often have a benign course; treatment focuses on the control of symptoms. Secondary vasospastic disorders occur owing to an underlying condition and have an increased risk of complications, including tissue loss and digital ulcerations; treatment should focus on the underlying condition. In this review, we discuss the pathophysiology, clinical presentation, diagnosis, and management of vasospastic disorders, including Raynaud syndrome, acrocyanosis, livedo reticularis, and pernio.
Topics: Humans; Raynaud Disease
PubMed: 34686269
DOI: 10.1016/j.ccl.2021.06.010 -
Vascular Medicine (London, England) Feb 2021Raynaud's phenomenon, which is characterized by episodic digital pallor, cyanosis and rubor upon exposure to cold environment or to stress, is relatively common,... (Review)
Review
Raynaud's phenomenon, which is characterized by episodic digital pallor, cyanosis and rubor upon exposure to cold environment or to stress, is relatively common, although the prevalence depends on the climate. Still, it is under-diagnosed, under-treated, and often confused with other conditions. Primary Raynaud's phenomenon (i.e., Raynaud disease) must be distinguished from secondary Raynaud's phenomenon (i.e., Raynaud syndrome) as long-term morbidity and outcomes differ vastly between the two conditions. Additionally, the practitioner must differentiate between Raynaud's phenomenon and related vascular disorders, such as acrocyanosis, pernio, and livedo reticularis. In this article, we review differences between the conditions and suggest an approach to diagnosis and treatment strategy for these disorders.
Topics: Humans; Raynaud Disease
PubMed: 33566754
DOI: 10.1177/1358863X20983455 -
International Journal of Dermatology Dec 2020Numerous unexplained pneumonia cases were reported to the World Health Organization (WHO) by Wuhan, China, in December 2020. Severe acute respiratory syndrome... (Review)
Review
Numerous unexplained pneumonia cases were reported to the World Health Organization (WHO) by Wuhan, China, in December 2020. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a zoonotic pathogen, came into sight, spreading coronavirus disease 2019 (COVID-19) all over the globe. Association of cutaneous signs and symptoms with COVID-19 is being studied worldwide, principally, to determine if these dermatoses can help in early recognition of SARS-CoV-2 infection. These dermatological manifestations can range from erythematous rash, urticaria to livedo reticularis, and acrocyanosis in patients of all age groups. Correspondingly, dermatologists treating COVID-19 patients, suffering from inflammatory dermatoses, with biologics or immunomodulators should exert caution and use specific protocols to adjust the doses of these medications. Prevention of person-to-person transmission of COVID-19 is being promoted universally, with the use of personal protective equipment (PPE), hand washes, and hand sanitizers around the clock. However, an array of cutaneous adverse effects such as contact dermatitis, irritant contact dermatitis, friction blisters, contact urticaria, acne, and infections are associated with the use of PPE. Extra-pulmonary manifestations of COVID-19 are still emerging in the community, and physicians and researchers are working together globally to strengthen the clinical management of these patients. Cases of COVID-19 continue to rise across the world, and an unprecedented approach has been taken to develop effective vaccines and therapeutic strategies against existing and forthcoming mutagenic strains of SARS-CoV-2.
Topics: Betacoronavirus; COVID-19; Communicable Disease Control; Coronavirus Infections; Dermatitis, Contact; Dermatology; Hand Hygiene; Humans; Pandemics; Personal Protective Equipment; Pneumonia, Viral; SARS-CoV-2; Skin Diseases, Infectious
PubMed: 33107038
DOI: 10.1111/ijd.15257 -
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