Paradigm shift in monogenic autoinflammatory diseases and systemic vasculitis: The VEXAS syndrome. / Cambio de paradigma en las enfermedades autoinflamatorias monogénicas y las vasculitis sistémicas: el síndrome VEXAS.

VEXAS syndrome was described by the end of 2020 as an autoinflammatory disease caused by post-zygotic variants in the UBA1 gene. VEXAS syndrome occurs in adult males with recurrent fever, arthralgia/arthritis, ear/nose chondritis, neutrophilic dermatosis, lung inflammation, venous thrombosis, and different types of vasculitis. Common laboratory changes include raised acute phase reactants and macrocytic anemia. The coexistence of myelodysplasia is frequent, and bone marrow vacuolization of myeloid and erythroid precursors is characteristic. Glucocorticoids are effective at medium-high doses, but the remaining immunosuppressive drugs, either conventional or biological, have showed limited or absent efficacy. Azacitidine has been associated with a good response, especially in patients with accompanying myelodysplastic syndrome. Allogeneic hematopoietic stem cell transplantation appears to be the only curative therapy by now. VEXAS syndrome has become a paradigm shift in the diagnosis and treatment of autoinflammatory diseases and systemic vasculitis.

Effect of 2 Psoriasis Treatments on Vascular Inflammation and Novel Inflammatory Cardiovascular Biomarkers: A Randomized Placebo-Controlled Trial.

BACKGROUND: Psoriasis is a chronic inflammatory disease associated with dyslipidemia, cardiovascular events, and mortality. We aimed to assess and compare the effect of treatment of moderate-to-severe psoriasis with adalimumab or phototherapy on vascular inflammation and cardiovascular biomarkers. METHODS AND RESULTS: Randomized, double-blind, trial of adalimumab, phototherapy, and placebo (1:1:1) for 12 weeks, with crossover to adalimumab for 52 weeks total. Outcomes included vascular inflammation by 18F-fluorodeoxyglucose positron emission tomography/computed tomography and biomarkers of inflammation, insulin resistance, and lipoproteins. Ninety-seven patients were randomized, 92 completed the randomized controlled trial portion; 81 entered the adalimumab extension with 61 completing 52 weeks of adalimumab. There was no difference in change in vascular inflammation at week 12 in the adalimumab group (change compared with placebo, 0.64%; 95% confidence interval, -5.84% to 7.12%) or the phototherapy group (-1.60%; 95% confidence interval, -6.78% to 3.59%) or after 52-week adalimumab treatment (0.02% compared with initiation; 95% confidence interval, -2.85% to 2.90%). Both adalimumab and phototherapy decreased inflammation by serum CRP, interleukin-6. Only adalimumab reduced tumor necrosis factor and glycoprotein acetylation at 12 and 52 weeks. Neither had an impact on metabolic markers (insulin, adiponectin, and leptin). Only phototherapy increased high-density lipoprotein-p at 12 weeks. At 52-week of adalimumab cholesterol efflux and high-density lipoprotein-p were reduced. CONCLUSIONS: Adalimumab reduced key markers of inflammation including glycoprotein acetylation compared with phototherapy with no effect on glucose metabolism and vascular inflammation, and potential adverse effects on high-density lipoprotein. Glycoprotein acetylation improvement may partially explain the beneficial effects of adalimumab seen in observational studies. Larger studies with more detailed phenotyping of vascular disease should assess the comparative differences in the effects of adalimumab and phototherapy seen in our study. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01866592 and NCT01553058.

The Role of Hyperbaric Oxygen Therapy in Orthopedics and Rheumatological Diseases.

BACKGROUND: Hyperbaric oxygen therapy (HBOT) has been investigated as a primary/adjunctive treatment for a number of injuries and medical conditions including traumatic ischemia, necrotizing soft tissue injuries, non-healing ulcers and osteoradionecrosis, but the results are controversial. There is insufficient evidence to support or reject the use of HBOT to quicken healing or to treat the established non-union of fractures. However, in patients with fibromyalgia, HBOT reduces brain activity in the posterior cortex and increases it in the frontal, cingulate, medial temporal and cerebellar cortices, thus leading to beneficial changes in brain areas that are known to function abnormally. Moreover, the amelioration of pain induced by HBOT significantly decreases the consumption of analgesic medications. In addition, HBOT has anti-inflammatory and oxygenatory effects in patients with primary or secondary vasculitis. This review analyzes the efficacy and limitations of HBOT in orthopedic and rheumatologic patients.

Sustained remission after long-term biological therapy in patients with large vessel vasculitis: an analysis of ten cases / Remisión sostenida tras terapia biológica en pacientes con vasculitis de grandes vasos: análisis de 10 casos

Objectives. To describe the results obtained in clinical practice with the use of biological therapy (BT) in patients diagnosed with Takayasu arteritis (TA) and giant cell arteritis (GCA). Methods. Retrospective single center study of TA/GCA patients who received BT (infliximab [IFX], etanercept [ETN] and tocilizumab [TCZ]). In TA, active disease was defined according to a previous National Institutes of Health study. In GCA, active disease was defined with a modified criteria and clinical manifestations secondary to temporal artery involvement or polymyalgia rheumatica symptoms. Clinical data and outcomes are reported using descriptive statistics. Results. Five patients with TA and 5 with GCA were included. The main reason for starting BT was lack of response to prior therapy and/or ≥2 relapses during GC tapering. Five patients started IFX, four TCZ and 1 ETN. Remission was observed before 6 months in all cases. Only one patient had a relapse during long-term follow-up and the overall GC daily dose was reduced by 70%. Two AEs were considered attributable to IFX and one to TCZ. Conclusion. A favorable and sustained response to BT was observed in our patients with TA and GCA. Thus, BT might be considered as an alternative in patients with large vessel arteritis refractory to conventional treatment or with GC related comorbidities (AU)

Objetivos. Describir los resultados obtenidos en la práctica clínica diaria con el uso de la terapia biológica (TB) en pacientes con diagnóstico de arteritis de Takayasu (AT) y arteritis de células gigantes (ACG). Métodos. Estudio retrospectivo monocéntrico de pacientes con AT/ACG que recibieron TB (infliximab, etanercept y tocilizumab). En AT, la enfermedad activa se definió de acuerdo a un estudio previo del National Institutes of Health. En ACG, la enfermedad activa se definió con dichos criterios modificados y manifestaciones clínicas secundarias a afectación de la arteria temporal o síntomas de polimialgia reumática. Los datos y los desenlaces clínicos se muestran mediante estadística descriptiva. Resultados. Se incluyeron 5 pacientes con AT y 5 con ACG. La razón principal para el inicio de la TB fue la falta de respuesta al tratamiento previo y/o ≥2 recaídas durante la terapia con corticoides. Cinco pacientes comenzaron infliximab, 4 tocilizumab y uno etanercept. La remisión se observó antes de los 6 meses en todos los casos. Solo un paciente tuvo una recaída durante el seguimiento a largo plazo. La dosis diaria de corticoides se redujo globalmente en un 70%. Dos acontecimientos adversos se consideraron atribuibles a infliximab y uno a tocilizumab. Conclusión. Se observó una respuesta favorable y sostenida a la TB en nuestros pacientes con AT y ACG. Por lo tanto, la TB puede ser considerada una alternativa en pacientes refractarios al tratamiento convencional o con comorbilidades asociadas a los corticoides (AU)

Biologic Therapies for Autoimmune and Connective Tissue Diseases.

Biologic therapy continues to revolutionize the treatment of autoimmune disease, especially in rheumatology as the pathophysiology of both inflammation and autoimmune disease becomes better understood. These therapies are designed to dampen the response of the inflammatory cascades. Although the first biologic therapies were approved many years ago, expanding indications and new agents continue to challenge the traditional treatment strategies for rheumatic diseases. This article reviews the data supporting the current use of biologic therapies, including off-label indications, in a subset of rheumatic diseases including rheumatoid arthritis, lupus, inflammatory myositis, ankylosing spondylitis, psoriatic arthritis, vasculitis, and gout.

Granuloma faciale with disseminated extra facial lesions.

Granuloma faciale (GF) is a rare cutaneous disorder categorized as a localized form of small vessel vasculitis. Clinically, it manifests as single or multiple, well-demarcated, red-brown plaques, papules and nodules, nearly always confined to the face. Herein, we report a 39-year-old man with multiple red-brown, infiltrated plaques on his face and extrafacial lesions on the back, shoulders, and both arms. Skin biopsy revealed typical histopathological findings of GF. The patient failed to respond to pulsed dye laser, but intralesional triamcinolone combined with cryotherapy led to an acceptable response.

Etanercept. Otras indicaciones / Etanercept. Other indications

La utilización de los tratamientos biológicos en el campo de la Dermatología ha sido reciente y se ha centrado prioritariamente en el tratamiento de la psoriasis. Etanercept ha demostrado su eficacia y seguridad en este campo, si bien es cierto que, por su mecanismo de acción y por su perfil de seguridad, se ha utilizado en numerosas patologías diferentes a la psoriasis con resultados variables. Presentamos un caso de acrodermatitis de Hallopeau tratada con etanercept con buenos resultados. Dadas las características de cronicidad, progresividad y en general mala respuesta a los tratamientos convencionales, el empleo de etanercept supone una ayuda en las posibilidades terapéuticas de la acrodermatitis de Hallopeau. Se revisan además otras posibles indicaciones de etanercept en procesos diferentes a la psoriasis (AU)

The use of biological treatments in the field of Dermatology has been recent and priority focus has been given to the treatment of psoriasis. Etanercept has demonstrated its efficacy and safety in this field although it is true that it has been used in many different diseases other than psoriasis with variable results due to its action mechanism and safety profile. We present a case of Hallopeau’s Acrodermatitis treated with etanercept with good results. Given the characteristics of chronicity, progressiveness and, in general, poor response to conventional treatments, the use of etanercept is of help in the therapeutic possibilities of Hallopeau’s Acrodermatitis. In addition, other possible indications of etanercept in conditions other than Psoriasis are reviewed (AU)

Advances in childhood vasculitis.

PURPOSE OF REVIEW: To provide an update on new developments in paediatric vasculitis. RECENT FINDINGS: New classification criteria for childhood vasculitis have recently been proposed and are currently undergoing validation. Infectious triggers are still implicated in the aetiopathogenesis of Kawasaki disease and Henoch-Schonlein purpura. Several genetic polymorphisms in vasculitides have now been described that may be relevant in terms of disease predisposition or development of disease complications. Treatment regimens continue to improve, with the use of different immunosuppressive medications and newer therapeutic approaches such as biologic agents. However, new challenges are looming with regard to the role of inflammation in endothelial health and the long-term cardiovascular morbidity for children with primary systemic vasculitis. SUMMARY: As our understanding of disease pathogenesis in vasculitis of the young has advanced, novel therapeutic approaches have been adapted. International multicentre collaboration is of great importance to further increase and standardize the scientific base of investigating and treating childhood vasculitis.

A case of refractory vasculitic ulcers in a systemic lupus erythematosus patient responding to rituximab and hyperbaric oxygen therapy.

Large refractory vasculitic ulcers are not commonly seen in systemic lupus erythematosus (SLE) patients. We report a case of refractory vasculitic ulcers responding to rituximab, a monoclonal antibody directed against CD20 cells leading to prolonged B cell depletion. This treatment was initiated after treatment with high-dose steroids and other immunosuppressants were ineffective/associated with significant side-effects. Following treatment with rituximab, there was sustained clinical improvement and subsequent reduction of prednisolone dose. Rituximab was well-tolerated. Concomitant methotrexate therapy and hyperbaric oxygen therapy (HBOT) may have aided the recovery of the patient's vasculitic ulcers. This case and anecdotal reports have illustrated the efficacy and safety of rituximab in the treatment of refractory SLE-related vasculitic ulcers. Further studies to determine the long-term efficacy and side-effects would be useful.

[Therapy of vasculitides and vasculopathies]. / Therapie von Vaskulitiden und Vaskulopathien.

Treatment and course of leukocytoclastic immune-complex vasculitis (LcV) depend on absence or presence of IgA in immune complexes [Henoch-Schoenlein-Purpura (PSH)]. LcV due to IgG- or IgM-containing immune complexes has a better prognosis. If triggers cannot be detected or avoided, symptomatic treatments are usually sufficient due to a usually favourable course. When hemorrhagic blisters suggest incipient skin necrosis corticosteroids are indicated. For chronic or relapsing LcV we suggest colchicine or dapsone. In adults with PSH and severe glomerulonephritis there is insufficient evidence for the efficacy of glucocorticoids; but e.g. ACE inhibitors can be helpful depending on symptoms. In cryoglobulinemic vasculitis underlying diseases (often plasmocytoma or hepatitis C) should be treated, sometimes supplemented by plasmapheresis. Dapsone or colchicine are usually started for urticarial vasculitis. ANCA-associated systemic vasculitis requires rapid and aggressive induction therapy, usually with glucocorticoids and cyclophosphamide. In classic polyarteriitis nodosa glucocorticoids improve prognosis, in polyarteriitis nodosa cutanea colchicine or dapsone are more appropriate. Giant cell arteriitis requires rapid therapy with glucocorticoids. For livedo vasculopathy antithrombotic measures are required with low molecular heparin or antagonists to vitamin K, for maintenance dipyridamol und aspirin.

Indications for biotherapy in systemic vasculitides.

Biotherapy now holds a specific place in the therapeutic armamentarium for systemic vasculitides. Such therapy includes cytokines, such as (pegylated) alpha-interferon for hepatitis B virus-related polyarteritis nodosa and hepatitis C virus-related cryoglobulinemic vasculitis, and polyvalent immunoglobulin (IVIg), with well-defined indications and pending positive results. More specifically targeted monoclonal antibodies include antitumor necrosis factor-alpha or anti-CD20 for antineutrophil cytoplasmic antibody-associated vasculitides or anti-interleukin-5 and anti-IgE for Churg-Strauss syndrome. However, the exact indications of these latter new agents, as well as their optimal dosage and duration, are not defined. Therefore, they are prescribed mainly for patients with disease refractory to conventional therapy, in whom results are promising. Results of international ongoing trials will determine whether the agents may also have a place as first-line treatment.

Vasculitis y oxigenación hiperbárica / Vasculitis and hyperbaric oxygenation

Se presenta la experiencia del Servicio Provincial de Dermatología del Hospital Universitario Camilo Cienfuegos de Sancti Spíritus, sobre una paciente de 28 años, femenina que con el diagnóstico de Vasculitis Leucocitoclástica desde hace ocho años ha recibido múltiples tratamientos, usando varios esquemas de prednisona y ciclofosfamida, con varios ingresos por úlceras de miembros inferiores. Se hace revisión bibliográfica del tema, se aplica oxigenación hiperbárica y se exponen comentarios al respecto (AU)

The experience presented is that of the Provincial Service of Dermatology of the Camilo Cienfuegos University Hospital of Sancti Spíritus, on a 28 year-old female patient, with a diagnosis of leucocytoclastic vasculitis who for eight years has received multiple treatments, using several prednison and cyclophosphamid schemes, with several admissions for ulcers of lower limbs. A bibliographical review of the topic is made. Hyperbaric oxygenation is applied and comments are exposed in this respect

Hyperbaric oxygen therapy for nonhealing vasculitic ulcers.

BACKGROUND: Cutaneous nonhealing ulceration is a threatening manifestation of vasculitis. Hyperbaric oxygen (HBO), frequently used as adjuvant therapy for patients with ischaemic ulcers, exerts additional beneficial effects on the vascular inflammatory response. AIM: To evaluate the effect of HBO on vasculitis-induced nonhealing skin ulcers. METHODS: The study population comprised 35 patients aged >or= 18 years with severe, nonhealing, vasculitis-induced ulcers that had not improved following immunosuppressive therapy. Baseline ulcer tissue oxygenation was evaluated at room air concentration (21% O2), at 1 atmosphere absolute (ATA) breathing 100% O2, and at 2 ATA breathing 100% O2. The baseline treatment protocol consisted of a 4-week course of 100% O2 for 90 min at 2 ATA, five times/week. RESULTS: The mean baseline ulcer tissue oxygenation (3.1 +/- 2.4 kPa at room air concentration), was significantly increased to 13.9 +/- 11.9 kPa at 1 ATA breathing 100% O2 (P < 0.001), and subsequently increased further to 59.1 +/- 29.8 kPa at 2 ATA breathing 100% O2 (P < 0.001). At the end of the hyperbaric therapy, 28 patients (80%) demonstrated complete healing, 4 (11.4%) had partial healing and 3 (8.6%) had no improvement. None of the patients had any side-effects related to the HBO therapy. CONCLUSION: HBO therapy may serve as an effective safe treatment for patients with vasculitis having nonhealing skin ulcers. Further studies are needed to evaluate its role as primary therapy for this group of patients.

Maggot debridement therapy for serious horse wounds - a survey of practitioners.

Hoof disease and injuries are common and serious problems for equines. Maggot debridement therapy (MDT) has been used to treat problematic wounds in humans, but has been used only rarely in other animals. US veterinarians who had employed MDT were surveyed to investigate their reasons for the choice of this treatment and their clinical experiences with it. Between 1997 and 2003, 13 horses were treated by eight veterinarians who used MDT to control infection or debride wounds, which could not easily be reached surgically or were not responding to conventional therapy. Seven animals were lame, and six were expected to require euthanasia. Following maggot therapy, all infections were eradicated or controlled, and only one horse had to be euthanased. No adverse events were attributed to maggot therapy for any of these cases, other than presumed discomfort during therapy. The data collected suggest that maggot therapy could be useful for treating some serious equine hoof and leg wounds.

Major ozonated autohemotherapy in chronic limb ischemia with ulcerations.

This paper reports the beneficial effects of ozone autohemotherapy (OHT) in 2 patients afflicted with painful, intractable leg ulcers. One patient had diabetes mellitus type II (DM), the other had vasculitis. Both patients had seen multiple specialists, including a dermatologist, an internist, and a vascular surgeon, but their clinical course continued to worsen. When the pain became intolerable, the patients came to our pain clinic. Chemical lumbar sympathectomy as well as epidural blockade with bupivacaine and morphine were moderately effective in reducing their pain but had no effect on the ulcers. Only after OHT treatments were performed for several months was satisfactory healing observed.

Biologic therapies in the vasculitides.

Monoclonal antibody and recombinant DNA technologies have led to the development of biologic therapies capable of directly targeting selected components of the immune response. With the steady expansion of knowledge regarding the mechanisms of vascular inflammation, the safety and efficacy of biologic agents in the vasculitic diseases are being increasingly investigated. By targeting specific effector mechanisms involved in the pathogenesis of vasculitis, these agents may provide a less toxic means of inducing remission and lessening relapse. However, the study of biologic therapies in the vasculitides must be approached with caution, as unanticipated effects on disease activity and disease-specific toxicities can occur. Studies to examine these agents must recognize the potential for active vasculitis to be organ- or life-threatening as well as the current existence of effective therapies. In the research setting, investigation of biologic agents in the treatment of vasculitic diseases may also provide important insights into pathogenesis of these syndromes.