Role of Anti-Cyclic Citrullinated Peptide Screening in Patients with Lung Disease but without Connective Tissue Disorders

WADE L SCHULZ MD, PHD, THOMAS JS DURANT MD, CHRISTOPHER A TORMEY MDYALE SCHOOL OF MEDICINE, DEPARTMENT OF LABORATORY MEDICINE, NEW HAVEN, CT

PATHOLOGY AND LABORATORY MEDICINE SERVICE, VA CONNECTICUT HEALTHCARE SYSTEM, WEST HAVEN, CT

BackgroundInterstitial lung disease (ILD) is a leading cause of morbidity and mortality in patients with rheumatoid arthritis (RA) and other connective tissue disorders. Several studies have suggested that RA patients with anti-cyclic citrullinated peptide antibodies (anti-CCP) may have a worse prognosis and an increased risk of developing pulmonary complications.

We noticed a unique ordering pattern at our facility where providers evaluated anti-CCP in patients with ILD who lacked RA symptoms. While the presence of anti-CCP in patients with ILD and RA may lead to more aggressive therapy, it is unclear whether anti-CCP evaluation is useful or cost-effective in patients without rheumatologic symptoms.

MethodsTo determine whether anti-CCP testing in patients with ILD but without CTD symptoms is beneficial, we performed a retrospective analysis of patients at the West Haven VA Medical Center from 2009-2014. Patients who had both a rheumatoid factor (RF) and anti-CCP result within a one month time period were selected. The first set of values obtained for an individual patient in this time period was used for analysis. A detailed history was obtained by chart review to determine the ordering diagnosis. In addition, a history of concomitant arthralgia or lung disease was noted for each subject. For statistical analysis, the limit of detection was used for values below or above the limit of detection.

Patient Population

Conclusions

» Anti-CCP testing in patients with ILD but without CTD symptoms was not cost-effective ($1,667/positive test) in our study population compared to

patients with rheumatologic/CTD complaints ($366/positive test)

» Patients with ILD have the same rate of anti-CCP positivity as normal blood donors and control subjects identified in other cohorts (approximately 2%)

» Specific CTD symptoms, such as arthralgia, joint stiffness, and joint swelling may indicate a need for anti-CCP testing

» While anti-CCP testing in the absence of CTD symptoms may not be effective, studies have shown RA patients with elevated anti-CCP may be more likely

to develop later pulmonary symptoms

» A diagnosis that explains existing joint pain significantly decreases the likelihood to have an elevated RF or anti-CCP result

AcknowledgementsWe would like to thank Wendy Strelow and John Forno for their technical assistance with data extraction.

20

30

40

50

60

70

80

90

0 50 100 150Count

Age

GenderFemale Male

Age

20

30

40

50

60

70

80

90

790 Unique Patients

1 Research Subject

789 Clinical Subjects

773 Patient Histories

16 Unknown OrderDiagnosis

677 Male

96 Female

Order CategoryPulmonary Rheumatologic

0

100

200

300

400

500

600

700

97%

3.0%

86%

14%

Negative Positive

Anti-CCP Result

Negative Positive

Cou

nt

0

100

200

300

400

500

600

700

800

103

670

Pulmonary Rheumatologic/Musculoskeletal

Anti-

CC

P St

atus

Neg

ativ

ePo

sitiv

eNegative Positive

RF Status

Order Category

PulmonaryRheumatologic/Musculoskeletal

76% 3% 9%

12%

*AI WorkupChronic Cough

Chronic Lung DiseaseCOPD/Emphysema

DyspneaILD

Pleural EffusionPulmonary HTN

Pulmonary Nodule

AI WorkupAltered Mental Status

Back PainCarpal Tunnel

Chronic PainEye Pain

GoutJaw Pain

Joint StiffnessJoint Swelling

MyalgiaNeuroma

Neuropathy/ParasthesiaOsteoarthritis

PericarditisPolymyalgia Rheumatica

PsoriasisRadiculopathy

Septic JointTrauma

Mean Anti-CCP

15

25

35

45

55

65

*ILD

+ C

RES

T, S

arco

idos

isPu

lmon

ary

Wor

kup

Rhe

umat

olog

ic/M

uscu

losk

elet

al W

orku

p

Arthralgia

Known RA Mean anti-CCP: 138

2*AI Workup2Chronic Cough

1Chronic Lung Disease12COPD/Emphysema

5Dyspnea64ILD

5Pleural Effusion6Pulmonary HTN6Pulmonary Nodule

22AI Workup1Altered Mental Status

10Back Pain3Carpal Tunnel

11Chronic Pain2Eye Pain

16Gout1Jaw Pain

12Joint Stiffness23Joint Swelling

15Myalgia1Neuroma

16Neuropathy/Parasthesia62Osteoarthritis

1Pericarditis13Polymyalgia Rheumatica13Psoriasis

4Radiculopathy1Septic Joint

6Trauma

378Arthralgia

59Known RA Mean RF: 216

Mean RF

15

23

31

39

47

55

22

112

564

566

221

103

112

161

1223

151

1662

11313

41

6

378

59

0 10 20 30 40 50 60 70

Count

0 10 20 30 40 50 60 70

Count

Anti-

CC

P St

atus

Neg

ativ

ePo

sitiv

e

Negative Positive

RF Status

31% 5% 56%

8%

» Approximately 13% of orders were for patients with a pulmonary diagnosis who lacked any symptoms related to a connective tissue disorder » In patients with a known diagnosis of RA, our

local patient population had RF and anti-CCP findings consistent with previously published data

» Approximately 14% of patients who were evaluated for a musculoskeletal/rheumatologic complaint had a positive anti-CCP result » Only 3% of patients evaluated for pulmonary conditions had a positive anti-CCP, and only a single

value was “high positive” » None of the pulmonary patients with a positive anti-CCP result received a CTD diagnosis or change

in care due to the finding

» ILD was the second most common diagnosis for RF/anti-CCP orders » Except for COPD/Emphysema, pulmonary diagnoses were rarely positive for RF » Anti-CCP was rarely elevated for any pulmonary diagnosis » Several rheumatologic/musculoskeletal diagnoses were more frequently associated with an increased RF

or anti-CCP: » Arthralgia » Joint stiffness » Joint swelling » Osteoarthritis

» Patients with a known alternative diagnosis as the cause of joint pain (ie, gout, carpal tunnel, radiculopathy) were unlikely to have an elevated RF or anti-CCP

RF and Anti-CCP Levels by Ordering DiagnosisKnown RA Diagnosis

Arginine Citrulline

Peptidylarginine deaminase Anti-CCP

Order Statistics and RA Status of Patient Cohort

Anti-CCP Reactivity by Order Indication