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Seminars in Arthritis and Rheumatism 51 (2021) 219 229

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Seminars in Arthritis and Rheumatism

journal homepage: www.elsevier.com/locate/semarthrit

C-reactive protein and implications in rheumatoid arthritis and

associated comorbidities
Janet E. Popea, Ernest H. Choyb,*
a
Article Title
Janet E. Pope: Schulich School of Medicine, University of Western Ontario, St. Joseph’s Health Care, London, ON, Canada
b
Ernest H. Choy: Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom

Writers A B S T R A C T

C-reactive protein (CRP) is routinely assessed as a marker of systemic inflammation in rheumatoid arthritis
(RA). However, it is also an immune regulator that plays an important role in inflammatory pathways associ-
ated with RA and promotes atherogenic effects. Comorbidities linked to systemic inflammation are common
A quick summary of the article in RA, and CRP has been associated with the risk for cardiovascular disease, diabetes, metabolic syndrome,
pulmonary diseases, and depression. The relationship between systemic inflammation, CRP, and comorbid-
ities in RA is complex, and it is challenging to determine how changing CRP levels may affect the risk or pro-
gression of these comorbidities. We review the biological role of CRP in RA and its implications for disease
activity and treatment response. We also discuss the impact of treatment on CRP levels and whether reduc-
ing systemic inflammation and inhibiting CRP-mediated inflammatory pathways may have an impact on
A general Definition of the main conditions commonly comorbid with RA.
© 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
keywords in the articles (http://creativecommons.org/licenses/by-nc-nd/4.0/)
References

Introduction role in RA and its association with comorbidities has not been com-
prehensively investigated. In this narrative review, we discuss the
Rheumatoid arthritis (RA) is a chronic immune-mediated sys- role of CRP in RA, focusing on the relationship between CRP and
temic inflammatory disease characterized by chronic synovial inflam- comorbidities, and the effect of RA treatment on CRP levels and out-
mation and hyperplasia, which drive joint erosion and damage, and a comes. Articles were identified in PubMed using search terms CRP
range of systemic manifestations, which contribute to overall disease and RA together with: comorbidity, anaemia, asthma, cancer, chronic
burden [1]. This results in functional decline, disability, and reduced obstructive pulmonary disease (COPD), CVD, diabetes, interstitial
quality of life for patients with RA, particularly due to symptoms lung disease (ILD), disease-modifying anti-rheumatic drug (DMARD),
such as pain, fatigue, and morning stiffness [1 5]. Comorbidities are methotrexate, TNF inhibitor (TNFi), IL-6, JAK inhibitor, and steroids.
common in RA and require a holistic management approach, as mul- Results were limited to articles in English published in the last
tiple comorbidities are associated with poorer clinical outcomes 10 years and supplemented by inclusion of relevant citations found
[6 8]. Patients with RA have an almost 2-fold higher cardiovascular within identified articles.
(CV) risk than the general population, [9,10] and more than 50% of writes start to dig in the specific
premature deaths among RA patients are due to CV disease (CVD)
Roles of CRP in RA
definitions of the main problem
[11].
Proinflammatory pathways result in localized joint and systemic
inflammation, [1] with cytokines, such as interleukin-6 (IL-6), tumour In general, CRP plays an important role in host defence mecha-
necrosis factor-a (TNF-a), IL-1b, as well as downstream signalling nisms against infectious agents and in the inflammatory response.
pathways, eg, the Janus kinase (JAK)/signal transducers and activators [17,18] CRP binding to immunoglobulin Fc gamma receptors (Fcg R)
of transcription pathway, playing important roles [1,12,13]. One func- promotes the production of proinflammatory cytokines leading to an
tion of IL-6 is to drive production of the acute-phase reactant C-reac- amplification loop of inflammation [27 29]. It is produced predomi-
tive protein (CRP) following an inflammatory event [14 16]. While nantly by hepatocytes in response to stimulation by IL-6, [14,15] but
CRP is a key marker of systemic inflammation in RA, its overarching CRP has also been reported to be expressed by smooth muscle cells,
macrophages, endothelial cells, lymphocytes, and adipocytes (Fig. 1)
[18]. A significant correlation has been seen between serum CRP lev-
* Corresponding author. els and tissue inflammation scores from knee synovium biopsy sam-
E-mail address: [email protected] (E.H. Choy). ples in patients with RA (n = 197; p < 0.0001) [46]. Analyses of serum

https://doi.org/10.1016/j.semarthrit.2020.11.005
0049-0172/© 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
 a structure of the idea to
summarize the whole article idea
220 J.E. Pope and E.H. Choy / Seminars in Arthritis and Rheumatism 51 (2021) 219 229

Fig. 1. The biological role of C-reactive protein (CRP).

C1q, complement component 1q; CRP, C-reactive protein; eNOS, endothelial nitric oxide synthase; ICAM-1, intercellular adhesion molecule-1; IL, interleukin; LDL-C, low-den-
sity lipoprotein cholesterol; mCRP, monomeric CRP; MCP-1, monocyte chemoattractant protein-1; NO, nitric oxide; pCRP, pentameric CRP; RANKL, receptor activator of nuclear fac-
tor-kB ligand; ROS, reactive oxygen species; TNF, tumour necrosis factor; VCAM-1, vascular cellular adhesion molecule-1.

and synovial fluid CRP in patients with RA have shown that CRP levels used for evaluation of conditions potentially associated with inflam-
closely correlate with IL-6 levels [19 23]. mation in otherwise healthy individuals [33].
CRP is an immune regulator not just a marker of inflammation CRP levels are often persistently elevated in patients with RA, with
or infection [17,18]. There has been controversy over the direct role levels of >20 mg/L frequently reported at baseline in randomized
of CRP in inflammation and infection, but the identification of CRP clinical trials (RCTs) of drugs to treat RA [35]. However, retrospective
isoforms with different biological properties provided a potential and observational real-world studies show that many patients have
explanation for conflicting observations [24]. CRP is synthesized in normal CRP levels despite exhibiting RA disease activity, [36,37] sug-
hepatocytes and secreted into the circulation as pentameric CRP gesting that CRP levels reflect only one of the signs of disease activity
(pCRP), also known as native CRP. pCRP is thought to act as an and should be assessed in the context of other measures. Addition-
immune regulator [25]. When bound to cell membranes or lipo- ally, multiple factors influence baseline serum CRP levels in patients
somes, pCRP can irreversibly dissociate via a conformationally with RA. Single nucleotide polymorphisms in CRP and their haplo-
changed intermediate into monomeric CRP (mCRP), which is a types have been associated with higher or lower CRP levels, [38 40]
proinflammatory isoform able to activate platelets, leucocytes, although no association was found in a prospective observational
and endothelial cells as well as bind complement component 1q study of a patient population with much higher average baseline CRP
to activate complement [18,25,26]. mCRP has limited solubility levels (34 mg/L) [41]. Body fat, female hormone levels, dietary qual-
compared with pCRP and is considered to be tissue bound, ity, and stress have also been shown to influence CRP levels in
although transmission via microparticles and ligand complexes patients with RA [42 45]. As pharmacological treatments for RA
has been postulated [25]. Depending on its structural form, CRP reduce systemic inflammation, CRP levels generally decrease with
interacts with a variety of leucocytes and endothelial cells, stimu- treatment, to differing degrees depending on the drug class and
lating proinflammatory cytokine release, including IL-6, IL-1b, mechanism of action.
and TNF-a, upregulating adhesion molecules, increasing mono-
cyte chemoattractant protein-1 release to recruit monocytes, Biological effects of CRP in RA
inhibiting nitric oxide production, and activating platelets,
thereby inducing proinflammatory and atherogenic effects (Fig. 1) There is growing preclinical evidence that CRP may play a direct
[18,24,26 30]. Reference to CRP hereafter signifies circulating role in bone destruction in RA. Bone destruction is initiated via induc-
CRP without distinction between isoform unless specified. tion of receptor activator of nuclear factor-kB ligand (RANKL) expres-
sion, which stimulates osteoclastogenesis, resulting in bone-
Circulating CRP levels resorption. CRP induces RANKL expression in peripheral blood mono-
Sub-titles cytes and stimulates osteoclast differentiation in the absence of
In healthy adults, plasma CRP concentration is usually <10 mg/L, RANKL [20]. However, the effects of CRP on osteoclast differentiation
although there is considerable inter-individual variability [17,31,32]. might depend on CRP isoform. mCRP has been shown to inhibit
CRP levels >10 mg/L are generally considered elevated, although the RANKL-induced osteoclast differentiation in vitro, by neutralizing
normal reference range can differ between assays [33]. Obesity is RANKL, potentially exerting a protective effect [47,48]. Additionally,
associated with elevated CRP levels. [34] Serum CRP levels can be patients with RA who have a monocyte imbalance (M1/M2 ratio >1)
tested using standard or high-sensitivity (hsCRP) assays; hsCRP is exhibit significantly higher levels of CRP than those with M1/M2 ratio
 J.E. Pope and E.H. Choy / Seminars in Arthritis and Rheumatism 51 (2021) 219 229 221

1 (4.5 versus 0.8 mg/L; p = 0.032) and greater in vitro osteoclasto- DAS28-CRP may underestimate residual disease activity [187,189].
genesis [49]. More research is needed to fully elucidate the role of Consequently, new disease activity thresholds for DAS28-CRP of
CRP in bone destruction. >4.6, <2.9, and <2.5 have been proposed. [187,189] Additionally,
there may be challenges in assessing remission with DAS28-CRP
CRP as a marker of RA disease activity when patients are treated with IL-6 inhibitors and other drugs that
directly affect levels of CRP, as a reduction in CRP may not reflect a
Higher CRP levels are associated with greater RA disease activity decrease in disease activity. Thus, a more stringent threshold for
based on the core components of the 28-joint Disease Activity Score DAS28-CRP remission of <1.9 has been proposed [190]. Moreover,
(DAS28) [50,51]. Individual aspects of disease activity, such as swol- many patients with active RA may not have an elevated CRP and this
len joint count, and patient-reported measures, including functional is a common reason for screen failures in RA treatment trials
status (Health Assessment Questionnaire score), morning stiffness, [36,191].
fatigue, and pain, have also been associated with CRP [52 56].
Indeed, CRP levels are widely used for monitoring systemic inflam- Association of CRP with comorbidities in RA
mation and disease activity in RA. CRP level is a component of several
composite disease activity measures: DAS28-CRP, SDAI, and Ameri- There is a high prevalence of comorbidities in patients with RA,
can College of Rheumatology (ACR) and European League Against the most common of which include CVD, metabolic syndrome, diabe-
Rheumatism (EULAR) definitions of remission. [57 59] Yet, the use- tes, pulmonary diseases, and depression [6]. While the biological
fulness of CRP testing as a routine measure of RA disease activity is relationships between CRP levels and comorbidities in RA have not
not universal due to the substantial proportion of treated patients been fully established, elevated CRP levels have been shown to be
who experience flares in their RA but still have normal CRP levels. In associated with an increased risk for several common comorbidities
fact, as RA clinical trials often specify elevated CRP (for example (Fig. 2). Understanding these associations is important from a clinical
6 mg/L) [60] as an eligibility criterion, patients with active RA but perspective to help in the identification of patients at risk for comor-
without elevated inflammatory markers are commonly excluded. bidities, especially those that may be associated with an increased
Along with disease activity, CRP is known to be associated with risk for mortality.
radiological damage in RA. Numerous studies in patients with early
RA have shown that elevated CRP levels both at baseline and using Cardiovascular comorbidities
time-integrated measures correlate with rapid radiological progres-
sion and joint damage within 1 year. [61 66] Elevated baseline CRP Data from large observational cohorts have shown that RA is asso-
levels are also a more general predictive factor for radiographic pro- ciated with an up to 2-fold increased CV risk compared with the gen-
gression and joint destruction in patients with early, moderate and eral population, [9,10,69,70] including reported increased risks of
severe RA [64,67,68]. However, a CRP threshold level that could be myocardial infarction (MI; 33 96%), [70 72] heart failure (61 87%),
used as a marker for radiographic progression has not been estab- [70,72] stroke (24 29%), [71] and major adverse CV events (MACE;
lished. 30 58%), [71,73] along with a 50% higher incidence of CV-related
As noted above, CRP is a standard component of many RA com- mortality, [71,74] independent of traditional CV risk factors. In a
posite disease activity measures (DAS28-CRP, SDAI, ACR/EULAR meta-analysis, the relative risk for patients with RA to develop CVD
remission) [57 59]. ACR and EULAR recommend DAS28 using either was age dependent, with higher CV risk seen in patients aged <50
CRP or erythrocyte sedimentation rate (ESR) without differentiating than 50 65 or >65 years (risk ratio (RR) 2.59, 1.86, and 1.27 versus
between them in terms of disease activity thresholds [57]. However, the general population). [75] Moreover, there is evidence from epide-
there is evidence that DAS28-CRP scores are consistently lower than miological studies of a strong association between CRP and IL-6 levels
DAS28-ESR values [187 189]. Given disease activity thresholds (high and CV risk. [76 79] In the general population, CRP is considered an
>5.1, low disease activity [LDA] <3.2, and remission <2.6) were origi- independent predictor of CV risk, [80,81] with a 58% increased risk
nally validated using DAS28-ESR, using the same thresholds for for coronary heart disease with CRP levels >3.0 versus <1.0 mg/L

figures to Simplify ideas

Fig. 2. The interplay of C-reactive protein (CRP) and common comorbidities in RA.
CHF, chronic heart failure; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; HBV, hepatitis B; HCV, hepatitis C;
ILD, interstitial lung disease; MACE, major adverse cardiovascular event; MI, myocardial infarction; RA, rheumatoid arthritis.
222 J.E. Pope and E.H. Choy / Seminars in Arthritis and Rheumatism 51 (2021) 219 229

[80]. CRP is also a predictor of CV risk in RA. Large observational [122 124] and tocilizumab does not appear to significantly affect
cohort studies have reported associations between elevated CRP lev- body mass index, waist circumference, or atherogenic index
els in RA and a more atherogenic lipid profile and hyperlipidaemia, [118,125]. so the overall impact of RA treatments on metabolic syn-
[83,84] an increased risk for MI (hazard ratio [HR] 2.12, 95% CI drome is, as yet, not firmly established.
1.02 4.38 for CRP >10 versus <1 mg/L), [85] heart failure (HR 1.25,
95% CI 1.06 1.48 per 100 mg/L increase in CRP), [86] stroke (HR 2.02,
Diabetes
95% CI 1.32 3.08 for CRP >21.7 mg/L versus <2.6 mg/L), [87] and CV-
related death (14% increase for each mg/L and HR of 3.3 [95% CI
Patients with RA are up to twice as likely to be diagnosed with
1.4 7.6] for CRP 5 mg/L) [88,89]. Higher CRP levels also increase risk
diabetes mellitus (DM) than are the general population, [126 128]
for atherosclerosis and increase subclinical atherosclerosis as measured
and the prevalence of DM in RA is about 13 20%. [6,126,129] Higher
by carotid intima media thickness in patients with RA [90 94].
CRP levels have been seen in RA patients with type 2 diabetes
Systemic inflammation is a key driver of atherosclerosis. Specifi-
(T2DM) compared with those without [126]. High CRP levels in RA
cally, CRP has been shown to have a direct biological role in the
have also been correlated with impaired glucose tolerance and
development and progression of atherosclerosis and thrombosis [82].
metabolism and to insulin resistance, [130] and are significantly asso-
CRP increases during the progression of atherosclerosis and can acti-
ciated with small increased likelihood of impaired fasting glucose (OR
vate the complement system, inducing apoptosis, and contributes to
1.02, 95% CI 1.001 1.034, p = 0.02) [128]. Significant positive associa-
endothelial dysfunction by inhibiting nitric oxide and upregulating
tions between the homeostatic model assessment of insulin resis-
endothelial cell adhesion molecules. It also promotes monocyte
tance and CRP and IL-6 levels have also been seen in patients with
recruitment into atherosclerotic plaques and increases the inflamma-
RA. [111,113,114] However, as for metabolic syndrome in RA, no
tory response by inducing leucocyte adhesion and migration and
direct biological link between CRP levels and diabetes in patients
generation of reactive oxygen species (Fig. 1). CRP also contributes to
with RA has yet been established.
plaque instability by inducing metalloproteinase expression and pro-
There is evidence that treatment with DMARDs may reduce the
motes thrombus growth via induction of platelet activation.
risk for T2DM, [131 133] and reduce glycosylated haemoglobin lev-
A reduction in disease activity in RA has been shown to be associ-
els (HbA1c) [134] in patients with RA. In the CORRONA registry, treat-
ated with a reduction in CV risk in numerous studies. Indeed, data
ment with TNFis significantly reduced the risk for T2DM (OR 0.35,
from the longitudinal CORRONA registry demonstrated that a 10-
95% CI 0.13 0.91, p = 0.03), while other bDMARDs (OR 0.44, 95% CI
point reduction in time-averaged CDAI was associated with a 21%
0.08 2.57, p = 0.36), methotrexate (OR 0.67, 95% CI 0.44 1.02,
decrease in CV risk [95]. In a meta-analysis of clinical studies, metho-
p = 0.34), and hydroxychloroquine (OR 0.45, 95% CI 0.13 1.53,
trexate and TNFis each appeared to reduce the CV risk by approxi-
p = 0.21) numerically reduced the risk for T2DM versus patients
mately 30% (RR 0.72, 95% CI 0.57 0.91, p = 0.007 and RR 0.70, 95% CI
treated with other csDMARDs [133]. In contrast, the risk for T2DM
0.54 0.90, p = 0.005, respectively) [96]. Abatacept showed a modest
escalates with increasing doses of glucocorticoids (HR 2.33, 95% CI
reduction in risk for a composite CV endpoint compared with TNFis
1.68 3.22, p = 0.02 for patients using 7.5 mg glucocorticoid versus
in a large population-based RA cohort (HR 0.86, 95% CI 0.73 1.01)
no glucocorticoid) [133]. In a retrospective analysis in Japan, HbA1c
[97]. Despite the known effect of IL-6 inhibitors for increasing lipid
levels significantly decreased after 3 months of treatment with either
levels, [98] in the randomized, open-label ENTRACTE trial, the esti-
TNFis or tocilizumab (p < 0.001 for both treatments) in patients with
mated risk for MACE was similar between tocilizumab (an IL-6R
RA, including in the subgroup of patients with DM. In this analysis,
inhibitor) and etanercept (HR 1.05, 95% CI 0.77 1.43) [99]. Likewise,
tocilizumab was associated with greater reductions in HbA1c levels
an integrated safety analysis of clinical trials of the IL-6R inhibitor,
than were TNFis (OR 5.59, 95% CI 2.56 12.2, p < 0.001) [134]. In a
sarilumab, reported exposure-adjusted incidence rates of MACE of
post-hoc analysis of sarilumab phase III trials, patients with RA and
0.2 0.5/100 patient-years, comparable to the incidence in the gen-
diabetes had greater improvements in HbA1c with sarilumab 200 mg
eral RA population (1.2/100 patient-years) [100]. Pooled safety analy-
every 2 weeks (q2w) than with adalimumab 40 mg q2w
ses for JAK inhibitors report similar incidence rates of MACE for
( 0.43 versus 0.02 at 24 weeks) or placebo ( 0.60, 0.33, and 0.18
tofacitinib of 0.4/100 patient-years and baricitinib (4 mg) of 0.8/
at 24 weeks for sarilumab 200 mg, 150 mg, and placebo q2w, respec-
100 patient-years. [101,102] Further research is needed to determine
tively) [135]. Given the prevalence of DM in RA, the decrease in risk
whether the biological link between elevated CRP in RA and in CVD
for T2DM and improvements in HbA1c levels with different DMARD
and the reduction in CRP levels during treatment for RA contributes
treatments should be considered when personalizing RA treatment.
to the reduction in CV risk reported in these studies.

Metabolic syndrome Pulmonary disease

The prevalence of metabolic syndrome appears to be greater in RA is associated with a 70 100% increased risk for COPD com-
patients with RA than the general population, with rates of 30 40% pared with controls, [136 139] and the prevalence of COPD among
reported compared with about 20% in controls [103 107]. Higher RA patients is about 4 8%. [6,137,138] COPD has been shown to
CRP levels have been associated with increased prevalence of meta- increase the risk for mortality almost 3-fold in patients with RA.
bolic syndrome in RA, [107,108] greater abdominal adiposity, [109] [140,141] High CRP levels have been associated with increased risk
decreased insulin sensitivity, [110 114] and increased lipid levels for COPD, [142] and higher CRP levels are seen in patients with stable
[83]. However, two North American cross-sectional cohort studies COPD than controls [143,144]. As COPD exacerbations are often
did not find a significant association between CRP and metabolic syn- caused by infections, the finding that CRP levels are significantly
drome in patients with RA (odds ratio [OR] about 1 in both studies). higher in patients with acutely exacerbated versus stable COPD
[103,106] CRP levels have been associated with lipid abnormalities, (p < 0.05) is not surprising [144]. In the USA NHANES survey, ele-
[77,115] negatively correlating with high-density lipoprotein choles- vated CRP (>10 mg/L) was associated with increased risk for mortal-
terol (HDL-C) [116]. However, a direct biological link between CRP ity (HR 4.45, 95% CI 1.91 10.37) in patients with COPD, [145] and a
levels and metabolic syndrome in RA has yet to be established. separate analysis showed that CRP 3 mg/L was associated with
Conventional synthetic DMARDs (csDMARDs), targeted synthetic increased mortality (HR 1.61, 95% CI 1.12 2.30) [146]. CRP levels
DMARDs (tsDMARDs), and bDMARDs all increase lipid levels, 3 mg/L in stable COPD are associated with poor predicted forced
[117 121] but TNFis improve insulin resistance and sensitivity, vital capacity and patient-reported health status [147,148].
 J.E. Pope and E.H. Choy / Seminars in Arthritis and Rheumatism 51 (2021) 219 229 223

Data on the effects of RA treatments on COPD are limited, but due adjusted OR 0.80, 95% CI 0.64 0.98) [176]. Etanercept has also shown
to more frequent respiratory adverse events seen among patients small but significant effects (7 28%) in reducing depression scores
with COPD in the ASSURE trial, the risk for COPD exacerbations with compared with methotrexate in patients with RA [177]. Analyses of
abatacept has recently been described [149]. In retrospective popula- patient-reported outcomes in phase III trials in RA showed improved
tion-based cohort studies of patients with RA and COPD, abatacept Mental Health and Role Emotional domain scores of Short Form 36
was not associated with significantly increased risk for COPD exacer- with sarilumab, tocilizumab, and tofacitinib [178 180]. Further, in
bation or respiratory adverse events compared with csDMARDs, an interim analysis of the ARATA study of tocilizumab treatment in
tsDMARDs, TNFis, or other bDMARDs [150,151]. Data from RCTs for routine practice, tocilizumab improved depressive symptoms over
patients with RA and comorbid COPD would be valuable to further 2 years, [181] and in the ACT-AXIS prospective observational study,
investigate the effects of DMARD treatment to determine whether tocilizumab significantly decreased depression score (p < 0.005).
reducing the generally higher CRP levels seen in patients with RA [182] Given the complex interplay of depression with RA disease
may impact positively their COPD. activity, inflammation, and RA symptoms, poorer RA treatment out-
The lifetime risk for patients with RA developing ILD has been come may be influenced, at least in part, by presence of depressive
reported at 6 15%, compared with 1% for the general population symptoms [183].
[152,153]. ILD may occur before the development of articular mani-
festations in RA [152,154,155]. A population-based study in Denmark Clinical implications of CRP in the management of patients with
found that 14% of ILD cases in patients with RA were diagnosed RA
1 5 years before RA diagnosis, and 34% within 1 year prior to and 1
year after RA diagnosis [155]. Pulmonary abnormalities compatible Circulating CRP level is routinely tested, as it is an inexpensive and
with ILD were present in 21/36 patients (58%) with recent onset RA readily available biomarker to assess systemic inflammation and clin-
(duration of joint symptoms <2 years) who were referred to a uni- ical outcomes in RA. CRP levels can be assessed via standard or hsCRP
versity rheumatology department [156]. The main risk factors for assays, with values <10 mg/L and <1 mg/L, respectively, generally
developing RA-ILD are smoking, older age, male sex, rheumatoid fac- considered normal, although thresholds may differ between assays
tor, and anti-cyclic citrullinated peptide antibody levels [154,157]. Of [33,184]. In RA, given the generally elevated levels of CRP due to sys-
the RA-ILD subtypes, usual interstitial pneumonia (UIP) is generally temic inflammation, the hsCRP assay is typically considered unneces-
the most common, followed by non-specific interstitial pneumonia sary. There are limitations of conventional CRP testing: for the
(NSIP) [157,158]. RA-ILD is associated with poor prognosis, with haz- substantial proportion of patients who have normal CRP levels while
ard rate ratios for death 2 10 times higher in RA-ILD than in RA exhibiting RA disease activity or flare, [36,37] a low CRP level may
without ILD [155]. Patients with a UIP histological pattern have the provide false reassurance of reduced inflammation. Additionally,
worst prognosis, with mortality rates similar to those observed while CRP is a marker of systemic inflammation, it is not useful as an
among patients with idiopathic pulmonary fibrosis [159 162]. independent factor for predicting the risk for developing RA,
It is uncertain if high CRP is related to progression of ILD in RA. [185,186] and it does not confirm a diagnosis of RA. In the context of
Although higher CRP levels in patients with RA-ILD versus RA with- comorbidities in RA, a specific CRP level/threshold is not a predictor
out ILD have been observed in several retrospective studies in Asia, for any particular comorbidity.
[163 165] this pattern was not seen in an Italian retrospective study
[166]. Additionally, the association of high CRP levels with risk for Screening for CV risk factors in patients with RA
ILD was not significant in a multivariate analysis in Chinese patients,
suggesting that CRP level may not be an independent risk factor for Given the increased morbidity and mortality associated with CVD
ILD [163]. in RA compared with the age- and gender-matched population, CV
risk should be assessed for all patients [192]. General CV risk calcula-
Depression tors, such as SCORE and the Framingham risk score, may underesti-
mate the CV risk in RA, and RA-specific calculators like EULAR
Depression is highly prevalent in patients with RA, with a multiplier and expanded CV risk prediction score (ERS-RA) do not
reported prevalence of 15 40%, and it is more common in patients appear to perform better than the general risk calculators [193,194].
with RA than in the general population [6,167]. Elevated CRP, TNF-a, The Reynolds risk score is the only measure that includes CRP, and it
and IL-6 levels have been noted in some studies in RA patients with may be sensitive to the fluctuating inflammation seen in patients
depression [168,169]. Elevated CRP has been associated with higher with RA [195]. The addition of CRP to the Framingham risk score and
depression scores in patients with RA [170 172]. However, the asso- QRISK algorithms was not associated with significant improvement
ciation between systemic inflammation and depressive symptoms is in reclassification of CV risk [196]. There is controversy about which
complicated by factors such as pain and disease activity, which may risk calculator to use as the rates of CV events in people with RA are
attenuate the link between CRP and depression [170 172]. decreasing, but so are those of the matched population, so a gap still
The relationship between depression and treatment response in exists with more CV events in RA [197,198].
RA appears to be bidirectional. In the CARDERA RCT in patients with
early RA who received methotrexate or methotrexate plus predniso- Effects of treatment for RA on CRP levels
lone and/or cyclosporine, patients reporting persistent depression/
anxiety were significantly less likely (62 90%; p < 0.05) to achieve Treatment of RA with DMARDs aims to reduce systemic inflam-
clinical remission (DAS28 <2.6) over 2 years [173]. In a large UK mation and improve disease activity. As a measure of systemic
observational study, depressive symptoms at baseline did not predict inflammation it would be expected that CRP levels will fall in
non-response to methotrexate after 6 months of treatment [174]. response to treatment and indeed this is observed during treatment
Additionally, compared with RA patients without depressive symp- with the different DMARD classes as shown in Supplementary Table
toms, patients with depressive symptoms at bDMARD initiation were 1. Corticosteroids and csDMARDs lead to small decreases in CRP lev-
20 40% less likely to achieve a EULAR good treatment response after els [60,199 205]. TNFis decrease CRP levels, generally slightly more
1 year [175]. Conversely, in a USA retrospective observational study, than csDMARDs in equivalent patient populations [41,206 209]. JAK
patients with RA but no depressive symptoms at baseline who inhibitors that target downstream signalling pathways of IL-6 and
responded to TNFi treatment were 20% less likely to develop depres- other cytokines decrease CRP levels by about 10 mg/L, with the
sion than were non-responders (7.1% versus 9.4%; p < 0.005; reduction tending to be dose dependent [205,209 211]. Overall, the
224 J.E. Pope and E.H. Choy / Seminars in Arthritis and Rheumatism 51 (2021) 219 229

most rapid, largest, and sustained decreases in CRP levels occur in CRP levels resulting from DMARD treatment and the impact on
response to treatment with IL-6R inhibitors, generally resulting in comorbidities.
normalization of CRP levels [60,200,201,207,212,213]. Given the pre- In conclusion, CRP is a valuable marker and regulator of systemic
dominant role of IL-6 in stimulating CRP production, these results are inflammation in RA that also appears to play a direct role in bone
not surprising. destruction and radiographic progression. CRP has also been impli-
Consistent with the decreases in CRP levels resulting from IL-6 cated in the aetiology of common comorbidities associated with RA.
inhibition, improvements in clinical outcome measures that include Reducing CRP levels with RA treatment may contribute to reductions
CRP have been reported. Indeed, clinical trials have demonstrated in disease activity, although beneficial effects of RA treatment seem
that treatment with sarilumab (MOBILITY, MONARCH, and TARGET) to occur irrespective of CRP values.
results in improvements in DAS28-CRP scores (up to 2.8-point
decreases) and higher rates of DAS28-CRP LDA and remission (using Contributions
standard thresholds of 3.2 [33 49%] and <2.6 [25 34%]) and of
ACR20/50/70 response [61 72%/40 46%/16 25%] compared with The authors contributed equally to researching data for the article,
placebo or, in MONARCH, with adalimumab [60,200,206]. Similar substantial discussion of content and writing, reviewing and editing
levels of efficacy have been seen with tocilizumab in the BREVACTA the manuscript before submission.
and SUMMACTA studies [204,214]. Higher rates of SDAI remission
with tocilizumab than with TNFi treatment have also been seen in a Declaration of Competing Interest
real-world observational study (SDAI 3.3 32% versus 22%, p < 0.05
at Week 52) [207]. The JAK inhibitor upadacitinib demonstrated J.P. reports Grant/research support from AbbVie, BMS, Merck,
superiority to adalimumab for DAS28-CRP LDA and remission in a Pfizer, Roche, UCB, and Seattle Genetics; Consultant for AbbVie,
phase III trial of patients with RA and an inadequate response to Amgen, Boehringer Ingelheim, BMS, Gilead, Janssen, Lilly, Medexus,
methotrexate [215]. Importantly, RA drugs that influence CRP levels Merck, Novartis, Pfizer, Roche, Sanofi, Sandoz, Teva, and UCB.
have also been shown to improve RA disease activity using scores E.C. reports Grant/research support from Amgen, Bio-Cancer, Chu-
that do not include a CRP component, indicating their effects on dis- gai Pharma, Ferring Pharmaceuticals, Novimmune, Pfizer, Roche, and
ease activity in RA extend beyond those driven by systemic inflam- UCB; Consultant for AbbVie, Amgen, AstraZeneca, Biogen, Boehringer
mation. For example, in the most recent sarilumab phase III trial Ingelheim, Bristol-Myers Squibb, Celgene, Chelsea Therapeutics, Chu-
(MONARCH), the primary efficacy endpoint was change in DAS28- gai Pharma, Daiichi Sankyo, Eli Lilly, Ferring Pharmaceuticals, Gilead,
ESR at 24 weeks, and sarilumab produced significantly greater GlaxoSmithKline, Hospira, Ionis, Janssen, Jazz Pharmaceuticals, MedI-
improvement than adalimumab ( 3.28 versus 2.20, respectively; mmune, Merck Sharp & Dohme, Merrimack Pharmaceutical, Napp,
p < 0.0001) [206]. Novartis, Novimmune, ObsEva, Pfizer, R-Pharm, Regeneron Pharma-
Subgroup analyses of IL-6R inhibitor RCTs are suggestive of how ceuticals, Inc., Roche, SynAct Pharma, Sanofi Genzyme, Tonix, and
clinical outcomes may be associated with CRP. Evaluation of baseline UCB; member of speakers bureau for Amgen, Boehringer Ingelheim,
CRP subgroups in MOBILITY and MONARCH showed that the treat- Bristol-Myers Squibb, Chugai Pharma, Eli Lilly, Hospira, Merck Sharp
ment effect of sarilumab was greater in the group with baseline CRP & Dohme, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche,
>15 mg/L both for radiographic progression (mean modified total Sanofi-Aventis, and UCB.
Sharp score change at Week 52, sarilumab 0.90 1.00 versus placebo
4.25) [216] and for greater improvement versus adalimumab even Role of the funding source
when using the DAS28-ESR score [217]. In MOBILITY, patients receiv-
ing sarilumab who achieved DAS28-CRP <3.2 versus those who did The authors received no payment or other compensation for
not exhibited a slightly greater percentage decrease from baseline in developing this paper. Medical writing support, under the sole direc-
CRP after 24 weeks ( 97% versus 90%, nominal p < 0.01) [218]. Sim- tion of the authors, was provided by Gregory Bezkorovainy (Adelphi
ilar trends were seen in TARGET for ACR50 responders versus non- Communications, Ltd, Macclesfield, UK) and was funded by Sanofi
responders [201]. However, despite the link between IL-6 inhibition Genzyme, Cambridge MA in accordance with Good Publications Prac-
and CRP levels, CRP does not appear to be a consistent predictive bio- tices (GPP3).
marker for response to tocilizumab treatment. An analysis of BRE-
VACTA and SUMMACTA demonstrated that baseline CRP levels were Supplementary materials
not predictive of clinical outcomes after tocilizumab treatment [213].
In contrast, the RADIATE study demonstrated that tocilizumab treat- Supplementary material associated with this article can be found,
ment led to a significant decrease in a matrix metalloproteinases- in the online version, at doi:10.1016/j.semarthrit.2020.11.005.
degraded fragment of CRP, reducing tissue inflammation, with the
decrease correlating with improvements in pain, functional status, References
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