Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that primarily affects the lining of the synovial joints and is associated with progressive disability, premature death, and socioeconomic burdens.1 RA affects 0.5–1% of adult population. The disease affects women three times more than men.2 RA diagnostic criteria and regular follow up are mainly based on clinical manifestations, laboratory tests, and imaging studies. Laboratory tests include autoantibodies and inflammatory markers; such as anti-cyclic citrullinated peptide antibodies (ACPAs), rheumatoid factor (RF), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and others.3

Hemogram parameters have been recently proposed as markers of inflammation in various studies from different parts of the world. Beside their importance in homeostasis, authors have implied them to reflect the inflammatory burden. Two of these hemogram parameters are red cell distribution width (RDW) and mean platelet volume (MPV).4

RDW is a parameter included in the hemogram with automatic analyzers that reflects the variation in the volume and size of RBCs. Many reports suggest that RDW may be indicative of a person's underlying general health status, and more specifically may reflect the degree of inflammation an individual may possess. The different factors that might increase the heterogeneity in size, such as the red blood cell circulation half-life and membrane deformability, can be influenced by inflammation too.5 Any process that releases reticulocytes in the circulation will result in an increase in RDW.6 RDW has also been linked to single and multiple organ dysfunction reflecting the degree of anisocytosis in many disorders such as cardiac disease, venous thromboembolism, malignancy, diabetes mellitus, pulmonary disease, liver and kidney failure. Also, RDW is thought as an independent risk factor for mortality. However, in RA we do not know if an increased value of RDW is a risk factor or should only be considered an epiphenomenon of an underlying biological and metabolic imbalance involving both impaired erythropoiesis and abnormal red blood cell survival.7–11 Hence, it could be increased in autoimmune diseases and was found in some studies related to disease activity or its complications. It is now reasonable to suggest RDW as a potential biomarker similar to C-reactive protein (CPR) or erythrocyte sedimentation rate (ESR).12

MPV reflects the rate of platelet production in the bone marrow and the platelet size in circulation, and it may be used as an indicator of platelet activation and the severity of inflammation. MPV has been studied as an indicator of disease activity in various inflammatory conditions.13 Platelet receptors such as CD40, GPIb/IX/V, and selectins have all been implicated in perpetuation of atherosclerosis, rheumatoid arthritis (RA), and tumors.14 In autoimmune diseases such as systemic lupus erythematosus (SLE), immune complexes activate platelets by interacting with Fc receptors; in RA, the platelet is a well-known source of prostaglandins within the inflamed synovium. IL-1-containing platelet-derived vesicles are abundant in synovial fluid and stimulate synovial fibroblast to produce inflammatory mediators. Moreover, serotonin released by platelets enhances vascular permeability within the inflamed synovium.15

The association of RDW and MPV with clinical disease activity indices of RA has not yet been established. Literatures are full of data about the association of inflammation with RDW and also MPV. Although they are both inexpensive and easy to use, clinical usefulness of these parameters is still controversial and results of different studies about MPV levels in various inflammatory diseases are incompatible.4,16 So, the present study aimed to indicate RDW and MPV levels in RA patients, and to study their association with the clinical disease activity indices.

RA is an autoimmune chronic disease which is usually accompanied with anemia, which may increase RDW.19 However, RDW was significantly higher in non-anemic RA patients. This suggests that RDW may also be affected by inflammation, not only anemia. MPV has also been studied as a marker of disease activity in various inflammatory conditions.13

In this study, we investigated the association between RDW and disease activity in 60 patients with RA. In our study, RDW values positively correlated with DAS28, ESR and CRP. These findings were in agreement with Tecer et al.16 who also found significant correlation between RDW and DAS28. Also, in agreement with Lippi et al.,20 in a large cohort study in 2009, who demonstrated a strong and graded association of RDW with CRP and ESR. In 2010 these findings were confirmed by another cohort study by Lee and Kim.21 Our results were also similar to Calabria et al.22 who found direct association between RDW and CRP, ESR and DAS28. These findings also agree with a more recent study by Hassan et al.,23 who found a significant correlation between RDW and disease activity markers suggesting the usefulness of using RDW to reflect disease activity.

On the other hand, in this study we found no significant correlation between MPV and any of disease activity markers (DAS28, ESR or CRP). These findings agree with the findings of Tecer et al.16 and Moghimi et al.24 Also, these findings agree with a more recent study of Hassan et al.,22 revealing the non-usefulness of MPV as disease activity marker. In contrast to our findings Yazici et al.25 found significant correlation between MPV and ESR, CRP and DAS28. This discrepancy may be due to difference in number of sample size used in both studies.

We found that AUC of RDW, specifically sensitivity and specificity was better than ESR and CRP to assess disease activity. As consistent with our results, Song et al. found that the diagnostic accuracy of RDW was superior to the CRP and ESR levels.26 Although, Tecer et al.16 found that AUC of RDW, namely sensitivity and specificity, was similar to ESR, but better than CRP to indicate of disease activity. We also found that AUC of MPV was less than ESR and CRP and these findings disagree with Tecer et al.16 in which AUC of MPV similar to ESR and CRP.

In our work, we further studied the influence of various comorbidities and the use of different medications on both RDW and MPV. RDW has long been used to differentiate the etiology of anemia, and it is easy to measure and cost-effective.27 In our studied RA patients, we found that anemia of chronic disease and iron deficiency anemia, but not megaloblastic anemia, significantly influenced RDW. Whilst, it did not significantly influence MPV. It is well known that anemia of chronic disease correlates with disease activity, and also more use of NSAIDS due to disease activity may be related to more iron deficiency anemia, so to consider the influence of anemia part of the theories by which RDW may be influenced in RA patients make us not looking it as a confounding point against its use to monitor disease activity, whether influenced directly by inflammation or indirectly by anemia as a complication of activity. The fact that inflammation prevents erythrocyte maturation by inhibiting iron metabolism and the response to erythropoietin, supports the indirect role of anemia leading to an increase in RDW during inflammation.27

RDW is increased in various liver diseases, including hepatitis, alcoholic liver cirrhosis, biliary cirrhosis, and liver cancer.28–30 Hepatic dysfunction in our patients was associated with increased RDW. However, other comorbidities discussed in our study like diabetes did not significantly affect neither RDW nor MPV. Although in another study, RDW was significantly and positively associated with HbA1c, corresponding an increase in HbA1c of 0.10% per 1 SD increase in RDW.31 According to our results, the use of different medications did not significantly influence RDW, nor did it affect MPV in this studied population. Although methotrexate is well known to affect folic acid metabolism, in our studied sample methotrexate did not influence RDW nor did megaloblastic anemia. None of our patients received biological therapy, but in some studies Anti-TNFa therapy resulted in a significant increase in MPV over the duration of the study.32

The main limitation in our work was being a single-center study, further larger multi-centered studies may be more beneficial. Moreover, prospective studies may be required to test its sensitivity to change over the time. We also recommend that RDW should be tested more widely in other rheumatologic diseases such as systemic lupus and systemic sclerosis to depict its value being a marker of single and multiple organ failure.

We finally conclude that RDW was strongly correlated with disease activity and was superior to ESR and CRP in detecting RA disease activity. According to these findings we suggest that RDW can be used in clinics as a disease activity marker. Whether replacing or in conjugation with other acute phase reactants is still controversial due to the presence of other factors influencing RDW like anemia and liver disease. In addition, RDW is widely available as it is usually included in routine complete blood picture and there will be no need for further cost. Unfortunately, MPV was not found to be a promising marker of activity in our study.

No funds, No grants.

None to declare.