Serum Levels of Anti-Cyclic Citrullinated Peptide Antibodies in Patients with Sjögren Syndrome Accompanied by Rheumatoid Arthritis

Abstract

A 47-year-old woman demonstrated bilateral wrist joint pain during 4 weeks. Her status did not fulfill the ACR classification criteria for RA, and her symptoms had almost disappeared 4 weeks later. After about 1 year, she again complained of tenderness and swelling in the bilateral wrist joints. The laboratory data were as follows: ESR:61 mm/hour, CRP: 1.0 mg/dl, RF: 172 IU/ml, MMP-3: 178.7 ng/ml, and anti-cyclic citrullinated peptide antibodies (aCCP): 488 U/ml. Based on these findings, we diagnosed the patient as having RA. She was treated with several anti-rheumatic drugs, and joint symptoms decreased. This case was regarded as undifferentiated arthritis at the first visit. We later found the high titers of aCCP using her frozen sera after she fulfilled with ACR critera for RA, although aCCP was not checked at first time because its analysis was not covered by national health insurance in Japan. Thus, it is possible that this patient should have been treated as having RA from the first visit. In general, aCCP shows excellent specificity for RA diagnosis although sensitivity is lower. In contrast, it has demonstrated that aCCP is positive in about 40% of patients 1 year before the onset of RA. The clinical outcomes of patients with joint symptoms and positive aCCP analysis, but do not fulfill the ACR criteria for RA, should be assessed in plural patients.

Introduction

The early diagnosis of rheumatoid arthritis (RA) is important in order to prevent crippling. In very early RA, it is necessary to distinguish this disease from other disorders showing similar early findings or are not anticipated to progress to destructive arthritis. Recently, anti-cyclic citrullinated peptide antibodies (aCCP) were proposed as a useful diagnostic and predictive marker in RA.^1–3 It has been reported that aCCP had a positive predictive value (PPV) of approximately 90% for RA although aCCP was positive in 50%–70% of patients with early RA. ⁴ In this regard, Symmons et al have emphasized that there is no set of predictive criteria that has been able to discriminate between indivisuals destined to develop RA and those not developing RA. ⁵ This letter describes the time-course of serum aCCP levels in a patient with sjögren syndrome (SS) accompanied by RA during the observation of SS, and a literature review of the clinical significance of positive aCCP preceding the fulfillment with ACR criteria for RA.

Case Report

A 47-year-old woman demonstrated bilateral wrist joint pain. She consulted a local hospital and was treated with meloxicam 5 mg/day. After 4 weeks, her symptoms persisted and she consulted our hospital in August 2006. She complained of moderate pain in the bilateral wrist joints, and incidentally bilateral gonalgia, but not morning stiffness. There were no significant findings on physical examination of the neck, chest and abdomen. X-ray of the bilateral hands did not show any erosive injury (Fig. 1A). Laboratory data were as follows: hemoglobin (Hb):13.9 g/dl, erythrocyte sedimentation rate(ESR): 20 mm/hour, C-reactive protein (CRP): 0.1 mg/dl, rheumatoid factor (RF): 37 IU/ml, matrix metalloproteinase-3 (MMP-3): 28.0 ng/ml, anti-SS-A antibody (aSS): 82.6Index, anti-nuclear antibody (ANA): 40X (speckled). Anti-U1-RNP, anti-Sm antibodies were negative, respectively. On ophthalmological examination, keratoconjunctivitis sicca (KCS) was demonstrated by positive Rose bengal staining, and schirmer test was also positive (right 3 mm, left 8 mm). Hepatic, renal and thyroid function was normal. Her status did not fulfill the ACR classification criteria for RA, therefore we considered her arthralgia was induced by primary SS. We treated her with ampiroxicam 27 mg/day and Keishikajutubuto (Traditional herbal medicine; Kampo). Four weeks later, her symptoms had almost disappeared.

Figure 1

X-ray of the bilateral hands. The erosive change had not progressed one year after the first visit. A) At the first visit (Aug. 2006). B) About 21 months later (May 2008).

In September 2007, she again complained of polyarthralgia and especially, the bilateral wrist joints were tender and swollen. The duration of morning stiffness was about 30 minutes. At that time, laboratory data were as follows: Hb:12.5 g/dl, ESR:61 mm/hour, CRP: 1.0 mg/dl, RF: 172 IU/ml, MMP-3: 178.7 ng/ml, and aCCP: 488 U/ml. Based on these findings, we diagnosed the patient as having RA with secondary SS. However, X-ray of the bilateral hands did not show any erosive change at that time while magnetic resonance imaging has not been performed (Fig. 1B). She was treated with methotrexate 4 mg/week, salazosulfapyridine 1000 mg/day and prednisolone 5 mg/day, and joint symptoms decreased (Fig. 2).

Figure 2

Joint symptoms and changes in serological markers are shown. A high titer of aCCP (607) was detected at the first visit although some inflammatory markers remained within the normal limits.

Discussion

Present case at the first visit was regarded as primary SS. aCCP was not checked at that time because its analysis was not covered by national health insurance in Japan. However, we later measured the titers of aCCP using her frozen sera by an aCCP ELISA kit (Medical and Biological Laboratories CO., Ltd. Japan) after she fulfilled with ACR critera for RA. As a result, a high titer of aCCP was demonstrated at the first visit (Fig. 2). Thus, it is possible that this patient should have been treated as having RA from the first visit. In general, aCCP shows excellent specificity for RA diagnosis although sensitivity is lower. It has been reported that its positive predictive value (PPV) is 93%. However, this patient did not fulfill the ACR citeria for RA, and did not demonstrate an elevation in serum levels of CRP and MMP-3. It has also been demonstrated that aCCP is positive in 5%–20% population with SS. ¹ Neilen et al demonstrated that both the acute phase response and autoantibody formation develop years before the first symptoms of RA occur. ⁶ Therefore, we consider that the present case showed SS with positive aCCP, then about one year later she demonstrated RA. In fact, joint damage had not progressed on wrist joint X-rays when the ACR criteria for RA was fulfilled (Fig. 1). It has demonstrated that aCCP is positive in about 40% of patients 1 year before the onset of RA. ⁷ Additionally, Annette et al demonstrated the score containing aCCP to predict the disease outcome in undifferentiated arthritis. ⁸

We presented a patient with SS who showed a high titer of aCCP, then developed typical RA one year later. The clinical outcomes of patients with joint symptoms and positive aCCP analysis, but do not fulfill the ACR criteria for RA, should be assessed in plural patients, since our data are observed in only one patient.

Disclosure

The authors report no conflicts of interest.