Association between the Ile164 ß2 Adrenergic Receptor Polymorphism and Fatigue in Patients with Rheumatoid Arthritis.

INTRODUCTION: In the present work, the frequency of inherited polymorphisms of the beta 2 adrenergic receptor (ß2AR) gene and their association with fatigue in patients with rheumatoid arthritis (RA) was examined. METHODS: An allele-specific polymerase chain reaction was used to determine the common variants of the ß2AR at position 16, 27, and 164 in 92 German RA outpatients. Health Assessment Questionnaire (HAQ-DI), Beck Depression Inventory (BDI), Perceived Stress Questionnaire (PSQ-30), Multidimensional Fatigue Inventory (MFI-20) were utilized. RESULTS: 34.7% of German RA patients were diagnosed with associated fatigue. Fatigued patients were more likely to carry the Ile allele at position 164 (OR 7.33, 95% CI 1.09-59.8, p = 0.049). Comparing these risk factors' contribution to different fatigue dimensions revealed that Ile164 carriers only had significantly higher MFI-20 mean values for general fatigue (p = 0.014) while the clinical difference among other MFI subscales was the largest for mental fatigue (carrier: 8.23, SD: 4.22, noncarrier: 5.67, SD: 1.56, p = 0.089, Cohen's d = 0.629). Disease activity, perceived stress, and depression were also associated with fatigue with higher mean values for DAS28CRP (p = 0.038), PSQ (p < 0.001), and BDI-II (p < 0.001) in fatigued patients. Physical fatigue was correlated with disease activity (p = 0.009) and depression (p = 0.001) while mental fatigue showed associations with depression (p = 0.001) and perceived stress (p = 0.028). CONCLUSION: The discovery study indicates that the Ile164 polymorphism might in contrast to other ß2AR polymorphisms affect fatigue levels in RA patients. This association was observed especially with mental fatigue. Further replication studies are warranted to determine further role of ß2AR polymorphisms in RA patients.

[Recommendations of the committee on complementary medicine and nutrition in ayurvedic medicine, homeopathy, nutrition and Mediterranean diet]. / Empfehlungen der Kommission Komplementäre Heilverfahren und Ernährung zu ayurvedischer Medizin, Homöopathie, Ernährung und mediterraner Kost.

Methods of complementary and alternative medicine (CAM) are appealing for many patients with rheumatic diseases. The scientific data are currently characterized by a large number of publications that stand in contrast to a remarkable shortage of valid clinical studies. The applications of CAM procedures are situated in an area of conflict between efforts for an evidence-based medicine and high-quality therapeutic concepts on the one hand and ill-founded or even dubious offers on the other hand. In 2021 the German Society of Rheumatology (DGRh) launched a committee for CAM and nutrition, which aims to collect and to evaluate the current evidence for CAM applications and nutritional medical interventions in rheumatology, in order to elaborate recommendations for the clinical practice. The current article presents recommendations for nutritional interventions in the rheumatological routine for four areas: nutrition, Mediterranean diet, ayurvedic medicine and homeopathy.

Expansion of CD4+CD8+ double-positive T cells in rheumatoid arthritis patients is associated with erosive disease.

OBJECTIVES: CD4+CD8+ double-positive (DP) T cells are expanded in the peripheral blood of a subset of patients with RA. This study examines the clinical significance of DP T cells in RA. METHODS: In 70 RA patients, DP T cells were measured by flow cytometry. Clinical data were obtained, and hand and feet radiographs were scored according to the Sharp/van der Heijde (SvdH) method. The association between DP T cell frequency and erosive joint destruction was analysed by correlation and multiple logistic regression analysis. RESULTS: Nineteen RA patients (27.1%) displayed increased DP T cell frequencies, which correlated with age (r = 0.288, P =0.016). Expansion of DP T cells was associated with the occurrence of erosions (94,7% vs 43,1%, P <0.001), with a higher SvdH joint damage score (24.5 vs 6, P =0.008) and with more frequent use of biologic or targeted-synthetic DMARDs (68.4% vs 38%, P =0.02). In patients with non-erosive disease, DP T cell frequencies correlated with the joint space narrowing score (n = 28, r = 0.44, P =0.02). Logistic regression revealed DP T cells to be associated with erosive disease (OR 1.90, P <0.05). CONCLUSION: Expansion of DP T cells is associated with joint damage and frequent escalation of therapy, possibly suggesting a contribution to more severe RA.

Humoral and cellular response to COVID-19 vaccination in patients with autoimmune inflammatory rheumatic diseases under real-life conditions.

OBJECTIVES: Successful vaccination is key to overcoming the COVID-19 pandemic. Immunosuppressive medication is known to potentially compromise vaccination responses, and expansion of our knowledge on vaccination efficacy in patients with autoimmune inflammatory rheumatic diseases (AIIRD) is therefore of utmost importance. METHODS: We conducted a single-centre observational study and evaluated the efficacy of approved COVID-19 vaccines in 303 adult AIIRD patients. Serum levels of IgG antibodies against the S1 subunit of SARS-CoV-2 spike proteins (anti-S IgG) were measured at least two weeks after vaccination. In a subgroup of patients without humoral response, T-cell responses were determined using an interferon-γ gamma release assay. RESULTS: Overall seropositivity rate was 78.5% and was significantly lower in patients under immunosuppressive therapy (75.7 vs 93.2%, P = 0.009). No difference regarding the vaccination type was observed. Glucocorticoids, mycophenolate-mofetil, TNF inhibitors, tocilizumab, abatacept and rituximab were all associated with non-response after proper vaccination. The risk was highest under RTX therapy (OR 0.004, 95% CI 0.001, 0.023, P < 0.0001). A strong negative correlation was observed between time since vaccination with an mRNA vaccine and anti-S antibody levels (r=-0.6149, P < 0.0001). In patients without humoral response, a T-cell response was found in 50%. CONCLUSIONS: COVID-19 vaccination in patients with AIIRD is effective using any approved vaccine. Humoral response might be impaired depending on the individual immunosuppressive medication. The risk of non-response is highest under rituximab therapy. Anti-S IgG antibody levels wane over time after mRNA vaccination. Importantly, 50% of humoral non-responders showed a T-cellular response, suggesting T-cell-mediated protection to a certain extent.

Sepsis Mortality Is high in Patients With Connective Tissue Diseases Admitted to the Intensive Care Unit (ICU).

OBJECTIVES: Patients with connective tissue diseases (CTD) such as systemic lupus erythematosus (SLE) have an increased risk for infections. This study investigated the outcome and characteristics of CTD patients under intensive care unit (ICU) treatment for sepsis. METHODS: A single-center retrospective analysis was conducted and reviewed all patients with a CTD diagnosis admitted to the ICU of a university hospital for sepsis between 2006 and 2019. Mortality was computed and multivariate logistic regression was used to detect independent risk factors for sepsis mortality. Furthermore, the positive predictive value of ICU scores such as Sequential Organ Failure Assessment (SOFA) score was evaluated. RESULTS: This study included 44 patients with CTD (mean age 59.8 ± 16.1 years, 68.2% females), most of them with a diagnosed SLE (61.4%) followed by systemic sclerosis (15.9%). 56.8% (n = 25) were treated with immunosuppressives and 81.8% (n = 36) received glucocorticoids. Rituximab was used in 3 patients (6.8%). The hospital mortality of septic CTD patients was high with 40.9%. It was highest among systemic sclerosis (SSc) patients (85.7%). SOFA score and diagnosis of SSc were independently associated with mortality in multivariate logistic regression (P = 0.004 and 0.03, respectively). The Simplified Acute Physiology Score II (SAPS II), SOFA and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were good predictors of sepsis mortality in the investigated cohort (SAPS II AUC 0.772, P = 0.002; SOFA AUC 0.756, P = 0.004; APACHE II AUC 0.741, P = 0.007). CONCLUSIONS: In-hospital sepsis mortality is high in CTD patients. SSc diagnoses and SOFA were independently associated with mortality. Additionally, common ICU scores were good predictors for mortality.

Outcome of Patients With Necrotizing Vasculitis Admitted to the Intensive Care Unit (ICU) for Sepsis: Results of a Single-Centre Retrospective Analysis.

INTRODUCTION/BACKGROUND: Vasculitis patients have a high risk for infections that may require intensive care unit (ICU) treatment in case of resulting sepsis. Since data on sepsis mortality in this patient group is limited, the present study investigated the clinical characteristics and outcomes of vasculitis patients admitted to the ICU for sepsis. METHODS: The medical records of all necrotizing vasculitis patients admitted to the ICU of a tertiary hospital for sepsis in a 13-year period have been reviewed. Mortality was calculated and multivariate logistic regression was used to determine independent risk factors for sepsis mortality. Moreover, the predictive power of common ICU scores was further evaluated. RESULTS: The study included 34 patients with necrotizing vasculitis (mean age 69 ± 9.9 years, 35.3% females). 47.1% (n = 16) were treated with immunosuppressives (mostly cyclophosphamide, n = 35.3%) and 76.5% (n = 26) received glucocorticoids. Rituximab was used in 4 patients (11.8%).The in-hospital mortality of septic vasculitis patients was 41.2%. The Sequential Organ Failure Assessment (SOFA) score (p = 0.003) was independently associated with mortality in multivariate logistic regression. Acute Physiology And Chronic Health Evaluation II (APACHE II), Simplified Acute Physiology Score II (SAPS II) and SOFA scores were good predictors of sepsis mortality in the investigated vasculitis patients (APACHE II AUC 0.73, p = 0.02; SAPS II AUC 0.81, p < 0.01; SOFA AUC 0.898, p < 0.0001). CONCLUSIONS: Sepsis mortality was high in vasculitis patients. SOFA was independently associated with mortality in a logistic regression model. SOFA and other well-established ICU scores were good mortality predictors.

Mortality of Sepsis in Patients With Rheumatoid Arthritis: A Single-Center Retrospective Analysis and Comparison With a Control Group.

INTRODUCTION/BACKGROUND: Patients with rheumatoid arthritis (RA) have a high risk of infections that may require intensive care unit (ICU) admission in case of resulting sepsis. Data regarding the mortality of these patients are very limited. This study investigated clinical characteristics and outcomes of patients with RA admitted to the ICU for sepsis and compared the results to a control cohort without RA. METHODS: All patients with RA as well as sex-, age-, and admission year-matched controls admitted to the ICU of a university hospital for sepsis between 2006 and 2019 were retrospectively analyzed. Mortality was calculated for both the groups, and multivariate logistic regression was used to determine independent risk factors for sepsis mortality. The positive predictive value of common ICU scores was also investigated. RESULTS: The study included 49 patients with RA (mean age 67.2 ± 9.0 years, 63.3% females) and 51 matched controls (mean age 67.4 ± 9.5 years, 64.7% females). Among the patients with RA, 42.9% (n = 21) were treated with conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) and 30.6% (n = 15) received glucocorticoids only. Seven (14.3%) patients received biologic (b) DMARDs. The hospital mortality was higher among patients with RA (42.9% vs 15.7%, P = .0016). Rheumatoid arthritis was independently associated with mortality in multivariate logistic regression (P = .001). In patients with RA, renal replacement therapy (P = .024), renal failure (P = .027), and diabetes mellitus (P = .028) were independently associated with mortality. Acute Physiology and Chronic Health Evaluation II (APACHE II), Simplified Acute Physiology Score II (SAPS II), and Sequential Organ Failure Assessment (SOFA) scores were good predictors of sepsis mortality in patients with RA (APACHE II area under the curve [AUC]: 0.78, P = .001; SAPS II AUC: 0.78, P < .001; SOFA AUC 0.78, P < .001), but their predictive power was higher among controls. CONCLUSIONS: Hospital sepsis mortality was higher in patients with RA than in controls. Rheumatoid arthritis itself is independently associated with an increased sepsis mortality. Renal replacement therapy, renal failure, and diabetes were associated with an increased mortality. Common ICU scores were less well predictors of sepsis mortality in patients with RA compared to non-RA controls.

Low vaccination rates among patients with rheumatoid arthritis in a German outpatient clinic.

Patients with rheumatoid arthritis (RA) are at an increased risk of acquiring infections due to two reasons: the disease itself and the immunosuppressive therapy. Vaccinations against preventable diseases are therefore of utmost importance for these group of patients. To estimate vaccination frequencies among patients with rheumatoid arthritis, we studied patients in a survey and calculated vaccination rates based on their vaccination documents. Patients have been recruited from our outpatient clinic during one of their routine visits. For the statistical analysis, they have been divided by age (≥60 vs <60 years) and medication (DMARD, Biologics, TNF inhibitors) for further subgroup analysis. Among the studied patients (n = 331), we found rather low vaccination rates, in particular for the strongly recommended vaccines against Pneumococcus and Influenza (33 and 53%, respectively). Furthermore, protection rates for important basic vaccinations, e.g. against Pertussis, were found to be very low with 12% only. Beside these findings, we saw age-dependent differences for a variety of vaccines: while Pneumococcus and Influenza vaccines were more often given to patients ≥60 years, MMR, Pertussis, Diphtheria and Hepatitis were significantly more often applied to younger patients. Vaccination rates have to be improved among RA patients, in particular for vaccines protecting from respiratory tract infections such as Pneumococcus.

CD4+CD8αlow T cells in rheumatoid arthritis are clonally expanded and dependent on co-stimulation.

OBJECTIVES: CD4+CD8+ T cells are increased in patients with rheumatoid arthritis (RA). They are not only associated with joint erosions in established disease, but are also present in the pre-clinical stages of RA. This study aims to further investigate their expansion in the context of T cell clonality in patients with RA, as well as their responsiveness to T cell targeted treatment. METHODS: Single-cell-(sc)RNA- and scTCR-sequencing data were used to determine co-receptor expression and T cell receptor sequences to assess clonality of CD4+CD8+ T cells in RA (n=3) patients and healthy controls (n=2). Peripheral CD4+CD8+ T cells and their subpopulations were measured in patients with RA (n=53), PsA (n=52) and healthy donors (n=50) using flow cytometry. In addition, changes in CD4+CD8+ T cell frequency were prospectively followed in RA patients receiving therapy with abatacept for 12 weeks. RESULTS: We observed an increase of CD4+ T cells expressing CD8α in RA patients, both in comparison to PsA patients and to healthy controls. Clonality analysis revealed, that these CD4+CD8αlow T cells are part of large T cell clones, which cluster separately from CD4+CD8- T cell clones in the scRNA-seq gene expression analysis. Treatment with abatacept significantly reduced the frequency of peripheral CD4+CD8αlow T cells, and this was linked to reduction in disease activity. CONCLUSION: In RA, clonal expansion of CD4+ T cell clones culminates in the emergence of peripheral CD4+CD8αlow T cells, which are associated with disease activity and diminished upon abatacept treatment, and which could contribute to disease pathogenesis.

Influenza, Pneumococcal and Herpes Zoster Vaccination Rates in Patients with Autoimmune Inflammatory Rheumatic Diseases.

BACKGROUND: Vaccination rates are known to be low in patients with autoimmune inflammatory rheumatic diseases (AIIRD). We therefore aimed to determine current vaccination rates against influenza, Streptococcus pneumoniae and herpes zoster in a cohort of patients with AIIRD in Germany. METHODS: Consecutive adult patients with an AIIRD were recruited from our outpatient clinic during their regular consultations. The individual vaccination status regarding influenza, Streptococcus pneumoniae and herpes zoster was obtained by reviewing the vaccination documents. RESULTS: A total of 222 AIIRD patients (mean age 62.9 ± 13.9 years) were included. In total, 68.5% were vaccinated against influenza, 34.7% against Streptococcus pneumoniae and 13.1% against herpes zoster (HZ). The pneumococcal vaccination was outdated in 29.4% of the vaccinated patients. Vaccination rates were significantly higher in patients ≥60 years old (odds ratio (OR) 2.167, 95% confidence interval (CI) 1.213-3.870, p = 0.008 for influenza, OR 4.639, 95% CI 2.555-8.422, p < 0.0001 for pneumococcal and OR 6.059, 95% CI 1.772-20.712, p = 0.001 for HZ vaccination). Ages > 60 years, female sex, glucocorticoid use and influenza vaccination were all independently associated with a pneumococcal vaccination. Regarding influenza vaccination, only a positive pneumococcal vaccination history remained independently associated. In patients with HZ vaccination, glucocorticoid use and a preceding pneumococcal vaccination were independently associated with HZ protection. CONCLUSIONS: The frequencies of vaccinations against influenza, Streptococcus pneumoniae and HZ have increased during recent years. While this can be partly explained by continuous efforts in patient education during the outpatient visits, the COVID-19 pandemic might also have contributed. Nevertheless, the persistently high incidence and mortality of these preventable diseases in patients with AIIRDs mandates further efforts to increase vaccination coverage, particularly in SLE patients.

COVID-19 Vaccination Coverage in Patients with Rheumatic Diseases in a German Outpatient Clinic: An Observational Study.

BACKGROUND: In the second year of the COVID-19 pandemic, highly effective and safe vaccines became available. Since patients with rheumatic diseases show increased susceptibility to infections and typical medications raise the risk of severe COVID-19, high vaccination coverage is of significant importance to these patients. METHODS: Consecutive patients with different rheumatic diseases were asked for their vaccination status regarding COVID-19, influenza and Streptococcus pneumoniae during their routine consultations. Any reported vaccination was validated with their personal vaccination card and/or by reviewing the CovPass smartphone app. Reasons for not having a COVID-19 vaccination were documented. RESULTS: A total of 201 patients (mean age 62.3 ± 14.1 years) were included, the majority of them (44.3%) with rheumatoid arthritis, followed by spondyloarthritis (27.4%) and connective tissue diseases (21.4%). Vaccination coverage for SARS-CoV-2 was 80.1%; 85.6% got at least the first vaccination shot. Both valid influenza and pneumococcus coverage were associated with a higher probability of SARS-CoV-2 vaccination (odds ratio (OR) 6.243, 95% confidence interval (CI) 2.637-14.783, p < 0.0001 and OR 6.372, 95% CI 2.105-19.282, p = 0.0003, respectively). The main reason for a missing SARS-CoV-2 vaccination (70%) was being sceptical about the vaccine itself (i.e., the subjective impression that the vaccine was not properly tested and fear of unwanted side effects). CONCLUSIONS: Vaccination coverage against SARS-CoV-2 is high in patients with rheumatic diseases. Nevertheless, there are unmet needs regarding vaccination education to further increase vaccination rates.

Danger signal extracellular calcium initiates differentiation of monocytes into SPP1/osteopontin-producing macrophages.

The danger signal extracellular calcium is pathophysiologically increased in the synovial fluid of patients with rheumatoid arthritis (RA). Calcium activates the NLRP3-inflammasome via the calcium-sensing receptor in monocytes/macrophages primed by lipopolysaccharide, and this effect is mediated by the uptake of calciprotein particles (CPPs) formed out of calcium, phosphate, and fetuin-A. Aim of the study was to unravel the influence of calcium on monocytes when the priming signal is not present. Monocytes were isolated from the blood of healthy controls and RA patients. Macrophages were characterized using scRNA-seq, DNA microarray, and proteomics. Imaging flow cytometry was utilized to study intracellular events. Here we show that extracellular calcium and CPPs lead to the differentiation of monocytes into calcium-macrophages when the priming signal is absent. Additional growth factors are not needed, and differentiation is triggered by calcium-dependent CPP-uptake, lysosomal alkalization due to CPP overload, and TFEB- and STAT3-dependent increased transcription of the lysosomal gene network. Calcium-macrophages have a needle-like shape, are characterized by excessive, constitutive SPP1/osteopontin production and a strong pro-inflammatory cytokine response. Calcium-macrophages differentiated out of RA monocytes show a stronger manifestation of this phenotype, suggesting the differentiation process might lead to the pro-inflammatory macrophage response seen in the RA synovial membrane.

Humoral Immunity to Varicella Zoster Virus in Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis Compared to Healthy Controls.

BACKGROUND: The prevalence of herpes zoster (HZ) is high in patients with rheumatic diseases. Systemic lupus erythematosus (SLE) doubles the risk for developing HZ. However, little is known about natural humoral immunity against varicella zoster virus (VZV) in patients with SLE. Hence, we compared VZV IgG antibody concentrations in a group of SLE patients with healthy controls and patients with rheumatoid arthritis (RA). METHODS: n = 56 patients with SLE, n = 54 patients with RA, and n = 56 healthy controls were included in this study. The VZV IgG antibody concentration was measured using an enzyme-linked immunosorbent assay (ELISA). The antibody concentrations were compared between the groups. RESULTS: Overall IgG antibody titers for VZV in SLE patients were comparable to healthy controls but higher when compared to patients with rheumatoid arthritis (p = 0.0012). In consequence, antibody levels in controls were higher than in RA patients (p = 0.0097). Stratification by age revealed highest titers among SLE patients in the fourth life decade (p = 0.03 for controls, p = 0.0008 for RA patients) whereas RA patients in their sixth decade had the lowest antibody concentration (p = 0.03 for controls, p = 0.04 for SLE patients). Regarding the individual HZ history, antibody levels of SLE patients with a positive history exceeded all other groups. CONCLUSIONS: Although humoral VZV immunity in SLE patients is comparable to healthy controls it seems to be pronounced in young SLE patients between 30 and 39. The lowest VZV IgG levels were found in RA patients. HZ seems to induce antibody production, particularly in patients with SLE. Immunological processes might contribute to VZV antibody levels in SLE patients, but further investigations are needed to substantiate this hypothesis. Even though the increased HZ prevalence seems to be independent of humoral immunity in SLE patients, reduced humoral immunity might contribute to HZ in RA patients. The available HZ subunit vaccination might be an appropriate way to reduce the HZ risk in patients with rheumatic diseases.

Impact of clinical and psychological factors associated with depression in patients with rheumatoid arthritis: comparative study between Germany and Brazil.

OBJECTIVE: To investigate the prevalence of depressive symptoms and its association with clinical and psychological factors in patients with rheumatoid arthritis (RA) in Germany and in Brazil. METHOD: A convenience sample of 267 RA patients, 176 from Germany (age 62.4 ± 12.3 years) and 91 from Brazil (age 56.3 ± 12.6 years), was used in this cross-sectional study. The following questionnaires were used: Beck Depression Inventory (BDI), painDETECT test, Perceived Stress Questionnaire, fatigue questionnaire (FACIT), Health Assessment Questionnaire Disability Index (HAQ-DI), and the SF-36 questionnaires (Short-Form 36 Health Survey). Disease activity score (DAS 28-CRP) and visual analogue scale (VAS) for pain were also evaluated. Statistical analysis is based on comparison of means and proportions. Statistical significance for non-normal data was evaluated by non-parametrical tests. RESULTS: Depressive symptoms were more prevalent in the Brazilian sample (44% vs 22.9%, p = 0.025). Compared to German patients, the Brazilian ones also experienced more pain (current pain status on VAS: 4.67 ± 3.4 vs 3.67 ± 2.31 respectively, p < 0.01), were physically more limited (1.89 ± 1.85 vs 1.01 ± 0.75, p = 0.012), and had higher C-reactive protein levels (7.78 ± 18.3 vs 5.82 ± 10.45, p = 0.028). Despite receiving a more intensive treatment, German patients presented similar disease activity when compared to Brazilian patients (DAS28-CRP: Brazil 3.4 ± 1.5 vs Germany 3.3 ± 1.3, p = 0.307). CONCLUSION: Depressive symptoms are frequent in RA patients from different countries and interact with psychological disorders and the experience of pain. They contribute negatively to their well-being suggesting the need for psychoeducational strategies. Key Points • New psychoeducational strategies for RA management.• Higher inflammation marker in rheumatoid arthritis patients is associated with depression.• Medical treatment in RA influences depressive symptoms.• Depressive symptoms are dependent on population group.• High disease activity is related to depression.

Calcium-sensing receptor-mediated NLRP3 inflammasome response to calciprotein particles drives inflammation in rheumatoid arthritis.

Increased extracellular Ca2+ concentrations ([Ca2+]ex) trigger activation of the NLRP3 inflammasome in monocytes through calcium-sensing receptor (CaSR). To prevent extraosseous calcification in vivo, the serum protein fetuin-A stabilizes calcium and phosphate into 70-100 nm-sized colloidal calciprotein particles (CPPs). Here we show that monocytes engulf CPPs via macropinocytosis, and this process is strictly dependent on CaSR signaling triggered by increases in [Ca2+]ex. Enhanced macropinocytosis of CPPs results in increased lysosomal activity, NLRP3 inflammasome activation, and IL-1ß release. Monocytes in the context of rheumatoid arthritis (RA) exhibit increased CPP uptake and IL-1ß release in response to CaSR signaling. CaSR expression in these monocytes and local [Ca2+] in afflicted joints are increased, probably contributing to this enhanced response. We propose that CaSR-mediated NLRP3 inflammasome activation contributes to inflammatory arthritis and systemic inflammation not only in RA, but possibly also in other inflammatory conditions. Inhibition of CaSR-mediated CPP uptake might be a therapeutic approach to treating RA.

Impact of fatigue on rheumatic diseases.

Fatigue is a common, disabling, and difficult-to-manage problem in rheumatic diseases. The concept of fatigue is difficult to define. No clear and widely accepted definition of fatigue is available. The symptoms of fatigue are defined as an overwhelming, debilitating, and sustained sense of exhaustion that decreases the ability to function and carry out daily activities. Prevalence estimates of fatigue within musculoskeletal diseases vary considerably (35%-82%). In this review, we present data about the role of fatigue for the patients' quality of life, tools for diagnosing fatigue, factors contributing to fatigue like disease activity and psychological factors, and some experimental studies to verify the biological background of fatigue. Management of fatigue including pharmacological and non-pharmacological treatment is also part of this publication. Overall data are scarce for fatigue in rheumatic diseases, and further studies are warranted to identify the role of biological mechanism such as inflammation, hormonal changes, and autonomic nervous system in the pathogenesis of fatigue.