Healing refractory livedoid vasculopathy-related skin ulcers by ozone therapy: a case-based review.

Chronic skin wounds represent a prominent etiological factor in the occurrence of non-traumatic foot amputations on a global scale and pose a substantial threat to the patient's well-being and mortality in the absence of effective treatment strategies. There exists a subset of patients that exhibit an insufficient response to different treatment options, comprising antibiotics, dressings, gauze bandages, debridement, rehabilitation, collagen patch, and vacuum-assisted closure. In this patient group, distinct treatment strategies emerge before surgery and amputation. Ozone therapy is one of them. Ozone exhibits a wide variety of effects such as antimicrobial, anti-inflammatory, antioxidant, and trophic. Its trophic effect is mediated by disinfection, stimulation of granulation tissue, acceleration of the angiogenesis process, and detoxification mechanisms. In this article, we presented the beneficial effect of ozone therapy in a case of chronic skin ulcer associated with livedoid vasculopathy. In this context, we aimed to discuss the role of ozone therapy in the management of chronic skin ulcers. Finally, we focused on ozone therapy as a promising method in inflammatory rheumatic diseases.

Endothelial dysfunction, thrombophilia, and nailfold capillaroscopic features in livedoid vasculopathy.

BACKGROUND: Livedoid vasculopathy (LV) is a rare, disabling disease characterized by painful ulcers, livedo reticularis and atrophy blanche. Hypercoagulation, endothelial, and microcirculatory dysfunction are believed to be responsible for the pathogenesis of this difficult-to-treat disease. OBJECTIVES: This study sought to investigate the frequency of endothelial dysfunction, hypercoagulability, and nailfold capillaroscopic features in LV patients to shed light on its etiology. METHODS: This case-control study included 16 patients with LV, 24 with systemic sclerosis (SSc), and 23 control subjects. Serum markers of endothelial dysfunction soluble endoglin, endocan, endothelin-1, lipoprotein a, plasminogen activator inhibitor-1 (PAI-1), soluble thrombomodulin, and von Willebrand factor were measured using enzyme-linked immunosorbent assays. Flow-mediated dilation and carotid intima-media thickness were examined as markers of endothelial dysfunction, and microcirculation was assessed with nailfold capillaroscopy. Thrombophilia-related parameters, including gene polymorphisms of factor V Leiden, prothrombin, PAI-1 genes, methylenetetrahydrofolate reductase (MTHFR) and factor XIII mutation and serum levels of protein C, protein S, antithrombin, homocysteine, D-dimer and antiphospholipid antibodies were investigated in LV patients. RESULTS: Plasminogen activator inhibitor-1 and soluble thrombomodulin levels were significantly higher in LV patients compared to control subjects (2.3 [2.05-2.79] ng/ml vs. 1.89 [1.43-2.33] ng/ml, p = 0.007; 1.15 [0.88-1.4] ng/ml vs. 0.76 [0.56-0.9] ng/ml, p = 0.004, respectively). Flow-mediated dilation was 25.4 % lower in the LV patients compared to the control group (14.77 % [11.26-18.26] vs. 19.80 % [16.47-24.88], p = 0.034). Capillaroscopic features, including ramifications (75 % vs. 8.7 %, p < 0.001), avascular areas (25 % vs. 0 %, p = 0.011) and dilatations (33.2 % vs. 0 %, p = 0.016), were significantly higher in LV patients than in controls. LV patients had multiple biochemical or genetic abnormalities related to thrombophilia, including heterozygous factor V Leiden mutations (6.3 %), MTHFR (C677T) mutations (heterozygous 43.8 %, homozygous 18.8 %), MTHFR (A1298C) mutations (heterozygous 37.5 %, homozygous 12.5 %), factor XIII heterozygous mutation (12.5 %), antithrombin deficiency (31.3 %), protein S deficiency (12.5 %), hyperhomocysteinemia (31.3 %), D-dimer elevation (25 %), anti-ß2-glycoprotein I (12.5 %), lupus anticoagulant antibodies (6.3 %), and anticardiolipin antibodies (6.3 %). CONCLUSIONS: In conclusion, LV patients were characterized by an increased presence of thrombophilia-related parameters, and also exhibited vascular endothelial and microcirculatory dysfunction, resembling SSc. These findings support the complex interaction of thrombophilia, endothelial dysfunction, and microcirculation dysregulation in the pathogenesis of LV. Thus, the treatment of LV patients should be individualized, based on the identification of the predominant pathological pathways.

Punch grafting for the treatment of ulcerated atrophie blanche.

Case report: A 79-year-old woman presented with a large painful ulcer on the lateral aspect of her left leg over a 6-month period and was diagnosed of ulcerated atrophie blanche. On an outpatient basis punch grafting was performed and 3 weeks after, complete epithelization was achieved. Discussion: Ulcerated atrophie blanche is a misdiagnosed disorder with painful lesions and, consequently, a high impact on quality of life. Atrophie blanche describes porcelain-white colored, red-dotted atrophic plaques on legs or feet. It may be due to multiple causes, usually associated with alterations in the microcirculation. All causes of atrophie blanche can be included in the term livedoid vasculopathy, a type of occlusive vasculopathy without vasculitis. Many patients with atrophie blanche and livedoid vasculopathy have also chronic venous insufficiency. Etiological treatment should be prescribed in order to avoid progression of the lesions. In case of chronic venous insufficiency, control of venous hypertension is essential. Without anti-edema measures, superficial, very painful, and resistant ulcers may appear. These ulcers can be considered a wound on scar tissue; therefore, it must be treated as a hard-to-heal wound. As we show in this case, punch grafting is an effective therapeutic alternative for wound closure and pain reduction of ulcerated atrophie blanche.

Detection of Bartonella henselae DNA in the blood of patients with livedoid vasculopathy.

BACKGROUND: Livedoid vasculopathy (LV) manifests as ulcers and atrophic white scars on the lower extremities. The main known etiopathogenesis is hypercoagulability with thrombus formation, followed by inflammation. Thrombophilia, collagen and myeloproliferative diseases may induce LV, but the idiopathic (primary) form predominates. Bartonella spp. may cause intra-endothelial infection and skin manifestations caused by these bacteria may be diverse, including leukocytoclastic vasculitis and ulcers. OBJECTIVE: The aim of this study was to investigate the presence of bacteremia by Bartonella spp. in patients with difficult-to-control chronic ulcers diagnosed as primary LV. METHODS: Questionnaires and molecular tests (conventional PCR, nested PCR and real-time PCR) were applied and liquid and solid cultures were performed in the blood samples and blood clot of 16 LV patients and 32 healthy volunteers. RESULTS: Bartonella henselae DNA was detected in 25% of LV patients and in 12.5% of control subjects but failed to reach statistically significant differences (p = 0.413). STUDY LIMITATIONS: Due to the rarity of primary LV, the number of patients studied was small and there was greater exposure of the control group to risk factors for Bartonella spp. CONCLUSION: Although there was no statistically significant difference between the groups, the DNA of B. henselae was detected in one of every four patients, which reinforces the need to investigate Bartonella spp. in patients with primary LV.

[A particular presentation of a T cell large granular lymphocytic leukaemia]. / Une présentation particulière de leucémie à grands lymphocytes granuleux.

T cell prolymphocytic leukemia (T-PLL) is a rare, aggressive neoplasm derived from post-thymic T cells. Patients are typically middle-aged with a slight male predominance who present with a high white blood cell count, hepatosplenomegaly, lymphadenopathy, and other symptoms typically associated with leukemia. Although cutaneous involvement has been reported in up to 30% of cases of T-PLL, to our knowledge, none have presented with a presentation resembling livedoid vasculopathy. In the correct clinical context, an underlying hematolymphoid neoplasm should be included in the differential diagnosis of a patient presenting with livedoid vasculopathy.

Patients with laboratory criteria of anti-phospholipid syndrome and 'non-criteria' manifestations: a multicenter cohort.

OBJECTIVES: Patients with laboratory criteria for anti-phospholipid syndrome (APS) but presenting only 'non-criteria' clinical manifestations are scarcely characterized in the literature. We aimed to analyse a cohort of these patients regarding the most prevalent manifestations, antibody profile, and treatments, while establishing a comparison with definite APS patients. METHOD: A retrospective analysis was conducted of individuals fulfilling APS laboratory criteria assessed in two tertiary European hospitals between 2005 and 2020. Patients without clinical criteria but with non-criteria manifestations (termed 'clinical non-criteria') and age-/gender-matched controls were included. RESULTS: Altogether, 75 clinical non-criteria patients were analysed, with haematological (thrombocytopenia, haemolytic anaemia) and 'mild' neurological manifestations (white-matter lesions, migraine) as the most prevalent non-obstetric involvements. These patients displayed more thrombocytopenia [odds ratio (OR) = 3.6, 95% confidence interval (CI) 1.7-7.6; p = 0.001] than controls with APS, but severe manifestations, such as valvular heart disease (p < 0.001), livedoid vasculopathy, seizures, chorea, transverse myelitis, bone necrosis, and alveolar haemorrhage, occurred only in definite APS patients. Corticosteroids were required by 40% of patients with thrombocytopenia. Manifestations in anticoagulated patients included white-matter lesions, nephropathy, superficial vein thrombosis, amaurosis fugax, and livedoid vasculopathy. Suspicion of progression towards systemic lupus erythematosus (SLE) occurred in 19% of non-SLE individuals. CONCLUSION: 'Clinical non-criteria' patients displayed significant treatment use, predominantly haematological involvement, and less severe manifestations than definite APS controls. Some patients may additionally progress to future SLE. The impact of certain manifestations flags them as potential future contributors to classifying individuals as definite APS.

Enfermedad de Buerger o el endotelio como laberinto: a propósito de un caso clínico / Buerger's disease or the endothelium as a labyrinth: case report

La enfermedad de Buerger, también llamada tromboangeítis obliterante, es una enfermedad vascular inflamatoria transmural no aterosclerótica, segmentaria, que afecta pequeños y medianos vasos de las extremidades, de especial asociación etiopatogénica con el tabaquismo. Ocurre comúnmente en hombres menores de 50 años, siendo un diagnóstico diferencial en el escenario de pacientes con isquemia crónica. Se presenta el caso de un hombre de 43 años, con antecedente de tabaquismo pesado, quien cursaba con claudicación intermitente llegando hasta el dolor en reposo, asociado a úlceras de aspecto vasculopático en miembros inferiores, en ausencia de pulsos distales (pedio, tibial posterior); la pletismografía reportó mayor compromiso infrapoplíteo, con circulación colateral segmentaria por arteriografía, sin posibilidad de revascularización endovascular. Se consideró un caso compatible con enfermedad de Buerger, planteándose un manejo híbrido: médico (con agentes antiagregantes) y quirúrgico (con puente femoropoplíteo directo). Se realiza una breve revisión de tema de esta enfermedad de rara aparición

Abstract. Buerger's disease, also called thromboangiitis obliterans, is a non-atherosclerotic, segmental, transmural inflammatory vascular disease affecting small and medium-sized vessels of the extremities with a special etiopathogenic association with smoking; it commonly occurs in men under 50 years of age, and is a differential diagnosis in the setting of patients with chronic ischemia. We describe the case of a 43-year-old man, with a history of heavy smoking, who presented with intermittent claudication reaching pain at rest, associated with ulcers of vasculopathic appearance in the lower limbs, in the absence of distal pulses (pedius, posterior tibial); plethysmography reported greater infrapopliteal involvement, with segmental collateral circulation by arteriography, without the possibility of endovascular revascularization. The case was considered compatible with Buerger's disease, and hybrid management was weighed: medical (with antiplatelet agents) and surgical (with direct femoropopliteal bridging). A brief review of this rare disease is presented

Baricitinib is potentially effective in the treatment of refractory livedoid vasculopathy.

Background: Livedoid vasculopathy is a rare, chronic, and recurrent disease with limited effective treatments. Its etiopathogenesis remains incompletely understood. Baricitinib, a selective Janus kinase 1 and 2 inhibitor, has been used to treat rheumatoid arthritis and could reduce the disease severity in patients with livedoid vasculopathy. Methods: We retrospectively observed eight patients who received 2 mg/day of baricitinib for the treatment of refractory livedoid vasculopathy. We evaluated their clinical scores before and after treatment to determine its effectiveness and safety. Results: Improvement in livedoid vasculopathy was observed with significant regression in the clinical scores after baricitinib treatment. The mean clinical scores were 7.0 ± 1.6 and 1.4 ± 1.2 before and after baricitinib treatment, respectively (P <0.01). Furthermore, six out of the eight patients achieved a clinical score of 0 or 2 after treatment. These scores indicated remission. Clinical findings, including erythema, ulceration, and pain, improved in all the patients. The remission times ranged from 3 to 13 weeks, with a mean remission time of 7.75 ± 3.45 weeks. There were no reports of adverse events in any patient. Conclusions: Our study showed that baricitinib treatment was safe and could significantly relieve the signs and symptoms of livedoid vasculopathy. However, randomized controlled studies should be conducted to confirm these results.

Medium-pressure hyperbaric oxygen therapy for livedoid vasculopathy.

Livedoid vasculopathy (LV) is a cutaneous manifestation of several diseases that lead to noninflammatory thrombosis of dermal vessels. We report the case of a 26-year-old female with a 4 years and 8 months-old history of diagnosis of LV and a non-healing ulcer of more than a year of evolution. Because of refractory response to standard care, low-pressure hyperbaric oxygen (LPHBOT) was added to the therapeutic scheme (azathiopine 2.5 mg/kg, folic acid and acetylsalicylic acid). After 12 sessions of LHBOT (60 min, 1.45 ATA ≈ 100% O2), ulcers achieved complete healing with significant pain relief and no recurrence was present over 6 months. More studies are necessary to determine the effectiveness of HBOT for LV treatment.

La vasculopatía livedoide (VL) es una manifestación cutánea de varias enfermedades que conducen a una trombosis no inflamatoria de los vasos dérmicos. Se presenta el caso de una mujer de 26 años con antecedente de diagnóstico de vasculopatía livedoide de 4 años y 8 meses, además de una úlcera no cicatrizante de más de un año de evolución. Debido a la respuesta refractaria a la atención estándar, se añadió oxígeno hiperbárico a baja presión (LPHBOT) al esquema terapéutico (azatriopina 2.5 mg/kg, ácido fólico y ácido acetilsalicílico). Después de 12 sesiones de LHBOT (60 min, 1,45 ATA ≈ 100% O2), las úlceras tuvieron una curación completa con un alivio significativo del dolor y no hubo recurrencia durante 16 meses. Se necesitan más estudios para determinar la eficacia de TOHB para el tratamiento del VL.

Platelet count and plateletcrit: Potential haematological biomarkers for livedoid vasculopathy?

BACKGROUND: The pathogenesis of livedoid vasculopathy (LV) remains unknown. Although platelet activation occurs in LV, little research has been conducted on LV platelet morphology parameters. The purpose of this study was to investigate whether platelet morphology changes in LV and its clinical significance. METHODS: Twenty-seven LV patients and 21 cutaneous small vessel vasculitis (CSVV) patients, all at the active stage, were included. Platelet parameters in active- and stable-stage LV and CSVV patients were compared. Correlations between these platelet parameters and LV composite clinical scores were analysed. RESULTS: LV patients' mean age was 25.48 years (range: 9-62 years), and 81.48% (22/27) were women and 18.52% (5/27) were men. The platelet counts and plateletcrit (PCT) levels were significantly elevated in LV patients compared with CSVV patients and in active-stage LV patients compared with stable-stage LV patients after treatment. LV patient composite clinical scores that reflected disease severity and activity were positively correlated with the platelet count and PCT levels. CONCLUSION: Altered platelet morphology was detected in LV patients. Platelet count and PCT might be haematological biomarkers for early prediction of LV activity and relapses and for differential identification between LV and CSVV.

Peripheral neuropathy and livedoid vasculopathy.

BACKGROUND: Livedoid vasculopathy (LV) is a chronic dermatosis associated with micro-thrombosis of the vessels of the dermis, leading to ischemic lesions and painful skin ulcerations of the lower limbs. This thrombosing occlusive vasculopathy, clearly distinct from 'classical vasculitis' (not related to alteration of vessel walls), may lead to peripheral neuropathy. OBJECTIVE: To clarify the main clinical, electrophysiological and pathological characteristics of peripheral neuropathy linked to LV. METHOD: We presented a series of personal cases of peripheral neuropathy due to LV. We also conducted a review of the literature (since the first description of LV in 1974) using multiple combinations of keywords from 'PubMed', 'Google Scholar' and 'ScienceDirect' databases according to the 'Preferred Reporting Items for Systematic reviews and Meta-Analyses' guidelines. RESULTS: We identified 16 patients (6 personal cases and 10 cases from the medical literature). Our personal cases were five females and one male, with a median age (at the onset of cutaneous signs of LV) of 38 (range 25-62). Several types of skin lesions of the lower limbs were observed. Median age at the onset of peripheral neuropathy symptoms was 48 years (range 29-66), with a main clinical and electrophysiological pattern of mononeuropathy multiplex. DISCUSSION: We observed a typical pattern of peripheral neuropathy, mostly mononeuropathy multiplex, whose pathophysiology might be related to occlusions of the small vessels of the nerves, as seen in the dermis. Moreover, LV may also be associated with other types of peripheral neuropathies (sometimes of autoimmune etiology) not directly related to the skin lesions. CONCLUSION: The 'ischemic form' of peripheral neuropathy linked to LV is mainly responsible for sensory disturbances (with multifocal distribution), sometimes for motor disturbances. This type of peripheral neuropathy has to be distinguished from 'classical vasculitic neuropathies' which are usually treated with antithrombotic therapies.