CAM 205

General Inflammation Testing

Category:Laboratory   Last Reviewed:January 2020
Department(s):Medical Affairs   Next Review:July 2020
Original Date:November 2018    

Description 
Inflammatory response can occur due to tissue injury and/or various disorders, including arthritis, lupus, and infection. Acute phase reactants, such as serum C-reactive protein (CRP), are released in the acute phase response during inflammation and can be used to monitor inflammation. Inflammation can also be measured using the simple laboratory technique of erythrocyte sedimentation rate (ESR) (Kushner, 2017).  

Conditions Associated with Acute Inflammatory Responses
Diseases most associated with an acute inflammatory response measured by CRP and/or ESR include arthritis, especially rheumatoid arthritis (RA), polymyalgia rheumatica (PMR), giant cell arteritis (GCA), systemic lupus erythematosus (SLE), cardiovascular disease (CVD) (Kushner, 2017), and Hodgkin lymphoma (HL) (NCCN, 2018b). RA is an idiopathic, systemic polyarthritis that can lead to joint loss, as well as tendon and ligament deformation to the point of affecting day-to-day living. RA is suspected in patients who present inflammatory polyarthritis and is typically diagnosed via rheumatoid factor (RF) testing, anti-cyclic citrullinated peptide antibody (anti-CCP) testing, ESR, and/or CRP testing, as well as imaging techniques (Venables & Maini, 2017).

PMR "is an inflammatory rheumatic condition characterized clinically by aching and morning stiffness about the shoulders, hip girdle, and neck (Docken, 2017)." PMR is frequently associated with GCA (also known as Horton disease), which is vasculitis of medium-to-large blood vessels and can include the aorta and cranial arteries. Cranial arteritis can lead to permanent vision loss. Forty-50% of patients with GCA also suffer from PMR, whereas 15% of all PMR patients are also diagnosed with GCA. Due to the inflammation of the aorta and aortic branches, aortic aneurysm and aortic dissection can occur in patients with GCA (Docken & Rosenbaum, 2017). In both PMR and GCA, ESR and CRP levels are typically elevated. SLE "is a complex autoimmune disease with a chronic relapsing-remitting course and variable manifestations leading a spectrum from mild mucocutaneous to devastating, life-threatening illness. ... Epigenetic modifications mediate the effect of the environment on immunologic responses, eventually leading to an inflammatory, autoimmune, multi-systemic disease characterized by autoantibody production and tissue injury (Gergianaki & Bertsias, 2018)." Since patients with SLE can be prone to infection, ESR and CRP may be used in monitoring inflammation. CVD is a very common inflammatory disorder in the United States. Although serum CRP is a non-specific inflammatory marker and is not a causative agent of CVD, serum CRP can be used as a biomarker for CVD (Black, Kushner, & Samols, 2004; Kushner, 2017). Hodgkin lymphoma accounts for 10% of lymphomas and is characterized as a B-cell lymphoma "containing a minority of neoplastic cells (Reed-Sternberg cells and their variants) in an inflammatory background (Aster & Pozdnyakova, 2018)." ESR is elevated in HL, and an ESR ≥50 is considered as an "early-stage unfavorable factor" (NCCN, 2018b).

Erythrocyte Sedimentation Rate (ESR)
Erythrocyte sedimentation rate (ESR) is a common laboratory method used to monitor general inflammation. ESR is used to analyze many different conditions, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), arteritis, and polymyalgia rheumatica (PMR) (Kushner, 2017; Wu et al., 2010). The simple Westergren method of ESR consists of measuring the distance a blood sample travels in a tube within one hour. The International Council for Standardization in Hematology (ICSH) established a calibration reference to this method using citrate-diluted samples. Automated ESR methods have been established; however, some of these analyzers use different dilution solutions, such as EDTA, rather than citrate. EDTA is commonly used as an anticoagulant in hematology measurements, whereas the use of citrate is less prevalent. Horsti et al. compared blood samples from 200 patients using the traditional Westergren method versus an EDTA-based method. Their data has an R2 value of only 0.72, and 55 subjects had a difference of over 30%, clearly indicating that ESR is significantly affected by sample preparation methods (Horsti, Rontu, & Collings, 2010). ESR can also be affected by red blood cell morphology, ambient conditions (such as high room temperature or tilting of the ESR tube), anemia, renal disease, obesity, heart failure, and hypofibrinogenemia (Kushner, 2017; Taylor & Maini, 2017).

The ICSH established a Working Group to investigate the ESR methodology used in laboratories, and it published its findings in 2017. It examined the data from over 6,000 laboratories on four different continents. Of the laboratories included in the study, only 28% used the "gold standard" Westergren method exclusively (i.e., the method with the established validation by the ICSH), "while 72% of sites used modified or alternate methods." The data obtained from the new methodologies could deviate from the Westergren method by up to 142% and could differ "from each other by up to 42%." The ICSH released recommendations based up the results of these studies. One such recommendation for labs using the non-Westergren method of ESR is to "consider adding an interpretative comment to every result stating that. ‘This result was obtained with an ESR instrument that is not based on the standard Westergren method. The sensitivity and specificity of this method for various disease states may be different from the standard Westergren method’ " (Kratz et al., 2017).

C-reactive Protein (CRP)
C-reactive protein (CRP) was first discovered in the early 20th century when it was isolated in a co-precipitation reaction with the pneumococcal C polysaccharide. The polysaccharide component bound by CRP later was identified to be phosphocholine. Since then, studies have shown that CRP can bind a number of ligands other than bacterial cell wall components. During an acute inflammatory response, hepatocytes can upregulate CRP synthesis more than 1,000-fold. The increase in serum CRP "after tissue injury or infection suggests that it  contributes to host defense and that it is part of the innate immune response" (Black et al., 2004). Determining CRP concentration and fluctuations in plasma CRP can be useful in monitoring inflammatory response; however, what dictates "normal" CRP levels is of debate, since CRP concentrations can vary considerably between individuals, groups, and laboratory testing methodology. The units used to denote CRP concentrations also vary between laboratories (Kushner, 2017).

Clinical Validity and Utility of CRP and ESR in Measuring Inflammatory Processes
Both CRP and ESR have been used to monitor RA. Elevated CRP and ESR does correlate to observed radiologic damage in RA. Unlike ESR, CRP can be evaluated on stored serum, which could be advantageous due to the time constraints of ESR testing (Taylor & Maini, 2017). A 2009 study by Crowson et al. shows that the use of both ESR and CRP testing in the case of RA is not warranted. They examined the data from three randomized trials of 1,247 RA patients. "Where available, the CRP alone may be preferred for disease activity assessment as a simple, validated, reproducible, non age-dependent test" (Crowson, Rahman, & Matteson, 2009). Since both ESR and CRP have been incorporated into composite scoring for RA, the elimination of one or the other will not hinder the quantitative evaluation of the patient using a composite scoring system such as DAS (Disease Activity Score) or SDAI (Simplified Disease Activity Index). A 2015 Danish study clearly shows that the data obtained in DAS using either ESR or CRP "are interchangeable when assessing RA patients and the two versions of DAS28 are comparable" (Nielung et al., 2015). This study compared the baseline data and one-year follow-up of 109 different patients with RA using the DAS28-ESR and DAS28-CRP. Using the EULAR (European League Against Rheumatism response criteria, only 14 patients show a divergence using the ESR and CRP methods. Of those 14, "12 showed a better response (in terms of responder category) using DAS28-CRP, while two patients showed a better response using DAS28-ESR." However, a 2006 study by Fransen and van Riel shows that it is still possible for a patient to have a high number of swollen joints and yet receive a low DAS28-ESR score within the remission range, due to a low ESR value, since ESR has a significant weight on the DAS28-ESR algorithm (Fransen & van Riel, 2006). This study did not include CRP measurements to compare its validity to that of the DAS28-ESR. Another study released in 2010 (Hensor, Emery, Bingham, & Conaghan, 2010) shows that the DAS28-CRP could also underestimate RA remission rates, since those values are usually lower than the corresponding DAS28-ESR values, but the discrepancy is not significant if age and gender are added as factors into the DAS28-CRP methodology. To confound issues, "newer biologic agents that target specific inflammatory cytokines are differentially reflected in the ESR and CRP and may, therefore, disproportionately deflate the composite score (Anderson et al., 2012)."

ESR cannot be used to predict RA as a screening method. Suarez-Almazor and colleagues investigated the predictive value of ESR for connective tissue diseases (CTD) and RA. Their review of 711 records by more than 300 different primary care physicians in Alberta shows that ESR positively predicted 35% for CTD and only 17% for cases of RA. For SLE, the positive predictive value for ESR was even lower at only 3%. They did not include CRP testing in this study. The authors note that "most tests were negative, and were often requested in patients without CTD, resulting in low positive predictive values and questionable clinical utility" (Suarez-Almazor et al., 1998). A study by Keenan and colleagues (Keenan, Swearingen, & Yazici, 2008) compared the utilization of ESR and CRP in RA, SLE, and osteoarthritis. Their data show that for the 188 patients with RA, the number of patients with both ESR and CRP elevated were statistically the same as those with normal test levels or those with only one test elevated. They concluded "that another look at the role of ESR and CRP as markers of inflammation in RA patients seen in routine care may be in order (Keenan et al., 2008)."

Bitik and colleagues researched the use of elevated ESR and CRP levels in distinguishing the definitive diagnosis of a rheumatic disorder from patients with nonspecific inflammation. In their study of 112 patients, 47 had a previously diagnosed rheumatic disorder and 65 had no history of a rheumatism. Of the 65 patients with no history of a rheumatic disorder, 52.3% were diagnosed with a new rheumatic disorder, with PMR/GCA comprising 38.2%, while 47.7% had a non-rheumatic diagnosis. Within this latter group, only the "CRP levels were significantly higher in infections when compared with new onset RD or malignancies (p < 0.05) (Bitik et al., 2015)." The ESR levels among the three groups were statistically insignificant. This indicates that CRP is more sensitive to acute infections than ESR. The authors state that "although ESR and CRP levels have a very low specificity in differentiating between these conditions, in cases of unusually high levels of CRP (especially aove 200), more consideration should be given to infections or malignancies."

A 2014 study of 60 different PMR patients compared the efficacy of ESR and CRP in assessing disease activity versus patient-reported outcomes and plasma fibrinogen. In this study, the VASDA (visual analog scale disease activity) and VASQOL (VAS quality of life), two patient-reported outcome methods, were the most responsive to changes in disease activity. Of the serum biomarkers -- fibrinogen, ESR, and CRP -- fibrinogen was the most accurate, with a correlation coefficient of 1.63, whereas 1.2 and 1.05 were the correlation coefficients of ESR and CRP, respectively. These data suggest that plasma fibrinogen would be a more sensitive measure of PMR disease activity, compared to either ESR or CRP (McCarthy et al., 2014).

A two-year retrospective study released in 2010 (Ernst, Weiss, Tracy, & Weiss, 2010) researched the validity of using either ESR and/or CRP in assessing septic joints. This study consisted of 163 patients and included both genders, as well as patients with alcohol or drug histories. The mean ESR value for the 119 control non-septic joints was 46, while the septic joint mean ESR value was 56, which was not significant (with a P > 0.05); however, the mean CRP value was 14 in the septic joints and 8 in the non-septic joints (P < 0.01, significant). The conclusion of the authors is: "CRP is helpful in determining the presence of a septic joint; ESR is not (Ernst et al., 2010)."

ESR is used in determining the algorithm to follow in the treatment of Hodgkin lymphoma (CHL). For example, in stage 1A CHL, a patient with an ESR <50 would follow either the NCCN HODG-3 or HODG-4 algorithm with an initial 2-3 cycles of ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine), most likely, whereas a stage 1A patient with an ESR >50 would follow the NCCN HODG-6 algorithm with a possible involved-site radiation therapy (ISRT) initially, along with the chemotherapy, since an ESR >50 is considered an "unfavorable factor" (NCCN, 2018b).

CRP elevation is associated with a number of inflammatory disorders (including RA), tissue damage (such as after a myocardial infarction), as well as bacterial infections; however, CRP levels in SLE do not mirror disease progression (Kushner, 2017). Even during cases of severe disease phenotypes, CRP levels can be normal to modestly increased. One possible reason is CRP suppression by type I interferons, which are increased in SLE. Another possibility is that low concentrations of wild-type CRP play a role in lupus. "Three lines of investigation have raised the possibility that low plasma levels of CRP may be related to the pathogenesis of SLE: 1) an association between SLE and several CRP genetic polymorphisms, at least one of which is associated with low CRP levels, 2) the possibility that low CRP levels may contribute to defective clearance of autoantigens during apoptosis, and 3) the therapeutic efficacy of CRP in mouse models of SLE (Gaitonde, Samols, & Kushner, 2008)." Also, CRP and anti-CRP may form large complexes in patients with SLE, which could also decrease the serum concentrations of free CRP (Gordon et al., 2018). A study by O’Neill and colleagues in 2010 shows that anti-CRP levels are directly proportional in an increase to disease activity (32.6, 24.8, and 16.8 AU, respectively, for high activity, low activity, and control groups) and that anti-CRP levels were above the upper limit of normal in 26.3% of the high activity cases, versus only 12.8% for the low activity cases (O'Neill et al., 2010). Patients with SLE usually have elevated ESR, but this elevation may be due to persistent polyclonal hypergammaglobulinemia (Gordon et al., 2018).

Regulatory Status 
Testing of serum acute phase reactants and ESR is performed in laboratories meeting Clinical Laboratory Improvement Act (CLIA) quality standards. The FDA has approved multiple tests for human CRP, including assays for conventional CRP, high sensitivity CRP (hsCRP), and cardiac CRP (cCRP). On September 22, 2005, the FDA issued guidelines concerning the assessment of CRP (FDA, 2005). A search of the FDA Medical Devices database (FDA, 2018) on June 12, 2018, shows that the FDA has approved ESR systems from multiple companies, including the ESR Control-M Hematology Erythrocyte Sedimentation system (K972172) and the ESR Control-HC Hematology Erythrocyte Sedimentation system (K972170) by R & D Systems, the Seditainer Erythrocyte Sedimentation Rate System (K953994) from Becton Dickinson Vacutainer Systems, the Westergren Dispette for ESR (K831195) by Ulster Scientific, and the Dade ESR Kit (K823368) from American Dade.

Policy  

  1. Measurement of erythrocyte sedimentation rate (ESR) for patients with Hodgkin Lymphoma is considered MEDICALLY NECESSARY.
  2. Measurement of either C-Reactive Protein (CRP) or ESR in the diagnosis, assessment and monitoring of inflammatory disorders, and/or undiagnosed conditions, and/or to detect acute phase inflammation is considered MEDICALLY NECESSARY.
  3. Conurrent measurement of CRP and ESR is consiered MEDICALLY NECESSARY in the diagnosis of periprosthetic joint infections (PJI).
  4. For any condition other than PJI, measurement of both CRP and ESR, at the same visit, in the diagnosis, assessment and monitoring of inflammatory disorders, and/or undiagnosed conditions, and/or to detect acute phase inflammation is considered NOT MEDICALLY NECESSARY
  5. Measurement of either CRP and/or ESR during general exam without abnormal findings is considered NOT MEDICALLY NECESSARY.  

Rationale  

1. 2018 World Health Organization (WHO) (Ghebreyesus, 2018)

On May 16, 2018, the WHO released its first edition of the Model List of Essential In Vitro Diagnostics (EDL), to advance universal health coverage, address health emergencies, and promote healthier populations. This list of in vitro diagnostics (IVD) is to be used as a reference of the essential diagnostic tools for laboratories to complement its Model List of Essential Medicines. With respect to the diagnostic tool, to detect inflammation as an indicator of various conditions, the WHO recommends CRP either in an EIA (enzyme immunoassay) or RDT (rapid diagnostic test) assay format. The specimen type can be venous whole blood, serum, or plasma.  

2. 2018 National Comprehensive Cancer Network (NCCN) 

The 2018 NCCN guidelines concerning Hodgkin Lymphoma (NCCN, 2018b) use ESR as a diagnostic tool in characterizing the type of Classic Hodgkin Lymphoma (CHL) as well as the primary treatment of the disease. In the diagnosis/workup of Hodgkin Lymphoma in adults (age 18 years) (recommendation 2A), it lists erythrocyte sedimentation rate (ESR) as "essential" and says that ESR should be tested within 6 months of diagnosis; in fact, ESR is used extensively in the treatment algorithm for CHL, as depicted in the table below (NCCN, 2018b).  

Treatment Algorithms For Classic Hodgkin Lymphoma (CHL) 

Clinical Stage Bulky Disease (mediastinal or peripheral) Number of Nodal Sites¹ Erythrocyte Sedimentation Rate (ESR) Guidelines Page
IA No 1 <50 HODG-3 or HODG-4
IA No 1 >50 HODG-6
IB No 1 Any HODG-6
IIA, no extralymphatic (E) lesions No <3 <50 HODG-3 or HODG-4
IIA ± extralymphatic (E) lesions No <4 <50 HODG-4
  No ≥4 or ±50 HODG-4 or HODG-6
  Yes Any Any HODG-7
IIB-IIB ± extralymphatic (E) lesionsk No Any Any HODG-6
  Yes Any Any HODG-7
III-IV Yes/No Any Any HODG-10

In the guidelines concerning follow-up after completion of treatment (recommendation 2A), it lists under laboratory studies "ESR (if elevated at time of initial diagnosis)" up to five years. ESR is also used in determining the dosage of involved-site radiation therapy (ISRT). "A dose of 20 Gy following ABVD X 2 is sufficient if the patient has non-bulky stage I-IIA disease with an ESR <50, no extralymphatic lesions, and only one or two lymph node regions involved." An ESR ≥50 is considered as an "early-stage unfavorable factor." Please note that the NCCN guidelines concerning Hodgkin lymphoma do not contain any information concerning the use of CRP as a diagnostic or prognostic tool (NCCN, 2018b).

In the NCCN guidelines concerning the B-cell lymphomas under the section concerning Castleman’s Disease (NCCN, 2018a), the NCCN recommends (category 2A) as "essential" laboratory tests "LDH, CRP, [and] ESR." Within the discussion of the text, it does not mention if all three are required or if only a minimum of one of the three tests is essential in the workup. The guidelines for B-cell lymphomas do not list either CRP or ESR for follow-up testing post-treatment.

In the NCCN guidelines concerning the T-cell lymphomas, they state that the "evaluation of serological markers such as rheumatoid factor (RF), antinuclear antibodies (ANA), and erythrocyte sedimentation rate (ESR) are useful in patients with autoimmune disease" (NCCN, 2018c). [Please note that the Avalon policy AHS-G2022 covers ANA testing.] The guidelines concerning T-cell lymphomas do not mention the diagnostic or prognostic use of CRP.   

3. 2015 American Society for Clinical Pathology (ASCP) (Pathology, 2015)

In the Choosing Wisely site of the ABIM Foundation, the ASCP released the recommendation to not "order an erythrocyte sedimentation rate (ESR) to look for inflammation in patients with undiagnosed conditions. Order a C-reactive protein (CRP) to detect acute phase inflammation" due to the sensitivity and specificity of CRP for acute phase of inflammation. "In the first 24 hours of a disease process, the CRP will be elevated, while the ESR may be normal. If the source of inflammation is removed, the CRP will return to normal within a day or so, while the ESR will remain elevated for several days until excess fibrinogen is removed from the serum."   

4. 2009-2018 European League Against Rheumatism (EULAR) (Colebatch et al., 2013; Combe et al., 2017; Dejaco et al., 2018; Dejaco et al., 2015; Mukhtyar et al., 2009) 

In 2009, EULAR issued its recommendations concerning the management of large vessel vasculitis. With a "Level of Evidence 3, Strength of recommendation C," it recommended "monitoring of therapy for large vessel vasculitis should be clinical and supported by measurement of inflammatory markers. ... For patients with giant cell arteritis, a relapse is usually associated with a rise in ESR and CRP" (Mukhtyar et al., 2009). In this paper, there is no mention of the frequency of ESR and/or CRP testing.

In 2013, in EULAR recommendations for the use of imaging of the joints in the clinical management of rheumatoid arthritis (Colebatch et al., 2013), it states that "baseline inflammatory disease measured by scintigraphy appears to be associated with radiographic progression. In addition, multiple regression analysis has demonstrated that progression of radiographic joint destruction was primarily predicted by 99mTc-IgG scintigraphy; joint swelling, ESR and IgM RF (Rheumatoid Factor) were not predictive. This suggests that scintigraphy may be superior to conventional clinical and laboratory measurements in the prediction of joint destruction." This set of guidelines did not include any mention concerning CRP or the frequency of ESR testing.

In 2015, EULAR and the American College of Rheumatology (ACR) issued joint recommendations concerning the management of polymyalgia rheumatica (PMR) (Dejaco et al., 2015). Within their recommendations, they list assessments that "every case of PMR should have …p rior to the prescription of therapy (primary or secondary care)." They include a basic laboratory workup "to exclude mimicking conditions and establish a baseline for monitoring of therapy," and they state that this includes "rheumatoid factor and/or anti-cyclic citrullinated peptide antibodies (ACPA), C-reactive protein and/or erythrocyte sedimentation rate (ESR), blood count, glucose, creatinine, liver function tests, bone profile (including calcium, alkaline phosphatase) and dipstick urinalysis." They do not state a specific preference of either CRP or ESR, nor do they state the frequency of testing.   

EULAR in 2016 updated its 2007 recommendations concerning the management of early arthritis (Combe et al., 2017). The 2016 updates included the following recommendation: "Monitoring of disease activity should include tender and swollen joint counts, patient and physician global assessments, ESR and CRP, usually by applying a composite measure. Arthritis activity should be assessed at 1-month to 3-month intervals until the treatment target has been reached." The recommendation concerning including both ESR and CRP did not change between the 2016 and 2007 recommendations. Within the discussion of the recommendations, it states, "In every patient with active arthritis, closely monitoring disease activity is now considered of particular importance in the therapeutic strategy to provide a good outcome. ... Monitoring disease activity should be as frequent as the level of disease activity mandates, usually every 1-3 months, then potentially less frequently (such as every 6-12 months), once the treatment target has been achieved. Nevertheless, three changes were proposed to this item. ... First, a composite measure was recommended as the method of choice to monitor disease activity; second, a specific time frame for monitoring structural damage was deliberately left out; and third, patient-reported outcomes were expanded beyond functional assessments" (Combe et al., 2017).

In 2018, EULAR issued EULAR recommendations for the use of imaging in large vessel vasculitis in clinical practice (Dejaco et al., 2018). It makes no recommendation concerning the preference of ESR or CRP nor does it state the frequency of testing; it does state: "in patients with a high clinical suspicion of GCA (>50%), for example, in case of new-onset headache, visual symptoms, jaw claudication and elevated erythrocyte sedimentation rate (ESR) and C reactive protein, a positive ultrasound would result in a post-test probability of >95%."

5. 2012-2016 American College of Rheumatology (ACR) (Anderson et al., 2012; National Guideline, 2016; Singh et al., 2015; Ward et al., 2016) 

In 2012, ACR released its recommendations concerning the clinical practice of using disease activity measures of rheumatoid arthritis (RA) (Anderson et al., 2012). It recommends using the Disease Activity Score with 28-joint counts (DAS28), the Clinical Disease Activity Index, the Patient Activity Scale (PAS), the PAS-II, the Simplified Disease Activity Index (SDAI), and Routine Assessment of Patient Index Data with 3 measures. The DAS28 is a composite test that can use either CRP or ESR data. The ACR states that both the CRP or ESR used in the DAS28 have been validated in RA. Of the six activity measures recommended by the ACR, only DAS28 received "excellent" recommendations for all three psychometric properties — reliability, validity, and responsiveness. Within the guidelines, the ACR also issued the scores corresponding to remission, low/minimal, moderate, and high/severe RA for all of the disease activity measures, including the DAS28, as well as the mathematical formula using either CRP or ESR data to determine the DAS28. CRP is also used in the SDAI; however, the SDAI is rated as "good" for reliability because it states that "test-retest reliability for composite has not been evaluated" for the SDAI. No mention of frequency of testing is made. It does note that the "inclusion of acute-phase reactants in the DAS28 and SDAI complicates the logistics and timing using these measures in point-of-care clinical decision-making. Although these measures have traditionally been used in clinical trials, academic medical centers, and large multispecialty clinics, logistical barriers have likely delayed their widespread adoption in smaller practice settings (Anderson et al., 2012)."  

The ACR in 2015 (Singh et al., 2015) issued guidelines for the treatment of RA. While not specifying a preference of either CRP or ESR in diagnosing or predicting the prognosis of RA, it does state in its "Key provisos and principles" that "functional status assessment using a standardized, validated measure should be performed routinely for RA patients, at least once per year, but more frequently if disease is active." It also states that disease activity should be measured using ACR-validated scales, including the aforementioned DAS28 and/or SDAI. Moreover, it defines RA remission as "a tender joint count, swollen joint count, C-reactive protein level (mg/dl), and patient global assessment of ≤1 each or a Simplified DAS of ≤3.3, 1 of 6 ACR-endorsed disease activity measures."  

Also in 2015 (but published in 2016), the ACR and the Spondylitis Association of America (SAA) issued their joint recommendations concerning the treatment of ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (National Guideline, 2016; Ward et al., 2016). Regarding "the treatment of patients with either active or stable AS. ... We conditionally recommend regular-interval use and monitoring of the CRP concentrations or erythrocyte sedimentation rate (ESR) over usual care without regular CRP or ESR monitoring." This received a "very low-quality evidence; vote 100% agreement" rating. They do make note that as of the time of publication "no studies addressed the effect of routine monitoring of a disease activity measure" but that "the panel thought that monitoring would be most helpful in patients with active symptoms as a guide to treatment." Testing is not required for every clinic visit.

6. 2013 American Academy of Family Physicians (AAFP) (Caylor & Perkins, 2013) 

In 2013, the AAFP released Recognition and Management of Polymyalgia Rheumatica and Giant Cell Arteritis. For polymyalgia rheumatica (PMR), it notes that "a normal ESR is found in 6% to 20% of persons with [PMR], although in those cases, C-reactive protein level is elevated. ESR predicts relapse more reliably, but C-reactive protein is more sensitive, and is less affected by age and other factors (Caylor & Perkins, 2013)." For giant cell arteritis (GCA), ESR is elevated in up to 89% of patients, but the sensitivity and specificity increase to 99% and 97%, respectively, if both ESR and CRP are tested. Regardless of using either ESR or CRP testing, the AAFP recommends that either ESR or CRP is tested at each clinic visit for patients with either PMR or GCA.

7. 2014 American College of Radiology (ACR) (Ha et al., 2014; National Guideline, 2014) 

The ACR released its updated guidelines concerning the follow-up of Hodgkin lymphoma in 2014. They state that "limited data are available on the role of routine blood work in detecting relapses." ESR is listed as one of the tests conducted as routine blood work in follow-up of Hodgkin lymphoma. They summarize their findings as: "In general, a majority of recurrences can be detected initially by history and physical examination rather than by routine imaging studies or blood tests such as ESR, CBC, and chemistry (Ha et al., 2014)." Four of the five variants they reviewed had ESR tests conducted 1 – 2 times per year, and the ACR rated the use of ESR as a 3, 5, 5, and 7 in these four variants where a "3" indicates "usually not appropriate," a "5" is "may be appropriate," and a "7" falls in the "usually appropriate" category.  

8. 2010-2018, The British Society for Rheumatology (BSR) & British Health Professionals in Rheumatology (BHPR) (Dasgupta, 2010; Dasgupta, Borg, Hassan, Alexander, et al., 2010; Dasgupta, Borg, Hassan, Barraclough, et al., 2010; Gordon et al., 2018)

In 2010, BSR and BHPR issued joint guidelines concerning the management of giant cell arteritis (GCA) (Dasgupta, 2010; Dasgupta, Borg, Hassan, Alexander, et al., 2010). They recommend "early recognition and diagnosis of GCA is paramount. Particular attention should be paid to the predictive features of ischaemic neuro-ophthalmic complications." As part of this diagnostic recommendation, they specifically list laboratory tests that should be included — "full blood count, urea and electrolytes, liver function tests, CRP, ESR." They note that, although elevated ESR and CRP levels are hallmarks of GCA, "GCA can occur in the face of lower levels of inflammatory markers, if the clinical picture is typical." Another specific recommendation states, "Monitoring of therapy should be clinical and supported by the measurement of inflammatory markers (C; this is a consensus statement)" and that at each visit "full blood count, ESR/CRP, urea and electrolytes, [and] glucose" lab tests be performed.

Also, in 2010, BSR and BHPR issued joint guidelines concerning the management of polymyalgia rheumatica (PMR) (Dasgupta, Borg, Hassan, Barraclough, et al., 2010). For PMR, they recommend initial lab testing for diagnosis to include either ESR and/or CRP prior to initiating long-term steroid therapy. Also, during such therapy, they recommend monitoring either ESR or CRP every three months. This is a portion of the recommendation (B) of "vigilant monitoring of patients for response to treatment and disease activity."

The BSR alone issued its guidelines for the management of systemic lupus erythematosus (SLE) in 2018 (Gordon et al., 2018). For the statement "CRP low or normal unless infection," the BSR gives an overall level of evidence of 2++ with a B grade of recommendation, whereas it grades the statement "ESR correlates with active lupus" a 2+ and only a C grade of recommendation. "ESR is often raised in active SLE, but can also reflect persistent polyclonal  hypergammaglobulinaemia, and is not a reliable marker of disease activity. ... A significantly raised CRP is more likely to indicate infection, and patients with raised CRP will need, therefore, to be thoroughly screened for infection, given that infection is the commonest cause of death in lupus patients. In contrast, a raised ESR does not discriminate between active lupus and infection." It recommends that CRP be tested at initial diagnosis and then every 1-3 months during active disease states. Once stabilized, testing frequency can be every 6-12 months. It also states that CRP testing should be conducted on mothers with SLE during pregnancy, but it does not state the frequency of the testing during pregnancy.  

9. 2012 Canadian Rheumatology Association (CRA) (Bykerk et al., 2012)

The 2012 guidelines by the CRA titled Canadian Rheumatology Association Recommendations for Pharmacological Management of Rheumatoid Arthritis with Traditional and Biologic Disease-modifying Antirheumatic Drugs recommend (with Level II and Strength B) "the presence of the following poor prognostic features should be assessed at baseline and considered when making treatment decisions: RF positivity, anti-CCP positivity, functional limitation, high number of swollen and tender joints, early erosions, extra-articular features, high ESR or CRP." They also recommend (with Level I and Strength A): "RA care providers should monitor disease activity as frequently as every 1 to 3 months in patients with active RA." The disease activity should be monitored by a validated method, such as DAS28 or SDAI.   

10. 2009, The National Collaborating Centre for Chronic Conditions (NCC-CC) (Conditions, 2009)

The NCC-CC produced extensive guidelines for RA on behalf of the National Health Service of the U.K. in 2009. It clearly states in its guidelines: "in people with recent-onset active RA, measure C-reactive protein (CRP) and key components of disease activity (using a composite score such as DAS28) monthly until treatment has controlled the disease to a level previously agreed with the person with RA [Recommendation 35]." Regarding using CRP for prognostication, it states that "baseline CRP is a poor predictor of who will go on to develop RA." Another recommendation [Recommendation 34] within the guidelines says to "measure CRP and key components of disease activity (using a composite score such as DAS28) regularly in people with RA to inform decision-making about increasing treatment to control disease [and] cautiously decreasing treatment when disease is controlled."  

11. 2009, The Rheumatoid Arthritis Working Group of The Royal Australian College of General Practitioners (RACGP) (March et al., 2009)

The RACGP released guidelines concerning the diagnosis and management of early rheumatoid arthritis for the National Health and Medical Research Council of Australia in 2009. They recommend (Grade A) the use of ESR and/or CRP. "For patients presenting with painful and swollen joints, GPs should support clinical examination with appropriate tests to exclude other forms of arthritis and other differential diagnoses, and to predict patients likely to progress to erosive disease. Base investigations should include erythrocyte sedimentation (ESR) and/or C-reactive protein (CRP)." Prior to beginning treatment with an antirheumatic drug therapy, they also recommend CRP testing as good practice. ESR/CRP testing should be a part of basic therapy "to monitor for continuing efficacy" (Grade A). With a Grade B recommendation, "general practitioners should be involved in monitoring disease progression, response to treatment and comorbidities in conjunction with the treating rheumatologist and other members of the multidisciplinary team. ... Arthritis activity should be assessed at least three times per year. Treatment should be adjusted to keep the swollen and tender joint count, and the CRP levels, as low as possible."   

12. 2008-2017, National Institute for Health and Care Excellence (NICE) (National Guideline, 2015; NICE, 2017)

NICE first issued the guidelines concerning irritable bowel syndrome (IBS) in 2008, with updates in 2015 and 2017. After initial assessment for IBS, they recommend ESR and CRP, along with full blood count and antibody testing, for celiac disease or tissue transglutaminase to exclude other possible diagnoses. They do not state anything concerning follow-up testing of either ESR or CRP.

 Table Summarizing Guidelines and Recommendations

Society

Year

Condition

Test Preference (if stated)

Frequency of Testing (if stated)

Recommendations

WHO

2018

General Inflammation

CRP

NS

CRP in either EIA or RDT assay is an essential diagnostic tool

NCCN

2018

Hodgkin Lymphoma

ESR

At least once within 6 months of diagnosis

Can be used in evaluating therapy

NCCN

2018

Castleman’s Disease

CRP and ESR

NS

"Essential" tests but does not explicitly state to use both

NCCN

2018

T-cell lymphomas

ESR

NS

"Useful" but does not state as requirement

ASCP (Choosing Wisely)

2015

General Inflammation

CRP

NS

Specifically recommends to NOT use ESR

EULAR

2009

Large Vessel Vasculitis

CRP and ESR

NS 

Level of evidence is 3 with only a "C" strength of recommendation

EULAR 

2013 

Rheumatoid Arthritis 

NS 

NS 

ESR is not useful in disease progression prediction  

EULAR/ACR (Rheumatology)

2015 

Polymyalgia Rheumatica 

CRP and/or ESR 

1-3 months initially; 6-12 months later

At initial workup prior to prescription of therapy 

EULAR

2016 

Arthritis

CRP and ESR 

NS 

Composite measure is best recommendation for monitoring disease

EULAR

2018 

Large Vessel Vasculitis 

CRP or ESR

NS 

With respect to the use of imaging techniques, they recommend doing so in case of elevated CRP or ESR levels 

ACR (Rheumatology) 

2012 

Rheumatoid Arthritis 

CRP or ESR 

At least once per year or more frequently for active disease

To be used as part of composite (such as DAS28)

ACR (Rheumatology) 

2015 

Rheumatoid Arthritis 

CRP or ESR 

At least once per year or more frequently for active disease

Preference not specifically stated, but CRP specifically mentioned in RA remission

ACR (Rheumatology)/SAA

2015 

Ankylosing Spondylitis 

CRP or ESR 

Regular-interval use

"Very low-quality evidence" 

AAFP 

2013 

Polmyalgia Rheumatic & Giant Cell Arteritis 

CRP or ESR 

Follow-up lab with each clinic visit

For either PMR or GCA, CRP or ESR levels should be checked at each clinical visit

ACR (Radiology)

2014 

Hodgkin Lymphoma 

 ESR

1-2 times per year, depending on variant

Does not mention CRP; limited data

BSR/BHPR

2010 

Giant Cell Arteritis

CRP and/or ESR

Follow-up lab with each clinic visit

Their recommendation is a "consensus statement, level C" 

BSR/BHPR

2010 

Polymyalgia Rheumatica

CRP and/or ESR

At initial diagnosis; every 3 months during long-term steroid therapy

Generic recommendation (level B) of vigilant monitoring

BSR

2018 

Systemic Lupus Erythematosus

CRP 

At initial assessment; every 1-3 months during active disease; every 6-12 months during stable disease; during pregnancy

At initial assessment; every 1-3 months during active disease; every 6-12 months during stable disease; during pregnancy

CRA 

2012 

Rheumatoid Arthritis 

CRP or ESR 

At initial assessment prior to treatment; every 1-3 months during active disease

During active disease, CRP/ESR monitoring is part of composite testing, such as DAS28 or SDAI 

NCC-CC 

2009 

Rheumatoid Arthritis 

CRP 

At initial assessment; monthly until disease is controlled

Recommendation 34: regular use of CRP and DAS28 to inform decision-making

Recommendation 35: use of CRP/DAS28 for initial assessment and then monthly until disease is controlled

RACGP 

2009 

Rheumatoid Arthritis 

CRP and/or ESR 

At initial assessment, to monitor therapy efficacy, CRP testing at least every 4 months

For initial assessment, CRP and/or ESR should be used for diagnosing/assessing RA; however, in Recommendation 29, only CRP testing is specifically mentioned. Recommendation 29 is concerning disease monitoring.

NICE 

2015 

Irritable Bowel Disorders 

CRP and ESR 

NS 

Only at initial assessment for exclusionary purposes. 

NS = Not specified; NA = Not applicable; EIA = enzyme immunoassay; RDT = rapid diagnostic test; DAS = Disease Activity Score; SDAI = Simplified Disease Activity Index

References

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  29. Keenan, R. T., Swearingen, C. J., & Yazici, Y. (2008). Erythrocyte sedimentation rate and C-reactive protein levels are poorly correlated with clinical measures of disease activity in rheumatoid arthritis, systemic lupus erythematosus and osteoarthritis patients. Clin Exp Rheumatol, 26(5), 814-819.
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Coding Section

CPT 85651 Sedimentation rate, erythrocyte; non-automated
  85652 Sedimentation rate, erythrocyte; automated
  86140 C-reactive protein

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each Policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association.  All Rights Reserved" 

History From 2018 Forward     

01/13/2020 

 Interim review to add coverage for CRP and ESR concurrently with the management of periprosthetic joint infections. No other changes.

07/12/2019 

Annual review, no change to policy intent. 

09/04/2018 

This policy has an effective date of 11/01/2018.

08/01/2018

New Policy


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