Introduction

Primary Sjögren’s syndrome (pSS) is a chronic, indolent and relatively benign auto-immune disease of unknown aetiology. The condition is characterized by lymphocytic infiltrates and destruction of the salivary and lacrimal glands, leading to clinical signs of xerophthalmia, xerostomia and swelling of the parotid glands. Additionally, systemic manifestations may occur such as neuropathy, polyarthritis, interstitial lung disease and renal disease [1].

The presence of systemic auto-antibodies (SAA) is a hallmark of the disease, with the presence of anti-Sjögren’s syndrome-related antigen A (anti-SSA) and/or anti-Sjögren’s syndrome type B (anti-SSB) being a classification criterion [2]. A few years ago, our group reported on and confirmed the association of systemic auto-antibodies and extra-glandular manifestations (EGM) in primary Sjögren’s syndrome [3]. We found a statistically significant association between the number of systemic auto-antibodies and the total number of EGM [3].

In primary Sjögren’s syndrome, many patients exhibit rheumatological manifestations such as intermittent, symmetrical, non-erosive/non-deforming (poly)arthritis, arthralgia, myalgia, etc. [4]. Some patients have generalised musculoskeletal pain classified as a so-called widespread pain syndrome [5]. Articular manifestations (AM), mostly mild and with a good response to treatment, occur in 30–60 % of pSS patients, depending on patient selection [4]. They can be the presenting symptoms and may even precede the complaints of dryness [4]. Polyarthritis in pSS may mimic rheumatoid arthritis, particularly as more than half of these patients are rheumatoid factor (RF)-positive [6]. Hence, these patients may be misdiagnosed as having rheumatoid arthritis (RA).

The primary goal of our study was to investigate, in a clinical-based (real-life) setting, whether patients with polyarthritis and primary Sjögren’s syndrome form a distinct subset with respect to demographic characteristics, other extra-glandular manifestations, serological profile and hypergammaglobulinaemia. The secondary goal was to describe the characteristics of polyarthritis in our pSS cohort. We are not aware of any previous studies specifically investigating only polyarthritis in pSS.

Materials and methods

The primary goal of this study was to define whether pSS patients with polyarthritis (polyarthritis-positive (PA+)) differ from pSS patients without polyarthritis (polyarthritis-negative (PA−)) with respect to demographic characteristics, other EGM, serological profile and hypergammaglobulinaemia. For this purpose, one treating rheumatologist (EJtB) screened the medical files of all outpatient clinic patients (from a large non-academic teaching hospital in the Netherlands) who had been diagnosed with primary Sjögren’s syndrome [2] from June 1991 until August 2015. From 1991 up to the present, all pSS patients were followed up prospectively at least once a year, with a specific focus on EGM. Additional investigations were only conducted when clinically indicated. Only patients fulfilling the 2002 European criteria for primary Sjögren’s syndrome were included for analysis [2]. Patients fulfilling criteria for concomitant connective tissue diseases, except from rheumatoid arthritis, such as systemic lupus erythematosus, systemic sclerosis, polymyositis, etc., were excluded from the final analysis.

Laboratory data were collected from all the selected patients concerning the presence of systemic auto-antibodies (ANA, anti-SSA, anti-SSB and IgM-RF antibodies), anti-cyclic citrullinated peptide (CCP) antibodies, levels of complement C3/4 and cryoglobulins and gammaglobulin and IgG levels. All laboratory tests were performed at the clinical chemistry and immunology laboratory of St. Antonius Hospital. ANA were tested using indirect immunofluorescence on HEp-2 cells; a positive ANA test was defined as ≥1:80 on at least two occasions. Anti-SSA and anti-SSB antibodies were tested by ELISA and had to be positive on at least two occasions. IgM-RF was tested by nephelometry (positive value ≥25 IU/ml on at least two occasions). Anti-CCP antibodies were tested with ELISA; a positive test was defined as >10 U/ml. Complement (C3/4) levels were tested by nephelometry; decreased levels were defined for C3 as <90 mg/dl (normal values 90–180 mg/dl) and for C4 as <15 mg/dl (normal values 15–40 mg/dl) on at least two occasions. Cryoglobulins were tested by visual examination of cryoprecipitate formation after one night’s incubation at 4 °C and were scored as being present or absent. Gammaglobulin and IgG levels were tested using electrophoresis and nephelometry, respectively. For the purpose of this study, hypergammaglobulinaemia was defined as ≥17 g/L (normal values 7–15 g/L) and increased levels of IgG as ≥18 g/L (normal values 7–16 g/L), both on at least two occasions.

Furthermore, medical charts were checked systematically for the cumulative prevalence of EGM related to primary Sjögren’s syndrome, in particular cytopenia (leucopenia was defined as a repeated leucocyte count below 2.5 × 109/L, thrombocytopenia as a repeated platelet count below 150 × 109/L, haemolytic anaemia as a haemoglobin level <6.0 mmol/L with biochemical signs of haemolysis and a positive direct Coombs test), vitiligo (localized depigmentation without scarring), cutaneous vasculitis (clinical diagnosis with or without histological confirmation), discoid lupus/subacute cutaneous LE (clinical diagnosis with or without histological confirmation), polyneuropathy (with abnormal neurophysiological studies), interstitial lung disease (confirmed by high-resolution computed tomography and/or histology), pleuritis (confirmed by high-resolution computed tomography and/or histology), renal tubular acidosis (urinary pH >6.0 and serum bicarbonate <15 mmol/L), celiac disease (positive histology and serology), Graves’ disease/Hashimoto’s disease (both laboratory parameters and positive auto-antibodies), pernicious anaemia (vitamin B12 deficiency and antibodies against parietal cells and/or intrinsic factor), uveitis (diagnosed by an ophthalmologist), pericarditis (confirmed by echocardiography), central nerve system involvement (with compatible MRI findings), primary biliary cirrhosis (elevated cholestatic liver enzymes and positive anti-mitochondrial antibodies), auto-immune hepatitis (laboratory parameters and positive ANA/antibodies against smooth muscles and/or histology), monoclonal gammopathy of unknown significance (by immunofixation) and non-Hodgkin lymphoma (histology).

If the patients had concomitant conditions which could also account for an EGM (such as polyneuropathy by diabetes mellitus, cutaneous vasculitis or interstitial lung disease by drugs, etc), this manifestation was not attributed to primary Sjögren’s syndrome for the purpose of the analysis and was regarded as being absent.

Arthritis was defined as a painful articular swelling observed by a highly experienced rheumatologist (EJtB). If there was any doubt about the presence of arthritis, ultrasound investigation of the joints was considered. Data were collected on the time of onset of the arthritis and its distribution, course and treatment. When arthritis could possibly be attributed to other causes such as osteoarthritis, it was considered to be absent.

At regular intervals (each year in the first 3 years after the diagnosis of polyarthritis), X-rays of the hands and feet were performed to detect radiological abnormalities compatible with rheumatoid arthritis. If these abnormalities were present, the patient was excluded. For analysis, patients with polyarthritis had to be followed up for at least 1 year.

The nature of this study makes ethical approval unnecessary according to the ethics guidelines of our hospital.

Data analysis

Standard descriptive statistics were computed. The correlations of binomial variables were computed by means of the phi coefficient. Hypothesis testing for continuous variables was performed by means of a Student’s t test or Mann-Whitney test where appropriate; a Fisher’s exact test was used for categorical variables.

Results

Basal characteristics of the study subjects

A total of 148 patients fulfilled the diagnosis of pSS. Five of them also fulfilled the criteria of systemic lupus erythematosus, two had limited systemic sclerosis, one had polymyositis and one had mixed connective tissue disease (MCTD); these nine patients were excluded. Thus, 139 patients with “pure” pSS remained for the initial evaluation, and 22 of them (16.4 %) had arthritis. One pSS patient had monoarthritis of a wrist, while oligoarthritis was not observed. Four patients developed RA, three of them 2 years after the diagnosis of pSS and one 10 years after diagnosis. All these four patients were RF-positive, and three were also anti-CCP-positive. Three of the four above-mentioned patients developed erosive abnormalities, and one manifested cystic changes on X-rays compatible with RA. These four subjects and the one patient with monoarthritis were excluded from the final analysis.

This left a total of 134 patients with “pure” primary Sjögren’s syndrome and polyarthritis but without RA-like changes on X-rays for the final analysis (Table 1).

Table 1 Basal and cumulative characteristics of included patients with “pure” primary Sjögren’s syndrome and polyarthritis (n = 134)
Full size table

They were predominantly Caucasian women with an average age of 55.3 years at the time of diagnosis of pSS. The median follow-up was 86 months (range 0–368 months). Polyarthritis occurred in 22 (16.4 %) of the 134 patients. In 118 patients, minor salivary gland biopsies had been performed, of which 98 (83.1 %) had a focus score ≥1.

Systemic auto-antibodies (ANA, anti-SSA, anti-SSB, IgM-RF antibodies) were abundant, with 76.1 % of the patients being positive for anti-SSA and 43.3 % for anti-SSB, often found together in the same patient. Four cases tested positive for anti-CCP, and they had no radiological signs of rheumatoid arthritis after a follow-up time of 2.5–4 years. The one anti-CCP positive but PA negative patient had normal X-rays after 14 years of follow-up. All the four anti-CCP positive cases were IgM-RF-positive and had a positive minor salivary gland biopsy with focus score >1, and two were anti-SSA-positive but none of them had hypergammaglobulinaemia.

Only 11 patients (8.3 %) tested negative for all four screened systemic auto-antibodies. All combinations of SAA were moderately correlated (data not shown; p < 0.05). Hyper-IgG and hypergammaglobulinaemia occurred in 36 and 43 % of the patients, respectively, and also showed significant correlations with the presence of all the particular systemic auto-antibodies (data not shown; p < 0.05).

Differences between PA+ and PA− patients (Tables 2 and 3)

Table 2 Basal and cumulative clinical characteristics and serological data from patients with and without polyarthritis
Full size table
Table 3 Cumulative extra-glandular manifestations (EGM) from patients with and without polyarthritis
Full size table

Twenty-two patients had polyarthritis (PA+). None had detectable rheumatoid nodules and/or deformities. All fulfilled the 2010 ACR/EULAR classification criteria for rheumatoid arthritis. At the time of diagnosis of pSS, the PA+ patients were significantly older (p = 0.002), but at the end of follow-up, there was no statistically significant difference with respect to age, as the follow-up time was shorter for the PA+ patients (p = 0.020). There was no gender difference. The prevalence of systemic auto-antibodies did not differ.

Not surprisingly, anti-CCP occurred much more frequently in the PA+ patients (13.7 vs 0.9 %; p = 0.015).

Hypergammaglobulinaemia (p = 0.002) and increased levels of IgG (p = 0.013) occurred much less frequently in the PA+ group compared with the PA− group.

The mean total number of EGM was 1.0 per patient in the PA+ group and 0.9 per patient in the PA− group, respectively (NS). There was no difference with respect to the frequency of any specific EGM between both groups, probably due to their low numbers.

Characteristics of polyarthritis

Almost all patients had a mild, symmetrical polyarthritis (PA) predominantly involving the finger joints (proximal interphalangeal joints/metacarpophalangeal joints (PIP/MCP)) and/or wrists and/or metatarsophalangeal (MTP) joints (Table 4). The median number of joints involved was 3 (range 1–7). Significant morning stiffness (lasting ≥1 h) was not found very often (32 %). The onset of PA generally (n = 16) occurred during the period of establishing the diagnosis of pSS, but in a few patients, it occurred prior to (n = 4) or after (n = 2) that diagnosis. Four patients were previously misdiagnosed and treated for rheumatoid arthritis. The median follow-up of polyarthritis was 4 years. All patients were treated with a classic (c) disease-modifying antirheumatic drug (DMARD). The most commonly prescribed anti-rheumatic drugs for PA were hydroxychloroquine (72 %) and/or low-dose prednisone (44 %). Other prescribed cDMARDs were sulfasalazin (n = 2), d-penicillamine (n = 2), intramuscular (n = 1) or oral gold (n = 1) and methotrexate (MTX) (24 %). With these cDMARDs, the response was favourable in almost all cases. However, in two patients, treatment with anti-tumour necrosis factor (TNF) agents was necessary. Three of the six MTX users were anti-CCP-positive, as was one of the two anti-TNF users.

Table 4 Distribution of joint sites involved (in most cases more than one site was involved)
Full size table

In confirmation with the selection criteria, structural damage was not found on X-rays of the hands and feet. On rare occasions (20 %), C-reactive protein (CRP) levels exceeded the upper limit of 10 mg/dl. Among the 22 PA+ patients, 11 had EGM other than PA.

Discussion

We found a frequency of PA of 16.4 % in our pSS patients, which is comparable to the prevalence of all types of arthritis from previous studies [4, 7–9]. However, exact figures on the frequency of polyarthritis were not given in those studies [4, 7–9]. As far as we know, this is the first study focussing on polyarthritis in pSS. Other studies on AM in pSS included arthralgia and/or all types of arthritis [7, 10].

In a recent French study, AM (including arthralgia and/or arthritis) were reported to be mostly polyarticular and predominantly found in the peripheral joints, manifesting prior to, simultaneously with, or after the diagnosis of pSS [4]. These articular manifestations were related to certain clinical and serological findings such as RF positivity [4]. After a mean follow-up of 76 months, the prevalence of articular manifestations was 45 % and of symmetrical arthritis (probably polyarthritis) 16 % [4]. A more recent study from Italy, also retrospective, with a mean follow-up of 5.8 years and including 1115 pSS patients (excluding rheumatoid arthritis) demonstrated a cumulative prevalence of arthritis of 11 % [8], while the Ramos-Casals group reported a frequency of 15 % after a mean follow-up of 74.9 months [7]. A study from Finland mentioned a frequency of arthritis of 22 % (again without details on the type) after a median follow-up of 9 years [9]. An English study of 144 pSS patients found no case of rheumatoid arthritis after a mean follow-up of 10.5 years, although erosive changes were reported in one case [11]. It seems clear that the reported rate of (poly)arthritis in the literature strongly depends on the selection procedures.

In our study, PA occurred prior to, concurrent with (68 %, the majority), and after the diagnosis of pSS, which reflects the findings from the literature [4, 10].

Our PA+ patients were younger than the PA− patients at the time of establishing the diagnosis of pSS, probably due to referral bias, as the pSS patients were recruited from a department of rheumatology with a greater awareness of the diagnosis of pSS. At the end of a long-term follow-up (mean 86 months), there was no statistically significant difference with respect to age between the PA+ and PA− pSS patients.

We did not find a statistically significant difference in the prevalence of RF positivity between the PA+ and PA− patients. This is in line with the results of a relatively old study which was smaller in scale [10].

It could be argued that many of our patients had RA with secondary Sjögren’s syndrome (sSS). Indeed, the clinical distinction between RA with sSS and pSS with polyarthritis may be difficult at times, if not impossible, especially if the frequency of RF positivity in pSS is >50 % [6]. However, we confirmed that our patients had no X-ray abnormalities compatible with RA during follow-up.

Most experts believe that (poly)arthritis in pSS is a typically non-erosive disease, though erosive changes have sporadically been reported in the literature [12]. In order to avoid possible contamination with RA and sSS, we excluded patients with X-ray changes compatible with RA. A transition from pSS to RA can occur [13] but is thought to be rare. We observed three such patients after long-term follow-up; they were excluded from the final analysis.

Anti-CCP antibodies occur in pSS at a frequency of 5.2 % [6] and therefore cannot be employed to exclude this diagnosis. In a study from Japan, anti-CCP antibodies only occurred in pSS with AM [14]. We found a prevalence of 3 % of anti-CCP antibodies in our whole patient population. There was only one patient with anti-CCP in the PA− group. It is conceivable that anti-CCP-positive pSS patients are more prone to progress to RA [15]. Indeed, three of our four patients showing transition to RA were anti-CCP-positive.

The PA+ patients had a much lower prevalence of hypergammaglobulinaemia and increased IgG compared with the PA− patients. This has not been reported in the literature before. We therefore believe that the PA+ patients represent a subset of pSS with less pronounced B cell proliferation.

There was no difference in the frequency of the total number of EGM or of any specific EGM between PA+ and PA− patients, possibly due to the low frequency of these specific EGM in both groups. In contrast, Fauchais found more systemic involvement in their patients with AM [4].

Arthritis mostly occurred in the finger joints, wrist and MTP joints, which corresponds to previous reports [4, 10, 12, 15]. Despite lacking a formal control group, our PA+ pSS patients seemed to have a milder clinical expression with less significant morning stiffness, a lower rate of elevated CRP levels and milder articular manifestations than our outpatient clinic RA patients. This is in agreement with a report from Castro et al. [10]. The use of MTX (24 %) was also lower in our PA+ pSS patients than in our outpatient clinic RA patients (estimated rate in our clinical practice 70 %). The same was the case for the use of anti-TNF in our PA+ pSS patients (8 %) versus an estimated rate in our outpatient clinic RA patients of 30 %. The treatment modalities with cDMARD and anti-TNF were in accordance with a recent article from France [4].

In conclusion, PA+ patients with pSS are more frequently anti-CCP-positive but have a less pronounced B cell proliferation than PA− patients. They have a relatively mild articular expression and with a favourable course when compared to rheumatoid arthritis.