Background

Autoimmune diseases are immune-mediated disorders affecting joints, kidneys, and others that usually alternate activity with quiescent stages [1]. These inflammatory disorders are characterised by, increased production of proinflammatory cytokines [2]. Which include tumor necrosis factor alpha (TNFα), interleukin-17 (IL-17), and interleukin (IL-6) [3]. Biologic therapy gives patients chance to improve their life by controlling the disease. Biologic therapy includes many drugs and biosimilars of different mechanisms. However, many patients showed minimal improvement while receiving biologics [4].

The use of anti-TNF agents has been also associated with laboratory abnormalities: hematological dyscrasias such as aplastic anemia, pancytopenia, and neutropenia have been rarely described, while it is more frequent the occurrence of non-organ specific auto-antibodies. However, related clinical autoimmune syndromes are rare and mostly reversible after anti-TNF treatment withdrawal [3]. It was found that neutropenia in patients treated with disease-modifying anti-rheumatic drugs occurs more in those with previous history of neutropenia. Seventy-four percent of patients developed neutropenia within 2 weeks of the treatment while the lymphocytes, monocytes, and basophils were increased. So, complete blood picture should be monitored after 1 month and every 3 to 6 months of biologic therapy [5]. Non-biologic disease modifying anti-rheumatic drugs (DMARDs) may also cause neutropenia and thrombocytopenia need regular monitoring as well [6].

In autoimmune rheumatic diseases, inflammatory markers and white blood cell count (WBC) can be used in assessing the disease activity. Recent studies suggested that the neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and RDW may be considered as markers of autoimmune rheumatic diseases (ARDs). The inflammation in ARDs leads to changes in the count, morphology, and sizes of blood cells. The blood cells indices could reflect the severity of inflammatory response in autoimmune diseases [7]. The complete blood picture and blood cell indices are cheap and easy tests that reflect the inflammatory status and the disease activity of ankylosing spondylitis (AS). All these indices could be affected with the use of DMARDs as well as biologics as their therapeutic role is to decrease inflammatory process in rheumatic diseases [8]. To our knowledge, there is no independent comparative retrospective study of this design has been published previously.

Aim of the study

To analyze the impact of biological and non-biological treatment on hematological indices in patients with ankylosing spondylitis and psoriatic arthritis.

Patients and methods

This cross-sectional study included 120 Egyptian patients, 60 with ankylosing spondylitis diagnosed according to the Assessment of Spondyloarthritis International Society (ASAS criteria) [9] and 60 psoriatic arthritis patients fulfilled the Classification criteria for the diagnosis of Psoriatic Arthritis (CASPAR) [10].

Patients recruited randomly from the outpatient clinics of Ain Shams University hospitals over 6 months. Patients with hematologic diseases, malignancy, chronic renal or liver disease and other autoimmune diseases were excluded. The study was approved from the Ethical Committee of Scientific Research, Faculty of Medicine, Ain Shams University. An informed consent was given by all participants. Full medical history was taken and detailed drug history including drug duration and type of DMARDs received by patients. General and musculoskeletal examination and complete blood picture were done to all patients. Different blood indices were assessed including WBCs, neutrophil and lymphocyte counts, red blood cell (RBCs) count, hemoglobin(Hb), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), red cell distribution width (RDW), platelets (PLTs), mean platelet volume (MPV), and platelet distribution width (PDW). Patients were divided according to therapy received into 2 groups: group I—patients on csDMARDs and group II—patients on biologic DMARDs. Comparison between both groups was done regarding the WBCs, RBCs, and platelet indices. Then, the patients on biologic therapy subdivided to groups according to the type of biologic drug.

Statistical analysis

Collected data were tabulated and statistically analysed using the statistical package for social sciences (SPSS) version 17.0. Variables were presented as frequencies and percentages, mean ± standard deviation and range. A comparison was done using chi-square and Mann–Whitney U tests. P value 0.05 was considered significant.

Hemoglobin/platelet ratio, RDW/PLT ratio, RBCs/PLT ratio, Hb/RDW ratio, neutrophil/lymphocyte ratio, and PLR:platelet/lymphocyte ratio.

Results

The study included 120 Egyptian patients, 60 have ankylosing spondylitis (AS) and 60 have psoriatic arthritis (PSA). The PSA patients mean age was 44.7 ± 12.18 years. Twenty-two males and 38 females. The mean disease duration was 10.75 ± 6.32 years. Forty-three (71.67%) patients tested positive HLA B-27. The range and mean of blood indices, ESR, and CRP are shown in Table 1. 40 (66.67%) of these patients are on biological treatment in the form of anti-TNF, anti-TNF biosimilar, and anti-IL-17.

Table 1 Descriptive data of PsA patients
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The AS patients mean age was 39.600 ± 12.048 years. Forty-one males and 19 females. The mean disease duration was 7.250 ± 5.634 years. 37 (61.67%) patients tested positive HLA B-27. The average and mean of blood indices all shown in Table 2. 28 (46.67%) of these patients are on biological treatment in the form of anti-TNF and anti-IL-17.

Table 2 Descriptive data of AS patients
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On comparing the blood indices between the biologics and non-biologics groups of PSA patients, there was a statistically highly significant reduction in red cell distribution width (RDW%) at the biologics group than non-biologics (p < 0.006), where there was a statistically highly significant increase in Hb/RDW ratio and Hb/platelets ratio at the biologics group than non-biologics (p < 0.005). There was an increase in the hemoglobin (Hb), WBCs count (neutrophils and lymphocytes) and platelets distribution width, as well, in the biologics group than non-biologics group, however not statistically significant. There was a decrease in the RBCs, and platelets count in the biologics group than non-biologics, although not statistically significant (Table 3).

Table 3 Comparison between PSA patients with and without biologic therapy as regards WBCs, RBCs, platelets indices
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On comparing the blood indices between the biologics and non-biologics groups of AS patients, there was a statistically highly significant reduction in red cell distribution width (RDW%) at the biologics group than non-biologics (p < 0.001), where there was a statistically highly significant increase in Hb/RDW ratio at the biologics group than non-biologics (p < 0.001). There was a statistically insignificant increase in the PLT/Lymphocyte ratio, in the biologics group than non-biologics group. There was a decrease in the WBCs count (mainly lymphocytes) in the biologics group than non-biologics, although not statistically significant (Table 4).

Table 4 Comparison between AS patients with and without biologic therapy as regards WBCs, RBCs, and platelets indices
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The PSA patients on anti-IL-17 were able to significantly increase the WBCs count and MCH level compared to patients on anti-TNF and anti-TNF biosimilar respectively (p < 0.04). While patients on anti-TNF biosimilar showed statistically significant increase in RDW%/PLT ratio compared to patients on anti-IL17 and anti-TNF (p < 0.023), the treatment with anti-TNF significantly increase PLT/lymphocyte ratio in comparison to other patients on anti-IL17 and anti-TNF biosimilar (p < 0.031) Table 5.

Table 5 Comparison between different types of biologics in PsA as regards WBCs, RBCs, and platelets indices
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In comparing between different types of biologics in AS as regards WBCs, RBCs, platelets indices, it did not show significant changes as shown in Table 6.

Table 6 Comparison between different types of biologics in AS as regards WBCs, RBCs, and platelets indices
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There was a statistically significant correlation between the changes in the WBCs count mainly neutrophils and the duration of biologic therapy (p < 0.03). However negative correlation between the duration of biologic therapy and HCT, RBCs, Hb. MCV, RDW, PLT, MPV/fl, PDW, Hb/PLT ratio, RDW%/PLT ratio, RBCs/PLT ratio, Hb/RDW% ratio, neutrophil/lymphocyte ratio, PLT/lymphocyte ratio, but it was not statistically significant (Table 7).

Table 7 Correlation between the WBCs, RBCs and Platelets indices with duration of biologic therapy
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No significant correlation between the duration of biologic treatment in AS patients and the levels of blood indices as shown in Table 8.

Table 8 Correlation between the WBCs, RBCs, and Plptelets indices with duration of biologic therapy
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Discussion

Blood cell abnormalities are common in autoimmune rheumatic diseases [11]. In addition to the potentially adverse effect of the treatment therapy of inflammatory arthritis as in PSA and AS on blood counts.

White blood cells and platelets are involved in the inflammatory response in autoimmune diseases and malignancies. Neutrophils activate the antigen-presenting cells and platelets boost the leukocyte recruitment [12]. In this cross-sectional study, we performed a comprehensive analysis of different hematological indices, such as Hb/PLT ratio, RDW%/PLT ratio, RBCs/PLT ratio, Hb/RDW% ratio, neutrophil/lymphocyte ratio, and PLT/lymphocyte ratio, in 120 Egyptian patients, 60 have ankylosing spondylitis (AS) and 60 have psoriatic arthritis some receiving DMARDs and others on biologic therapy, to distinguish the different effects of biologic therapy on these indices.

Many studies suggested that treatment with biologic therapy leads to neutropenia [13,14,15]. However, in the current study, we had discovered that some TNF inhibitors studied here like Golimumab, TNF inhibitors biosimilar like Adalimumab-atto, and anti-IL-17 like Secukinumab used in treatment of PSA patients, may increase WBCs count above the non-biologics group, with no significant difference between each of them, this was in concordance with Pereckova, J et al. 2022 who reported the significant increase in the WBCs count in RA biologic group than healthy control group. A reported increase in neutrophils and lymphocytes count in the biologic group than non-biologic group although non-significant, it might reflect the role of anti-TNF in the growth of hematopoietic stem and progenitor cells and its suppression is associated with lymphoproliferative disorders and pathological abnormalities [16].

The RDW is a traditional hematologic index and used to estimate erythrocyte variability, and determine the type of anemia, it is also used as a novel index for inflammation, assessment of diseases activity and prognosis of various diseases including rheumatic diseases [17]. While the Hb/RDW ratio has a strong prognostic role in many diseases as it was mentioned that patients with a lower Hb/RDW ratio were more likely to have more comorbidities [18]. Corresponding to the data of this study, there was a significant decrease in the RDW in the biologically treated group than non- biologic treated group in PSA and AS patients as well, and this may refer to the improvement of the activity and anemia of chronic diseases this was in agreement with Moreno-Torres V et al. 2022, while the Hb/RDW ratio showed significant increase in biologic group than non-biologic group in PSA as well as AS patients, this could be attributed to the lower levels of RDW and improvement of prognosis and comorbidities associated with autoimmune rheumatic diseases [19]. However, other hematological indices did not show any significant differences between biologic and non-biologic groups in AS and PSA patients.

On comparing the effect of each biologic drug on the hematological parameters and indices, it showed no significant difference between different types of biologics in AS patients, while in PSA patients there was a significant difference in the WBCs count which showed significant increase in Secukinumab group than Adalimumab-atto and Golimumab groups, this was explained by Karataş A et al. 2022 [20] who concluded that no negative effects on hematological parameters were observed in patients with AS and PSA who received Secukinumab therapy. While the RDW/platelets ratio and platelets/lymphocytes ratio showed higher levels in Adalimumab-atto and Golimumab groups, respectively, than Secukinumab group. RDW/platelets ratio and platelets/lymphocytes are related to laboratory and clinical parameters of disease activity in rheumatic diseases. These indices may be used in identifying and following active patients. TNF-alpha is a key cytokine of the immune system that induces several chemokines, endothelial adhesion molecules (ICAM-1, VCAM-1 …), inflammatory cytokines and also enhances leukocyte recruitment and migration. Thus, it has a key role in systemic inflammation, all of these can explain the higher values of hematologic indices in anti-TNF patients [21].

An I, et al. [22] showed that the NLR was decreased in psoriatic arthritis patients treated with biologics irrespective to the type of the drug used. In our study, we observed that, unlike the above data, it showed, there was a positive correlation between WBCs/neutrophils count and the duration of biologic therapy. However, in AS patients there was no significant correlation between the duration of the biologic therapy and the hematological indices.

Limitations of this study

Retrospective design of the study, being a single-center and small sample size; with small number of patients receiving biologic therapy. All were limitations of this study.

The small presented number of patients can explain some unusual findings like the relatively higher incidence of HLAB-27 positivity in PsA than AS patients and high ESR, which is also could be explained by the co-incidence of COVID-19 infection in 2 patients (who skipped one dose of Golimumab), and a resistant urinary infection in another patient, and blood tests were taken only once from each patient.

Conclusion

Biologic drugs used in rheumatic diseases may affect the hematological parameters. In current study, no major negative effects on hematological parameters were observed in patients with AS and PsA who received Secukinumab, Adalimumab-atto, or Golimumab biologic therapy. However, the changes in the hematological indices correlate with their potent anti-inflammatory action in rheumatic patients.