Dual seropositive nonerosive lupus arthritis: rhupus or not?Abstract
Background There is no consensus on the classification of lupus arthritis (LA). In this study, we aimed to investigate patients with LA who were clinically and serologically very similar to those patients with rheumatoid arthritis (RA).
Methods The electronic medical files of systemic lupus erythematosus (SLE) patients from a single tertiary rheumatology department between 2017 and 2022 were reviewed. The inclusion criteria were being age ≥ 18 years, having nonerosive peripheral arthritis lasting longer than six months, and having dual seropositive (rheumatoid factor (RF) and anti-citrullinated protein antibody (anti-CCP)) serology. A nonerosive course of arthritis was demonstrated by both conventional radiography and joint ultrasound. Images were assessed by two blinded rheumatologists. Patients with drug-induced lupus and those with other rheumatologic diseases were excluded.
Results The cases of 528 patients were reviewed, and eight patients were included in the study. All patients were female, and the median age was 48.5 years. The median SLE and arthritis durations were 12 and seven years, respectively. The most common SLE symptom was photosensitivity (n = 8). Only one patient had life-threatening involvement (LTI), which was a seizure and autoimmune haemolytic anaemia. All patients had arthritis affecting the wrist and hand. Anti-dsDNA was the most common anti-ENA antibody (n = 7), followed by anti-SSA (n = 5). The median RF and anti-CCP titres were 82.5 IU/ml and 81.5 U/ml, respectively. Five patients had high titres of autoantibodies, and only one patient had slight hypocomplementemia. Three patients needed biologic agents, and remission was achieved after treatment with rituximab.
Conclusion Despite a long arthritis duration and dual seropositive serology with high titres of RF and anti-CCP, our patients had SLE rather than rhupus syndrome. The low frequency of LTIs, such as lupus nephritis, was a remarkable feature of our patients. Lupus arthritis may be clinically and serologically indistinguishable from RA. Prospective studies are needed to better define LA.
Keywords
Anti-citrullinated protein antibody; Arthritis; Rheumatoid factor; Systemic lupus erythematosus
Introduction
Systemic lupus erythematosus (SLE) is an autoimmune and multisystemic rheumatologic disease that is associated with increased morbidity and mortality. The prevalence of SLE is 8 to 180 per 100,000 individuals in the general population. The female-to-male ratio is 6–13/1, and SLE usually affects women of childbearing age. Systemic lupus erythematosus can affect many organs/tissues in the human body and has distinctive clinical heterogeneity. Multiple autoantibodies are produced over the disease course, which is a serological signature of SLE [1]. Arthritis or arthralgia is the first symptom in 60-80% of patients with SLE [2]. Moreover, joint involvement is a common sign of SLE flares affecting different systems, such as renal or vascular systems [3]. Inflammatory arthritis occurs in 69–95% of patients with SLE, and it is less inflammatory than rheumatoid arthritis (RA). The metacarpophalangeal (MCP), proximal interphalangeal (PIP), wrist, and knee joints are the most commonly involved joints, and they are very similar anatomical areas to the joints most commonly involved in RA; the shoulder, ankle, and elbows are less commonly affected joints. The duration of arthritis varies from a few days to months, and it is usually transient, migratory, and reversible. Symmetrical polyarthritis involving small joints of the hands is the typical pattern of lupus arthritis (LA) [4]. Joint involvement meets all SLE classification criteria, including the 1997 American College of Rheumatology (ACR), 2012 Systemic Lupus International Collaborating Clinics (SLICC), and 2019 ACR/European Alliance of Associations for Rheumatology (EULAR) [5, 6, 7].
The clinical spectrum of inflammatory arthropathy varies across patients with SLE. This spectrum includes arthralgia; nondeforming nonerosive arthritis (NDNE: 80–85%); radiologically nonerosive deforming arthropathy, known as Jaccoud’s arthropathy (3–13%); and erosive arthritis, such as RA (3–5%). Erosive arthritis, such as RA, is characterized by the positivity for rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide (anti-CCP) antibodies. This type of erosive arthritis is referred to as ‘rhupus syndrome (RS)’, which indicates an overlap syndrome of SLE and RA [8].
Rheumatoid factor (RF) is directed against the Fc portion of immunoglobulin G and can be detected in multiple rheumatic diseases, malignancies, infectious diseases, cirrhosis, and healthy individuals. Approximately 70–90% and 15–35% of patients with RA and SLE are positive for rheumatoid factor, respectively. Rheumatoid arthritis patients positive for RF have more radiological erosions, higher disease activity, and extra-articular manifestations; therefore, RF positivity is a poor prognostic factor for RA [9]. Anti-CCP is also a commonly used antibody in the diagnosis of RA and has greater specificity than RF; furthermore, anti-CCP is also associated with radiological erosions [10]. Approximately 70% and 16% of patients with RA and SLE, are positive for anti-CCP, respectively [11]. The 2010 ACR/EULAR RA classification criteria include both RF and anti-CCP; higher titres of these autoantibodies have greater diagnostic value [12].
To date, there is no consensus on the classification of LA and RS [8]. Differentiating LA from RS is important because patients with RS have two rheumatic diseases; therefore, the treatments and prognoses of these two clinical entities are not the same. In this case-based study, we evaluated dual seropositive (both RF and anti-CCP) SLE patients with nonerosive chronic peripheral arthritis who were clinically and serologically very similar to those with RA. Therefore, we aimed to discuss the following question: ‘When should SLE patients be classified as having rhupus syndrome?.
Methods
Patient selection
We analysed patients with SLE who were followed up at our rheumatology department. The electronic files of patients at a tertiary university hospital between 2017 and 2002 were retrospectively reviewed. Demographic, clinical, laboratory and treatment data were recorded. The study’s inclusion criteria were as follows: being aged 18 years or older; meeting the 2019 ACR/EULAR classification criteria for SLE [7]; having nonerosive peripheral arthritis persisting for at least six months; and being positive for both RF and anti-CCP, which was confirmed by at least two measurements taken three months apart. The nonerosive course was demonstrated by both X-ray and joint ultrasound (US). Patients with drug-induced lupus overlapping with another rheumatologic disease (such as psoriatic arthritis or systemic sclerosis), having a history of distal interphalangeal or first carpometacarpal joint arthritis (which are common sites of osteoarthritis), or having specific radiological evidence for a rheumatologic disease such as chondrocalcinosis (which indicates calcium pyrophosphate deposition disease) or a saw-tooth/gull-wing sign (which indicates erosive osteoarthritis) were excluded.
Clinical and laboratory assessments
Demographic features, smoking status, comorbidities, disease duration, SLE manifestations (including articular and nonarticular involvement), patterns of arthritis (number, localization, duration, and distribution of the affected joints), and laboratory and treatment data were recorded. Life-threatening involvement (LTI) included renal involvement (according to the 2019 ACR/EULAR SLE criteria), haematological involvement (serum platelet levels < 100.000/mm3, thrombotic thrombocytopenic purpura, or autoimmune haemolytic anaemia (AIHA)), neuropsychiatric (NPS) involvement (such as seizures, psychosis, mononeuritis multiplex, myelitis/demyelinating diseases, peripheral or cranial neuropathy, optic neuritis, or acute confusional state), vasculitis, diffuse alveolar haemorrhage, or acute lupus pneumonitis.
Complete blood count examination, biochemical profile examination, complete urinalysis, and serum complement C3 and C4 measurement were routinely performed at each visit. Titres of anti-nuclear antibodies (ANAs) and autoantibodies against extractable nuclear antigens (ENAs) were measured via ELISA. Rheumatoid factor (determined by nephelometric assay; samples with results ≥ 14 IU/ml were defined as positive) and anti-cyclic citrullinated peptide-2 IgG (referred to as anti-CCP: determined by ELISA; samples with results ≥ 5 U/ml were defined as positive) titres were measured in patients with arthralgia or arthritis. A high value for RF or anti-CCP was defined as > 3 times the upper limit of normal for the laboratory assay [12].
The most recent anteroposterior wrist/hand X-rays of patients (within the last three months) were read by two rheumatologists (MP, MK). If there was any disagreement between readers, X-rays were re-read, and the final decision was made on the basis of complete agreement between readers. The ACR/EULAR 2010 criteria were used to define typical joint erosions on X-ray [13]. B-mode and power Doppler joint US (using a 10–13 MHz probe) was performed according to the EULAR guidelines [14] by a rheumatologist (MP) and an experienced musculoskeletal radiologist who was blinded to the patient data. We defined synovitis and erosion according to the OMERACT definitions for ultrasonographic pathologies [15].
Statistical analysis
The Statistical Package for the Social Sciences 21.0 software package was used for data analysis. Descriptive statistics are presented as the frequency (minimum-maximum) or median (interquartile range (IQR)). Informed consent was obtained from all participants included in the study. Ethics committee approval was obtained from the Mustafa Kemal University where the study was conducted (date: 08/29/2023, number: 27).
Results
We reviewed the records of 528 patients with SLE; only eight patients were included in the study. All of the patients were female, and the median age was 48.5 years (IQR = 21.5 years). Only one patient had a smoking history, and she was an active smoker. There was no family history of rheumatologic diseases. The median disease duration was 12 years (IQR = 7.5 years). Only one patient had LTI, including seizure and AIHA. The most common symptom was photosensitivity (n = 8, 100%). In all patients, vital signs were normal, with no SLE disease activity according to the BILAG-2004 scoring system. The last visit included an evaluation of all BILAG items in category D or E [16]. Patients had achieved remission of musculoskeletal system symptoms lasting longer than six months with their current therapy; they had no tender or swollen joints. The median arthritis duration was 84 months (IQR = 99 months), and all patients had wrist-hand (MCP or PIP) involvement; seven patients had polyarthritis affecting the hand and wrist, and only one patient had chronic monoarthritis affecting the wrist. We did not observe Jaccoud’s arthropathy in any of the patients. Table 1 shows the demographic and clinical characteristics of the patients. A representative hand radiograph is shown in Fig. 1.
Radiograph of Patient 4; no findings suggestive of rheumatoid arthritis, such as bone erosion or joint space narrowing, are observed
All patients were positive for anti-nuclear antibody; anti-dsDNA was the most commonly detected anti-ENA antibody (n = 7), followed by anti-SSA (n = 5). The median RF and anti-CCP titres were 82.5 IU/ml and 81.5 U/ml, respectively. All patients met the 2010 ACR/EULAR RA classification criteria. Only one patient had slightly low serum C3 levels, at 0.73 g/l (normal range = 0.9–1.8 g/l). Laboratory characteristics are presented in Table 2.
Nonsteroidal anti-inflammatory drugs (NSAIDs) were the initial treatment option but were ineffective for all patients after four weeks. Hydroxychloroquine (HQ: 200 mg/day, n = 8), methotrexate (MTX: 10–20 mg/week, n = 4), and leflunomide (LEF: 20 mg/day, n = 7) were used as conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Azathioprine (AZA: 150 mg/day) and mycophenolate mofetil (MMF: 2 g/day) were selected as immunosuppressive (IS) drugs for two patients who were resistant to combined low-dose prednisolone (<7.5 mg/day) + HQ for three months. Patient 4 had been diagnosed with RA in another rheumatology department before being referred to us; she used etanercept (ETA) for three months and certolizumab pegol (CER) for six months before being referred to us. She had experienced a cutaneous flare (as acute cutaneous lupus) with ETA and an articular flare with CER. Rituximab (RTX) was the single biologic agent that we used at the same dosage as for RA (infusions in two steps; the first infusion was 1000 mg on Day 1, and the second infusion was 1000 mg on Day 15; a total of 2000 mg RTX was administered). Three patients achieved remission after one course of RTX. We did not observe RTX-related adverse events, such as infusion-related reactions or infection events. All patients were followed up at our rheumatology department. Treatment characteristics are shown in Table 3.
Discussion
In this retrospective case-based study, we reviewed the cases of patients with dual seropositive nonerosive LA, providing the most extensive case series on this topic in the medical literature. The remarkable features of our patients were the involvement of the small joints of the hands, polyarthritis, photosensitivity, anti-dsDNA positivity, the lack of nephritis/serositis, the low rate of LTI, and normocomplementaemia. Despite longstanding arthritis, dual seropositivity, and high titres of autoantibodies in five out of eight patients, lupus flared after anti-TNF therapy, and no patients experienced joint erosion. These findings suggest that our patients were more likely to have isolated SLE than RS.
If Patient 4 had accompanying RA, arthritis would have been more likely to go into remission with anti-TNF therapy; however, she experienced articular flares because anti-TNF agents induce the overproduction of type 1 interferons, B-cell hyperactivity, and immune complex formation, which can cause lupus flares [17]. If our patients had accompanying RA, joint erosion would be highly likely because dual seropositivity has an additive effect on joint erosion in patients with RA [18]. Bone erosions develop in more than 10% of patients with RA during the first eight weeks after disease onset, up to 60% during the first year [19]; within six years after disease onset, 95% of patients have ≥1 eroded joint or narrowed joint space [20]. However, the absence of bone erosion does not exclude the diagnosis of RA, and this scenario should be kept in mind. Therefore, we could not completely exclude a diagnosis of RS. Compared with those in SLE and RA patients, the frequency of human leukocyte antigen (HLA)-DR1 and HLA-DR2 alleles is significantly greater in patients with RS [21]. Moreover, synovial biopsy specimen analysis reveals different pathogenetic mechanisms in patients with SLE and RA [22]. Therefore, genetic and histopathological evaluation could help in the accurate diagnosis of RS.
The rate of joint erosion in LA varies depending on sample size, study design and geographic region. In a systematic meta-analysis that included seven studies and 609 patients with LA, the erosion rate was 11.5%, and the anti-CCP positivity rate was 47% in the erosive group, whereas it was 14.6% in the nonerosive group. The sensitivity and specificity of anti-CCP in the diagnosis of arthritis were 47.8% and 91.8%, respectively, in patients with SLE. These findings suggest that anti-CCP can be considered a highly specific marker for erosive arthritis in LA [23]. Zhao et al. conducted a study in China and reported five dual seropositive patients with LA with median RF and anti-CCP titres of 120 IU/ml and 168 RU/ml, respectively. All of them had symmetrical polyarthritis involving the small hand joints as a first symptom of SLE, and all of them had erosive changes. Two of the five patients had LTI (one had nephritis and interstitial pneumonia and one had haemolytic anaemia and interstitial pneumonia), and the most common anti-ENA was anti-RNP (n = 3/5). Anti-CCP was found to be a predictor of arthritis and bone erosion in patients with SLE [24]. Taraborelli et al. analysed 512 patients with SLE and reported that anti-CCP was an independent predictor of erosivity for LA. Seven of 174 patients with LA (4%) had dual sero-positive serology, and two of them had erosive arthritis [25]. Hoffman et al. analysed 235 patients with SLE and reported only five dual seropositive patients. All of them had arthritis; four met the 2010 ACR RA criteria, two out of five patients had proteinuria, and only two of them had nonerosive arthritis. The authors suggested that the presence of anti-CCP did not exclude a diagnosis of SLE [26]. Chan et al. analysed 104 patients with SLE; five of them were dual seropositive, but only one (20%) had nonerosive arthritis with ANA/anti-dsDNA/anti-Ro positivity, skin involvement, and a lack of LTI. These authors also reported that anti-CCP+ patients with SLE tended to have erosive arthritis [27]. Previous studies have shown that nonerosive arthritis is possible despite dual seropositive serology [23, 24, 25, 26, 27].
In a prospective study from Italy, Tani et al. reviewed the cases of 103 consecutive patients with SLE and classified ten patients (9.7%) as having RS less kidney involvement than SLE patients. Rates of haematological, NPS and serosal involvement were similar between the groups. Six of the 10 patients had bone erosions on X-ray, but the incidence of bone erosions was 100% according to magnetic resonance imaging (MRI). Four of the 10 patients were dual seropositive, and only one had class IV lupus nephritis (LN). All dual seropositive patients were anti-dsDNA positive; three were anti-Ro positive, but imaging data were absent. The low incidence of LTI and the most common anti-ENA antibody were similar to those observed in our patients [28]. Rottenberg et al. evaluated 16 patients with RS; seven had dual seropositive serology, but only one out of seven had nonerosive arthritis, and two out of seven had LTI (one had class IIIc LN, and one had psychiatric involvement) [29].
Kaplan et al. reported that patients with SLE who have chronic RA-like arthritis are less likely to develop LN than patients without joint involvement or intermittent arthritis; our results support this finding [30]. Additionally, RF is protective against nephritis and associated with anti-Ro antibodies [31]. None of our patients had LN, and five out of eight (62.5%) had anti-Ro antibodies. Secondary Sjögren’s syndrome (SjS) in SLE is associated with a lower frequency of LN and hypocomplementemia [32]. Half of our patients (Patients 2, 4, 5, and 8) met the 2016 ACR/EULAR Sjögren syndrome classification criteria [33] and were diagnosed with SLE+SjS overlap syndrome, and none had nephritis or hypocomplementemia. A study from Korea showed that patients with RS had lower SLE disease activity and a lower frequency of haemolytic anaemia, renal or neurological involvement, and hypo-complementemia than patients with SLE [34]; our results were consistent with these findings.
Currently, no randomized controlled trial has demonstrated the efficacy of immunomodulatory (IM)∕immunosuppressive (IS) drugs for treating LA. In the 2019 EULAR guidelines for the management of SLE, MTX, AZA, or MMF are recommended for nonresponders to hydroxychloroquine alone or in combination with low-dose corticosteroids. Belimumab (BEL: the single approved biologic agent for SLE) and RTX are the recommended biological agents if the patient does not respond to conventional IM/IS drugs [35]. In our study, three patients needed biological agents, and we preferred RTX because we had more experience with RTX. The current evidence demonstrates that the efficacy of RTX is greater than that of BEL in patients with SLE. The efficacy of off-label use of rituximab in SLE patients was evaluated in a meta-analysis, which showed that 91% of patients achieved articular remission [36]. Our patients achieved remission after one course of RTX, and we did not observe any adverse events.
The retrospective design, small sample size, and lack of control hand-wrist radiographs and magnetic resonance imaging (MRI) were the significant limitations of our study. Ultrasound and MRI are more sensitive than conventional radiography for the detection of bone erosions in SLE patients, and the highest prevalence of bone erosion is observed with MRI. Therefore, US is recommended as a first-line imaging tool in patients with LA [37]. We measured ANA and anti-ENA antibody titres by ELISA, not indirect immunofluorescence, which is the gold standard test for ANA measurement according to the ACR [38]. The lack of genetic and histopathological analyses may be another limitation [21, 22].
In conclusion, our results suggest that clinical and serological findings are indistinguishable between patients with SLE and those with RA. A combination of RF and anti-CCP may reach up to 95% specificity for diagnosing patients with RA [12], but we hypothesized that our patients could not be classified as having an overlap syndrome of SLE and RA. The absence of joint erosion despite a long arthritis duration and dual seropositive serology (usually) with high titres were the major clues excluding RA in our patients. Photosensitivity, a lack of LN despite the high frequency of anti-dsDNA antibodies, a low incidence of LTI, and normocomplementaemia were noteworthy features of our patients. Prospective, histopathology-based, and larger sample-size studies are needed to identify LA.
Acknowledgements
None.
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Funding
No funding was received.
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Ethics approval and consent to participate
Ethics committee approval was obtained from the university where the study was conducted (date: 08/29/2023, number: 27). Informed consent was obtained from all participants included in the study.
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Consent for publication
All the authors agree to be published in this journal.
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Clinical trial number
Not applicable.
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Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Data availability
No datasets were generated or analysed during the current study.
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Publication Dates
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Publication in this collection
10 Mar 2025 -
Date of issue
2025
History
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Received
28 May 2024 -
Accepted
07 Feb 2025 -
Published
11 Feb 2025
