Rheumatoid arthritis and myasthenia gravis: a case-based review of the therapeutic options

Introduction Myasthenia gravis is an autoimmune disease affecting the neuromuscular junction, often associated with other autoimmune diseases, including rheumatoid arthritis. Patients with rheumatoid arthritis present an increased prevalence of myasthenia gravis compared to the general population. While these two diseases share some therapeutic options, such as glucocorticoids, methotrexate, and rituximab, there are no guidelines for treating concomitant disease. We aim to review the available evidence and to discuss the efficacy and safety of the therapeutic options in patients with rheumatoid arthritis associated with myasthenia gravis. Method We described three patients with rheumatoid arthritis associated with myasthenia gravis and we performed a systematic review of the associated literature. Results A 48-year-old man and two women (48 and 55 years old) with concomitant diagnoses of active rheumatoid arthritis and well-controlled myasthenia gravis are described. They were treated with methotrexate, leflunomide, upadacitinib, and adalimumab. None of them experienced changes in their myasthenic symptoms. We found 9 additional cases from our literature review. Methotrexate, rituximab, upadacitinib, diphenyl sulfone, auranofin, and loxoprofen sodium did not show an impact on the seven patients with previously well-controlled myasthenia. Glucocorticoids, methotrexate, and rituximab proved effective in active myasthenia gravis and arthritis. Conflicting data emerged for Tumor-necrosis factor inhibitors. Conclusions Although the available evidence remains scarce, we consider glucocorticoids, methotrexate, and rituximab as safe and effective options. The role of tumor-necrosis factor inhibitors remains uncertain. Eventually, Janus Kinase inhibitors are a novel interesting option for these patients. Key Points• To date, the only evidence on the treatment of patients with rheumatoid arthritis and concomitant myasthenia gravis derives from case reports.• Based on the review of the available case reports and on the cases we described, we consider glucocorticoids, methotrexate, and rituximab as safe and effective options, while the role of Tumor-necrosis factor inhibitors remains uncertain.• Based on the cases we described, Janus Kinase inhibitors are a novel interesting option for patients with concomitant rheumatoid arthritis and myasthenia gravis.

Human endothelial cells display a rapid and fluid flow dependent tensional stress increase in response to tumor necrosis factor-α

As endothelial cells form the inner layer of blood vessels they display the first barrier to interstitial tissues, which results in a crucial role for inflammation. On the global, systemic level an important element of the complex process controlling the inflammatory response is the release of the cytokine tumor necrosis factor-α (TNF-α). While other pro-inflammatory agents like thrombin or histamine are known to induce acute but transient changes in endothelial cells which have been well studied biologically as well as mechanically, TNF-α is primarily known for its sustained effects on permeability and leukocyte recruitment. These functions are associated with transcriptional changes that take place on the timescale of hours and days. Here we show that already 4 minutes after the addition of TNF-α onto monolayers of human umbilical vein endothelial cells, a striking rise in mechanical substrate traction force and internal monolayer tension can be recorded. As expected, the traction forces act primarily at the boundary of the monolayer. While the traction forces increase monotonically during the initial cellular response, we find that the internal monolayer tension displays a rapid peak that can be abolished when applying a shear flow to the cells. The increased internal monolayer tension may provide a mechanical signal for the cells to prepare for the recruitment of leukocytes, additionally to the well studied biochemical response.

Prognostic Value of The Ratio of Maximum To Minimum Diameter of Primary Tumor In Metastatic Clear Cell Renal Cell Carcinoma

Background: Several models and markers were developed and found to predict outcome of advanced renal cell carcinoma. This study aimed to evaluate the prognostic value of the ratio of maximum to minimum tumor diameter (ROD) in metastatic clear cell renal cell carcinoma (mccRCC).Methods: Patients with mccRCC (n=213) treated with sunitinib from January 2008 to December 2018 were identified. Cut-off value for ROD was determined using receiver operating characteristic. Patients with different ROD scores were grouped and evaluated. Survival outcomes were estimated by Kaplan-Meier method.Results: The optimal ROD cutoff value of 1.34 was determined for progression free survival (PFS) and overall survival (OS). Patients in ROD≥1.34 group had shorter PFS (9.6 versus 17.7 months, p<0.001) and OS (25.5 versus 32.6 months, p<0.001) than patients in ROD<1.34 group. After adjustment for other factors, multivariate analysis showed ROD≥1.34 was an independent prognostic factor for PFS (p<0.001) and OS (p=0.006). Patients in ROD³1.34 group presented higher proportions of T3/4 stage (92.9% versus 7.1%, p=0.012), WHO/ISUP grade III/IV (72.0% versus 28.0%, p=0.010), tumor necrosis (71.0% versus 29.0%, p=0.039), sarcomatoid differentiation (79.1% versus 20.9%, p=0.007), poor MSKCC risk score (78.4% versus 21.6%, p<0.001) and poor IMDC risk score (74.4% versus 25.6%, p<0.001) than ROD<1.34 group.Conclusion: Primary tumor with higher ROD was an independently prognostic factor for both PFS and OS in patients with mccRCC who received targeted therapy. Higher ROD was also associated with high T stage, high WHO/ISUP grade, sarcomatoid features, tumor necrosis, poor MSKCC and IMDC risk score.

Low Levels of Tumor Necrosis Factor-α will Prevent Periodontitis Exacerbation in Type 2 Diabetes Mellitus

Objectives Diabetes mellitus (DM) is a major risk factor for periodontitis. Susceptibility to periodontitis increases approximately three times in people with DM. There is a clear relationship between the degree of hyperglycemia and the severity of periodontitis. This study aimed to analyze the reduction of tumor necrosis factor-α (TNF-α) in diabetics who came for periodontitis examination to prevent exacerbations. Materials and Methods This was an analytic observational study using a cross-sectional approach at health centers in Surabaya, Indonesia. Measurement of periodontal status used the community periodontal index of treatment needs by measuring bleeding at probing and pocket depth. TNF-α was measured using enzyme-linked immunosorbent assay, and behavior and lifestyle using a questionnaire. Statistical Analysis The Kolmogorov–Smirnov test was performed to identify data normality (p < 0.05). A nonparametric test was used to measure the degree of association between different characteristics and the incidence of periodontitis in type 2 DM patients with and without periodontitis. Spearman's test was done to examine the correlation between TNF-α level and severity of periodontitis in diabetics. The significant level was at p <0.05. Results There was a correlation between age, predisposing factors, reinforcing factors, drug consumption, and TNF-α levels in patients with type 2 DM and the incidence of periodontitis. Conclusions Poor glycemic control can induce oxidative stress on the gingiva, thereby aggravating damage to periodontal tissue. An important factor in preventing periodontitis for type 2 DM patients is controlling blood sugar levels through regular consumption of drugs and regular maintenance of oral cavity health. Knowledge is a predisposing factor that affects adherence of people with type 2 DM to consuming drugs regularly, which can be strengthened by family support. These will ultimately play a role in reducing TNF-α levels.

Biochemical profile in mixed martial arts athletes

The study aimed to evaluate changes in selected biochemical indicators among mixed martial arts competitors in subsequent periods of the training cycle. The research involved 12 mixed martial arts athletes aged 25.8 ± 4.2 years competing in the intermediate category. Selected somatic indicators were measured twice. Biochemical indicators were assessed five times during the 14-week study period. Serum concentrations of testosterone, cortisol, uric acid, myoglobin, total protein, interleukin 6, and tumor necrosis factor, as well as creatine kinase activity were determined. One hour after sparring completion, there were significant increases in cortisol (by 54.9%), uric acid (22.0%), myoglobin (565.0%), and interleukin 6 (280.3%) as compared with the values before the simulated fight. The highest creatine kinase activity (893.83 ± 139.31 U/l), as well as tumor necrosis factor (3.93 ± 0.71 pg/ml) and testosterone (5.83 ± 0.81 ng/ml) concentrations (p = 0.00) were recorded 24 hours after the simulation. Systematic observation of selected blood biochemical indicators in the training process periodization in mixed martial arts helps understand adaptive, compensatory, and regenerative mechanisms occurring in training athletes.

Microglia-secreted TNF-α affects differentiation efficiency and viability of pluripotent stem cell-derived human dopaminergic precursors

Parkinson's Disease is a neurodegenerative disorder characterized by the progressive loss of dopaminergic cells of the substantia nigra pars compacta . Even though successful transplantation of dopamine-producing cells into the striatum exhibits favourable effects in animal models and clinical trials; transplanted cell survival is low. Since every transplant elicits an inflammatory response which can affect cell survival and differentiation, we aimed to study in vivo and in vitro the impact of the pro-inflammatory environment on human dopaminergic precursors. We first observed that transplanted human dopaminergic precursors into the striatum of immunosuppressed rats elicited an early and sustained activation of astroglial and microglial cells after 15 days post-transplant. This long-lasting response was associated with Tumor necrosis factor alpha expression in microglial cells. In vitro conditioned media from activated BV2 microglial cells increased cell death, decreased Tyrosine hydroxylase -positive cells and induced morphological alterations on human neural stem cells-derived dopaminergic precursors at two differentiation stages: 19 days and 28 days. Those effects were ameliorated by inhibition of Tumor necrosis factor alpha, a cytokine which was previously detected in vivo and in conditioned media from activated BV-2 cells. Our results suggest that a pro-inflammatory environment is sustained after transplantation under immunosuppression, providing a window of opportunity to modify this response to increase transplant survival and differentiation. In addition, our data show that the microglia-derived pro-inflammatory microenvironment has a negative impact on survival and differentiation of dopaminergic precursors. Finally, Tumor necrosis factor alpha plays a key role in these effects, suggesting that this cytokine could be an interesting target to increase the efficacy of human dopaminergic precursors transplantation in Parkinson's Disease.