Current Rheumatology Reviews - Volume 21, Issue 4, 2025

Rheumatoid arthritis (RA) is a chronic inflammatory disease that requires early detection and treatment. Currently, we have three categories of slow-acting disease-modifying antirheumatic drugs (DMARDs): (1) conventional synthetic (csDMARD), (2) biologic (bDMARD), and (3) directed or targeted synthetic (tsDMARD).

This review explores innovative therapeutic modalities for RA, discussing their potential advantages and challenges. The objective is to assess the safety, efficacy, and feasibility of these novel therapies to improve the quality of life for RA patients. Also, focus has been laid on non-pharmacologic modalities in comparison to pharmacologic modalities.

This review discusses several innovative therapies for RA, including acrylamide derivatives, coumarin derivatives, JAK1-selective inhibitors, monoclonal antibody adjuvants with methotrexate, the pros, and cons of NRF2 activation as adjunctive therapy, glucocorticoids, bioactive molecules, combination therapy, gene therapy, and other therapies. Each approach presents unique advantages and challenges, reflecting the complexity of RA and the need for personalized treatment strategies.

Ongoing research and clinical trials are crucial for assessing the safety, efficacy, and feasibility of these novel therapies. By overcoming the limitations of conventional treatments and tailoring treatment approaches to individual patients, these innovative therapies have the potential to enhance the quality of life for RA patients.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and joint destruction, leading to significant disability and reduced quality of life. Current treatment options for RA have limitations, highlighting the need for novel therapeutic approaches. In this study, we employed network pharmacology methods to identify potential bioactive compounds from Persea Americana (avocado) for the treatment of RA.

We collected information on the phytoconstituents of avocados from the IMPPAT database and used Data Warrior software to filter out 64 plant constituents based on ADMET criteria. Target genes associated with avocado compounds were identified using the Bindingdb web server, resulting in 209 genes from Persea Americana. Protein-protein interaction (PPI) network analysis was performed using Cytoscape software to identify key genes and proteins involved in RA. Protein-drug interactions were analyzed, and ten avocado constituents with high binding affinity were identified.

Our network pharmacology analysis revealed that avocado constituents, particularly Luteolin, have the potential to be developed as novel therapeutics for RA. The PPI network analysis identified key genes and proteins associated with RA, providing insights into the molecular mechanisms of the disease. The high binding affinity observed between Luteolin and PTGS2, a protein involved in joint inflammation, suggests its potential effectiveness in mitigating RA-related inflammation.

Our study highlights the potential of avocado constituents, particularly Luteolin, as promising therapeutics for the treatment of rheumatoid arthritis (RA). Through network pharmacology analysis, we identified key target genes and proteins associated with RA, shedding light on the underlying molecular mechanisms of the disease.

In Rheumatoid Arthritis (RA), pulmonary involvement is one of the most frequent extra-articular manifestations. Several studies have demonstrated an association between RA-related lung disease and the positivity of anti-cyclic citrullinated peptide (anti-CCP) antibodies.

Our aim is to describe the frequency of pulmonary involvement in the RA population and investigate the association between anti-CCP antibodies and diverse lung compartment involvement in RA patients.

An observational retrospective cross-sectional study was conducted, during which data were collected from the medical records of the patients with RA who had been tested for anti-CCP antibodies and had thoracic high resolution computerized tomography (HRCT) evaluation from January 2011 to March 2022. The univariate and multivariate analyses using logistic regression models was performed to calculate odds ratios (ORs) with 95% CIs.

A total of 390 patients with RA were included, the mean age of patients was 58.99 ± 12.44 years, with a predominance of females (85.9%). Two hundred and fifty-two (64.6%) patients were positive for anti-CCP antibodies. The frequency of RA-related lung diseases was 14.4% (n=56). The different manifestations observed in the thoracic HRCT included Nodules (67.9%), Interstitial lung disease (ILD) (28.6%), bronchiectasis (25%), fibrosis (21.4%), obliterative bronchiolitis (7.1%), and pleuritis (1.8%). In univariate and multivariate analysis, pulmonary involvement was associated with positive anti-CCP antibodies with an odds ratio (OR) of 5.25 (95% CI: 2.17-12.70, p < 0.0001).

The study demonstrated a positive association between anti-CCP antibodies and pulmonary involvement in RA and highlighted the importance of tight monitoring in RA patients with positive anti-CCP for pulmonary complications.

Despite advances in the treatment of Chronic Inflammatory Rheumatic Disease (CIRD), pain remains a significant burden for patients and doctors. This study explored the prevalence and associated factors of central sensitization (CS) in patients with CIRD.

This is a cross-sectional study that included patients with CIRD followed at the University Hospital Center in Tangier. Sociodemographic and clinical data were collected. Nociceptive pain was assessed by the Visual Analogue Scale (VAS), disease activity by DAS-28 and ASDAS, and CS by the validated Moroccan version of the Central Sensitization Inventory part A (CSI-A). The Pain Catastrophizing Scale (PCS) was used to assess pain-related catastrophic thoughts, and the PHQ-9 (Pain Health Questionnaire) was used to determine the severity of depressive symptoms.

We included 189 patients; 107 (56.61%) had rheumatoid arthritis. The median duration of evolution of CIRD was 8 years, and the mean age was 47.49 ± 13.70 years, and 75.7% were women. The mean pain VAS was 4.77+-2.76, and 37.6% of patients were in remission. The mean central sensitization score was 37.42+- 16.75, with 44.9% having a CSI score ≥ 40. In univariate and multivariate analysis, our study showed that central sensitization is associated with pain severity (β = 1.945(0.050-1.916), p = 0.039) and depression (β = 1.790(1.221-2.154), p ≤ 0.001)(8). A statistically significant correlation was found between the CSI-A score and pain VAS (r = 0.32, p < 0.001).

Our study showed that almost half of our patients with CIRD had CS. The main factors associated with CS in our patients were pain severity and depression. We also found a significant correlation between pain VAS and CSI.

Osteoarthritis (OA) is a prevalent joint disorder categorized into phenotypic subtypes, including those associated with age, traumatic events, and metabolic syndrome. In the aging population, type 2 diabetes mellitus (T2DM) and osteoarthritis (OA) frequently coexist. This can result in higher rates of disability and a greater financial burden. This study aimed to investigate the protective effects of melatonin and atorvastatin together against oxidative stress and apoptosis induced by high glucose in C28I2 human chondrocytes.

After being pretreated for 6 hours with melatonin (10 and 100 μM) and atorvastatin (0.01 and 0.1 μM), C28I2 cells were exposed to a high concentration of D-glucose (75 mM) for 72 hours. The impact of a high D-glucose concentration (75 mM), with or without melatonin and/or atorvastatin, on cell viability, intra-cellular ROS generation, lipid peroxidation level, antioxidant activities, and the expression of proteins, including Bax, Bcl-2, and caspase-3, was analyzed.

Melatonin and atorvastatin combination effectively inhibited high glucose-induced cytotoxicity, ROS production, and MDA and mitochondrial membrane potential levels. The combination of melatonin and atorvastatin was more successful in reducing ROS production compared to each of the drugs alone. Melatonin, but not atorvastatin, reversed high glucose-induced alteration in the catalase activity. Furthermore, the combination of melatonin and atorvastatin significantly enhanced the ability of each medication to lower the expression of pro-apoptotic protein Bax.

The combination of melatonin and atorvastatin exerted greater protective effects against hyperglycemia-induced toxicity in chondrocytes.

Earlier treatment in axial spondyloarthritis (axSpA) was proposed to alter disease prognosis in this often-challenging condition. We aimed to assess the proportion of patients and prognostic factors associated with axSpA remission.

The aim was to determine the number of patients with Ankylosing Spondylitis Disease Activity Score with C-reactive protein (ASDAS-CRP) of <2.1 (inactive/moderate disease activity). We also evaluated global functioning and health using the Assessment of Spondyloarthritis International Society-Health Index (ASAS-HI).

Patients with axSpA who were receiving targeted synthetic/biological disease-modifying anti-rheumatic drug (ts/bDMARDs) treatments and visited the rheumatology units at two tertiary-care centers between December 2021 and December 2022 were prospectively interviewed. Data regarding patient demographics, disease features, active and previous ts/bDMARDs treatments, and disease activity scores were obtained. Patients were assessed using the ASDAS-CRP, ASDAS-erythrocyte sedimentation rate (ASDAS-ESR), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and ASAS-HI.

Overall, 60 patients with axSpA were included in this study (women, n = 35); 25 (41.7%) and 36 (62.1%) achieved an ASDAS-CRP of <2.1 and an ASAS-HI of ≤5 (good health), respectively. Out of the 60 patients, 75% (n = 45) were treated with anti-tumor necrosis factor. Factors associated with achieving the target ASDAS-CRP included age (p = 0.019), sex (p = 0.015), employment status (p = 0.015), education level (p = 0.030), and the number of previous ts/bDMARDs treatments (p = 0.019). Additionally, the ASDAS-CRP strongly correlated with spinal pain and moderately correlated with the ASAS-HI, BASDAI, and the number of previous ts/bDMARDs treatments.

Remission was observed in 41.7% of patients, indicating a challenge in achieving target disease activity. However, 62.1% attained good health. Achieving remission was associated with younger age, male sex, a higher level of education, lower level of spinal pain, better global function by ASAS-HI, being employed and receiving their first treatment with ts/bDMARDs (i.e. non-biologic switchers) at the time of interview. Our findings may potentially improve disease prognosis with the earlier use of ts/bDMARDs in those without favorable features by implementing an early axSpA intervention strategy.

The aim of this study is to investigate the effect of a high oral dose of omega-3 on serum magnesium (Mg) and calcium (Ca) levels and their effects on clinical measures of pain threshold.

One hundred twenty patients were recruited and randomized 1:1 to omega-3 or placebo and blinded to their treatment group. At baseline and after 8 weeks of treatment, the Widespread Pain Index (WPI), the Symptom Severity Scale (SSS), the Visual Analogue Scale (VAS), and the FM Impact Questionnaire (FIQ) were completed. In addition, serum was taken for Ca and Mg analysis at the same time point.

The WPI, SSS, VAS, and FIQ scores improved significantly in the omega-3 group compared to the placebo group (P < 0.001). Serum Ca levels were negatively correlated with WPI (r = -0.308), SSS (r = -0.28), VAS (r = -0.311) and FIQ (r = -0.348) scores after 8 weeks of treatment (P < 0.001), while serum Mg levels were negatively correlated with SSS (r = -0.212) and VAS (r = -0.231) scores after 8 weeks of treatment.

The results of this study showed that a high dose of omega-3 could have a positive effect on the relief of FM pain, which could be due to an increase in serum Mg and Ca levels.

Research4877#.

Upadacitinib, a selective JAK1 inhibitor, has demonstrated promising results in the treatment of axial Spondyloarthritis (AxSpA). AxSpA management remains challenging since there is a gap in knowledge regarding the potential effect of upadacitinib in axSpA patients. Exploring novel therapeutic options is crucial. Therefore, we performed this systematic review and meta-analysis to summarize and synthesize results collected from available randomized- controlled trials (RCTs) about the efficacy and safety of upadacitinib for patients with axSpA.

A systematic literature search of Medline via PubMed, Web of Science, Scopus, EBSCO, and Cochrane Central was conducted in October 2023. Relevant RCTs were selected, and their data were extracted and analyzed using the RevMan 5.4 software. The main outcomes were assessment in Spondylarthritis International Society (ASAS) 20, ASAS40, SPARCC MRI sacroiliac joint, and Bath Ankylosing Spondylitis disease activity index (BASDAI) 50.

Three RCTs with a total of 920 participants were included in this study. Upadacitinib showed significant improvement in the ASAS40 response, ASAS20 response, BASDAI50 response, and SPARCC MRI Sacroiliac Joint change from baseline compared to placebo at 14-week duration (RR 2.19, 95% CI (1.79 to 2.68), P < 0.00001), (RR 1.62, 95% CI (1.42 to 1.84), P < 0.00001), (RR 2.16, 95% CI (1.75 to 2.67), P < 0.00001), and (MD -3.32 points, 95% CI (-3.96 to -2.68), P < 0.00001) respectively. However, this efficacy decreased after the 52-week duration in terms of ASAS40 RR 2.19 vs. 1.02, ASAS20 RR 1.62 vs. 0.98, BASDAI 50 RR 2.16 vs. 1.05, and ASAS Partial Remission RR 3.82 vs. 1.07.

Upadacitinib 15 mg showed satisfactory and promising efficacy in the treatment of AxSpA, with no difference in safety profile compared to the placebo.

The p53 protein has important roles in apoptosis, proliferation, and prevention of DNA damage. Several studies have reported that TP53 gene polymorphism is associated with various autoimmune diseases, including Rheumatoid arthritis (RA) and Systemic lupus erythematosus (SLE).

Evaluation of the correlation between TP53 gene rs1042522 polymorphism and RA and SLE risk by meta-analysis.

Databases, including PubMed and Scopus, were searched to find studies assessing the association between TP53 gene polymorphism and RA and SLE risk in different populations up to August 2022. The protocol of this article was registered on the International Prospective Register Of Systematic Reviews.

Herein, 7 case-control studies, including 2498 cases and 3799 controls in the SLE group, and 6 case-control studies comprising 1593 cases and 4460 controls in the RA group that investigated rs1042522 SNP were included in the meta-analysis. Herein, CG genotypes were more frequent in healthy participants compared to SLE patients and may associated with a decreased SLE risk (OR=0.85, CI: 0.76-0.95, P-value = 0.006). Besides, dominant and recessive models of CC+ CG vs. GG were also protective for SLE risk (OR=0.85, CI: 0.76-0.95, P-value = 0.004).

In summary, this study discloses a weak correlation between rs1042522 and a decreased risk of SLE. However, no significant association was found in RA.

CRD42022309655.

Sjögren’s syndrome is a chronic autoimmune disorder that results in dry eyes and mouth. It is rarely associated with cryoglobulinemia, the agglutination of cryoglobulins at cold temperatures that leads to systemic inflammation and organ damage. We have, herein, presented a case of Cryoglobulinemic Vasculitis (CryoVas), which presents as cryoglobulinemic glomerulonephritis and Central Nervous System (CNS) vasculitis and peripheral neuropathy.

A 52-year-old woman with a past medical history of Sjögren's syndrome was admitted to the intensive care unit with severe hyponatremia, orthopnea, and progressive lower extremity weakness, and was found to have an intradural extramedullary hematoma with mass effect in the thoracic spine and diffuse hyperintense cord signal abnormality in thoracic spine suggestive of intermixed proteinaceous or hemorrhagic material. Further testing demonstrated that the patient experienced worsening neuropathy, proteinuria, hematuria, declining renal function, and the presence of cryoglobulins in the blood. After a thorough examination and a renal biopsy, the patient was diagnosed with cryoglobulinemic glomerulonephritis and cryoglobulinemic vasculitis of the spine. The patient was treated with rituximab and pulse-dose steroids, with which the patient exhibited improved renal function and resolution of a previously seen intradural hematoma on repeat MRI.

We have, herein, discussed a rare case of cryoglobulinemic vasculitis that has led to a rare CNS manifestation and concomitant cryoglobulinemic glomerulonephritis. This suggests that clinicians should consider cryoglobulinemic vasculitis as the etiology that could manifest with multiorgan involvement, especially in patients with underlying rheumatic diseases.

Axial melorheostosis is a rare clinical condition with only a few cases identified worldwide. The combination of axial and peripheral melorheostosis has not reported before, to the best of our knowledge.

Here, we present a case of a 9-year-old boy, who was referred with pain and swelling over the medial upper right leg with slight limping of insidious onset over a 3-month period. In addition, there was discomfort and irregular patchy skin lesions over the lower back. On examination, a tender swelling with irregular borders was felt over the right upper tibia. A diagnosis of axial and peripheral melorheostosis was confirmed by radiological imaging. A single dose of intravenous zolendronic acid (0.05 mg/kg) was administered. The patient showed significant improvement of symptoms within 2 months of treatment, with complete alleviation of symptoms after 6 months.

Axial and peripheral melorheostosis can present together; however, peripheral lesions may adequately respond to zolendronic acid treatment.

Systemic sclerosis (SSc) is an autoimmune disorder characterized by progressive fibrosis and vascular complications. Osteomyelitis is a rare but serious complication in patients with systemic sclerosis, particularly those with advanced vascular compromise. This case is notable for the rapid progression of osteomyelitis and highlights the importance of early intervention and thorough clinical monitoring.

We report the case of a 68-year-old female with SSc (Scl-70 positive), treated with iloprost IV, nifedipine, bosentan, prednisone, and mycophenolate for pulmonary involvement. In January 2024, she developed acrocyanosis and severe pain in the fifth toe of the right foot. A small ulcer formed, and subsequent radiographic evaluation revealed rapid progression of osteolysis. Despite negative culture swabs, an infectious process was suspected, and combination antibiotic therapy was initiated. This treatment led to a gradual resolution of symptoms, with subsequent imaging showing detachment of the fifth toe.

This case highlights the critical need for vigilant radiographic monitoring and timely antibiotic intervention in patients with SSc who develop vascular complications. Early diagnosis and treatment are crucial for optimizing patient outcomes and preventing severe bone damage.