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Abstract Number: 1482

Is 14.3.3η a Predictor of Development of Rheumatoid Arthritis in Patients with Early Undifferentiated Arthritis?

Karen Marie Carlsen1, Nina Schmidt2, Anne Duer3, Kim Hørslev-Petersen4, Cecilie Heegaard Brahe5, Merete Lund Hetland2, Norma K Biln6, Michelle L Zaharik7, Bo Jannik Ejbjerg8, Lene Bak9, Michael Sejer Hansen10, Julia Sidenius Johansen11, Hanne Merete Lindegaard12, Jakob M. Møller13 and Mikkel Østergaard14, 1Center for Rheumatology and Spine Diseases,, Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet Hillerød, Denmark, Hillerød, Denmark, 2Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark, Glostrup, Denmark, 3Department of Radiology, Rigshospitalet Glostrup, Denmark, Glostrup, Denmark, 4King Christian the Xth Hospital for Rheumatic Diseases, Denmark, Graasten, Denmark, 5Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Rigshospitalet, Centre for Head and Orthopaedics, Rigshospitalet, Glostrup, Denmark, 6Augurex Life Sciences Corp, Vancouver, BC, Canada, 7Augurex Life Sciences Corp, Vancouver, DC, Canada, 8Rheumatology, Department of Rheumatology, Køge Hospital, Denmark, Køge, Denmark, 9Department of Radiology, Odense University Hospital, Denmark, Odense, Denmark, 10Reuma-Klinik Roskilde, Denmark, Roskilde, Denmark, 11Dept. of Oncology, Department of Oncology, Copenhagen University Hospital, Herlev and Gentofte, Herlev, Denmark, 12Dept. of Rheumatology, Department of Rheumatology, Odense University Hospital, Denmark, Odense, Denmark, 13Department of Radiology, Copenhagen University Hospital Herlev, Copenhagen, Denmark, 14Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark, Copenhagen, Denmark

Meeting: ACR/ARHP Annual Meeting 2018

Keywords: , ,

Session Information

Date: Monday, October 22, 2018

Title: Rheumatoid Arthritis – Diagnosis, Manifestations, and Outcomes Poster II: Diagnosis and Prognosis

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: Optimal management of rheumatoid arthritis (RA) requires early diagnosis and therefore sensitive methods for early identification of RA to prevent joint damage and disability. 14.3.3η is a novel protein biomarker involved in the upregulation of inflammatory and joint damage factors. The serum/plasma concentration of 14.3.3η has been shown to differentiate patients with established RA from healthy controls1 and may therefore have predictive value in early arthritis.

The purpose of the study was to investigate if the serum 14.3.3η concentrations can predict development of RA in patients with early undifferentiated arthritis.

 

Methods: In this study, 117 patients with early undifferentiated arthritis, i.e. without a specific rheumatological diagnosis, but with ≥2 tender and/or 2 swollen joints among the metacarpophalangeal, proximal interphalangeal, wrist, or metatarsophalangeal joints for >6 weeks but <24 months, were included2. Clinical examination, imaging and blood samples were obtained at baseline with follow-up after 1-2 years.

Baseline serum samples were analysed with 14.3.3η ELISA kits (JOINTstatTM, Augurex, Canada). Previously established cut-offs for 14.3.3η were applied, as follows: negative (-): <0.19 ng/ml, mildly-moderately positive (+): 0.19-0.79 ng/ml, strongly positive (++): ≥0.80 ng/ml.

Twenty-one healthy controls were also examined. Descriptive statistics were used to describe baseline characteristics, and Fisher’s exact test and univariate logistic regression analysis were used to assess the ability of 14.3.3η to predict development of RA according to the American College of Rheumatology (ACR) 1987 criteria within the follow-up period of 1-2 years (Table 2).

Results: Baseline data are shown in Table 1. Significantly more patients with baseline positive (+ and ++) 14.3.3η values developed RA compared to patients with negative (-) 14.3.3η (Fisher’s exact test p=0.003, Table 2). The sensitivity and specificity of a 14.3.3η cutoff at <0.19 ng/ml vs ≥0.19 ng/ml were 0.36 and 0.90, respectively. The negative predictive value of a 14.3.3η <0.19 ng/ml was 0.82. If the 14.3.3η cut-off was set at 14.3.3η ≥0.80 ng/ml (++), the sensitivity decreased to 0.21 while the specificity increased to 0.94.

Univariate logistic regression analysis confirmed a relation between baseline 14.3.3η and development of RA (p=0.003-0.02 depending on the selected cut-off, Table 2).

 

Conclusion: Serum 14.3.3η predicted development of RA in patients with early undifferentiated arthritis.

 

1 Maksymowych et al, J Rheumatol 2014; 41: 2104-13

2 Duer-Jensen et al., Arthritis Rheum 2011; 63: 2192-202

 

Table 1: Baseline clinical, biochemical, and radiographic characteristics of the patients with early undifferentiated arthritis and healthy controls.

 

 

 

Patients with early UA

 

 

 

 

All patients
(n=117)

RA(+)
(n=28)

RA(-)
(n=89)

P, RA(+) vs.
RA(-)

Healthy controls (n=21)

P, healthy controls vs. RA(+)

Clinical data

 

 

 

 

 

 

Sex, no. W/M (% W)

89/28 (76.1)

23/5 (82.1)

66/23 (74.2)

ns

14/7 (66.6)

ns

Symptom duration, months*

6 (4-12)

4.5 (4-10.3)

7 (4-12)

ns

 -

–

Age*

48 (40-57)

49.5 (37-57.3)

48 (41-57)

ns

46 (36-61)

ns

Morning stiffness >1 hour ᵞ

36/66 (35.3)

15/10 (60.0)

21/56 (27.3)

<0.001

–

–

Arthritis in ≥ 3 joint areas ᵞ

9/107 (7.8)

2/25 (7.4)

7/82 (7.9)

ns

–

–

Arthritis of the hand (wrist/MCP/PIP joints) ᵞ

62/54 (53.4)

21/6 (77.8)

41/48 (46.1)

<0.01

–

–

Symmetric arthritis ᵞ

22/94 (81.0)

9/18 (33.3)

13/76 (14.6)

<0.05

–

<0.01

Rheumatoid factor positive ᵞ

33/83 (28.4)

16/12 (57.1)

17/71 (19.3)

<0.001

3/18 (14.3)

<0.01

40-joint tender joint count ᵞ

8 (4-15)

10 (6-19)

7 (4-15)

ns

–

–

40-joint swollen joint count ᵞ

0 (0-2)

1 (0.5-2.5)

0 (0-1.5)

0.01

–

–

Elevated CRP (≥ 5 mg/liter) ᵞ

49/66 (42.6)

16/11 (59.3)

33/55 (37.5)

ns

2/18 (10.0)

<0.001

Elevated anti-CCP (≥10 units/ml) ᵞ

16/99 (13.9)

8/18 (30.8)

8/81 (9.0)

0.01

2/19 (9.5)

ns

HAQ score*

0.4 (0-0.9)

0.6 (0-1.1)

0.4 (0-0.8)

ns

–

–

Pain VAS (0-100 mm)*

34 (17-54)

47.5 (22.3-68.3)

29 (15.5-51.5)

<0.05

–

–

Patient global health VAS (0-100 mm)* 

39 (17.3-59)

46 (28-70)

34.5 (14.8-57.3)

ns

–

–

DAS28 score*

3.6 (2.8-4.3)

4.0 (3.1-4.3)

3.5 (2.7-4.2)

ns

–

–

Radiographic data

 

 

 

 

 

 

X-ray positive†ᵞ

18/96 (15.8)

4/23 (14.8)

14/73 (16.1)

ns

0/21 (0)

ns

Circulating biomarker

 

 

 

 

 

 

Serum 14.3.3η (ng/ml)*

0.0 (0-0.1)

0.0 (0-0.5)

0 (0-0)

<0.05

0 (0-0.1)

ns

14.3.3η status -/+/++ (%) ᵞ

98/8/11 (83.3/6.8/9.4)

18/4/6 (64.3/14.3/21.4)

80/4/5 (89.9/4.5/5.6)

–

18/2/1 (85.7/9.5/4.8)

–

 

 

 

 

 

 

 

anti-CCP: Anti-cyclic citrullinated peptide, CRP: C-reactive protein, DAS28: disease activity score 28, 14.3.3η(-): <0.19 ng/ml, 14.3.3η(+): 0.19-0.79 ng/ml, 14.3.3η(++): ≥ 0.80 ng/ml, HAQ: health assessment questionnaire, M men, MCP: metatarsophalangeal joint, ns: not significant, PIP: proximal interphalangeal joint,  RA(+): patients who had developed rheumatoid arthritis at follow up, RA(-): patients who had not developed rheumatoid arthritis at follow up, UA: undifferentiated arthritis, VAS: visual analogue scale, W: women.
For certain variables (but not serum 14.3.3η and 14.3.3η status) there were missing data (range 1-15) in some patients.
* Numerical data. Values are median (IQR)
ᵞ Categorical parameters. Values are numbers of patients with yes/no (%yes)
† Typical radiographic rheumatoid arthritis erosion in the hand and/or periarticular osteopenia

 

 

Table 2: Sensitivity, specificity, positive predictive value, negative predictive value and logistic regression analysis of s-14.3.3η as a predictor of development of RA in patients with early undifferentiated arthritis

 

 

Development of RA based on baseline 14.3.3η (-) vs 14.3.3η(+/++)

 

 

 

RA(-)

RA(+)

Total

Sensitivity

0.36

14.3.3η(-)

80

18

  89

Specificity

0.90

14.3.3η(+/++)

 9

10

  19

NPV

0.82

Total

89

28

117

PPV

0.53

 

 

P-value*

0.003

 

 

 

 

Development of RA based on baseline 14.3.3η (-/+) vs 14.3.3η (++)

 

 

 

RA(-)

RA(+)

 

Sensitivity

0.21

14.3.3η(-/+)

84

22

106

Specificity

0.94

14.3.3η (++)

  5

  6

  11

NPV

0.79

Total

89

28

117

PPV

0.55

 

 

 

 

P-value*

0.02

 

 

 

 

 

 

Univariate logistic regression, prediction of RA based on baseline 14.3.3η

 

 

Estimate (logit)

P

OR

 

14.3.3η (ng/ml)

0.2624

0.02

1.30†

 

14.3.3η (-) vs 14.3.3η (+/++)

1.5970

0.003

4.94

 

14.3.3η (-/+) vs 14.3.3η (++)

1.5221

0.02

4.58

 

 

 

 

 

 

CI: confidence interval, 14.3.3η(-): <0.19 ng/ml, 14.3.3η(+): 0.19-0.79 ng/ml, 14.3.3η(++): ≥ 0.80 ng/ml, NPV: negative predictive value, OR: odds ratio, PPV: positive predictive value, RA: rheumatoid arthritis, RA(+): patients who had developed rheumatoid arthritis at follow up, RA(-): patients who had not developed rheumatoid arthritis at follow up
† Odds ratio based on a 1 unit increment of the independent variable
* Fisher’s exact test

 

Disclosure: K. M. Carlsen, None; N. Schmidt, None; A. Duer, None; K. Hørslev-Petersen, None; C. H. Brahe, None; M. Lund Hetland, None; N. K. Biln, Augurex Life Sciences Corp, 3; M. L. Zaharik, Augurex Life Sciences Corp, 3; B. J. Ejbjerg, None; L. Bak, None; M. Sejer Hansen, None; J. Sidenius Johansen, None; H. Merete Lindegaard, None; J. M. Møller, None; M. Østergaard, None.

To cite this abstract in AMA style:

Carlsen KM, Schmidt N, Duer A, Hørslev-Petersen K, Brahe CH, Lund Hetland M, Biln NK, Zaharik ML, Ejbjerg BJ, Bak L, Sejer Hansen M, Sidenius Johansen J, Merete Lindegaard H, Møller JM, Østergaard M. Is 14.3.3η a Predictor of Development of Rheumatoid Arthritis in Patients with Early Undifferentiated Arthritis? [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/is-14-3-3%ce%b7-a-predictor-of-development-of-rheumatoid-arthritis-in-patients-with-early-undifferentiated-arthritis/. Accessed .

ACR Meeting Abstracts - https://acrabstracts.org/abstract/is-14-3-3%ce%b7-a-predictor-of-development-of-rheumatoid-arthritis-in-patients-with-early-undifferentiated-arthritis/