Rheumatoid Arthritis: Monitoring Disease With Neutrophil-To-Monocyte Ratio
Overview
A recent case-control study conducted in Ibb City, Republic of Yemen, focused on identifying effective hematological markers for monitoring disease activity in patients with chronic rheumatoid arthritis (RA). This autoimmune disease is characterized by chronic inflammation. The study explored three novel inflammatory markers: neutrophil-monocyte ratio (NMR), lymphocyte-monocyte ratio (LMR), and neutrophil-lymphocyte ratio (NLR). Researchers aimed to determine which of these markers was most useful for assessing RA disease activity and how well they correlated with conventional markers like C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and rheumatoid factor (RF).
The study involved 62 individuals with chronic RA who had been previously diagnosed and experienced recurrent symptoms. These patients sought care at various public and private rheumatology clinics between September 1 and November 30, 2021. Additionally, 20 healthy volunteers were included in the study. For all participants, a range of tests was conducted, including complete blood count, CRP, ESR, and RF level measurements.
The results showed positive correlations between the total leukocyte count, neutrophil count, platelet count, NMR, LMR, and NLR with CRP and ESR. However, the monocyte count exhibited a reverse correlation. Notably, the study found that NMR performed exceptionally well as an inflammatory marker for assessing RA activity. It demonstrated an area under the curve (AUC) value of 0.861, which was comparable to CRP and close to ESR. An NMR cutoff value of 4.7 was identified, with 87% sensitivity and 80% specificity.
In comparison, LMR and NLR had lower AUC values (0.807 and 0.699, respectively) with cutoff values of 4.35 and 1.35, respectively. The sensitivity and specificity for LMR were 62.3% and 90%, while for NLR, they were 57.4% and 80%, respectively.
In conclusion, this study suggests that NMR is a cost-effective and convenient inflammatory marker for assessing disease activity in RA patients, outperforming LMR and NLR. These findings could have implications for improving the monitoring and management of RA in clinical practice.
Introduction
Rheumatoid arthritis (RA) is a systemic autoimmune disease that primarily affects the synovium of joints, leading to chronic inflammation, bone damage, and ultimately disability. The key underlying feature of RA is inflammation, which drives disease activity and can fluctuate over time. Effective management of RA involves promptly suppressing this inflammation to achieve better disease control. This inflammation is triggered by pro-inflammatory cytokines like interleukin (IL)-1, IL-6, IL-15, IL-18, and tumor necrosis factor-alpha (TNF-α), which lead to classic signs of inflammation such as redness, swelling, pain, and the sensation of heat on the affected area. Conversely, some cytokines, like IL-4 and IL-10, act as anti-inflammatory agents. Pro-inflammatory cytokines play a role in the formation of inflammatory swelling, which contributes to stiffness in joints.
Various markers have been explored as potential prognostic indicators for assessing disease activity in RA. These include traditional inflammatory markers like rheumatoid factors (RF), anti-cyclic citrullinated peptide (anti-CCP) antibodies, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR), which are commonly used to gauge disease activity. Additionally, other markers such as high-sensitivity CRP, IL-6, TNF-α, and IL-10 have been investigated and found to have elevated serum levels in RA patients compared to healthy individuals.
Recent research has focused on the neutrophil-to-monocyte ratio (NMR), lymphocyte-to-monocyte ratio (LMR), and neutrophil-to-lymphocyte ratio (NLR) as novel, simple, and cost-effective inflammatory markers for various diseases, including RA. This study aims to identify the most useful among these new markers (NMR, LMR, and NLR) based on their strength of association with RA disease activity and their correlation with classical markers such as CRP, ESR, and RF.
Methods
This case-control study involved 62 individuals with chronic rheumatoid arthritis (RA) who had previously been diagnosed with the condition for at least one year and had experienced recurring symptoms. These patients sought follow-up care at both private and public rheumatology clinics in Ibb City, located in the Republic of Yemen. The study was conducted over a period spanning from September 1 to November 30, 2021. To serve as a control group, 20 healthy volunteers were included in the study, and they were matched with the RA patients in terms of age and gender.
The diagnosis of RA in the patients was carried out by specialized rheumatology practitioners, adhering to international clinical and laboratory criteria, including guidelines set forth by the American Rheumatism Association and the European League Against Rheumatism in 2010. A comprehensive questionnaire was completed for each RA patient, which included sociodemographic data, such as local practices like Qat chewing (a stimulant plant commonly chewed daily in Yemen and a few other West African countries). The questionnaire also collected information related to the disease history and patterns of symptom fluctuation, including the date of initial RA diagnosis, onset and severity of symptoms, as well as specific details about joint and movement symptoms like pain, swelling, warmth, stiffness, and mobility difficulties. All participants provided informed consent to participate in the study, and the study design adhered to ethical regulations, particularly the WMA Declaration of Helsinki’s ethical principles for medical research involving human subjects, as outlined in 2013.
Before initiating treatment, approximately 5 ml of blood was collected from each participant for laboratory analysis, which included both RA patients and healthy control volunteers. A complete blood count (CBC) analysis was performed on EDTA-treated blood samples using an automated hematology analyzer (Sysmex xsi-500). This CBC analysis provided a comprehensive report on blood cell counts, and new inflammatory markers associated with leukocytes were computed for each participant. Additionally, classical, routine tests for monitoring RA activity were conducted on both EDTA-treated blood and serum samples, encompassing modified Westergren erythrocyte sedimentation rate (ESR), agglutination-based methods for C-reactive protein (CRP), and rheumatoid factor (RF).
Statistical Analysis
For the data analysis in this study, Statistical Package for Social Sciences (SPSS) version 19 was employed. The data were subjected to systematic analysis, utilizing descriptive statistical methods such as calculating the mean, standard deviation (SD), range, frequency, and percentage as applicable. To assess the differences in various parameters, independent t-tests or Mann–Whitney rank-sum tests were employed.
To explore potential correlations between different variables, the Spearman’s correlation test was utilized for the analysis. This test is suitable for assessing relationships between variables, especially when dealing with non-normally distributed data or ordinal variables.
In order to determine useful cutoff values for the new inflammatory markers, Receiver Operating Characteristic (ROC) curve analysis was conducted. This involved calculating the Youden index, which aids in identifying the optimal cutoff value for diagnostic tests or markers. A statistical test was considered significant when the p-value was less than or equal to 0.05, indicating a level of significance at or below 5%.
Results
The gender distribution among rheumatoid arthritis (RA) patients in this study was predominantly female, comprising 77.4% of the patients, while males accounted for 22.6%. The majority of RA patients were aged 50 years and older, representing 46.7% of the total. Additionally, 54.8% of the patients reported qat chewing as a local habit, while a substantial portion, approximately 90.3%, did not smoke. In terms of disease duration, the study found that 53.2% of RA patients had a duration of 2 to 5 years.
The clinical presentation of RA was characterized by joint symptoms such as pain, swelling, warmth, and stiffness, which were prevalent among the majority of patients, exceeding 85%. Furthermore, movement-related problems, including difficulty walking, climbing stairs, and experiencing disability, were observed in 98.3%, 80.6%, and 30.6% of RA patients, respectively.
Laboratory investigations revealed significant differences between RA patients and healthy controls. In RA patients, most of the analyzed parameters showed elevated levels, except for the mean monocyte count and hemoglobin level, which were lower compared to healthy volunteers. Notably, both erythrocyte sedimentation rate (ESR) and the neutrophil-to-monocyte ratio (NMR) were elevated approximately fourfold in RA patients compared to healthy controls, with values of 40.13 ± 26.4 vs. 10.3 ± 4.6 and 12.87 ± 15.47 vs. 3.70 ± 2.58, respectively. The lymphocytes to monocytes ration (LMR) also exhibited a significant increase in RA patients, approximately 2.6 times higher than in healthy controls (8.39 ± 11.44 vs. 3.16 ± 1.07).
Correlation analyses demonstrated statistically significant weak to moderate correlations. Parameters like total leukocyte count and platelet count were positively correlated with classic markers such as C-reactive protein (CRP), ESR, and rheumatoid factor (RF). Notably, the absolute neutrophil count showed stronger positive correlations with these markers compared to total white blood cell count, while the absolute monocyte count exhibited negative correlations.
Moreover, the new inflammatory markers, including NMR, LMR, and NLR, displayed positive correlations with ESR and RF, though the correlations were relatively weaker. Notably, the correlation coefficient between NMR and ESR was similar to that between ESR and RF.
For NMR, a cutoff value of 4.7 yielded an area under the curve (AUC) of 0.861, which was comparable to CRP (AUC = 0.862) and close to ESR (AUC = 0.945). The sensitivity of NMR was higher (85%) than CRP (80%) and similar to ESR (87%), while the specificity for these markers varied (80%, 100%, and 95%, respectively).
LMR and NLR had cutoff values of 4.35 and 1.35, respectively, resulting in AUCs of 0.807 and 0.699. These markers exhibited high specificity but relatively lower sensitivity values (90%, 80%, 62%, and 57%, respectively).
These findings suggest that NMR, among the new inflammatory markers, may serve as a useful and convenient marker for assessing RA disease activity, exhibiting comparable performance to traditional markers like CRP and ESR.
Discussion
Rheumatoid arthritis (RA) is a complex autoimmune disease characterized by chronic inflammation, particularly in the synovial joints, which leads to joint damage and functional impairment. The disease follows a dynamic course with different phases, including early and late stages, each associated with distinct immunological processes.
In early RA, the involvement of antibodies and the IL-23/Th17 axis plays a pivotal role in the pathogenesis of the disease. Late-stage RA, on the other hand, is characterized by altered cell death pathways in synoviocytes after prolonged exposure to inflammation. The systemic nature of RA and the role of innate immune cells, such as neutrophils and monocytes, in inflammation can impact the distribution of white blood cells in the peripheral blood, creating a new balance. This shift is hypothesized to be directly proportional to RA disease activity. Consequently, novel inflammatory markers like the neutrophil-to-monocyte ratio (NMR), lymphocyte-to-monocyte ratio (LMR), and neutrophil-to-lymphocyte ratio (NLR) have gained attention as potential indicators of RA activity.
The patients included in this study were experiencing RA symptoms, such as joint pain, swelling, warmth, stiffness, and movement difficulties, indicating a raised disease activity stage, often associated with the late phase of the disease. Most of these patients had a disease duration of 2 to 10 years.
Laboratory investigations revealed significant differences between RA patients and healthy controls. RA patients exhibited increased levels of inflammatory cells, including total white blood cells, neutrophils, lymphocytes, and platelets, as well as classical RA markers like C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and rheumatoid factor (RF). However, monocyte counts were significantly lower in RA patients compared to the control group.
Correlation studies demonstrated that the new inflammatory markers (NMR, LMR, and NLR) were positively correlated with classical markers (ESR and RF), indicating their association with RA disease activity. Notably, NMR exhibited the highest significance in all statistical analyses, making it a promising marker for monitoring RA activity. It also had the highest correlation coefficient with ESR compared to the other markers, emphasizing its diagnostic significance.
The diagnostic utility of NMR is attributed to the roles of its components, neutrophils, and monocytes, in the inflammatory process during RA symptom episodes. Neutrophils are primary actors in inflammation, while monocytes play a role in amplifying inflammation through the secretion of various cytokines.
The study acknowledges certain limitations, including a relatively small number of patients due to the low prevalence of RA in Yemen and limited healthcare resources. Additionally, the absence of a robust registry system and limited public funding for research posed challenges. Nevertheless, the study provides valuable data on RA patients in Yemen, where information on this population is limited.
In conclusion, this study highlights the potential of NMR as a valuable inflammatory marker for monitoring RA disease activity. It offers insights into the immunological processes underlying RA in late-stage patients and provides important clinical data for the Yemeni population, where RA research is limited.
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