The Reclassification of Patients With Previously Diagnosed Eosinophilic Granulomatosis With Polyangiitis Based on the 2022 ACR/EULAR Criteria for Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVE: The American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR) have proposed the 2022 classification criteria for eosinophilic granulomatosis with polyangiitis (EGPA). This study applied the 2022 ACR/EULAR criteria to Korean patients with previously diagnosed EGPA to investigate the concordance rate between the 2022 ACR/EULAR criteria and the old criteria for EGPA. METHODS: In total, 51 patients with EGPA who met the 1990 ACR criteria, the 2007 European Medicines Agency algorithm, and the 2012 Chapel Hill Consensus Conference definitions were reclassified based on the 2022 ACR/EULAR criteria. RESULTS: Of 51 patients, 44 (86.3%) were reclassified as having EGPA according to the 2022 ACR/EULAR criteria. Among the 7 patients who failed to meet the 2022 ACR/EULAR criteria, 3 patients were reclassified as having microscopic polyangiitis (MPA) and 1 was reclassified as having granulomatosis with polyangiitis (GPA) based on the 2022 ACR/EULAR criteria; as well, 3 patients were reclassified as having unclassifiable vasculitis. Moreover, 6 patients who met the 2022 ACR/EULAR criteria for EGPA simultaneously met the criteria for MPA based on the 2022 ACR/EULAR criteria for MPA, and 1 who met the criteria for EGPA simultaneously met the criteria for GPA based on the 2022 ACR/EULAR criteria for GPA. CONCLUSION: The concordance rate between the 2022 ACR/EULAR criteria for EGPA and the old criteria was 86.3%. The most important factor in the failure to reclassify patients as having EGPA was the exclusion of nonfixed pulmonary infiltrates in the 1990 ACR criteria for EGPA. We cautiously suggest reconsidering nonfixed pulmonary infiltrates in cases reclassified as unclassifiable vasculitis. Further, additional classification strategies are needed for patients who simultaneously satisfy both antineutrophil cytoplasmic antibody-associated vasculitis subtypes.

New body mass index for predicting prognosis in patients with antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVES: Body mass index (BMI) is a known indicator of all-cause mortality. However, conventional BMI does not reflect the three-dimensional human body. To overcome this limitation, a new BMI has been proposed that provides a closer approximation of real human body shape. This study investigated the associations between the new BMI and poor outcomes in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHOD: We retrospectively reviewed the medical records of 242 patients with AAV in a single tertiary medical center. Based on the new BMI, the patients were categorized into four groups: underweight (<18.5 kg/m2.5 ), healthy weight (18.5 to <25.0 kg/m2.5 ), overweight (25.0 to <30.0 kg/m2.5 ), and obese (≥30.0 kg/m2.5 ). The association among the new BMI and death, relapse, end-stage renal disease (ESRD) development, cerebrovascular accident, and cardiovascular disease was analyzed. RESULTS: The underweight group, according to the new BMI, had higher hazard ratios (HRs) for all-cause mortality (HR: 3.180, 95% confidence interval [CI]: 1.134-8.922, p = 0.028), relapse (HR: 2.141, 95% CI: 1.019-4.368, p = 0.036), and ESRD development (HR: 2.729, 95% CI: 1.190-6.259, p = 0.018) than the healthy weight group. However, according to the conventional BMI, there were no differences in the risks for all poor outcomes between the underweight and healthy weight groups. Multivariate logistic regression analysis demonstrated that being underweight, according to the new BMI, was an independent risk factor for all-cause mortality (HR: 5.285; 95% CI: 1.468-19.018; p = 0.011). CONCLUSION: Being underweight, according to the new BMI, is associated with poor outcomes in patients with AAV.

Present and potential use of spinal cord stimulation to control chronic pain.

BACKGROUND: Spinal cord stimulation is an intervention that has become increasingly popular due to the growing body of literature showing its effectiveness in treating pain and the reversible nature of the treatment with implant removal. It is currently approved by the FDA for chronic pain of the trunk and limbs, intractable low back pain, leg pain, and pain from failed back surgery syndrome. In Europe, it has additional approval for refractory angina pectoris and peripheral limb ischemia. OBJECTIVE: This narrative review presents the current evidence supporting the use of spinal cord stimulation for the approved indications and also discusses some emerging neuromodulation technologies that may potentially address pain conditions that traditional spinal cord stimulation has difficulty addressing. STUDY DESIGN: Narrative review. RESULTS: Spinal cord stimulation has been reported to be superior to conservative medical management and reoperation when dealing with pain from failed back surgery syndrome. It has also demonstrated clinical benefit in complex regional pain syndrome, critical limb ischemia, and refractory angina pectoris. Furthermore, several cost analysis studies have demonstrated that spinal cord stimulation is cost effective for these approved conditions. Despite the lack of a comprehensive mechanism, the technology and the complexity in which spinal cord stimulation is being utilized is growing. Newer devices are targeting axial low back pain and foot pain, areas that have been reported to be more difficult to treat with traditional spinal cord stimulation. Percutaneous hybrid paddle leads, peripheral nerve field stimulation, nerve root stimulation, dorsal root ganglion, and high frequency stimulation are actively being refined to address axial low back pain and foot pain. High frequency stimulation is unique in that it provides paresthesia free analgesia by stimulating beyond the physiologic frequency range. The preliminary results have been mixed and a large randomized control trial is underway to evaluate the future of this technology. Other emerging technologies, including dorsal root ganglion stimulation and hybrid leads, also show some promising preliminary results in non-randomized observational trials. LIMITATION: This review is a primer and not an exhaustive review for the current evidence supporting the use of spinal cord stimulation and precursory discussion of emerging neuromodulation technologies. This review does not address peripheral nerve stimulation and focuses mainly on spinal cord stimulation and touches on peripheral nerve field stimulation. CONCLUSIONS: Spinal cord stimulation has demonstrated clinical efficacy in randomized control trials for the approved indications. In addition, several open label observational studies on peripheral nerve field stimulation, hybrid leads, dorsal root ganglion stimulation, and high frequency stimulation show some promising results. However, large randomized control trials demonstrating clear clinical benefit are needed to gain evidence based support for their use.

Brief report: carboxypeptidase B serves as a protective mediator in osteoarthritis.

OBJECTIVE: We previously demonstrated that carboxypeptidase B (CPB) protects against joint erosion in rheumatoid arthritis by inactivating complement component C5a. We also found that levels of CPB are abnormally high in the synovial fluid of individuals with another joint disease, osteoarthritis (OA). We undertook this study to investigate whether CPB plays a role in the pathogenesis of OA. METHODS: We compared the development of OA in CPB-deficient (Cpb2(-/-) ) mice and wild-type mice by subjecting them to medial meniscectomy and histologically assessing cartilage damage, osteophyte formation, and synovitis in the stifle joints 4 months later. We measured levels of proCPB, proinflammatory cytokines, and complement components in synovial fluid samples from patients with symptomatic and radiographic knee OA. Finally, we used enzyme-linked immunosorbent assay, flow cytometry, and hemolytic assays to assess the effect of CPB on formation of membrane attack complex (MAC)-a complement effector critical to OA pathogenesis. RESULTS: Cpb2(-/-) mice developed dramatically greater cartilage damage than did wild-type mice (P < 0.01) and had a greater number of osteophytes (P < 0.05) and a greater degree of synovitis (P < 0.05). In synovial fluid samples from OA patients, high levels of proCPB were associated with high levels of proinflammatory cytokines and complement components, and levels of proCPB correlated positively with those of MAC. In in vitro complement activation assays, activated CPB suppressed the formation of MAC as well as MAC-induced hemolysis. CONCLUSION: Our data suggest that CPB protects against inflammatory destruction of the joints in OA, at least in part by inhibiting complement activation.

Systematic review and meta-analysis on the use of honey to protect from the effects of radiation-induced oral mucositis.

Recently, 4 separate human controlled trials reported that honey appeared to protect from the effects of radiation-induced oral mucositis formation, a complication of radiation therapy that is responsible for pain and overall reduction in quality of life. In this systematic review and meta-analysis, the authors examined 3 of these controlled trials (n = 120) that met the inclusion and exclusion criteria to determine whether honey had protective effects against radiation-induced oral mucositis. The meta-analysis demonstrated an overall relative risk reduction of 80% in the honey treatment group compared with the control. Although favorable, the data must be approached with caution because of lack of description of the method of randomization and potential bias in all 3 of the individual studies included in the meta-analysis. The results are promising, and further studies are needed to strengthen the current evidence prior to a firm clinical recommendation being given.

Identification of a central role for complement in osteoarthritis.

Osteoarthritis, characterized by the breakdown of articular cartilage in synovial joints, has long been viewed as the result of 'wear and tear'. Although low-grade inflammation is detected in osteoarthritis, its role is unclear. Here we identify a central role for the inflammatory complement system in the pathogenesis of osteoarthritis. Through proteomic and transcriptomic analyses of synovial fluids and membranes from individuals with osteoarthritis, we find that expression and activation of complement is abnormally high in human osteoarthritic joints. Using mice genetically deficient in complement component 5 (C5), C6 or the complement regulatory protein CD59a, we show that complement, specifically, the membrane attack complex (MAC)-mediated arm of complement, is crucial to the development of arthritis in three different mouse models of osteoarthritis. Pharmacological modulation of complement in wild-type mice confirmed the results obtained with genetically deficient mice. Expression of inflammatory and degradative molecules was lower in chondrocytes from destabilized joints from C5-deficient mice than C5-sufficient mice, and MAC induced production of these molecules in cultured chondrocytes. Further, MAC colocalized with matrix metalloprotease 13 (MMP13) and with activated extracellular signal-regulated kinase (ERK) around chondrocytes in human osteoarthritic cartilage. Our findings indicate that dysregulation of complement in synovial joints has a key role in the pathogenesis of osteoarthritis.

Chemerin158K protein is the dominant chemerin isoform in synovial and cerebrospinal fluids but not in plasma.

Chemerin is a chemoattractant involved in immunity that may also function as an adipokine. Chemerin circulates as an inactive precursor (chem163S), and its activation requires proteolytic cleavages at its C terminus, involving proteases involved in coagulation, fibrinolysis, and inflammation. However, the key proteolytic steps in prochemerin activation in vivo remain to be established. Previously, we have shown that C-terminal cleavage of chem163S by plasmin to chem158K, followed by a carboxypeptidase cleavage, leads to the most active isoform, chem157S. To identify and quantify the in vivo chemerin isoforms in biological specimens, we developed specific ELISAs for chem163S, chem158K, and chem157S, using antibodies raised against peptides from the C terminus of the different chemerin isoforms. We found that the mean plasma concentrations of chem163S, chem158K, and chem157S were 40 ± 7.9, 8.1 ± 2.9, and 0.7 ± 0.8 ng/ml, respectively. The total level of cleaved and noncleaved chemerins in cerebrospinal fluids was ∼10% of plasma levels whereas it was elevated ∼2-fold in synovial fluids from patients with arthritis. On the other hand, the fraction of cleaved chemerins was much higher in synovial fluid and cerebrospinal fluid samples than in plasma (∼75%, 50%, and 18% respectively). Chem158K was the dominant chemerin isoform, and it was not generated by ex vivo processing, indicating that cleavage of prochemerin at position Lys-158, whether by plasmin or another serine protease, represents a major step in prochemerin activation in vivo. Our study provides the first direct evidence that chemerin undergoes extensive proteolytic processing in vivo, underlining the importance of measuring individual isoforms.

Plasma carboxypeptidase B downregulates inflammatory responses in autoimmune arthritis.

The immune and coagulation systems are both implicated in the pathogenesis of rheumatoid arthritis (RA). Plasma carboxypeptidase B (CPB), which is activated by the thrombin/thrombomodulin complex, plays a procoagulant role during fibrin clot formation. However, an antiinflammatory role for CPB is suggested by the recent observation that CPB can cleave proinflammatory mediators, such as C5a, bradykinin, and osteopontin. Here, we show that CPB plays a central role in downregulating C5a-mediated inflammatory responses in autoimmune arthritis. CPB deficiency exacerbated inflammatory arthritis in a mouse model of RA, and cleavage of C5a by CPB suppressed the ability of C5a to recruit immune cells in vivo. In human patients with RA, genotyping of nonsynonymous SNPs in the CPB-encoding gene revealed that the allele encoding a CPB variant with longer half-life was associated with a lower risk of developing radiographically severe RA. Functionally, this CPB variant was more effective at abrogating the proinflammatory properties of C5a. Additionally, expression of both CPB and C5a in synovial fluid was higher in patients with RA than in those with osteoarthritis. These findings suggest that CPB plays a critical role in dampening local, C5a-mediated inflammation and represents a molecular link between inflammation and coagulation in autoimmune arthritis.

Use of honey in wound care: an update.

The therapeutic use of honey in wound care has been used since ancient times. Honey has been shown to have antibacterial properties in vitro and animal studies have demonstrated accelerated wound healing with the use of honey. In human trials, there is currently not enough strong evidence to fully support the use of honey in wound care; however, use in minor burns and prevention of radiation mucositis appear to be 2 areas where honey shows therapeutic promise.

Thrombin-activatable carboxypeptidase B cleavage of osteopontin regulates neutrophil survival and synoviocyte binding in rheumatoid arthritis.

OBJECTIVE: Osteopontin (OPN) is a proinflammatory cytokine that plays an important role in the pathogenesis of rheumatoid arthritis (RA). OPN can be cleaved by thrombin, resulting in OPN-R and exposing the cryptic C-terminal alpha4beta1 and alpha9beta1 integrin-binding motif (SVVYGLR). Thrombin-activatable carboxypeptidase B (CPB), also called thrombin-activatable fibrinolysis inhibitor, removes the C-terminal arginine from OPN-R, generating OPN-L and abrogating its enhanced cell binding. We undertook this study to investigate the roles of OPN-R and OPN-L in synoviocyte adhesion, which contributes to the formation of invasive pannus, and in neutrophil survival, which affects inflammatory infiltrates in RA. METHODS: Using specifically developed enzyme-linked immunosorbent assays, we tested the synovial fluid of patients with RA, osteoarthritis (OA), and psoriatic arthritis (PsA) to determine OPN-R, OPN-L, and full-length OPN (OPN-FL) levels. RESULTS: Elevated levels of OPN-R and OPN-L were found in synovial fluid samples from RA patients, but not in samples from OA or PsA patients. Increased levels of OPN-R and OPN-L correlated with increased levels of multiple inflammatory cytokines, including tumor necrosis factor alpha and interleukin-6. Immunohistochemical analyses revealed robust expression of OPN-FL, but only minimal expression of OPN-R, in RA synovium, suggesting that cleaved OPN is released into synovial fluid. In cellular assays, OPN-FL, and to a lesser extent OPN-R and OPN-L, had an antiapoptotic effect on neutrophils. OPN-R augmented RA fibroblast-like synoviocyte binding mediated by SVVYGLR binding to alpha4beta1, whereas OPN-L did not. CONCLUSION: Thrombin activation of OPN (resulting in OPN-R) and its subsequent inactivation by thrombin-activatable CPB (generating OPN-L) occurs locally within inflamed joints in RA. Our data suggest that thrombin-activatable CPB plays a central homeostatic role in RA by regulating neutrophil viability and reducing synoviocyte adhesion.

Regulation of tissue inflammation by thrombin-activatable carboxypeptidase B (or TAFI).

Thrombin-activatable procarboxypeptidase B (proCPB or thrombin-activatable fibrinolysis inhibitor or TAFI) is a plasma procarboxypeptidase that is activated by the thrombin-thrombomodulin complex on the vascular endothelial surface. The activated CPB removes the newly exposed carboxyl terminal lysines in the partially digested fibrin clot, diminishes tissue plasminogen activator and plasminogen binding, and protects the clot from premature lysis. We have recently shown that CPB is catalytically more efficient than plasma CPN, the major plasma anaphylatoxin inhibitor, in inhibiting bradykinin, activated complement C3a, C5a, and thrombin-cleaved osteopontin in vitro. Using a thrombin mutant (E229K) that has minimal procoagulant properties but retains the ability to activate protein C and proCPB in vivo, we showed that infusion of E229K thrombin into wild-type mice reduced bradykinin-induced hypotension but it had no effect in proCPB-deficient mice, indicating that the beneficial effect of E229K thrombin is mediated through its activation of proCPB and not protein C. Similarly proCPB-deficient mice displayed enhanced pulmonary inflammation in a C5a-induced alveolitis model and E229K thrombin ameliorated the magnitude of alveolitis in wild-type but not proCPB-deficient mice. ProCPB-deficient mice also displayed enhanced arthritis in an inflammatory arthritis model. Thus, our in vitro and in vivo data support the thesis that thrombin-activatable CPB has broad anti-inflammatory properties. By specific cleavage of the carboxyl terminal arginines from C3a, C5a, bradykinin and thrombin-cleaved osteopontin, it inactivates these active inflammatory mediators. Along with the activation of protein C, the activation of proCPB by the endothelial thrombin-thrombomodulin complex represents a homeostatic feedback mechanism in regulating thrombin's pro-inflammatory functions in vivo.

Connective tissue growth factor (CTGF) acts as a downstream mediator of TGF-beta1 to induce mesenchymal cell condensation.

Mesenchymal cell (MC) condensation or the aggregation of MCs precedes chondrocyte differentiation and is required for subsequent cartilage formation during endochondral ossification. In this study, we used micromass cultures of C3H10T1/2 cells as an in vitro model system for studying MC condensation and the events important for this process. Transforming growth factor beta1 (TGF-beta1) served as the initiator of MC condensation in our model system and we were interested in determining whether CTGF functions as a downstream mediator of TGF-beta1. CTGF is a matricellular protein that has been found to be expressed in MC condensations and in the perichondrium. Micromass cultures of C3H10T1/2 cells condensed under TGF-beta1 stimulation concomitant with dramatic up-regulation of CTGF mRNA and protein levels. CTGF silencing by either CTGF siRNA or CTGF antisense oligonucleotide approaches showed that TGF-beta1-induced condensation was CTGF dependent. Furthermore, silencing of CTGF expression resulted in significant reductions in cell proliferation and migration, events that are crucial during MC condensation. In addition, up-regulation of Fibronectin (FN) and suppression of Sox9 expression by TGF-beta1 was also found to be mediated by CTGF. Immunofluorescence of developing mouse vertebrae showed that CTGF, TGF-beta1 and FN were co-expressed in condensations of MCs, while Sox9 expression was low at this stage. During subsequent chondrogenesis, Sox9 expression was high in chondrocytes while CTGF expression was limited to the perichondrium. Thus, CTGF is an essential downstream mediator of TGF-beta1-induced MC condensation through its effects on cell proliferation and migration. CTGF is also involved in up-regulating FN and suppressing Sox9 expression during TGF-beta1 induced MC condensation.

Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis.

Tyrosine kinases play a central role in the activation of signal transduction pathways and cellular responses that mediate the pathogenesis of rheumatoid arthritis. Imatinib mesylate (imatinib) is a tyrosine kinase inhibitor developed to treat Bcr/Abl-expressing leukemias and subsequently found to treat c-Kit-expressing gastrointestinal stromal tumors. We demonstrate that imatinib potently prevents and treats murine collagen-induced arthritis (CIA). We further show that micromolar concentrations of imatinib abrogate multiple signal transduction pathways implicated in RA pathogenesis, including mast cell c-Kit signaling and TNF-alpha release, macrophage c-Fms activation and cytokine production, and fibroblast PDGFR signaling and proliferation. In our studies, imatinib attenuated PDGFR signaling in fibroblast-like synoviocytes (FLSs) and TNF-alpha production in synovial fluid mononuclear cells (SFMCs) derived from human RA patients. Imatinib-mediated inhibition of a spectrum of signal transduction pathways and the downstream pathogenic cellular responses may provide a powerful approach to treat RA and other inflammatory diseases.

Mutation rate of MAP2K4/MKK4 in breast carcinoma.

The stress-activated protein kinase (SAPK) pathways represent phosphorylation cascades that convey pro-apoptotic signals. The relevant inputs include Ras proteins as well as exposure of cells to ultraviolet light, tumor-necrosis factor, and other stress-related inputs. The mitogen-activated protein kinase kinase (MAPKK) homolog MAP2K4 (MKK4, SEK, JNKK1) is a centrally-placed mediator of the SAPK pathways. MAP2K4 mutations or homozygous deletions are reported in about 5% of a wide variety of tumor types. The exception is breast cancer, where genetic inactivation in 3 of 22 (15%) cell lines had suggested that the mutational involvement of MAP2K4 might be accentuated in this tumor type. This finding might have represented an important difference, or solely a chance numerical variation. To address this question, we studied an independent panel of 20 breast cancer cell lines and xenografts for MAP2K4 alterations. We found a splice acceptor mutation accompanied by loss of the other allele in the cell line MPE600. This was the sole alteration in this panel (5% of tumors). These data seem to re-establish a rather consistent rate of genetic inactivation of MAP2K4 among most tumor types, including breast cancer. The genetic evaluation of other mediators of the SAPK pathways might offer insight into a promising, but as yet poorly defined, tumor-suppressive system.