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 MD
YALE SCHOOL OF MEDICINE, DEPARTMENT OF LABORATORY MEDICINE, NEW HAVEN, CT
PATHOLOGY AND LABORATORY MEDICINE SERVICE, VA CONNECTICUT HEALTHCARE SYSTEM, WEST HAVEN, CT
Background

Order Statistics and RA Status of Patient Cohort

800

300

Peptidylarginine
deaminase

Anti-CCP

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.

Pulmonary

50

Chronic Cough

1
12
5

ILD

64
5

Approximately 13% of orders were for patients

with a pulmonary diagnosis who lacked any
In patients with a known diagnosis of RA, our
symptoms related to a connective tissue disorder
local patient population had RF and anti-CCP
findings consistent with previously published data

Carpal Tunnel

Chronic Pain

11

Eye Pain
Jaw Pain

700

Rheumatologic

600

86%

400

3% 9%
76% 12%
Negative

300

100

97%

14%

3.0%
Negative

Positive

Negative

Positive

Negative

Anti-CCP Result

RF Status

677 Male

1 Research Subject

790 Unique Patients

Positive

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

773 Patient Histories

789 Clinical Subjects

96 Female

16 Unknown Order
Diagnosis

Myalgia
1

16
62
1

Polymyalgia Rheumatica

13

Psoriasis

13
4
1

Trauma

Female
90

80

80

70

60
50

Age

Age

70

60

40

50

30

40

20

30

50

100
Count

150
20

Male

10

Arthralgia

378
59

Mean RF: 216

45

35

11

25

2
1

Joint Stiffness

12

Joint Swelling

23

Myalgia
Neuroma

15

16

15
1

Neuropathy/Parasthesia

16

Osteoarthritis
Pericarditis

62
1

Polymyalgia Rheumatica

13

Psoriasis

13

Radiculopathy

4
1

Trauma

Arthralgia
Known RA

378
59

Mean anti-CCP: 138

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

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
90

Jaw Pain

65
55

Gout

Septic Joint
6

Mean Anti-CCP
22

Chronic Pain
Eye Pain

70

Carpal Tunnel

15

Conclusions
Gender

Back Pain

23

Known RA

Anti-CCP Status

Count

500

200

Patient Population

Pulmonary
Rheumatologic/
Musculoskeletal

Positive

Pulmonary

39

12

Radiculopathy

Order Category

Altered Mental Status

Joint Swelling

Septic Joint

47

15

16

Joint Stiffness

Neuroma

AI Workup

23

Gout

Pericarditis

Order Category

Pleural Effusion

55

31

60

64

10

50

ILD

Pulmonary Nodule

40

Osteoarthritis

Anti-CCP Reactivity by Order Indication

Dyspnea

Pulmonary Nodule

22

30

12

Back Pain

RF Status

COPD/Emphysema

Pulmonary HTN
Mean RF

20

Altered Mental Status

Positive

Chronic Lung Disease

Pulmonary HTN

AI Workup
Negative

10

Chronic Cough

Neuropathy/Parasthesia

To 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.

70

Dyspnea

Rheumatologic/Musculoskeletal

Methods

60

*AI Workup

COPD/Emphysema

Negative

103

100

40

Pleural Effusion

200

30

*AI Workup
Chronic Lung Disease

5% 56%
31% 8%

20

Count

*ILD + CREST, Sarcoidosis

400

10

Anti-CCP Status

500

Citrulline

Count

Pulmonary Workup

670

Rheumatologic/Musculoskeletal Workup

700
600

Arginine

RF and Anti-CCP Levels by Ordering Diagnosis

Known RA Diagnosis

Positive

Interstitial 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 anticyclic citrullinated peptide antibodies (anti-CCP) may have a worse
prognosis and an increased risk of developing pulmonary complications.

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

Acknowledgements

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