Glycolysis Rate-Limiting Enzymes: Novel Potential Regulators of Rheumatoid Arthritis Pathogenesis

Rheumatoid arthritis (RA) is a classic autoimmune disease characterized by uncontrolled synovial proliferation, pannus formation, cartilage injury, and bone destruction. The specific pathogenesis of RA, a chronic inflammatory disease, remains unclear. However, both key glycolysis rate-limiting enzymes, hexokinase-II (HK-II), phosphofructokinase-1 (PFK-1), and pyruvate kinase M2 (PKM2), as well as indirect rate-limiting enzymes, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), are thought to participate in the pathogenesis of RA. In here, we review the latest literature on the pathogenesis of RA, introduce the pathophysiological characteristics of HK-II, PFK-1/PFKFB3, and PKM2 and their expression characteristics in this autoimmune disease, and systematically assess the association between the glycolytic rate-limiting enzymes and RA from a molecular level. Moreover, we highlight HK-II, PFK-1/PFKFB3, and PKM2 as potential targets for the clinical treatment of RA. There is great potential to develop new anti-rheumatic therapies through safe inhibition or overexpression of glycolysis rate-limiting enzymes.

AB0797 THE ROLE OF ULTRASOUND CRITERIA IN ASSESSING PAIN SYNDROME IN THE KNEE JOINT IN PATIENTS WITH RHEUMATOID ARTHRITIS AND OSTEOARTHRITIS

Background:Pain syndrome and pathological changes in the synovium detected by ultrasound can be early signs of various diseases of the joints [1].Objectives:the use of ultrasound criteria for changes in the synovial membrane of the joint cavity to assess the severity of pain in patients with rheumatoid arthritis (RA) and osteoarthritis (OA).Methods:The study included 36 patients with RA (32 women and 4 men aged 22 to 55 years old) and 38 patients with OA (30 women and 8 men aged 30 to 50 years old) with lesions of the knee joints. A visual analogue scale (VAS) was used to determine the severity of pain. The severity of pain in the knee when walking was at least 40 mm according to the VAS in all examined patients. Joint ultrasound examination was carried out according to the standard technique using a linear transducer with a frequency of 5–12 MHz on an Accuvix V10 ultrasound diagnostic system (Samsung Medison, South Korea). The evaluation of ultrasound changes in the upper inversion of a knee joint was carried out according to the following criteria: the severity of intra-articular effusion (1), synovial proliferation (2), local vascularization of the synovial membrane using power Doppler (3) (Table 1).Table 1.Parameters of ultrasound criteria for assessing changes in the synovial membrane of the joint cavityNormal indicators1 - width of the suprapatellar turn is 6 mm2 - thickness of the synovial membrane is 3 mm (from the anterior approach)3 - lack of vascularization lociMinimum changes1 - delamination of the suprapatellar curl leaves from 7 to 9 mm2 - thickness of the synovial membrane 3.1–4.5 mm3 - appearance of single loci of vascularization (1-2 in the Doppler field)Moderate changes1 - delamination of the leaves of the suprapatellar twist 10-14 mm2 - thickness of the synovial membrane is 4.6–6.4 mm3 - appearance of moderate (> 5) vascularization lociSevere changes1 - delamination of suprapatellar folds of more than 15 mm2 - thickness of the synovial membrane is more than 6.5 mm3 - multiple foci of vascularization (> 5, merging in places)Results:Correlations of various severity were found between pain indices according to VAS and the thickness of the synovial membrane of the knee joint (r = 0.33, p = 0.019) and the number of vascularization foci (rS = 0.29, p = 0.04) in RA patients, as well as between pain according to VAS and the severity of intra-articular effusion (r = 0.28, p <0.002) in patients with OA.The patients were divided into three groups according to the severity of pain in the knee joint: group I - 41-59 mm (12 patients with OA and 9 patients with RA), group II - 60-79 mm (16 patients with OA and 12 patients with RA), group III - 80–100 mm on the VAS scale (10 patients with OA and 15 patients with RA). Group I was dominated by OA patients with minimal changes in intra-articular effusion and local vascularization of the synovial membrane, with moderate synovial proliferation (28.6% of the total number of patients in the group). In group II patients with OA with moderate severity of intra-articular effusion and local vascularization (21.4%) and patients with RA with moderate changes in the thickness of the synovium and local vascularization (25%) were equally common. Group III was dominated by RA patients with severe synovial proliferation and moderate local vascularization (28%), as well as patients with OA with moderate intra-articular effusion (20%).Significant differences in the thickness of the synovium in patients with RA in the first and third groups were noted (H-test = 5.9, p = 0.025).Conclusion:The additional use of ultrasound criteria for changes observed in the synovial membrane of the joint cavity in patients with RA and OA can help predict pain in the knee joint. The manifestation of pain syndrome in patients with OA is most associated with the severity of synovitis in the joint, and in patients with RA - with the severity of synovial proliferation.References:[1]Sarmanova A et al. Arthritis Res Ther. 2017;19(1):281.Disclosure of Interests:None declared

Reconsidering the Role of Melatonin in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is an inflammatory joint disorder characterized by synovial proliferation and inflammation, with eventual joint destruction if inadequately treated. Modern therapies approved for RA target the proinflammatory cytokines or Janus kinases that mediate the initiation and progression of the disease. However, these agents fail to benefit all patients with RA, and many lose therapeutic responsiveness over time. More effective or adjuvant treatments are needed. Melatonin has shown beneficial activity in several animal models and clinical trials of inflammatory autoimmune diseases, but the role of melatonin is controversial in RA. Some research suggests that melatonin enhances proinflammatory activities and thus promotes disease activity in RA, while other work has documented substantial anti-inflammatory and immunoregulatory properties of melatonin in preclinical models of arthritis. In addition, disturbance of the circadian rhythm is associated with RA development and melatonin has been found to affect clock gene expression in joints of RA. This review summarizes current understanding about the immunopathogenic characteristics of melatonin in RA disease. Comprehensive consideration is required by clinical rheumatologists to balance the contradictory effects.

Subcalcaneal bursitis as the initial manifestation of rheumatoid arthritis: ultrasonographic observation of two cases

In early rheumatoid arthritis (RA), proliferative synovitis sometimes occurs earlier in the tenosynovium or bursal synovium than in the articular synovium. Here we report two patients who presented with subcalcaneal bursitis while progressing from undifferentiated arthritis with high-titer anti-CCP antibodies (ACPA) to a diagnosis of RA. They had initially presented with palindromic transient pain in the hands and the feet. They were strongly positive for ACPA and negative for rheumatoid factor (RF) at the onset of symptoms. A few years later, they developed persistent plantar heel pain and underwent musculoskeletal ultrasonography (MSUS). MSUS revealed subcalcaneal bursitis with synovial proliferation. At that time, they became positive for RF and they were clinically diagnosed and began receiving treatment for RA. They developed overt synovitis in their wrists and fingers several months later. To the best of our knowledge, this is the first report on MSUS-detection of subcalcaneal bursitis with synovial proliferation in patients in the very early phase of RA, although there have been many reports of forefoot bursitis. These cases suggest that MSUS scanning of the plantar surface of the heel may be useful for patients with plantar heel pain who are suspected of having a very early phase of RA, because proliferative synovitis can be detected as subcalcaneal bursitis.

Influence of non-steroidal anti-inflammatory drugs on the inflammatory sonographic features in erosive hand osteoarthritis: an intervention study

Objective The aim was to examine whether inflammatory US features in erosive hand OA patients change when discontinuing intake of NSAIDs before US examination in a non-randomized study. Methods Patients (n = 99) were allocated to the NSAIDs or control group according to their intake at baseline. US was performed at baseline (T0) and 2 weeks after discontinuation of NSAIDs (T1). Inflammatory features (i.e. synovial proliferation, effusion and power Doppler signal) were scored using a semi-quantitative scale (from zero to three). Pain levels were scored on a numerical rating scale. Binomial mixed models were fitted for US features, and odds ratios of having a US score of at least two vs at most one for synovial proliferation and effusion, and zero vs at least one for power Doppler were calculated. Results At baseline, both groups [NSAIDs group (n = 47) vs control group (n = 52)] were comparable for numerical rating scale pain, disease duration, number of radiographically affected joints, BMI and US baseline data, but not for age (P = 0.005). At T1, more synovial proliferation and power Doppler signal was seen compared with T0 in the NSAIDs group (P = 0.018 and 0.031, respectively). However, the interaction term time*NSAIDs was not found to be significant for any variable. The numerical rating scale pain at T1 was higher compared with baseline, although statistically non-significant. Conclusion No significant changes in inflammatory US features were seen in patients with erosive hand OA after withdrawal of NSAIDs for 2 weeks. This study suggests that an NSAID-free period is not necessary before assessing inflammatory disease activity in erosive hand OA.

Wrist Swelling in Kienböck's Disease

Background and Purpose Wrist swelling is a frequent clinical manifestation of Kienböck's disease, but no study has reported the site and pathology of wrist swelling in this disease. The aim of this study is to elucidate the site and pathology of wrist swelling in Kienböck's disease. Materials and Methods Dorsal and palmar soft tissue thicknesses of the wrist were measured on standard lateral radiographs of the wrist in 26 patients with Kienböck's disease and 30 subjects without intra-articular lesion. Axial magnetic resonance imaging (MRI) views were examined to detect the site of swelling. The dorsal capsular ligament in three patients with Kienböck's disease underwent histological examination. Results Radiographic study confirmed dorsal wrist swelling in 24 of 26 (92%) patients examined compared with the contralateral unaffected wrists. MRI demonstrated thickening of the dorsal capsular ligament and extensor layer with synovial proliferation. Histological examination revealed nonspecific chronic inflammation. Conclusion Dorsal wrist swelling in Kienböck's disease is a common manifestation and constitutes a part of pathology of Kienböck's disease, although further study is required to clarify the relation between wrist swelling and etiology of Kienböck's disease. Level of Evidence This is a Level III study.