Current Rheumatology Reviews - Volume 19, Issue 3, 2023

A randomised double blinded clinical trial about high dose immunosuppression in Paraquat self-poisoning was published by Professor I. Gawaramanna et al. Before their research, it seems that a little overestimation might be present in the small previous non-randomised clinical trials. This new valuable work clarified the previous exaggerated favourable response to immunosuppression in paraquat self-poisoning; however, their analysis underestimated the favourable response to high dose immunosuppression. According to their results, high dose immunosuppression could decrease mortality considering serum paraquat level and effect time of immunosuppressive drugs but the opposite is concluded. They did not mention the impact of incomplete sample size on their results. Severe paraquat self-poisoning seems to be unresponsive to any treatment and these patients should be analyzed separately according to serum paraquat level. So after reanalysis of their results, the findings seem to be in favour of immunosuppression benefit in paraquat-self poisoning.

Lymphatic muscle cell (LMC) contractility and coverage of collecting lymphatic vessels (CLVs) are integral to effective lymphatic drainage and tissue homeostasis. In fact, defects in lymphatic contractility have been identified in various conditions, including rheumatoid arthritis, inflammatory bowel disease, and obesity. However, the fundamental role of LMCs in these pathologic processes is limited, primarily due to the difficulty in directly investigating the enigmatic nature of this poorly characterized cell type. LMCs are a unique cell type that exhibit dual tonic and phasic contractility with hybrid structural features of both vascular smooth muscle cells (VSMCs) and cardiac myocytes. While advances have been made in recent years to better understand the biochemistry and function of LMCs, central questions regarding their origins, investiture into CLVs, and homeostasis remain unanswered. To summarize these discoveries, unexplained experimental results, and critical future directions, here we provide a focused review of current knowledge and open questions related to LMC progenitor cells, recruitment, maintenance, and regeneration. We also highlight the high-priority research goal of identifying LMC-specific genes towards genetic conditional- inducible in vivo gain and loss of function studies. While our interest in LMCs has been focused on understanding lymphatic dysfunction in an arthritic flare, these concepts are integral to the broader field of lymphatic biology, and have important potential for clinical translation through targeted therapeutics to control lymphatic contractility and drainage.

Systemic lupus erythematosus (SLE) is a chronic autoimmune illness with an unclear etiology and a range of clinical manifestations. The therapeutic results of current conventional treatments are frequently unsatisfactory. Many B-cell-directed immunotherapies have recently been discovered, as B cells play a key role in the pathogenesis of SLE. However, large-scale rituximab trials found that the antibody against CD20 was no better than a placebo. Autologous CAR T-cell therapy has garnered considerable interest and is considered a potential treatment option for SLE. CD19+CD20- B cells are thought to play an essential role in the onset and progression of SLE. CD19-targeted CAR T-cells destroy B cells without requiring an accessory cell type, thereby decreasing B cells more efficiently. Preclinical trials of CAR T-cells in mice have shown promising results against SLE. The review aimed to shed light on autologous CD19-targeted CAR T-cells as a potential treatment for SLE.

Background: Statins are used to lower serum cholesterol. Recent preclinical and clinical research focuses on articular cartilage regeneration aspects of statin. This review summarizes the effects of statins on knee osteoarthritis (OA). Methods: Published preclinical and clinical literature till November 2021 were searched in PubMed and PubMed Central databases. Articles not written in English, not relevant for the review, and unpublished evidence were excluded. Finally, 27 papers were reviewed and presented in the study. Results: A total of 27 articles have been included-13 clinical and 14 preclinical studies. Preclinical studies showed statin-induced chondroprotective effects; these included in vitro studies on human or animal-derived degenerated articular cartilage as well as OA animal models. Chondroprotective effects of statins are thought to mediate by inhibiting the Wnt/β-catenin signaling pathway, preventing synovial inflammation, and inhibiting catabolic-stress-induced aging of cartilage. Preclinical study outcomes were based on biochemical, macroscopic, and microscopic (histology) assessments and seemed promising in cartilage regeneration. In the 13 clinical studies, the effect of statins on human OA is inconclusive: some showing improvement of OA symptoms, and others depict signs of aggravation and radiological progression. No randomized controlled trial (RCT) has tested the efficacy of intra-articular statins in clinical knee OA, and it seems feasible to avoid oral statinassociated severe adverse effects. Conclusion: There are no arguments to recommend oral statins in clinical OA-knee. An RCT testing the efficacy of oral statins in patients with OA knee was never done and still seems justified, as well as a prospective phase-II clinical trial for intra-articular statins in different types of OA.

Background: Systemic lupus erythematosus (SLE) is currently the most prevalent autoimmune disorder worldwide. A previous study reported the frequency of sarcopenia in patients with chronic inflammation and found a higher rate of sarcopenia in patients with SLE than in control. A preview study found that exercises management given to SLE patients can reduce fatigue and increase vitality. Objective: The objective of this study is to understand the relationship between sarcopenia and SLE from Physical Medicine and Rehabilitation (PM&R) standpoint and its intervention. Methods: Using the PubMed computer-aided search engine specific keywords: “sarcopenia” AND “Systemic lupus erythematosus” OR “lupus” OR “SLE” OR “physical medicine and rehabilitation” OR “rehabilitation” OR “physical therapy” OR “exercises” OR “physical activity” OR “training” OR “nutrition” OR “OR “diet.” Results: Exercise rehabilitation can increase energy level, cardiovascular fitness, functional status, and physical capabilities of muscle strength and are safe to be performed by patients with SLE. Resistance training has been shown to improve muscle strength and size, increase mitochondrial content, and reduce oxidative stress. Resistance exercise impacts sarcopenia through several mechanisms in the muscular and neuromotor levels. Aerobic exercises are also beneficial for skeletal muscles to increase mitochondrial bioenergy, improve insulin sensitivity, and reduce oxidative stresses. Nutritional interventions such as protein, amino acids, essential fatty acids, and vitamin D produce biological effects that will enhance the physiological adaptation of exercise. Conclusion: Intervention for maintaining muscle function in the prevention and management of sarcopenia in SLE and its complications is a combination of resistance training and nutritional intake through adequate protein intake.

Osteoarthritis (OA) is a chronic disease with both degenerative and inflammatory characteristics, affecting the osteochondral unit with the involvement of cartilage, subchondral bone and periarticular tissues. OA can produce chronic pain with neuropathic and inflammatory characteristics, leading to an increased disability. OA is secondary to many predisposing factors where the inflammatory process plays a key role. To manage OA, it would seem logical to block the factors influencing the inflammatory process at different levels, T lymphocytes, neutrophils, and the balance between phenotype-1 macrophages (M1, pro-inflammatory) and phenotype-2 macrophages (M2 anti-inflammatory), the managing cells. The efforts to repair and rebuild the lost cartilage and the attempts to implant autologous or heterologous material, with or without growth factors and the administration of drugs or the use of medical devices, have failed their objective. TNF-alpha and IL-1 inhibitors can only have a transient effect on pain; intra-articular oxidized Low-Density Lipoproteins are able to stimulate the activation of M2, while growth factors need to be better investigated. Also, intra-articular injections of mesenchymal stem cells (MSC) can inhibit the proliferation of T-lymphocytes, leading to cartilage repair and to osteophytes inhibition thanks to the release of exosomes, nanosized particles which are the active components. Gut microbiota has a potential role in the development of OA and could be able to influence the response to therapeutic agents.

Objectives: Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. It can be responsible for several rheumatological manifestations. Aims: This article aimed to review and summarize current knowledge on musculoskeletal diseases associated with Parkinson's disease and their management. Methods: We conducted a narrative review of musculoskeletal features associated with Parkinson's disease. Results: Rheumatological manifestations of Parkinson's disease include postural disorders (antecollis, cervical kyphosis, cervical positive sagittal malalignment, camptocormia, Pisa syndrome, scoliosis), bone disorders (osteoporosis, bone fractures), and joint disorders (frozen shoulder, hand, and foot deformities). Rheumatological manifestations lead to physical disability, long-term pain, and impaired quality of life. However, the management of these manifestations is not yet codified. It can associate botulinum toxin, thoraco-pelvic anterior distraction, orthosis, orthopedic surgical correction, pallidotomy, or deep brain stimulation in patients with camptocormia. Therapeutic management of osteoporosis includes calcium and vitamin D intake and bisphosphonates. Conclusion: Rheumatological manifestations are common in Parkinson’s disease. Optimal care of patients with Parkinson’s disease should include attention to management of postural, bone, and joint disorders since it remains a major cause of functional impairment and disability.

Objective: To investigate injection site pain (ISP) and other injection site outcomes caused by biologics administered alongside citrate-free (CF) and citrate-containing (CC) formulations. Methods: Electronic literature databases (Medline, Embase, and Cochrane Library) were systematically searched for clinical trials and observational studies reporting on injection site outcomes after subcutaneous administration of biologics. Studies with unknown excipient formulations were excluded. The primary outcome was ISP, and secondary outcomes included any other reported injection site reactions (ISRs). Meta-analysis approaches were used to aggregate evidence identified via the conducted systematic literature review. Results: A total of two observational studies, two cross-over/sequential trials, and three head-tohead comparison trials directly comparing CF with CC biologics were identified, as well as seven placebo-controlled trials. Evidence from five of the seven direct comparison studies suggested reduced pain perception at the injection site when CF formulations were applied. Findings for other ISRs were balanced between both formulations, with slightly favorable results for preparations without citrate. A meta-analysis of placebo-controlled trials found no significant difference between arms with CF formulations and placebo regarding the proportion of patients experiencing ISP (OR 0.62, 95% CI 0.30-1.28). Conclusion: Excipient formulations are rarely specified in studies assessing pain and other ISRs of subcutaneously administered biologics. The available data indicate that subcutaneous administration of biologic agents without citrate may be associated with lower pain perception outcomes compared with treatment using CC formulations. Importantly, ISP is influenced by many factors which may have affected the results. More research is needed to assess how formulation excipients influence ISRs.

Background: Rheumatoid Arthritis (RA) is a disease with a heavy functional, psychological, and socioeconomic impact. The management of Quality of Life (QoL) as a therapeutic objective is a fairly recent notion, especially in Tunisia. We aimed to evaluate QoL in RA patients and to identify its affecting factors. Methods: This was a cross-sectional study in a Tunisian rheumatology center. To assess QoL, we used the Short Form Health Survey (SF-36) and the Arthritis Impact Measurement Scales Short Form (AIMS2-SF). Health Assessment Questionnaire Disability Index (HAQ), the Hospital Anxiety and Depression Scale (HAD) for psychological disorders, Visual Analog Scale for Pain (VAS Pain), and for fatigue (VAS Fatigue) were also used. Disease activity was assessed by the Disease Activity Score (DAS28 CRP). Results: We enrolled 120 established RA, the mean age of our patients was 56.9 ± 11.4 years, with a predominance of women (83.3%). The mean disease duration was 10.97 ± 7.7 years. According to the HAD scale, 27% of our patients presented anxiety, and 26.7% had depressive disorders. There was significantly impaired QoL in patients with low educational level, dependent financial situation, long disease duration, high disease activity, high pain and fatigue levels, poor therapeutic education, functional disability, and psychological disorders (p < 0.001). A strong negative correlation was detected between inflammatory markers, structural damage, and the scores of QoL. Patients under biologics scored significantly higher in the SF36 mental health domain (p < 0.001). Conclusion: QoL is significantly poor in Tunisian RA. These patients should be managed using a multidisciplinary approach involving the patients themselves.

Background: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by joint inflammation and destruction. Objective: Establish the association between Porphyromonas gingivalis (P. gingivalis) infection, body mass index (BMI), joint involvement, and serum adipokines in first-degree relatives (FDR) of patients with rheumatoid arthritis (RA). Methods: The cross-sectional study evaluated 124 FDR and 124 healthy controls (HC). The clinical examination included joint and radiographic evaluation and calculation of BMI. Serum adipokine levels were measured (leptin, vaspin, adiponectin, resistin, and adipsin), as were the erythrocyte sedimentation rate, C-reactive protein, and anti-citrullinated protein antibodies. Investigations were performed to detect P. gingivalis, and anti-P. gingivalis antibodies. Statistical analyses were performed to confirm associations. Results: Leptin levels in FDR were associated with BMI >25 (OR, 2.64; 95%CI, 1.17-5.97; P=0.019), radiographic damage (Simple Erosion Narrowing Score [SENS])/hands, total SENS, and joint space narrowing in feet (P=0.037, 0.026, 0.020, respectively). FDR had more tender joints (P=0.018); this finding was associated with high levels of leptin and resistin and low levels of adipsin (P=0.040, 0.040, and 0.019, respectively). The presence of P. gingivalis was related to FDR, low levels of adipsin, resistin, adiponectin, and a trend toward higher levels of leptin (P=0.002, 0.001, 0.003, and 0.060, respectively), whereas anti-P. gingivalis antibodies were related to low levels of adipsin (P=0.001). Conclusion: In FDR, serum adipokine levels were associated with overweight and the presence of P. gingivalis. Adipokine levels were also associated with joint involvement. Hence, adipokines may be involved in the pathogenesis of RA in FDR and warrant further investigation.

Introduction: COVID-19 pandemic, an international emergency, raised concerns about the interaction of this infection and disease-modifying drugs used in the treatment of Systemic inflammatory diseases (SID). Understanding the relationship between COVID-19 and disease activity is crucial to adapt the treatment. Aim: The aim of our study was to determine the impact of COVID-19 on the disease activity of rheumatic diseases. Patients and Methods: We performed a cross-sectional study, including patients with SID (rheumatoid arthritis (RA) and spondyloarthritis (SpA)). Disease activity was evaluated during the last check-up before COVID-19 and within the period of 6 months after the infection. Activity scores were assessed with Disease Activity Score (DAS28) for RA and Ankylosing Spondylitis Disease Activity Score (ASDAS) for SpA. Correlation and regression coefficients were used to evaluate associations among the variables. Results and Discussion: Totally, thirty-two patients were included; twenty followed for RA and twelve for axial SpA. The mean disease duration of the underlying rheumatic disease was 10.2 years (2-30). RA was seropositive and erosive in 61% and 31%, respectively. Seventeen patients were on csDMARDs: 14 were on Methotrexate and three patients were on Salazopyrine. Ten patients (31%) were treated with bDMARDs; Tumor necrosis factor (TNF)-alpha inhibitors were used in eight cases. Rituximab and secukinumab were prescribed for one patient each. In 70%, COVID-19 was pauci-symptomatic. A severe form with a need for hospitalization was noted in 9%. Two patients were admitted to the intensive care unit (ICU). Overall, treatment with DMARDs was interrupted in all cases: when COVID-19 symptoms began in 82% and when PCR was positive in 18%. Both RA and axial SpA were not active after a mean period of 6 months after COVID-19 infection (p = 0.818 and p = 0.626, respectively). Conclusion: Although our patients interrupted their DMARDs, our study demonstrates that disease activity as assessed by ASDAS and DAS28 in SpA and RA remained unchanged after COVID-19.

Background: MicroRNA-146a (miR-146a) plays a critical role in the regulation of autoinflammatory diseases, including gout. There is growing evidence that miR-146a gene single nucleotide polymorphisms (SNPs) are associated with different diseases, but no genetic relevance studies of miR-146a gene polymorphisms to gout have been reported by now. Objective: The purpose of this study was to examine the relationship between the miR-146a rs57095329 genetic polymorphism and the susceptibility to primary gout in the Chinese Han population. Methods: A case-control study was performed in this report to examine the potential association between gout and the functional rs57095329 SNP of miR-146a in a Chinese population consisting of 448 primary gout patients (containing 76 tophi patients) and 418 healthy controls. MiR-146a expression in peripheral blood mononuclear cells (PBMCs) was measured in 81 gout patients (including 32 tophi patients and 49 non-tophi patients) and 47 healthy subjects. Results: There was no significant difference found in the distribution of miR-146a rs57095329 between 448 gout patients and 418 healthy subjects (P > 0.05). However, significant differences in genotypes and allele distributions were found between 76 gout with tophi patients and 418 healthy subjects, as well as between gout with tophi (76) and with no tophi patients (372) (P < 0.01, respectively). Gout patients with AG/GG genotypes had a 0.323-fold reduced risk for tophi than those with the AA genotype, and the G allele had a 0.362-fold reduced risk of tophi. Furthermore, in 32 tophi patients, the GG genotype was significantly associated with increased expression of miR- 146a. Conclusion: Our findings suggest that rs57095329 may play a protective role in tophi gout susceptibility, and rs57095329 A > G variant may modulate the expression of miR-146a in tophi patients.

Background: According to the World Health Organization, osteoarthritis (OA) is one of the 10 most disabling diseases in developed countries, with worldwide estimates of 9.6% prevalence in men and 18.0% in women over 60 years old. Its management is not well established and involves the use of high doses of painkillers coupled with anti-inflammatory agents. Objective: In the search for alternatives to manage the disease, previous studies have shown superior properties of Q-Actin^TM in managing OA-related pain compared with standard treatments. Qactin is a cucumber extract with the anti-inflammatory iminosugar idoBR1 standardised to over 1%. This study investigated the effects of different doses (20 mg, 100 mg) of Q-Actin in a longitudinal placebo-controlled experiment. Methods: There were 101 patients with knee OA enrolled for the 180-day study, with 91 patients completing it. Patients were grouped into a placebo group (PLBO), as well as a 20mg dose (Q-Actin 1) and 100 mg dose (Q-Actin 2) groups. The PLBO group received cellulose in capsules identical to the Q-Actin capsules. Results: There was a significant improvement in the pain-related parameters over time that was dose-dependent. Conclusion: This study clearly demonstrated the effectiveness of Q-Actin compared to placebo in the management of pain related to moderate osteoarthritis.

Background: Our group have recently reported that there is no evidence of an association between fibromyalgia and Borrelia-specific T lymphocytes. However, a small number of case reports has suggested that infection by the bacterial genus Borrelia may be associated with the presence of antinuclear antibodies (ANAs). Objective: To test the hypothesis that those fibromyalgia patients who are ANA seropositive are more likely to show evidence of Borrelia-specific T lymphocyte reactivity than those who are seronegative. Methods: T lymphocyte reactivity to Borrelia burgdorferi sensu stricto (full antigen) was assessed using the enzyme-linked immunospot and serum ANA status was assessed using immunofluorescence in 27 fibromyalgia patients fulfilling the revised diagnostic criteria of the American College of Rheumatology. Results: The ANA seropositive and seronegative groups were matched for age, sex and ethnicity; the T lymphocyte reactivity to Borrelia burgdorferi sensu stricto (full antigen) in the former group (mean 5.60) was significantly higher than that in the seronegative group (mean 1.77; p < 0.05). Conclusion: This novel study points to an association of ANA seropositivity in fibromyalgia with Borrelia-specific T lymphocytes.

Background: Knee osteoarthritis, a chronic degenerative disease, is becoming a public health problem around the world due to increasing life expectancy. Objectives: We aimed to assess the impact of knee osteoarthritis on the quality of life (QoL) of the patients and to identify factors associated with impaired QoL. Materials and Methods: We conducted a cross-sectional monocentric study including patients with knee osteoarthritis. The pain was evaluated by the Visual Analog Scale (VAS). The short form of the Knee injury and Osteoarthritis Outcome Score (KOOS-PS) was used to assess functional impact. QoL was assessed using the OsteoArthritis of Knee Hip Quality Of Life (OAKHQOL) questionnaire. Results: Fifty patients were included. The mean age of patients was 59 ± 9 years. The sex ratio was 0.25. At least one comorbidity was noted in 77% of patients. The mean disease duration was 8.82 years. Mean VAS pain and KOOS-PS were 6.8 ± 1.1 and 54.7 ± 9.6/100; respectively. Assessment of the QoL by OAKHQOL showed impaired QoL in all domains; the worst scores concerned the areas of social functioning and pain. Factors associated with an altered QoL were age > 65 years, longer disease duration, higher pain intensity, comorbidities, and functional impairment. Conclusion: Our patients showed an impaired QoL in all domains, particularly in terms of physical activity and social functioning. Lower QoL scores were associated with age, comorbidities, pain, function, and disease duration. Factors associated with QoL should be considered in the management program of these patients. Screening and the treatment of comorbidities are also useful for the management of knee OA.

Background: Synovial chondromatosis is an uncommon benign condition characterized by synovial membrane proliferation and metaplasia. Synovial chondromatosis cases in patients with rheumatoid arthritis have been reported. However, involvement of the glenohumeral joint is rare. Case Presentation: We herein report a case of a rare association of synovial chondromatosis involving the shoulder in a rheumatoid arthritis patient. The symptoms have improved with anti-tumor necrosis factor drugs. Consequently, there was no need for invasive therapy to treat synovial chondromatosis. Conclusion: Synovial chondromatosis can be aggressive and destructive. More trials are needed to establish a better clinical diagnostic strategy and pharmacological management.

Introduction: Necrotizing scleritis (NS) presents 30%-40% as having a systemic autoimmune condition. Objective: To present a clinical case report and a systematic review of necrotizing scleritis with ocular manifestation as the first sign of rheumatologic disease. Methods: The present study was elaborated according to the rules of CARE. Case Report: A female patient, 63 years old, a white, administrative assistant, presented irritation, low visual acuity (LVA) in the left eye (LE), and headache. Biomicroscopy (BIO) in the right eye (RE) was normal, and the LE showed hyperemia and scleral thinning. After 1 month, the patient returns without signs of infectious diseases in the exams, and after a rheumatological evaluation with a diagnosis of rheumatoid arthritis, methotrexate and prednisone are prescribed. After 2 months, she relapsed and started treatment with anti-TNF, with remission after the 4th dose. After 1 year, she evolved with LVA in LE. Results: A total of 244 articles were found, 104 articles were evaluated and 10 were included in the brief review. The symmetrical Funnel Plot does not suggest a risk of bias. Conclusion: Both in the present case report and the literary findings, it was evidenced that the ophthalmologic findings may precede the systemic changes of the disease for the early diagnosis of rheumatoid arthritis.

Introduction: Overweight and obesity are common in patients with Rheumatoid Arthritis (RA), with a probable impact on bearing foot joints. Aim: Our study aimed to explore the impact of Body Mass Index (BMI) on foot health parameters in RA patients. Methods: It was a cross-sectional study. Domains of foot health explored were: foot pain (Numeric Rating Scale), foot-related activity limitations (Foot Function Index (FFI), and WOMAC scale), foot synovitis, foot deformity (Platto Score (PS)), radiological joint damage and footwear problems. Results: Fifty RA were included, 82% were female. The mean age was 45.68 ± 10.3 years. The mean DAS28-CRP was 3.25 ± 0.98. Sixty-six percent were overweight or obese, with a mean BMI of 29 Kg/m² ± 5.74. The average foot pain intensity while walking was 6 ± 1.75. The mean swollen foot joint was 2.2 ± 1.55. The average foot structural index was 7.8 ± 2.73. The mean FFI Disability score was 32 ± 14.2 and WOMAC score was 33.8 ± 13.98. Half of our patients had footwear problems predominantly because of claw toe (40%). High BMI was significantly correlated with foot pain and foot-related activity limitations. It was also correlated with foot deformities assessed with PS (B=4.78; CI(3.87-5.68); p = 0.02), foot synovitis (OR=4.66, CI(2.61-8.32); p < 0.001) and problems with footwear (OR= 0.32; CI(0.18-0.56); p = 0.05). However, it was significantly associated with less radiological joint damage (CI(-0.7-1.1); p = 0.01) and lower foot sharp score (B = -13.9; CI(-0.34-0.01); P = 0.06). Conclusion: Despite our findings of a possible protective effect of obesity on structural damage, obesity is still an important cause of increased pain, functional disability, and impaired QoL in RA patients.