Neutrophil‐to‐lymphocyte ratio and platelet‐to‐lymphocyte ratio are associated with disease activity in polymyalgia rheumatica

Abstract Background The neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR), and monocyte‐to‐lymphocyte ratio (MLR) are indicators of systemic inflammation and are useful as markers in systemic rheumatic diseases. In this study, we compared the NLR, PLR, and MLR among patients with polymyalgia rheumatica (PMR) and rheumatoid arthritis (RA), and explored possible associations with clinical features, disease activity, and prognosis in patients with PMR. Methods The study enrolled 94 patients with PMR and 242 patients with RA who were initially diagnosed at the rheumatology clinic of a university‐based tertiary hospital. Symptoms, physical examination, and medical histories were collected with the results of laboratory tests. Results Neutrophil‐to‐lymphocyte ratio (4.5 ± 3.3 vs 2.8 ± 1.8), PLR (222.7 ± 115.5 vs 159.7 ± 78.1), and MLR (0.4 ± 0.3 vs 0.3 ± 0.2) were higher in patients with PMR compared with patients with RA (all P < .001). NLR, PLR, and MLR were correlated with specific laboratory values, including CRP and albumin, in patients with PMR. After disease activity resolved, NLR (2.95 ± 2.32, P < .001), PLR (137.5 ± 82.3, P < .001), and MLR (0.26 ± 0.16, P < .001) decreased significantly. By comparing patients according to the disease course, swollen joint counts were higher in the chronic course group compared with the remission group (P = .03), while the NLR, PLR, and MLR were similar. Conclusions Neutrophil‐to‐lymphocyte ratio, platelet‐to‐lymphocyte ratio, and monocyte‐to‐lymphocyte ratio levels were associated with disease activity and specific clinical features, although they could not predict prognosis in patients with PMR.


| INTRODUC TI ON
Polymyalgia rheumatica (PMR) is a systemic inflammatory disease, typically found in people over 50 years of age, affecting the shoulder and pelvic girdles. [1][2][3] Typical symptoms include inflammatory pain and stiffness of the involved joints with elevated inflammatory markers, such as the erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). There is no specific serological marker or test for PMR, and the diagnosis depends on clinical characteristics. Several classification criteria, including clinical characteristics and imaging tests, have been used. 4 Ultrasonography is used to identify bursitis or tenosynovitis in affected lesions, and magnetic resonance imaging and positron emission tomography scans with 18F-fluorodeoxyglucose have been investigated as imaging tools to assess inflammation around large joints in PMR. [5][6][7] Studies have shown that levels of circulating proinflammatory cytokines, such as interleukin (IL)-6 and fibrinogen, are increased in active PMR, and their levels represent disease activity. [8][9][10][11] In addition, levels of several other proinflammatory cytokines, including IL-1α, IL-1β, IL-8, and monocyte chemoattractant protein-1, are elevated in symptomatic muscles. 12 Systemic glucocorticoids are the treatment of choice to relieve disease manifestations. 13 Although PMR is generally considered a benign disorder with no adverse effects on long-term survival, most patients with PMR require long-term glucocorticoid therapy, which has several side effects, such as osteoporotic fractures and infection.
Moreover, 20%-55% of patients have relapses in the first year, requiring an increased dose of glucocorticoids. 14 Immunosuppressant agents including methotrexate (MTX) are added to taper glucocorticoids and prevent relapse. 15 Clinical characteristics such as female sex, peripheral arthritis, and high ESR or CRP levels are considered risk factors for relapse or prolonged glucocorticoid use. 16 However, there are few specific markers that predict the disease prognosis.
The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) are calculated from the complete blood count (CBC) and are known to represent systemic inflammation. 17,18 The NLR, PLR, and MLR have been studied in infectious or malignant diseases and have been shown to be useful markers for systemic rheumatic diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus. [19][20][21][22] Recent studies have shown that the NLR and PLR are higher in patients with RA than in healthy controls and associated with disease activity in such patients. 18 In addition, their correlations with disease activity markers, clinical features, and disease course were evaluated.

| Subjects
A total of 94 patients with PMR and 242 patients with RA aged 50 years or older who had been initially diagnosed at the rheumatology clinic of university-based tertiary hospitals were enrolled between January 2008 and June 2018. The diagnosis of PMR was based on Bird's criteria, and a diagnosis of probable PMR was made if more than three of seven criteria were met. 24 Patients were excluded if they had other rheumatic diseases, including systemic lupus erythematosus, systemic infections, or malignancy. The diagnosis of RA was based on the American College of Rheumatology 1987 revised criteria. 25

| Statistical analysis
The chi-square test was used to compare categorical variables for the clinical characteristics between patients with PMR and RA. The independent t test was used to compare the NLR, PLR, and MLR levels according to disease manifestations, and the clinical characteristics of patients with active and inactive PMR. Performing the Shapiro-Wilk test on all three ratios gave P-values < .0001, which does not indicate a normal distribution. However, each group was sufficiently large to apply the t test or chi-square test. Spearman's correlation was used to assess the correlations between disease activity markers and NLR, PLR, or MLR. The correlation coefficient, r, shows the statistical strength of the relationship between two variables. IBM SPSS 23.0 (SPSS) was used for the statistical analyses.

| Clinical characteristics of patients with PMR and RA
The study enrolled 94 patients with PMR and 242 patients with RA.
The mean age at disease onset differed with the diseases and was 64.7 ± 9.7 and 61.4 ± 8.7 years (P = .003), respectively (Table 1). No patients with PMR and 129 (76%) patients with RA had anti-CCP antibody. Symptom duration before presenting to the hospital was shorter in patients with PMR than in patients with RA (5.4 ± 5.8 vs 9.0 ± 10.7 months, P = .002). The number of tender and swollen joints was lower, and the visual analogue scale (VAS) score was higher in patients with PMR than in those with RA (all P < .001). In terms of the laboratory results, hemoglobin count was lower and the white blood cell (WBC) and platelet counts were higher in patients with PMR than in those with RA (all P < .001). Neutrophil count was higher, and lymphocyte count was lower in patients with PMR than in those with RA (all P < .001). ESR and CRP levels were higher in patients with PMR than in those with RA (all P < .001). Uric acid and albumin levels were lower in patients with PMR than in those with RA (P = .034 and P < .001). Table 2 shows the levels of NLR, PLR, and MLR in patients with PMR and RA. When they were matched by age and gender, NLR  TA B L E 1 Patient clinical characteristics of patients with platelet-lymphocyte ratio (PLR) and rheumatoid arthritis (RA) (P = .003, Figure 1C). When they were matched by ESR and CRP, NLR, PLR, and MLR did not differ between the patients with PMR and RA.

| Clinical characteristics including the levels of NLR, PLR, and MLR according to prognosis in PMR patients
We evaluated differences in NLR, PLR, and MLR levels between the remission group who had no relapse and chronic course group with relapse manifestations. However, the clinical manifestations, including NLR, PLR, and MLR, did not differ between the two groups (data not shown  relationship between platelets and headache. 29 Patients with migraine, a primary form of headache, had higher platelet counts and lower platelet membrane fluidity or activity compared with controls. 30,31 Platelet-leukocyte interaction releases inflammatory mediators, including interleukins, and platelet serotonin and nitric oxide are known to be secreted and cause headache symptoms. 32,33 Whether a patient with PMR reaches remission or continues with This study had several limitations due to the research method and the study population. There was no biopsy-proven giant cell arteritis (GCA), and GCA could not be analyzed. While GCA is a major comorbidity in patients with PMR, it is 20 times less common in Asian populations compared with Caucasian patients. 34,35 This study represents only the characteristics of Asian patients with PMR. In addition, we reviewed the clinical data retrospectively, so the data from some patients were missing. Furthermore, there may have been selection bias since the data were obtained from a single center.

| D ISCUSS I ON
TA B L E 4 Comparison of neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and monocyte-lymphocyte ratio (MLR) according to manifestations in patients with polymyalgia rheumatica In conclusion, patients with PMR had higher NLR, PLR, and MLR than patients with RA. NLR, PLR, and MLR levels were associated with CRP and albumin in patients with PMR. Fever in patients with PMR was associated with elevated NLR and MLR, and headache was associated with elevated PLR. After disease activity improved, NLR, MLR, and PLR levels decreased. Therefore, NLR and PLR levels at diagnosis are associated with disease activity in patients with PMR.

CO N FLI C T O F I NTE R E S T
No potential conflict of interest relevant to this article was reported.