Oral cinnarizine for the treatment of COVID-19-associated chilblain-like lesions: An old drug for a new disease?

During SARS-CoV-2 pandemic, an outbreak of chilblain-like lesions has been developed, even if the relationship with the virus infection is still debated. We report the good results obtained in 12 patients with chilblain lesions and the use of oral cinnarizine, a piperazine derivative with many pharmacological properties among whom antihistaminic and calcium channel blocking activities.

Pharmacologic Treatment of Idiopathic Chilblains (Pernio): A Systematic Review.

Idiopathic chilblains is a cold-induced inflammatory condition that causes significant morbidity. When preventative measures alone are inadequate, oral nifedipine is generally recommended as first-line pharmacologic therapy. Given the natural course of this spontaneously remitting/relapsing condition, controls are needed to critically appraise studies and determine the value of treatments. We report a systematic review of placebo-controlled or comparative therapeutic trials for the treatment of idiopathic chilblains. Our search of PubMed, Embase, and Cochrane databases, identified 11 studies that met our inclusion criteria for a combined study population n = 576. Therapies included nifedipine, pentoxifylline, tadalafil, topical glyceryl trinitrate (GTN), topical minoxidil, diltiazem, corticosteroids, and vitamin D. There was moderate evidence to support the use of nifedipine and pentoxifylline in the treatment of severe or refractory cases of idiopathic chilblains, while other therapies had inadequate evidence or nonsignificant results compared to placebo.

Incidence, Characteristics, Laboratory Findings and Outcomes in Acro-Ischemia in COVID-19 Patients.

AIM: In addition to its respiratory impact of SARS-CoV2, skin lesions of probable vascular origin have been described. This study intends to quantify the incidence of acro-ischemic lesions in COVID-19 infected adult subjects in our population, describing clinical patterns and associated findings. METHODS: All adult confirmed cases of COVID-19 infection who presented with acro-ischemic lesions and received care in our institution were prospectively enrolled up to May 15th, 2020. The variables included demographics, comorbidities, analytical parameters, clinical presentations and COVID-19 treatment. RESULTS: We enrolled 24 patients. The overall rate of acro-ischemic findings in COVID-19 patients was 1.2% [0.6% for outpatients and 2.9% for hospitalized (ICU and non-ICU patients)], but the observed incidence for acro-ischemia in ICU patients was remarkably higher (23.0%, p<0.001). We have described four different clinical patterns of acroischemia: atypical Raynaud´s phenomenon (ARP), (4); pseudo-pernio (PP), (5); severe microcirculatory ischemia with preserved pulse (SMI), (6); and dry gangrene with arteriosclerosis obliterans (AO), (9). Kendall´s τ correlation with lung disease severity was 0.877 (95% CI, 0.756 to 0.968); p<0.01). ARP individuals were predominantly female, while SMI appeared lately in elderly hospitalized subjects with better prognosis. AO occurred in patients with more comorbidity and younger than those with SMI. We observed other associated lesions of suggestive ischemic nature in other organs in all groups (15 patients of total sample). Plasma procalcitonin was significantly higher in patients who developed SMI (median and interquartile range: 9.99 (4.2, 12.3) mg/mL vs 0.26 (0.11, 0.89) mg/mL; p<0.001), and D-dimer level at hospital admission was significantly higher in AO patients (median and interquartile range: 1166 (1050, 2111) mg/L vs 502 (448, 777) mg/L; p<0.001). CONCLUSION: The observed risk for acroischemia in COVID-19 is high in ICU patients (23%). We have described four different clinical patterns of acroischemia (ARP, PP, SMI and AO) associated with lung disease severity. Authors have communicated various lesions of suggestive ischemic nature in other organs. Raynaud-like pattern is reported as a "novelty".

A case of chronic sarcoidosis presenting with lupus pernio.

Sarcoidosis is a systemic granulomatous disease of unknown cause. Skin involvement may be specific lesions in which granulomas are detected on biopsy or nonspecific lesions without granulomatous inflammation on biopsy. Lupus pernio (LP) occurs in the form of smooth, bright nodules and plaques on the nose, ear, lips, and cheeks. Although presence of skin involvement is frequent, lupus perio is reported as a rare form of extrapulmonary sarcoidosis. A 57-year-old female patient applied to the dermatology outpatient clinic with a lesion on the nose. We report a case of chronic sarcoidosis presenting with lupus pernio with clinical and radiological improvement.

JAK-inhibitors. New players in the field of immune-mediated diseases, beyond rheumatoid arthritis.

Janus kinase (JAK)/signal transducers and activators of transcription (STATs) are a group of molecules associated with one of the major pathways through which many cytokines exert and integrate their function, and as such they are increasingly recognized as playing critical role in the pathogenesis subserving various immune-mediated diseases, including RA, PsA, SpAs, IBD, skin disorders (e.g. alopecia areata, atopic dermatitis), single-gene disorders like interferonopathies, and others. JAKs are the key initiating players of the JAK/STAT pathway. Upon binding of their respective effector molecules (cytokines, IFNs, growth factors and others) to type I and type II receptors, JAKs are activated, and through phosphorylation of themselves and of other molecules (including STATs), they mediate signal transduction to the nucleus. A class of drugs-called JAK inhibitors or JAKinibs-that block one or more JAKs has been developed in the last decade, and now numbers >20 members. Although, so far, JAK inhibitors have been marketed only for RA and PsA, these drugs have been tested in phase 2 and phase 3 clinical trials for other inflammatory conditions and beyond. In this review, we summarize the clinical data, including efficacy and safety, available for JAK inhibitors used in some immune-mediated conditions other than RA.

Assessment of Clinical Response to Janus Kinase Inhibition in Patients With Familial Chilblain Lupus and TREX1 Mutation.

Importance: Familial chilblain lupus is a monogenic autosomal dominant form of cutaneous lupus erythematosus that in most cases is caused by mutations in the 3 prime repair exonuclease 1 (TREX1). Familial chilblain lupus presents in early childhood with cold-induced painful erythematous infiltrates leading to mutilation and is associated with systemic involvement illustrated by an elevated type I interferon (IFN) signature in the skin and blood. Effective treatment is currently not available. Objectives: To evaluate the clinical response to the Janus kinase inhibitor baricitinib in familial chilblain lupus and assess the effect of cold on patient fibroblasts. Design, Setting, and Participants: In this case series, 3 patients with familial chilblain lupus due to TREX1 mutation underwent treatment with baricitinib for 3 months. Interventions: Doses of baricitinib, 4 mg, were administered daily for 3 months. Main Outcomes and Measures: Reduction of cutaneous lupus lesions was measured by the revised cutaneous lupus area and severity index, pain due to skin and joint involvement was assessed by visual analog scale, type I IFN signature in blood was determined by polymerase chain reaction, and the in vitro response of fibroblasts to cold exposure was analyzed. Results: All 3 patients (2 women and 1 man; mean [SD] age, 51 [24] years) showed a significant improvement of cutaneous lupus lesions with suppression of systemic type I IFN activation. One patient had a complete remission regarding pain and, in 2 patients, pain associated with joint inflammation was partially reduced. No severe adverse reactions were reported. Exposure of patient fibroblasts to cold induced a stress response and enhanced senescence along with induction of IFN-stimulated gene in vitro. Conclusions and Relevance: These findings demonstrate the therapeutic efficacy of Janus kinase inhibition in a monogenic form of lupus among 3 patients and provide mechanistic insight into the process of disease exacerbation by cold in TREX1-deficient cells. This finding may be relevant to other type I IFN-mediated disorders and implicates Janus kinase inhibition as a potential therapeutic option also for multifactorial cutaneous lupus erythematosus.

Sarcoidosis: an unusual presentation / Sarcoidosis: un cuadro clínico inicial poco frecuente

A 35-year-old man presented with a 3-year history of arthralgia and purple coloration of the skin of his fingers and feet. Hand and foot radiography showed cystic bone lesions on phalanges suggestive of sarcoidosis. Lab tests revealed increased liver enzymes. Liver MRI evidenced an enlarged liver and retroperitoneal lymphadenopathy. Histological analysis of the finger skin, lymph nodes and liver demonstrated the presence of granulomas, confirming the diagnosis of sarcoidosis. The patient started prednisolone with rapid improvement of the symptoms. Skin lesions are divided into two groups: specific for sarcoidosis (with granulomas, lupus pernio-like) and nonspecific (without granulomas, erythema nodosum-like). Specific cutaneous lesions usually cause no other symptoms beyond cosmetic changes. Lupus pernio stands out for having distinctive features but, to the best of our knowledge, the simultaneous involvement of both hands and feet has never been reported (AU)

Se presenta el caso de un hombre de 35 años con una historia de artralgia y con la piel de los dedos y los pies de color violáceo, de 3 años de duración. La radiografía de pies y manos mostró lesiones quísticas óseas en las falanges, indicativas de sarcoidosis. Las pruebas de laboratorio revelaron una elevación de las enzimas hepáticas. La resonancia magnética hepática puso de manifiesto hepatomegalia y linfadenopatía retroperitoneal. El análisis histológico de la piel de los dedos, los ganglios linfáticos y el hígado mostró la existencia de granulomas, lo que confirmó el diagnóstico de sarcoidosis. El paciente comenzó el tratamiento con prednisolona con una rápida mejoría de los síntomas. Las lesiones de la piel se dividen en 2 grupos: específicas de la sarcoidosis (con granulomas y lupus característico del eritema pernio) e inespecíficas (sin granulomas y de tipo eritema nudoso). Las lesiones cutáneas específicas generalmente no causan más síntomas que los cambios estéticos. El lupus pernio destaca por presentar características distintivas, pero no nos consta que se haya descrito nunca la afectación simultánea de ambas manos y pies (AU)

Assessing the effectiveness of topical betamethasone to treat chronic chilblains: a randomised clinical trial in primary care.

BACKGROUND: GPs prescribe topical corticosteroids to patients with chronic chilblains despite poor evidence for their effectiveness. The authors of the current study therefore decided to assess the effectiveness of topical steroids in a primary care setting. AIM: To assess the effectiveness of topical application of betamethasone valerate 0.1% cream in patients with chronic chilblains. DESIGN AND SETTING: A placebo-controlled, double-blind, crossover, randomised clinical trial in a Dutch primary care setting. METHOD: The study population consisted of 34 participants suffering from chronic chilblains. Intervention was topical application of betamethasone valerate 0.1% cream twice a day for 6 weeks compared with placebo. Primary outcome was the visual analogue scale on complaints (VOC). Secondary outcome was the visual analogue scale on disability (VOD). Both were assessed with a diary of daily scores on a 100 mm visual analogue scale. The authors took ambient temperatures into account, checked for a carry-over effect, performed additional analysis, and monitored adverse effects. RESULTS: On the primary outcome mean VOC, there was a difference of 0.56 mm (95% confidence interval [CI] = -2.88 to 3.99 mm) in favour of placebo (P = 0.744). On the secondary outcome mean VOD, there was a difference of 0.88 mm (95% CI = -2.22 to 3.98 mm) in favour of placebo (P = 0.567). This study found no carry-over effect and no adverse effects. CONCLUSION: In this study, topical betamethasone was not superior to placebo in the treatment of chronic chilblains. Topical betamethasone should not be used for chronic chilblains without new evidence.

Familial chilblain lupus due to a gain-of-function mutation in STING.

OBJECTIVES: Familial chilblain lupus is a monogenic form of cutaneous lupus erythematosus caused by loss-of-function mutations in the nucleases TREX1 or SAMHD1. In a family without TREX1 or SAMHD1 mutation, we sought to determine the causative gene and the underlying disease pathology. METHODS: Exome sequencing was used for disease gene identification. Structural analysis was performed by homology modelling and docking simulations. Type I interferon (IFN) activation was assessed in cells transfected with STING cDNA using an IFN-ß reporter and Western blotting. IFN signatures in patient blood in response to tofacitinib treatment were measured by RT-PCR of IFN-stimulated genes. RESULTS: In a multigenerational family with five members affected with chilblain lupus, we identified a heterozygous mutation of STING, a signalling molecule in the cytosolic DNA sensing pathway. Structural and functional analyses indicate that mutant STING enhances homodimerisation in the absence of its ligand cGAMP resulting in constitutive type I IFN activation. Treatment of two affected family members with the Janus kinase (JAK) inhibitor tofacitinib led to a marked suppression of the IFN signature. CONCLUSIONS: A heterozygous gain-of-function mutation in STING can cause familial chilblain lupus. These findings expand the genetic spectrum of type I IFN-dependent disorders and suggest that JAK inhibition may be of therapeutic value.

Perniosis idiopática: reporte de un caso y revisión de la literatura / Chilblains: report of a case and literature review

Pernio (chilblains) is an inflammatory condition classically characterized by localized erythema and swelling of acral sites upon exposure to cool and damp conditions. It is reported a case of a 59-year-old otherwise healthy woman with acute primary perniosis. She had a 3-day history of lesions on the toes brought on by cold, damp weather. On initial presentation, a biopsy sample was taken of a hallux lesion, and the patient was given a trial course of oral pentoxifylline, topical corticoid and nifedipine therapy. Follow-up at 2 weeks showed complete relief of symptoms and the biopsy results confirmed the diagnosis. Pentoxifylline therapy has been shown to be effective and should be considered the standard of care in the treatment of perniosis along with conservative environmental measures.The etiology and pathogenesis of perniosis are reviewed and discussed, as well as differential diagnoses and treatment options. (AU)