Biologic therapy in large and small vessels vasculitis, and Behçet's disease: Evidence- and practice-based guidance.

OBJECTIVE: Vasculitis are a very heterogenous group of systemic autoimmune diseases, affecting large vessels (LVV), small vessels or presenting as a multisystemic variable vessel vasculitis. We aimed to define evidence and practice-based recommendations for the use of biologics in large and small vessels vasculitis, and Behçet's disease (BD). METHODS: Recommendations were made by an independent expert panel, following a comprehensive literature review and two consensus rounds. The panel included 17 internal medicine experts with recognized practice on autoimmune diseases management. The literature review was systematic from 2014 until 2019 and later updated by cross-reference checking and experts' input until 2022. Preliminary recommendations were drafted by working groups for each disease and voted in two rounds, in June and September 2021. Recommendations with at least 75% agreement were approved. RESULTS: A total of 32 final recommendations (10 for LVV treatment, 7 for small vessels vasculitis and 15 for BD) were approved by the experts and several biologic drugs were considered with different supporting evidence. Among LVV treatment options, tocilizumab presents the higher level of supporting evidence. Rituximab is recommended for treatment of severe/refractory cryoglobulinemic vasculitis. Infliximab and adalimumab are most recommended in treatment of severe/refractory BD manifestations. Other biologic drugs can be considered is specific presentations. CONCLUSION: These evidence and practice-based recommendations are a contribute to treatment decision and may, ultimately, improve the outcome of patients living with these conditions.

Biological therapy in systemic lupus erythematosus, antiphospholipid syndrome, and Sjögren's syndrome: evidence- and practice-based guidance.

Systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), and Sjögren's syndrome (SS) are heterogeneous autoimmune diseases. Severe manifestations and refractory/intolerance to conventional immunosuppressants demand other options, namely biological drugs, and small molecules. We aimed to define evidence and practice-based guidance for the off-label use of biologics in SLE, APS, and SS. Recommendations were made by an independent expert panel, following a comprehensive literature review and two consensus rounds. The panel included 17 internal medicine experts with recognized practice in autoimmune disease management. The literature review was systematic from 2014 until 2019 and later updated by cross-reference checking and experts' input until 2021. Preliminary recommendations were drafted by working groups for each disease. A revision meeting with all experts anticipated the consensus meeting held in June 2021. All experts voted (agree, disagree, neither agree nor disagree) during two rounds, and recommendations with at least 75% agreement were approved. A total of 32 final recommendations (20 for SLE treatment, 5 for APS, and 7 for SS) were approved by the experts. These recommendations consider organ involvement, manifestations, severity, and response to previous treatments. In these three autoimmune diseases, most recommendations refer to rituximab, which aligns with the higher number of studies and clinical experience with this biological agent. Belimumab sequential treatment after rituximab may also be used in severe cases of SLE and SS. Second-line therapy with baricitinib, bortezomib, eculizumab, secukinumab, or tocilizumab can be considered in SLE-specific manifestations. These evidence and practice-based recommendations may support treatment decision and, ultimately, improve the outcome of patients living with SLE, APS, or SS.

Vitamin D supplementation effects on FoxP3 expression in T cells and FoxP3+/IL-17A ratio and clinical course in systemic lupus erythematosus patients: a study in a Portuguese cohort.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multi-organ inflammation, linked to loss of immune tolerance to self-antigens and the production of a diversity of autoantibodies, with a negative impact on the patients' quality of life. Regulatory T cells have been reported as deficient in number and function in SLE patients. However, some authors also described an enrichment of this cell type. The hypothesis that certain forms of autoimmunity may result from a conversion of Treg cells into a Th17 cell phenotype has been suggested by some studies. In fact, in SLE patients' sera, the IL-17 levels were observed as abnormally high when compared with healthy individuals. Environmental factors, such as vitamin D, that is considered a potential anti-inflammatory agent, combined with genetic and hormonal characteristics have been associated with SLE phenotype and with disease progression. The aim of this study was to evaluate the effect of vitamin D supplementation on FoxP3 expression and IL-17A-producing T cells, through FoxP3+/IL-17A ratio. Additionally, disease evolution, serum vitamin D levels, serum autoantibodies levels and calcium metabolism (to assure safety) were also studied. We assessed 24 phenotypically well-characterized SLE patients. All patients were screened before vitamin D supplementation and 3 and 6 months after the beginning of this treatment. Peripheral blood lymphocyte's subsets were analysed by flow cytometry. Serum 25(OH)D levels significantly increased under vitamin D supplementation (p = 0.001). The FoxP3+/IL-17A ratio in SLE patients after 6 months of vitamin D supplementation was higher than that in the baseline (p < 0.001). In conclusion, this study demonstrated that vitamin D supplementation provided favourable, immunological and clinical impact on SLE.

Balneotherapy in rheumatoid arthritis-a systematic review.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by persistent inflammation of synovial joints with pain, often leading to joint destruction and disability, and despite intensive research, the cause of RA remains unknown. Balneotherapy-also called mineral baths or spa therapy-uses different types of mineral water compositions like sulphur, radon, carbon dioxin, etc. The role of balneotherapy is on debate; Sukenik wrote that the sulphur mineral water has special proprieties to rheumatologic diseases, including in the course of active inflammatory phases in RA. The aim of this review is to summarize the available evidence on the effects of balneotherapy on patients with rheumatoid arthritis. We have made a systematic search of the articles published from 1980 to 2014 on this topic in PubMed, Scopus, CRD, PEDro, Web of Science and Embase databases. We have followed the method set by the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA). These that have compared balneotherapy with other therapeutic modalities or with no intervention were considered. The inclusion criteria of these papers were randomized control trial (RCT); languages: English, French, Spanish, Italian and Portuguese; evaluation of efficacy (analysis of outcomes); use of natural mineral water baths; and participants with RA. A total of eight articles documenting RCTs were found and included for full review and critical appraisal involving a total of 496 patients. The studies selected highlighted an important improvement and statistically significant in several clinical parameters, in spite of their heterogeneity between the various studies. One study emphasized an important improvement on functional capacity up to 6 months of follow-up (FU). Some of the studies (std.) reveal an improvement on morning stiffness (5 std.), number of active joints (3 std.), Ritchie index (2 std.) and activities of daily living (2 std.) up to 3 months of FU. Three studies reveal the improvement on handgrip strength up to 1 month of FU. About pain (VAS), the three studies which evaluated this parameter were inconclusive about real significant improvement. Our tables summarize the published papers about this topic. Different authors emphasize the same problems: methodologies differing from study to study, treatment modalities, outcomes and their analysis. On the one hand, it is particularly difficult to have homogeneity on this population in all the parameters (patient's clinical heterogeneity, diverse clinical course of the disease, variety of the drugs), and on the other hand, natural mineral water composition is always unique with potential specific biological effects. This comprehensive review has revealed that there are very few published studies about the use of natural mineral water in RA. International multicentre studies, using the same methodologies, could be achieved by carrying the scientific arguments to support our clinical practice.

Balneotherapy and Rheumatoid Arthritis: A Randomized Control Trial.

BACKGROUND: The effects of balneotherapy on rheumatoid arthritis (RA) are still controversial partly due to poor methodology used in randomized controlled trials, as reported in the international medical literature. OBJECTIVES: To determine whether spa therapy plus pharmacological treatment offers any benefit in the management of RA as compared to pharmacological treatment alone. METHODS: We conducted a prospective, controlled, unblinded randomly assigned study of patients with RA according to American College of Rheumatology criteria. Following the 2007 recommendations of AFRETH, the method designed for this study was "immediate treatment versus delayed treatment." All patients were followed at the Centro Hospitalar do Porto and each physician observed the same patients throughout the study. Patients continued with their usual medications and maintained their daily life activities at home, at leisure and/or in the workplace. The spa therapy group received spa treatments for 21 days at S. Jorge Spa-Santa Maria da Feira. The main outcome measure was the HAQ-DI; the moderated regression analysis, together with the Johnson-Neyman technique, was used for statistical analysis. RESULTS: HAQ-DI at the end of treatment (21 days) and at the 3 month follow-up was improved in the spa group (odds ratio 0.37, confidence interval 0.09-0.64, P = 0.01 at 21 days, and 0.44, 0.15-0.72, P = 0.004 at 3 months). CONCLUSIONS: In individuals in whom pain (physical and psychological) predominates, any complementary gain in function is beneficial. The main goal is to enhance quality of life.

Hepatoprotective effect of the aqueous extract of Simarouba amara Aublet (Simaroubaceae) stem bark against carbon tetrachloride (CCl4)-induced hepatic damage in rats.

Simarouba amara stem bark decoction has been traditionally used in Brazil to treat malaria, inflammation, fever, abdominal pain, diarrhea, wounds and as a tonic. In this study, we investigate the hepatoprotective effects of the aqueous extract of S. amara stem bark (SAAE) on CCl4-induced hepatic damage in rats. SAAE was evaluated by high performance liquid chromatography. The animals were divided into six groups (n = 6/group). Groups I (vehicle-corn oil), II (control-CCl4), III, IV, V and VI were pretreated during 10 consecutive days, once a day p.o, with Legalon® 50 mg/kg b.w, SAAE at doses 100, 250 and 500 mg/kg b.w, respectively. The hepatotoxicity was induced on 11th day with 2 mL/kg of 20% CCl4 solution. 24 h after injury, the blood samples were collected and their livers were removed to biochemical and immunohistochemical analyzes. The SAAE decreased the levels of liver markers and lipid peroxidation in all doses and increased the catalase levels at doses 250 and 500 mg/kg. Immunohistochemical results suggested hepatocyte proliferation in all doses. These results may be related to catechins present in SAAE. Thus, SAAE prevented the oxidative damage at the same time that increased regenerative and reparative capacities of the liver.

Complement C3 as a marker of cardiometabolic risk in psoriasis.

Complement C3 is an emerging risk factor in metabolic and cardiovascular diseases. It is elevated in patients with cardiovascular disease, predicts future myocardial infarction, is closely related to insulin resistance and appears to be involved in atherogenesis. C3 levels have been associated with body fat. The aim of this study was to compare C3 levels in psoriasis patients and controls and to investigate within psoriasis patients the relationship between C3 levels with several measures of body fat, markers of cardiometabolic risk and subclinical atherosclerosis. Eighty adult patients with severe plaque-type psoriasis, without psoriatic arthritis or receiving systemic therapy/phototherapy in the previous 3 months, and 95 otherwise healthy patients were enrolled. Subjects with cardiovascular disease, other systemic inflammatory diseases, use of anti-inflammatory drugs or any infectious diseases in the 4 weeks prior to study enrollment were excluded. All subjects underwent clinical and laboratory evaluation and psoriasis patients underwent multidetector computed tomography scan for coronary artery calcification, abdominal fat and epicardial adipose tissue quantification. C3 levels were increased in psoriasis patients compared to controls (129.25 ± 20.92 vs 118.24 ± 17.86, P < 0.001), even after adjustment for age, sex and waist circumference (P = 0.043), indicating that this association was not solely mediated by the adipose tissue. Within psoriasis patients, C3 levels were independently associated with abdominal visceral fat, insulin resistance, metabolic syndrome and oxidized LDL-cholesterol, while C-reactive protein did not, showing that C3 may be a better marker of cardiometabolic risk than C-reactive protein. Although more studies are needed, C3 may be a useful marker of cardiometabolic risk in psoriasis.

Acute toxicity and laxative activity of Aloe ferox resin

Aloe ferox Mill., Xanthorrhoeaceae, resin is the solid residue obtained by evaporating the latex that drains from the leaves transversally cut. Aloe ferox has been used in folk medicine as anti-inflammatory, immunostimulant, anti-bacterial, anti-fungal, antitumor, laxative and to heal wounds and burns. The effects of the oral administration of A. ferox resin (10, 25, 50, 100 and 200 mg/kg) were evaluated on intestinal transit in mice and its acute toxicity (5.0 g/kg) in Wistar rats. The hydroxyanthracene derivatives present in the resin were expressed as aloin, identified by thin layer chromatography and quantified by spectrophotometry. The aloin (Rf 0.35) was identified and the percentage of hydroxyanthracene derivates expressed as aloin was 33.5%. A. ferox resin extract (50, 100 and 200 mg/kg) increased the gastrointestinal motility at a 30 min interval at 93.5, 91.8 and 93.8%, respectively, when compared to control group (46.5%). A single oral dose of the A. ferox resin extract did not induce signs of toxicity or death. Thus, the results demonstrate that A. ferox has laxative activity and that it is nontoxic, since LD50 could not be estimated and it is possibly higher than 5.0 g/kg.

Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis.

OBJECTIVES: To develop recommendations for the management of adult and paediatric lupus nephritis (LN). METHODS: The available evidence was systematically reviewed using the PubMed database. A modified Delphi method was used to compile questions, elicit expert opinions and reach consensus. RESULTS: Immunosuppressive treatment should be guided by renal biopsy, and aiming for complete renal response (proteinuria <0.5 g/24 h with normal or near-normal renal function). Hydroxychloroquine is recommended for all patients with LN. Because of a more favourable efficacy/toxicity ratio, as initial treatment for patients with class III-IV(A) or (A/C) (±V) LN according to the International Society of Nephrology/Renal Pathology Society 2003 classification, mycophenolic acid (MPA) or low-dose intravenous cyclophosphamide (CY) in combination with glucocorticoids is recommended. In patients with adverse clinical or histological features, CY can be prescribed at higher doses, while azathioprine is an alternative for milder cases. For pure class V LN with nephrotic-range proteinuria, MPA in combination with oral glucocorticoids is recommended as initial treatment. In patients improving after initial treatment, subsequent immunosuppression with MPA or azathioprine is recommended for at least 3 years; in such cases, initial treatment with MPA should be followed by MPA. For MPA or CY failures, switching to the other agent, or to rituximab, is the suggested course of action. In anticipation of pregnancy, patients should be switched to appropriate medications without reducing the intensity of treatment. There is no evidence to suggest that management of LN should differ in children versus adults. CONCLUSIONS: Recommendations for the management of LN were developed using an evidence-based approach followed by expert consensus.

Acute and subacute toxicity of Cassia occidentalis L. stem and leaf in Wistar rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Cassia occidentalis L. (syn. Senna occidentalis; Leguminosae) has been used as natural medicine in rainforests and tropical regions as laxative, analgesic, febrifuge, diuretic, hepatoprotective, vermifuge and colagogo. Herein, we performed a pre-clinical safety evaluation of hydroalcoholic extract of Cassia occidentalis stem and leaf in male and female Wistar rats. MATERIALS AND METHODS: In acute toxicity tests, four groups of rats (n=5/group/sex) were orally treated with doses of 0.625, 1.25, 2.5 and 5.0 g/kg and general behavior, adverse effects and mortality were recorded for up to 14 days. In subacute toxicity assays, animals received Cassia occidentalis by gavage at the doses of 0.10, 0.50 or 2.5 g/kg/day (n=10/group/sex) for 30 days and biochemical, hematological and morphological parameters were determined. RESULTS: Cassia occidentalis did not produce any hazardous symptoms or death in the acute toxicity test, showing a LD(50) higher than 5 g/kg. Subacute treatment with Cassia occidentalis failed to change body weight gain, food and water consumption and hematological and biochemical profiles. In addition, no changes in macroscopical and microscopical aspect of organs were observed in the animals. CONCLUSIONS: Our results showed that acute or subacute administration of Cassia occidentalis is not toxic in male and female Wistar rats, suggesting a safety use by humans.