Real-world treatment patterns of rheumatoid arthritis in Brazil: analysis of DATASUS national administrative claims data for pharmacoepidemiology studies (2010-2020).

Our study assessed DATASUS as a potential source for pharmacoepidemiologic studies in rheumatoid arthritis (RA) in the Brazilian population focusing on treatment patterns and determinants of initiating or switching to a novel therapy. This was a descriptive database study of RA patients with at least one claim of RA and ≥ 2 claims of disease-modifying anti-rheumatic drug (DMARD); conventional synthetic (cs), biologic (b) or targeted synthetic (ts) DMARD with more than 6 months of follow-up from 01-Jan-2010 to 31-Dec-2020. Analyses were stratified for SUS-exclusive and SUS+ private user cohorts. We identified 250,251 patients with RA in DATASUS: mean age of 58.4 years, majority female (83%) and white (58%). 62% were SUS-exclusive and 38% SUS+ private. Most common bDMARDs were adalimumab and etanercept. Age (adjusted odds ratio 1.78 [50+]; 95% CI 1.57-2.01), SUS exclusive status (0.53; 0.47-0.59), distance to clinic [160+ km] (0.57; 0.45-0.72), and pre-index csDMARD claims (1.23; 1.08-1.41) were independent predictors of initiating a novel oral tsDMARD. Switching from bDMARD to tsDMARD, associations were similar, except for the direction of associations for SUS exclusive status (adjusted hazard ratio 1.10; 1.03-1.18), distance to clinic (1.18; 1.03-1.35), and number of previous bDMARD (0.15; 0.14-0.16). DATASUS is a source suitable for treatment-related analyses in RA reflecting the public health system in Brazil.

Safety of upadacitinib in Latin American patients with rheumatoid arthritis: an integrated safety analysis of the SELECT phase 3 clinical program.

INTRODUCTION/OBJECTIVES: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by ongoing inflammation and degradation of synovial joints. The oral JAK inhibitor, upadacitinib, is approved for RA. We conducted an integrated safety analysis of upadacitinib 15 mg once daily (QD) in patients from Latin America (LATAM) versus the rest of the world (RoW). METHODS: Treatment-emergent adverse events (AEs) and laboratory data from six phase 3, randomized controlled trials, adjusted for upadacitinib 15 mg QD use in RA, were analyzed. RESULTS: Overall, 3209 patients received upadacitinib 15 mg QD for 7024 patient-years (PY). LATAM patients (n = 725) had a mean upadacitinib exposure of 1518 PY. Baseline characteristics were generally similar between LATAM and RoW populations. AE rates (including serious/opportunistic infections, tuberculosis, and herpes zoster) and deaths were comparable between populations. LATAM patients had lower serious AE rates per 100 PY (9.4 vs 14.0 E/100 PY) and discontinuation-related AEs (3.9 vs 6.0 E/100 PY) versus RoW. Rates of cardiovascular events were low (≤ 0.5 E/100 PY) and similar between populations. Malignancies, excluding non-melanoma skin cancer, were less common in the LATAM population versus RoW (0.2 vs 1.0 E/100 PY). Laboratory abnormalities were similar between populations, with decreases in hemoglobin, lymphocyte, and neutrophil counts, and elevations in liver enzymes and creatine phosphokinase. Mean change from baseline in low- and high-density lipoprotein cholesterol was generally comparable between LATAM and RoW populations. CONCLUSION: Upadacitinib 15 mg QD demonstrated a consistent safety profile across LATAM and RoW patient populations, with no new safety risks observed. TRIAL REGISTRATION NUMBERS: SELECT-EARLY, NCT02706873; SELECT-NEXT, NCT02675426; SELECT-COMPARE, NCT02629159; SELECT-MONOTHERAPY, NCT02706951; SELECT-BEYOND, NCT02706847; SELECT-CHOICE, NCT03086343.

Treatment with silica-gold nanostructures decreases inflammation-related gene expression in collagen-induced arthritis.

Gold salts have been used to treat rheumatoid arthritis (RA) since the 1940s, and, with advances in nanotechnology, the use of nanogold provides multiple options for anti-inflammatory therapies. This paper presents the synthesis and characterization of silica-gold nanostructures (SGNs) and their therapeutic effect in collagen-induced arthritis (CIA) in DBA/1 mice. At the end of the treatment, the synovial membranes, kidneys, livers, and spleens were dissected and analyzed by inductively coupled plasma mass spectroscopy (ICP) showing less than 0.0001 and 0.1% of the administered doses of Au and Si, respectively. Remains of the SGNs were visually identified in the synovial membrane by scanning electron microscopy (SEM), and the bone density of the hind paws was observed by computerized tomography (CT) indicating a reduction of porosity in the CIA-experimental group. The DNA microarray analysis carried out with RNA obtained from the hind paws showed 2628 differentially expressed genes (DEGs) by SGNs. The bioinformatic analysis showed that DEGs were significantly associated with several inflammatory signalling pathways including chemokines, cytokine-cytokine receptor interaction, PI3K-Akt, TNF, IL-17, NFκß, MAPK, and RA. SGNs downregulated relevant inflammatory genes in the arthritic joints, including Tnf, Ifng, Il6, and Cxcl5; immunohistochemistry (IHC) confirmed the reduction of TNFα, IL-6, NFκß, and VEGF in the joints due to the effect of SGNs. TNFα and IL-6 were also reduced in the serum of DBA/1 mice treated with SGNs.

Effects of different physical training protocols on inflammatory markers in Zymosan-induced rheumatoid arthritis in Wistar rats.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and involvement of the synovial membrane, causing joint damage and deformities. No effective drug treatment is available, and physical exercise has been utilized to alleviate the inflammatory processes. This study aimed to investigate the effects of different exercise training protocols on Zymosan-induced RA inflammatory markers in the right knee of Wistar rats. The rodents were subjected to aerobic, resisted, and combined physical training protocols with variations in the total training volume (50% or 100% of resistance and aerobic training volume) for 8 weeks. All physical training protocols reduced cachexia and systemic inflammatory processes. The histological results showed an increase in the inflammatory influx to the synovial tissue of the right knee in all physical training protocols. The rats that underwent combined physical training with reduced volume had a lower inflammatory influx compared to the other experimental groups. A reduction in the mRNA expression of inflammatory genes and an increase in anti-inflammatory gene expression were also observed. The physical training protocol associated with volume reduction attenuated systemic and synovial inflammation of the right knee, reducing the impact of Zymosan-induced RA in rats.

Suppression of nitrosative stress and inflammation of the knee joint synovium in collagen type ii-induced rheumatoid arthritis by the inhibition of glycogen synthase kinase-3ß / Supresión del estrés nitrosativo e inflamación de la sinovial de la articulación de la rodilla en la artritis reumatoide inducida por colágeno tipo ii mediante la inhibición de la glucógeno sintasa quinasa-3 ß

SUMMARY: Rheumatoid arthritis (RA), an inflammatory autoimmune disease that causes cartilage degradation and tissue destruction, can affect synovial joints such as the knee joint. The link between the nitrosative stress enzyme inducible nitric oxide synthase (iNOS) and the cytokine interleukin-1 (IL-1β) in RA-induced knee joint synovial membrane damage with and without the incorporation of the GSK3β inhibitor TDZD-8 has never been studied. As a result, we used active immunization method with collagen type II (COII) for twenty one days to induce RA in rats. TDZD-8 (1 mg/kg; i.p.) was given daily into matched immunized rats for three weeks after day 21 (COII+TDZD-8). Blood and tissue samples were taken 42 days after immunization. A dramatic increase in rheumatoid factor (RF) blood levels, as well as considerable synovial tissue damage and inflammatory cell infiltration of the synovial membrane, were used to validate the onset of RA following COII immunization. COII immunization increased tissue levels of iNOS protein and IL- 1β mRNA and protein expression, which TDZD-8 suppressed considerably (p<0.0001). Furthermore, there was a significantly (p<0.001) positive correlation between iNOS, inflammatory biomarkers, and RF. We concluded that TDZD-8 reduced RA-induced IL-1β -iNOS axis-mediated arthritis in the rat knee joint synovium.

RESUMEN: La artritis reumatoide (AR), es una enfermedad autoinmune inflamatoria que causa la degradación del cartílago y la destrucción del tejido, pudiendo afectar las articulaciones sinoviales, como la articulación de la rodilla. No se ha estudiado el vínculo entre la óxido nítrico sintasa inducible por la enzima del estrés nitrosativo (iNOS) y la citocina interleucina-1 (IL-1β) en el daño de la membrana sinovial de la articulación de la rodilla provocado por AR con y sin la incorporación del inhibidor de GSK3β TDZD-8. Utilizamos el método de inmunización activa con colágeno tipo II (COII) durante veintiún días para inducir AR en ratas. Se administró TDZD-8 (1 mg/kg; i.p.) diariamente a ratas inmunizadas emparejadas durante tres semanas después del día 21 (COII+TDZD- 8). Se tomaron muestras de sangre y tejido 42 días después de la inmunización. Se observó un gran aumento de los niveles sanguíneos del factor reumatoideo (FR), así como un daño considerable del tejido sinovial e infiltración de células inflamatorias en la membrana sinovial, para validar la aparición de la AR después de la inmunización con COII. La inmunización con COII aumentó los niveles tisulares de la proteína iNOS y la expresión de proteína y ARNm de IL-1β, que TDZD-8 suprimió considerablemente (p<0,0001). Además, hubo una correlación positiva significativa (p<0,001) entre iNOS, biomarcadores inflamatorios y FR. Concluimos que TDZD- 8 redujo la artritis mediada por el eje IL-1β-iNOS inducida por la AR en la sinovial de la articulación de la rodilla de rata.

LASSBio-596: a New Pre-clinical Candidate for Rheumatoid Arthritis?

Pain and inflammatory disorders are significant health problems because of prevalence and associated disabilities. In this context, LASSBio-596 is a hybrid compound able to modulate TNF-α and phosphodiesterases 4 and 5, exhibiting an anti-inflammatory effect in the pulmonary inflammatory model. Aiming at a better description of the activities of LASSBio-596, we initially conducted nociception tests (acetic acid-induced abdominal writhing, glutamate, and formalin-induced nociception and hot plate test) and later inflammatory tests (acute, peritonitis; and chronic, arthritis) that directed us to this last one. In the abdominal writhing test, there was a dose-dependent inhibition, whose response occurred at the maximum dose (50 mg/kg, p.o.), used in the subsequent tests. LASSBio-596 also inhibited nociception induced by chemical (glutamate by 31.9%; and formalin, in both phases, 1st phase: 25.7%; 2nd phase: 23.9%) and thermal agents (hotplate, by increased latency for pain at two different times). These effects were independent of the motor function, legitimated in rotarod. As there was a response in the inflammatory component of nociception, we performed the peritonitis test, in which migration was inhibited by LASSBio-596 by 39.9%. As the inflammatory process is present in autoimmune diseases, we also performed the arthritis test. LASSBio-596 reduced paw edema from the 15th day to the 21st day of treatment (no liver changes and with fewer paw injuries). In addition, LASSBio-596 decreased serum levels of TNF-α by 67.1%. These data demonstrated the antinociceptive effect of LASSBio-596 and reinforces its anti-inflammatory property (i.e., RA), amplifying the therapeutic potential of this molecule.

Integrative multiomics analysis of Premolis semirufa caterpillar venom in the search for molecules leading to a joint disease.

The joint disease called pararamosis is an occupational disease caused by accidental contact with bristles of the caterpillar Premolis semirufa. The chronic inflammatory process narrows the joint space and causes alterations in bone structure and cartilage degeneration, leading to joint stiffness. Aiming to determine the bristle components that could be responsible for this peculiar envenomation, in this work we have examined the toxin composition of the caterpillar bristles extract and compared it with the differentially expressed genes (DEGs) in synovial biopsies of patients affected with rheumatoid arthritis (RA) and osteoarthritis (OA). Among the proteins identified, 129 presented an average of 63% homology with human proteins and shared important conserved domains. Among the human homologous proteins, we identified seven DEGs upregulated in synovial biopsies from RA or OA patients using meta-analysis. This approach allowed us to suggest possible toxins from the pararama bristles that could be responsible for starting the joint disease observed in pararamosis. Moreover, the study of pararamosis, in turn, may lead to the discovery of specific pharmacological targets related to the early stages of articular diseases.

Lycopene used as Anti-inflammatory Nanodrug for the Treatment of Rheumathoid Arthritis: Animal assay, Pharmacokinetics, ABC Transporter and Tissue Deposition.

Lycopene is a carotenoid drug that has demonstrated several properties, including antioxidant and anti-inflammatory activity. The absorption in human body is very low (10-30 % only). In order to increase the bioavailability, lycopene nanoemulsion was formulated and characterized (atomic force microscopy, thermogravimetric analysis dynamic light scattering and differential scanning calorimetry). Also in vitro assay to evaluate the at-binding with MPR1 was performed. Finally, in vivo assay in animals inducted with rheumathoid arthritis were performed. The results showed that the formulated nanolycopene had superior efficacy when compared with the conventional lycopene (not nano-formulated) in inducted animals (rheumatoid arthritis). The results support the use of nanolycopene as an anti-inflammatory agent for rheumatoid arthritis therapy.

Effect of quercetin on E-NTPDase/E-ADA activities and cytokine secretion of complete Freund adjuvant-induced arthritic rats.

The effect of quercetin was assessed in rats induced with complete Freund adjuvant (CFA). Arthritis scores, paw oedema, latency, activities of myeloperoxidase (MPO), ectonucleoside triphosphate diphosphohydrolase (E-NTPDase), and ectoadenosine deaminase (E-ADA) in lymphocytes were determined. Furthermore, nucleotide and nucleoside levels as well as the secretion of pro- and anti-inflammatory cytokines were evaluated. Animals were treated with saline and quercetin in doses of 5, 25, and 50 mg/kg for 45 days. The result revealed that quercetin (50 mg/kg) reduced arthritis score and paw oedema, and increased the latency in the thermal hyperalgesia test. Histopathological analysis showed that all the doses of quercetin reduced infiltration of inflammatory cells. MPO activity was increased in the arthritis group; however, quercetin reduced this activity. E-NTPDase activity was increased in lymphocytes of arthritis rats, and treatment with quercetin reversed this increase. However, E-ADA activity was reduced in the arthritis group, and treatment with quercetin modulated the activity of this enzyme in arthritis rat groups. Serum adenosine levels were increased in arthritis, and the levels were lowered with quercetin treatment. Quercetin treatment in arthritis groups decreased the elevated levels of cytokines in the arthritis control group. Thus, quercetin demonstrated an anti-inflammatory effect, and this flavonoid may be a promising natural compound for the treatment of arthritis. SIGNIFICANCE OF THE STUDY: Quercetin may represent a potential therapeutic compound in the treatment of rheumatoid arthritis. Findings from this study indicate that quercetin suppresses swelling and attenuates the underlying inflammatory responses. This is the first report where quercetin was shown to modulate the immune response to arthritis via attenuation of the purinergic system (E-NTPDase and E-ADA activities) and the levels of IFN-gamma and IL-4. Thus, this work is relevant to basic research and may be translated into clinical practice.

Alpha-mangostin: Anti-inflammatory and antioxidant effects on established collagen-induced arthritis in DBA/1J mice.

Rheumatoid arthritis (RA) is an autoimmune disease that causes physical disability in people worldwide. Despite progress made in RA treatment in the past decade, new drugs with high efficacy but few long-term adverse effects are still needed. This study focused on evaluating the therapeutic potential of α-mangostin on established collagen-induced arthritis (CIA) in DBA/1J mice. Arthritic DBA/1J mice were orally administered with two doses of α-mangostin (10 and 40 mg/kg) daily, for 33 days. Alpha-mangostin significantly decreased the clinical score in the short term at both doses and decreased the histopathological score at the higher dose. This improvement was accompanied by a reduction on serum levels of anti-collagen IgG2a autoantibodies and of the production of LIX/CXCL5, IP-10/CXCL10, MIG/CXCL9, RANTES/CCL5, IL-6 and IL-33 in the joints of CIA mice. Alpha-mangostin also exhibited an anti-oxidant effect decreasing the NADPH oxidase activity and lipid peroxidation and preserving the levels of reduced glutathione in the arthritic joints. In vitro this xanthone demonstrated modulatory properties on LPS-activated dendritic cells, although in Th1 and Th17-polarized lymphocytes promotes a pro-apoptotic phenotype. Altogether this study illustrates the capacity of α-mangostin to ameliorate the early clinical and histological signs of established CIA by reducing the inflammatory and oxidative responses.

Pesticide Exposure and Risk of Rheumatoid Arthritis among Licensed Male Pesticide Applicators in the Agricultural Health Study.

BACKGROUND: The occupation of farming has been associated with rheumatoid arthritis (RA); pesticides may account for this association, but there are few studies. OBJECTIVES: We investigated associations between RA and use of pesticides in the Agricultural Health Study. METHODS: The study sample was drawn from male pesticide applicators enrolled in 1993­1997 who provided questionnaire data at baseline and at least once during follow-up (over a median 18 y; interquartile range 16­19). Incident RA cases (n=220), confirmed by physicians or by self-reported use of disease-modifying antirheumatic drugs, were compared with noncases (n=26,134) who did not report RA. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression, adjusting for enrollment age, state, smoking pack-years, and education. We evaluated the association of RA with the use of 46 pesticides and across 4 levels (never use and tertiles) of lifetime days of use for 16 pesticides with OR≥1.2 for ever use. RESULTS: Incident RA was associated with ever use of fonofos (OR = 1.70; 95% CI: 1.22, 2.37), carbaryl (OR = 1.51; 95% CI: 1.03, 2.23), and chlorimuron ethyl (OR = 1.45; 95% CI: 1.01, 2.07) compared with never use. Statistically significant exposure­response trends in association with RA were observed for lifetime days of use of atrazine [ORtertile3= 1.62 (95% CI: 1.09, 2.40); ptrend=0.01] and toxaphene [ORtertile3= 2.42 (95% CI: 1.03, 5.68); ptrend=0.02]. Exposure­response was nonlinear for fonofos [ORtertile1= 2.27 (95% CI: 1.44, 3.57); ORtertile2= 0.98 (95% CI: 0.54, 1.80); ORtertile3= 2.10 (95% CI: 1.32, 3.36); ptrend=0.005] and suggestive for carbaryl (ptrend=0.053). CONCLUSIONS: Our results provide novel evidence of associations between exposure to some pesticides and RA in male farmers. https://doi.org/10.1289/EHP1013.

Boron neutron capture synovectomy (BNCS) as a potential therapy for rheumatoid arthritis: radiobiological studies at RA-1 Nuclear Reactor in a model of antigen-induced arthritis in rabbits.

Rheumatoid arthritis is a chronic autoimmune pathology characterized by the proliferation and inflammation of the synovium. Boron neutron capture synovectomy (BNCS), a binary treatment modality that combines the preferential incorporation of boron carriers to target tissue and neutron irradiation, was proposed to treat the pathological synovium in arthritis. In a previous biodistribution study, we showed the incorporation of therapeutically useful boron concentrations to the pathological synovium in a model of antigen-induced arthritis (AIA) in rabbits, employing two boron compounds approved for their use in humans, i.e., decahydrodecaborate (GB-10) and boronophenylalanine (BPA). The aim of the present study was to perform low-dose BNCS studies at the RA-1 Nuclear Reactor in the same model. Neutron irradiation was performed post intra-articular administration of BPA or GB-10 to deliver 2.4 or 3.9 Gy, respectively, to synovium (BNCS-AIA). AIA and healthy animals (no AIA) were used as controls. The animals were followed clinically for 2 months. At that time, biochemical, magnetic resonance imaging (MRI) and histological studies were performed. BNCS-AIA animals did not show any toxic effects, swelling or pain on palpation. In BNCS-AIA, the post-treatment levels of TNF-α decreased in four of six rabbits and IFN-γ levels decreased in five of six rabbits. In all cases, MRI images of the knee joint in BNCS-AIA resembled those of no AIA, with no necrosis or periarticular effusion. Synovial membranes of BNCS-AIA were histologically similar to no AIA. BPA-BNCS and GB-10-BNCS, even at low doses, would be therapeutically useful for the local treatment of rheumatoid arthritis.

Etanercept administration prevents the inflammatory response induced by carrageenan in the murine air pouch model.

Rheumatoid arthritis (RA) is one of several inflammatory and autoimmune diseases that affect approximately 1% of world's population. The development of TNF inhibitors in the last decade represents a great advance in the treatment of mild and severe forms of RA. Etanercept is one of these drugs that is useful for RA treatment, but the mechanism of inhibition of the signaling pathway of inflammation was not completely elucidated. This study was conducted to evaluate the anti-inflammatory effect of etanercept in comparison to reference drugs (dexamethasone and indomethacin). Inflammation was induced by subcutaneal administration of carrageenan in the Swiss albino mice using the murine air pouch model. Exudation; leukocytes; myeloperoxidase (MPO); adenosine deaminase (ADA); nitric oxide metabolites (NOx); tumor necrosis factor (TNF); interferon gamma (IFN-γ); interleukins (IL) IL-6, IL-17, IL-10, IL-4, and IL-2; nuclear transcription factor kappa B (NF-κB) activation and apoptosis were evaluated 24 h after the induction of inflammation. Treatment with etanercept significantly inhibited exudate concentrations; leukocyte count; MPO and ADA activities; NOx, TNF, IFN-γ, and IL-17 levels; and NF-kappa B activation (p < 0.05). Etanercept induced apoptosis, reducing the number of viable neutrophils without increasing necrosis (p < 0.05). Our results suggest that the anti-inflammatory mechanism of action of etanercept may be via decrease of NF-κB activation. This effect promoted the reduction of pro-inflammatory cytokines and NOx and the induction of neutrophil apoptosis. The effect of etanercept upon neutrophils apoptosis may indicate the use of this drug therapy in the early stage of rheumatoid arthritis disease.

Commercial bovine proteoglycan is highly arthritogenic and can be used as an alternative antigen source for PGIA model.

Rheumatoid arthritis (RA) is the most common systemic autoimmune disease. It affects mainly the joints, causing synovitis, cartilage destruction, and bone erosion. Many experimental models are used to study the mechanisms involved in immunopathogenesis and new therapies for this disease. Proteoglycan-induced arthritis (PGIA) is a widely used model based on the cross-reactivity of injected foreign (usually human) PG and mice self-PG. Considering the complexity of the extraction and purification of human PG, in this study we evaluated the arthritogenicity of bovine PG that is commercially available. Bovine PG was highly arthritogenic, triggering 100% incidence of arthritis in female BALB/c retired breeder mice. Animals immunized with bovine PG presented clinical symptoms and histopathological features similar to human RA and other experimental models. Moreover, bovine PG immunization determined higher levels of proinflammatory and anti-inflammatory cytokines in arthritic mice compared to healthy ones. As expected, only the arthritic group produced IgG1 and IgG2a antibodies against PG. Thus, commercial bovine PG can be used as an alternative antigenic source to PGIA for the study of many RA aspects, including the immunopathogenesis of the disease and also the development of new therapies.

Ozone oxidative postconditioning ameliorates joint damage and decreases pro-inflammatory cytokine levels and oxidative stress in PG/PS-induced arthritis in rats.

Rheumatoid Arthritis (RA) is the most prevalent chronic condition present in ~1% of the adult population. Many pro-inflammatory mediators are increased in RA, including Reactive Oxygen Species such as nitric oxide NO, pro-inflammatory cytokines as tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1ß) and other molecules. Ozone oxidative postconditioning has regulatory effects on some pathological targets associated with RA. Thus, the aim of this study was to investigate the efficacy of ozone therapy in PG/PS-induced arthritis in rats in point of joints inflammation and morphology. Moreover, cytokines, nitric oxide and oxidative stress levels in spleen homogenates were evaluated. Ozone treatment ameliorated joint damage, reduced TNF-α concentrations as well as TNF-α and IL-1ß mRNA levels. Besides, cellular redox balance, nitric oxide and fructolysine levels were reestablished after ozone oxidative postconditioning. It was concluded that pleiotropic ozone's effects clarify its therapeutic efficacy in RA. Decreasing inflammation and joint injury, reduction of pro-inflammatory cytokines, TNF-α and IL-1ß transcripts and re-establishment of cellular redox balance after ozone treatment were demonstrated.

Low-level laser therapy in different stages of rheumatoid arthritis: a histological study.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease of unknown etiology. Treatment of RA is very complex, and in the past years, some studies have investigated the use of low-level laser therapy (LLLT) in treatment of RA. However, it remains unknown if LLLT can modulate early and late stages of RA. With this perspective in mind, we evaluated histological aspects of LLLT effects in different RA progression stages in the knee. It was performed a collagen-induced RA model, and 20 male Wistar rats were divided into 4 experimental groups: a non-injured and non-treated control group, a RA non-treated group, a group treated with LLLT (780 nm, 22 mW, 0.10 W/cm(2), spot area of 0.214 cm(2), 7.7 J/cm(2), 75 s, 1.65 J per point, continuous mode) from 12th hour after collagen-induced RA, and a group treated with LLLT from 7th day after RA induction with same LLLT parameters. LLLT treatments were performed once per day. All animals were sacrificed at the 14th day from RA induction and articular tissue was collected in order to perform histological analyses related to inflammatory process. We observed that LLLT both at early and late RA progression stages significantly improved mononuclear inflammatory cells, exudate protein, medullary hemorrhage, hyperemia, necrosis, distribution of fibrocartilage, and chondroblasts and osteoblasts compared to RA group (p < 0.05). We can conclude that LLLT is able to modulate inflammatory response both in early as well as in late progression stages of RA.

Brazilian propolis inhibits the differentiation of Th17 cells by inhibition of interleukin-6-induced phosphorylation of signal transducer and activator of transcription 3.

Propolis is a resinous substance collected by honeybees from leaf buds and cracks in the bark of various plants. It has been reported to show immunomodulatory activity. Previously, we reported the protective effect of Brazilian propolis ethanolic extract against the pathogenesis of collagen-induced arthritis (CIA), an experimental animal model of rheumatoid arthritis (RA). Moreover, we found that the protective effect against CIA was involved in suppression of the production of interleukin-17 (IL-17) in CIA mice. In the present study, we demonstrated for the first time that propolis inhibited IL-6 plus transforming growth factor-ß induced Th17 differentiation in vitro. Propolis also suppressed the IL-6-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3), a cytokine-activated essential transcription factor in Th17 development, concomitantly with the enhanced suppressor of cytokine signaling 3 expression involved in the downregulation of STAT3 phosphorylation. These data suggest that the suppressive effect of propolis on Th17 differentiation might be useful for controlling unbalanced cytokine networks in autoimmune diseases.

Neutral aminopeptidase and dipeptidyl peptidase IV in the development of collagen II-induced arthritis.

This study evaluated the hypothesis that neutral (APN) and dipeptidyl-IV (DPPIV) aminopeptidase activity levels would be critical for the susceptibility to arthritis in collagen-induced model (CIA). The macroscopic signs of arthritis in CIA rats were checked and peripheral blood, synovial fluid and synovial tissue from knee joint were withdrawn. Soluble (SF) and solubilized membrane-bound (MF) fractions from the synovial tissue and peripheral blood mononuclear cells (PBMCs) were obtained. APN and DPPIV activities were fluorometrically quantified. Severe swelling in both the entire hind paws was the minimum criterion to select CIA rats with arthritis. These arthritic rats had high APN in plasma, synovial fluid and SF of the synovial tissue, together with low APN and DPPIV in MF of PBMCs and hallmark histological changes in tibio-tarsal joint. CIA rats with no macroscopic signs of arthritis were diagnosed as resistant and they had low APN in MF of the synovial tissue, low DPPIV in SF of PBMCs and high DPPIV in plasma together with histological aspects of tibio-tarsal joint similar to healthy control rats. Data suggested that APN and DPPIV activity levels are related to the development of arthritis, being protective or inducer of the susceptibility. Understanding what is controlling the compartment-specific changes of these peptidases and looking at ways in which to manipulate their activities may lead to a better knowledge of the arthritic processes and novel treatments.

The immunomodulatory effects of Ipomoea carnea in rats vary depending on life stage.

Ipomoea carnea Jacq. ssp. fistulosa (Mart. Ex Choisy; Convolvulaceae; I. carnea) possesses a toxic component: an indolizidine alkaloid swainsonine (SW) that has immunomodulatory effects due to its inhibition of glycoprotein metabolism. It is also known that SW is excreted into both the amniotic fluid and milk of female rats exposed to I. carnea. Thus, the aim of this study was to determine whether SW exposure, either in utero or from the milk of dams treated with I. carnea, modulates offspring immune function into adulthood. In addition, adult (70 days old) and juvenile rats (21 days old) were exposed to I. carnea in order to evaluate several other immune parameters: lymphoid organs relative weight and cellularity, humoral and cellular immune responses. Offspring exposed to I. carnea during lactation developed rheumatoid arthritis (RA) in adulthood after an immunogenic challenge. In addition, both adult and juvenile rats exposed to I. carnea showed discrepancies in several immune parameters, but did not exhibit any decrease in humoral immune response, which was enhanced at both ages. These findings indicate that SW modulates immune function in adult rats exposed to SW during lactation and in juvenile and adult rats exposed to SW as juveniles and adults, respectively.

Basic aminopeptidase activity is an emerging biomarker in collagen-inducedrheumatoid arthritis

The objective of this study was to investigate the catalytic activity of basic aminopeptidase (APB) and itsassociation with periarticular edema and circulating tumor necrosis factor (TNF)-alpha and type II collagen(CII) antibodies (AACII) in a rat model of rheumatoid arthritis (RA) induced by CII (CIA). Edema does not occurin part of CII-treated, even when AACII is higher than in control. TNF-alpha is detectable only in edematousCII-treated. APB in synovial membrane is predominantly a membrane-bound activity also present in solubleform and with higher activity in edematous than in non-edematous CII-treated or control. Synovial fluid andblood plasma have lower APB in non-edematous than in edematous CII-treated or control. In peripheral bloodmononuclear cells (PBMCs) the highest levels of APB are found in soluble form in control and in membraneboundform in non-edematous CII-treated. CII treatment distinguishes two categories of rats: one with arthritic edema, high AACII, detectable TNF-alpha, high soluble and membrane-bound APB in synovial membrane and low APB in the soluble fraction of PBMCs, and another without edema and with high AACII,undetectable TNF-alpha, low APB in the synovial fluid and blood plasma and high APB in the membranebound fraction of PBMCs. Data suggest that APB and CIA are strongly related.