Clinical indices and laboratory markers for evaluating the immune-mediated inflammation in rheumatoid arthritis: the impact of COVID-19

Relevance

Rheumatoid arthritis (RA) is an immune-inflammatory (autoimmune) rheumatic disease of unknown etiology, characterized by chronic erosive arthritis and systemic damage to internal organs, leading to disability, development of severe comorbid pathology and, as a consequence, a reduction in the life expectancy of patients [1]. The average prevalence of RA in developed countries, according to the latest data, ranges from 0.5% to 1.0%, with significant variability depending on the socio-demographic and ethnic characteristics of the population studied, as well as the availability of medical resources. The age-standardized incidence of RA in the world is also heterogeneous, from 3.92 per 100,000 in Oceania to 21.46 per 100,000 in North America [2]. According to a Russian epidemiological study, RA affects about 0.6% of the general population. RA causes persistent disability in half of the patients during the first 3-5 years from the onset of the disease [3]. Modern tactics for managing patients with RA include careful control (treat-to-target strategy) of inflammation. Its main goal is to achieve remission or low disease activity. In patients in remission (or having low activity), the functional status, ability to work, and prognosis of the disease are better than in patients who have moderate or high disease activity [4].

Requirements and the evolution of the activity indices

Modern clinical practice, as well as the process of testing innovative drugs for the treatment of rheumatoid arthritis, cannot be imagined without generally accepted methods for assessing its activity. Relatively recently, formal activity criteria did not exist, and each clinician used what he considered necessary in the assessment. Thus, in 1980-1983, a study of RA activity criteria used by clinicians was conducted in the UK, the presentation of the results of which began with "... We know little about what disease activity criteria for RA are actually used by practicing rheumatologists, and what contribution each of them makes to the clinician's assessment of the course of the disease." The surveyed rheumatologists not only based their activity assessment on different sets of clinical (in particular, morning stiffness, subjective assessment of pain and activity, presence of extra-articular manifestations, side effects from therapy, functional class, joint index, grip strength), laboratory (erythrocyte sedimentation rate (ESR), rheumatoid factor (RF) level, C-reactive protein (CRP), immunoglobulins) and imaging (erosion characteristics) criteria, but also ranked their contribution to the overall activity value differently. [5]. Obviously, with this approach, both a one-time assessment of activity and an assessment of the dynamics of RA activity in the same patient by different rheumatologists may differ significantly. 

At the same time, the USSR already had a working classification of RA, adopted in October 1980. Domestic specialists used approaches adopted for systemic lupus erythematosus and acute rheumatic fever to determine RA activity. Within the framework of this classification, RA activity was assessed based on the values of three clinical signs (duration of morning stiffness, severity of hyperthermia and exudative changes in the joints) and three laboratory parameters (proportion of α₂-globulins, ESR in mm/h, and CRP (capillary precipitation test)), with the resulting point assessment corresponding to certain degrees (from “0” (absence) to “III” (maximum)) of disease activity [6]. 

In 1993, the American College of Rheumatology proposed a set of key criteria to be included in the design of clinical trials of RA treatments (including nonpharmacologic ones), citing the "...confounding heterogeneity of end points assessed in clinical trials." The proposed list included clinical (number of swollen and tender joints, known as ACR 66/68, based on the number of joints assessed; pain score; patient assessment of disease activity and functional status; physician assessment of activity), laboratory (ESR or CRP), and, in some cases, instrumental criteria. [7] However, the issue of threshold values that would allow one to judge the need for clinical decisions regarding a particular patient and his or her disease activity remained unresolved.

Over time, calculated activity indices have been proposed that allow rapid and, importantly, uniform assessment by all practicing rheumatologists of the current activity of RA and the effectiveness of its treatment. One of the first was the Disease Activity Score (DAS) [8], which used the Ritchie index, the number of swollen joints (NSJ), the patient's overall activity assessment (PAA), and ESR.

As for the joint score, a number of joint indices were proposed in the 20th century, both weighted (by the area of ​​the joints being assessed) and not. In 1957, Lansbury J. [9] proposed assessing the total area of the involved joints (based on the known value of the total area of ​​the joints – 1000 cm²). The index [10] developed in 1968 by Ritchie D.M. et al. included an assessment of 78 joints divided into 53 joint zones. The metacarpophalangeal, proximal interphalangeal, and metatarsophalangeal joints were allocated to separate groups, which were assessed by one, the most painful joint in the corresponding group. Each joint (or group of joints) received from 0 to 3 points depending on the severity of pain in it. The need for a point assessment of pain introduced significant variability into the results of examination of the same patient by different rheumatologists. In 1986, Hart L.E. et al. [11] proposed to evaluate the same groups of joints without using pain gradations. Analyzing the joint indices that existed at that time, Thompson P.W. et al. [12] in 1987 proposed their own version using 38 joints and assigning each its own “weight” corresponding to the area of the affected joint. Thus, the knee joint corresponded to 95 points, and the metatarsophalangeal joint corresponded to only 3. An alternative evaluation method was the above-mentioned ACR 66/68 score. In 1993, Prevoo M.L. et al. [13] in a prospective study assessed the validity and reliability of the joint counting methods used at that time and concluded that there was no significant advantage of any of them. Given the ease of measurement and comparable reliability, preference was given to the 28-joint score, which was used in all subsequent clinical indices of RA activity.

Despite the diversity of the proposed indices and differences in the methods of their calculation, each of them is based on the same clinical (number of painful joints (NPJ), PAA, GAP) and laboratory (ESR or CRP) indicators. Based on DAS, a version was developed using a 28-joint count – DAS28-ESR (DAS28-ESR = 0.56 * √ NPJ + 0.28 * √NPJ + 0.70 * lnESR + 0.014 * PAA) [14], as well as using CRP instead of ESR – DAS28-CRP (DAS28-CRP = 0.56 * √ NPJ + 0.28 * √ NPJ + 0.36 * ln(CRP+1) + 0.014 * PAA) [15]. Calculation of DAS varieties required mathematical transformations, the manual implementation of which during a rheumatologist's appointment presented certain difficulties, due to which foreign authors proposed the Simplified Disease Activity Index (SDAI) (SDAI = NSJ + NPJ + CRP + PAA + GAP) [16] and the Clinical Disease Activity Index (CDAI) (CDAI = NPJ + NPS + PAA + GAP) [17], which are distinguished by their simplicity of calculation. In 2005, Balabanova RM and Olyunin YuA [18] proposed using a simplified inflammatory activity index (SIA) RA = 10NSJ + PAA + ESR.

Rheumatoid arthritis disease activity indices in modern clinical practice

Clinical guidelines currently recommend the use of the DAS28-ESR scale to assess RA activity [19]. It includes the number of painful joints, the number of swollen joints, the ESR value determined by Westergren in mm/h, and the overall assessment of the patient's activity determined by a visual analog scale.

Once calculated, the DAS28 activity index value is the basis for judging the disease activity at a specific point in time. The dynamics of activity indices (primarily DAS28) during therapy are used to assess the effectiveness of therapy and make a decision on its continuation or further intensification.

Regarding RA remission, clinical guidelines suggest using the following definition: CRP, NPJ, CRP (in mg/dL), PAA should be equal to 1 or less. This definition, called the Boolean criteria, was given in 2011 jointly by the American College of Rheumatology and the European League Against Rheumatism [20]. It is noteworthy that in 2022, the authors propose a slightly different approach, with less stringent requirements for PAA, since this definition is more consistent with remission according to DAS28 [21].

The assessment of RA activity and remission, regardless of the scale used, is based on the same parameters — the number of painful and swollen joints, the ESR or CRP value, and the subjective assessment of activity by the patient or physician using a visual analogue scale. Each component of the activity indices used in modern clinical practice may be a source of inaccuracy. In particular, because it is difficult for the patient to differentiate between RA itself and accompanying fibromyalgia, the values of NPS and PAA may be overestimated; the concomitant inflammatory phenotype of osteoarthritis may affect the assessment of NPS and NPJ; ESR and CRP are not specific markers for RA; in addition, the degree of their decrease during therapy with some drugs – interleukin-6 (IL-6) inhibitors, tumor necrosis factor-alpha (TNF-α) inhibitors, and JAK kinase inhibitors – may not correspond to the degree of clinical improvement. [22] Finally, the quality of the assessment of clinical manifestations and the subjective assessment of activity depends to a certain extent on the qualifications of the specialist conducting such an assessment [23].

Multiparametric activity indices

In the search for an objective quantitative method for measuring the activity of rheumatoid arthritis, multiparametric indices using exclusively laboratory parameters were developed. Thus, in 2013, a study was published [24], which selected 12 biomarkers (CRP, interleukin-6, TNF receptor type 1, epidermal growth factor, vascular endothelial growth factor (VEGF), vascular endothelial adhesion molecule type 1, cartilage glycoprotein-39, matrix metalloproteinases 1 and 3, serum amyloid protein A, leptin and resistin), determined in blood serum using commercially available kits, and proposed the Multibiomarker Disease Activity (MBDA) index, calculated on their basis. According to the meta-analysis data [25], MBDA values can be used to assess RA activity and predict the radiographic progression of RA. However, it is not currently used in widespread clinical practice. Researchers from the V.A. Nasonova Research Institute of Rheumatology proposed another set of biomarkers: fibroblast growth factor 2 (FGF2), monocyte chemoattractant protein 1 (MCP1), IL-1β, IL-6, IL-15, TNF-α [26]. The introduction of multiparametric indices into routine clinical practice, based on biomarkers involved in the main links of RA pathogenesis, could serve as a valuable addition to the currently used clinical and laboratory activity indices.

Laboratory tests as an auxiliary method of activity evaluation

Routinely determined parameters of the general blood test are not components of the validated clinical indices of RA activity. Despite this, they can serve not only to monitor the safety of therapy but also for additional assessment of activity by the clinician. Thus, anemia due to chronic inflammation is the most common extra-articular manifestation of rheumatoid arthritis. Proinflammatory cytokines involved in the pathogenesis of RA are also involved in the development of anemia in RA by changing iron metabolism and suppressing erythropoiesis [27]. Anemic syndrome is associated with a more severe course of RA [28]. In addition, anemia can serve as a predictor of radiographic progression, including in patients in whom the calculated DAS28 value corresponds to remission [29]. An increase in the red blood cell distribution width (RDW), determined automatically by hematology analyzers, also correlates with elevated CRP and ESR levels in the general population [30], but in patients with RA, the predictive value of RDW in relation to other indicators of RA activity is low [31, 32].

A potential marker of inflammation in RA may be a change in the neutrophil-to-lymphocyte ratio (NLR). According to meta-analyses, an increase in this indicator positively correlates with RA activity [33, 34]. A study on the Russian population found a statistically significant correlation between NLR and NSJ, CRP, ESR and DAS28-ESR. According to the same study, the NLR value of 2.1 has an acceptable specificity (77%) with respect to an increase in CRP with absolute ease of calculation [35]. An increase in the platelet-to-lymphocyte ratio (PLR) may also be of interest to the clinician. The above-mentioned meta-analyses [33, 34] confirmed an increase in this ratio in RA. In addition, a reliable difference in the NLR value was revealed between patients with remission and those with active RA [36, 37]. NLR may also be a potentially valuable marker for identifying interstitial lung disease in RA [37].

The influence of COVID-19 on the evaluation of rheumatoid arthritis activity

Considering the COVID-19 pandemic, the clinical challenge is to differentiate the manifestations of RA activity directly from the variety of symptoms caused by SARS-Cov-2 infection. In 45% of individuals who have had COVID-19, symptoms persist for 4 months or more (so-called long-COVID, or post-COVID-19 syndrome) [38]. A number of patients with COVID-19 experience long-term clinical manifestations as well as instrumental, laboratory, and immunological disorders, which are characteristic of immune-inflammatory rheumatic diseases [39, 40], particularly RA. In addition, the risk of developing RA also increases after a new coronavirus infection, which has been shown in several large cohorts of patients [41, 42].

The clinical manifestations most commonly encountered in post-COVID-19 syndrome are arthralgia, fatigue, and muscle weakness [43, 44, 45]. The severity of these manifestations in a patient with RA will directly affect the patient's assessment of the overall disease activity and the NSJ, which are components of all RA activity indices used in routine practice, as well as RA remission criteria.

 A significant increase in acute-phase non-specific markers of systemic inflammation (ESR and CRP), which are included in the RA activity indices, also in some cases do not allow a clear distinction between the presence of an active immune-inflammatory process in RA and post-COVID-19 syndrome. According to a meta-analysis [46], the degree of increase in ESR correlates with the severity of acute coronavirus infection. In patients with post-COVID-19 syndrome, according to a systematic review, ESR values are also significantly elevated for a long time, compared with the control group (healthy patients) [38]. An increase (more than 10 mg/l) in CRP levels serves as an unfavorable prognostic criterion in the acute stage of COVID-19 [47]. A systematic review also proved a long-term increase in CRP concentration in patients with post-COVID-19 syndrome compared with the control group (healthy patients) and completely recovered patients [38]. CRP levels gradually decrease over the course of a year after COVID-19 infection, but generally do not return to reference values ​​[48].

The previously discussed general blood test parameters, which are potentially informative for the clinician in the context of RA activity, undergo changes similar to RA during the acute phase of COVID-19 and in post-COVID-19 syndrome. Thus, according to a meta-analysis, in severe cases of the new coronavirus infection, the level of erythrocytes and hemoglobin decreases, and RDW increases [49]. As for RDW, its higher values are associated with the severity of COVID-19 infection and mortality from it [50]. The previously mentioned systematic review showed a decrease in hemoglobin levels in patients with post-COVID syndrome compared with the control group (healthy patients) and patients who recovered from acute infection [38]. Neutrophilia, lymphopenia and increased neutrophil-lymphocyte ratio (NLR) are associated with a more severe course of coronavirus infection [47, 51, 52]. The applicability of NLR as a marker of post-COVID syndrome remains to be determined; according to a systematic review, increased lymphocyte levels are observed in post-COVID-19 syndrome [53].

Multiparametric indices of rheumatoid arthritis activity are also likely to be affected by the post-COVID-19 syndrome. Currently, there are no data on the experience of using such indices in patients with RA and post-COVID-19 syndrome, as well as the dynamics of changes in the values of these indices in patients who have completely recovered from the acute phase of the new coronavirus infection or have post-COVID-19 syndrome. However, according to a systematic review, post-COVID-19 syndrome is associated with an increase in the concentration of CRP, TNF, IL-6, and VEGF in the blood serum [38], which are components of existing multiparametric indices. In the absence of studies, it is reasonable to assume that the values of these indices may increase in patients with RA and post-COVID-19 syndrome.

Discussions 

The problem of early diagnosis and prognosis of the development of immune-inflammatory rheumatic diseases (IIRD) after COVID-19 infection, rheumatological symptoms of post-COVID-19 syndrome and differential diagnosis between them remains one of the central problems in modern rheumatology and has general medical significance [40]. Currently, clinicians do not have reliable methods for differentiating between the activity of RA itself and the manifestations of post-COVID-19 syndrome. This is largely due to the similarity of the pathogenetic mechanisms of immune-inflammatory rheumatic diseases, in particular RA, and the new coronavirus infection [40]. The question of the need for such differentiation also remains controversial; perhaps the dynamics of joint and laboratory manifestations of RA in post-COVID-19 syndrome is part of a common pathogenetic continuum for them?

In IIRD, post-Covid-19 syndrome introduces additional theoretical and clinical questions into such fundamental concepts in rheumatology that have been widely discussed previously in RA [54], such as the definition of "remission", its characteristics and types, biomarkers of efficacy, and resistance to therapy. Because most immunological laboratory tests have insufficient specificity, the appointment and evaluation of laboratory test results should be performed in strict accordance with the suspected diagnosis and data from a thorough clinical examination of patients. The degree of severity (exceeding the upper or lower value) of the deviation of each indicator from the reference values should also be considered. Unification of the studies conducted between laboratories plays an important role. The correct interpretation of the data obtained largely depends on the knowledge of doctors, a detailed and comprehensive assessment of the clinical picture, collection of anamnesis, knowledge of the possibilities of modern laboratory diagnostics and joint work with specialists in this field.

Conclusion

The new coronavirus infection COVID-19 has similar pathogenetic mechanisms with immune-inflammatory rheumatic diseases, and its clinical and laboratory consequences in the form of post-COVID-19 syndrome make it difficult to assess RA activity using existing activity indices, which raises the question of the need to take them into account when assessing the effectiveness and choosing treatment tactics for a patient with RA. Further prospective studies in this area are needed.