Abstract
Objective
The RNA‐binding region‐containing protein 3 (RNPC3) protein acts as a molecular bridge, promoting U11/U12 RNP complex formation. In previous reports, patients with systemic sclerosis (SSc) with anti‐RNPC3 autoantibodies had an increased risk of interstitial lung disease (ILD), severe gastrointestinal (GI) disease, and cancer. The aim of this study was to compare phenotypic features of patients with mixed connective tissue disease (MCTD) with and without anti‐RNPC3 autoantibodies.
Methods
A retrospective MCTD cohort was studied. Addressable laser bead immunoassay was used to detect anti‐RNPC3 autoantibodies with <1,000 mean fluorescence intensity (MFI) as normal reference range, 1,000 to 2,999 MFI as low‐titer positivity and ≥3,000 MFI as high‐titer positivity. Cancer occurrence within (±) five years of MCTD diagnosis and comparison of clinical features between anti‐RNPC3+ and anti‐RNPC3− subgroups were analyzed.
Results
Fifteen of 66 (23%) patients with MCTD were anti‐RNPC3+, which were associated with a higher frequency of sclerodactyly (anti‐RNPC3+ vs anti‐RNPC3−: 100% vs 67%, P = 0.007), but their frequency in ILD and GI involvement was similar (4 of 12, 33% vs 18 of 44, 41%, P = 0.73; and 13 of 14, 93% vs 43 of 46, 93% P = 0.91, respectively). Cancer was present in 3 of 15 (20%) anti‐RNPC3+ compared to 3 of 51 (5.9%) anti‐RNPC3− patients (P = 0.13). Numerically, more malignancy was observed among patients with high‐titer anti‐RNPC3+ (unadjusted odds ratio 16.00, 95% confidence interval 0.54–484.28, P = 0.07).
Conclusion
Anti‐RNPC3 autoantibodies were associated with a higher frequency of SSc skin involvement in patients with MCTD. Anti‐RNPC3 autoantibodies, especially in high titers, might be the markers for an increased risk of cancer in MCTD that needs to be confirmed in larger cohorts.
INTRODUCTION
RNA‐binding region‐containing protein 3 (RNPC3) acts as a molecular bridge, promoting U11/U12 RNP complex formation and intron bridging in the minor prespliceosome. 1 , 2 , 3 , 4 Small nuclear RNP are common antigen targets in patients with systemic sclerosis (SSc). 2 Anti‐RNPC3 autoantibodies were reported in patients with SSc with a prevalence ranging from 3% to 4%. 2 , 4 In previous studies, patients with SSc who expressed anti‐RNPC3 autoantibodies had an increased risk of interstitial lung disease (ILD), 2 , 3 severe gastrointestinal (GI) disease, 5 and an increased risk of cancer. 4 , 6
The presence of anti‐U1RNP is essential for the diagnosis of mixed connective tissue disease (MCTD) and are frequently found in other patients with systemic autoimmune rheumatic disease (SARD) presenting with an SSc phenotype. 2 We recently reported that in addition to anti‐U1RNP autoantibodies, patients with MCTD frequently coexpressed novel anti–survival of motor neuron (SMN) autoantibodies. 7 Their presence, especially at high titers, was associated with a more severe SSc phenotype, myositis, myocarditis, and lower GI involvement. 7
The aim of this study was therefore to evaluate the prevalence of anti‐RNPC3 autoantibodies in patients with MCTD, and to compare phenotypic features in patients with and without anti‐RNPC3 autoantibodies.
PATIENTS AND METHODS
Patients
Patients with MCTD were identified from a previously described clinically and serologically phenotyped retrospective cohort from the Centre Hospitalier de l'Université de Montréal (CHUM). 7 , 8 , 9 , 10 All patients had anti‐U1RNP autoantibodies and they fulfilled ≥1 MCTD classification of Alarcón‐Segovia (AS), Kahn (Kn), Kasukawa (Ka), 11 and/or Tanaka (Ta). 12
Study variables
A retrospective medical record review using a standardized protocol was performed to collect cumulative clinical data, laboratory, and imaging investigations, as described previously in detail. 7 , 8 , 9 , 10 Race was self‐reported by the patients. Esophageal dysmotility was defined either by manometry and/or evidence of lower esophageal dilation on chest computed tomography (CT) scan. Pulmonary arterial hypertension was defined as systolic pulmonary arterial pressure of 35 mm Hg on transthoracic echocardiogram or mean pulmonary arterial pressure of 25 mm Hg on right‐sided heart catheterization. At the time of data collection, the 1975 definition of pulmonary arterial hypertension was used in this historic cohort. 13 ILD was defined on chest CT scan. Myositis was defined as proximal (deltoid and/or psoas) muscle weakness on manual muscle testing in association with at least two of the following: (1) elevated serum creatine kinase levels, (2) abnormal electromyogram, and/or (3) abnormal muscle biopsy on chart review. Myocarditis was defined by signs and symptoms, laboratory findings, and/or cardiac imaging on chart review. Abnormal SSc‐type nailfold capillaroscopy was defined as previously published. 14 Cancer occurrence within (±) five years of MCTD diagnosis was documented.
Clinical features were assessed for American College of Rheumatology (ACR)/EULAR and non‐ACR/EULAR features of SSc, systemic lupus erythematosus (SLE), and Sjögren's disease (SjD). 15 , 16 , 17
Serology
Indirect immunofluorescence used HEp‐2 cell substrate to screen for antinuclear autoantibody with a positivity threshold value of 1:320. An extractable nuclear antigen panel was used to detect autoantibodies to U1RNP. Addressable laser bead immunoassay using a full‐length recombinant human protein (Cusabio) was used to detect specific anti‐RNPC3 autoantibodies. The normal reference range was established as <1,000 mean fluorescence intensity (MFI), 1,000 to 2,999 MFI as low‐titer positivity, and ≥3,000 MFI as high‐titer positivity. This anti‐RNPC3 assay was validated with an early‐stage commercial anti‐RNPC3 autoantibody immunoassay in development (Werfen).
Statistical analysis
Descriptive statistics were used to summarize the demographic and clinical characteristics of patients. Anti‐RNPC3+ and anti‐RNPC3– subgroups were compared using Fisher's exact test for categorical variables, and Mann–Whitney U test for continuous variables with nonnormal distribution. Univariable logistic regression analyses were used to study the association between anti‐RNPC3 status and risk of cancer within (±) five years. Furthermore, unadjusted Kaplan–Meier and Cox proportional hazards models were used to compare the delay between MCTD and cancer diagnosis according to anti‐RNPC3 status. P values of 0.05 or lower were considered statistically significant. No adjustment for multiple testing was performed as the analyses were considered exploratory.
Ethics statements
The study was approved by the CHUM Ethics Committee (reference number 2015‐5607‐CE14.238).
RESULTS
Twenty‐three percent of patients with MCTD coexpress anti‐RNPC3 autoantibodies
Sixty‐six patients with MCTD were included, 88% patients were female, and the median age at MCTD diagnosis was 41 years. MCTD criteria were fulfilled in 86% (AS), 73% (Kn), 97% (Ka), and 98% (Ta) of patients (Table 1). On first available serum, 15 of 66 (23%) patients were positive for anti‐RNPC3 autoantibodies: 13 (87%) patients had low titers, and 2 (13%) patients had high titers (Supplemental Figure 1). Median follow‐up duration was shorter in the anti‐RNPC3+ group compared to anti‐RNPC3− group (4.2 vs 14.1 years, P = 0.006).
Table 1.
Demographic and cumulative features of SSc in anti‐RNPC3+ compared to anti‐RNPC3− patients with MCTD*
| Features | All patients (n = 66) | MCTD anti‐RNPC3+ (n = 15) | MCTD anti‐RNPC3− (n = 51) |
|---|---|---|---|
| Female sex, n (%) | 58 (88) | 15 (100) | 43 (84) |
| Race, n (%) | |||
| White | 59 (89) | 12 (80) | 47 (92) |
| Black | 4 (6) | 1 (7) | 3 (6) |
| Other | 3 (5) | 2 (13) | 1 (2) |
| Smoker, n (%) | 30/60 (50) | 5/13 (38) | 25/47 (53) |
| Age at diagnosis, median [Q1, Q3], y | 40.6 [30.9, 53.4] | 47.8 [38.9, 53.5] | 38.9 [30.3, 51.3] |
| Duration of follow‐up from time of diagnosis, median [Q1, Q3], y | 10.5 [3.6, 18.9] | 4.2 [0.8, 9.4] a | 14.1 [4.4, 22.2] a |
| Speckled ANA ≥ 1:1,280, n (%) | 66 (100) | 15 (100) | 51 (100) |
| Anti‐RNPC3 value, median (range), MFI | 300 (47–11,113) | 1,838 (1,128–11,113) | 176 (47–906) |
| MCTD classification, n (%) | |||
| Alarcón‐Segovia criteria | 57 (86) | 12 (80) | 45 (88) |
| Kahn criteria | 48 (73) | 8 (53) | 40 (78) |
| Kasukawa criteria | 64 (97) | 15 (100) | 49 (96) |
| Tanaka criteria | 65 (98) | 15 (100) | 50 (98) |
| Definite SSc, n (%) b | 47 (71) | 11 (73) | 43 (84) |
| Definite SLE, n (%) c | 54 (82) | 11 (73) | 23 (85) |
| Definite SjD, n (%) d | 8 (12) | 0 (0) | 8 (16) |
| SSc features, n (%) | |||
| Sine scleroderma | 17 (26) | 0 (0) | 17 (33) |
| Limited cutaneous scleroderma | 42 (64) | 12 (80) | 30 (59) |
| Diffuse cutaneous scleroderma | 7 (11) | 3 (20) | 4 (8) |
| Skin thickening proximal to MCP | 11 (17) | 3 (20) | 8 (16) |
| Sclerodactyly | 49 (74) | 15 (100) e | 34 (67) e |
| Raynaud phenomenon | 65 (98) | 14 (93) | 51 (100) |
| Abnormal nailfold capillaroscopy | 34/46 (74) | 7/10 (70) | 27/36 (75) |
| Puffy fingers | 43/64 (67) | 11/14 (79) | 32/50 (64) |
| Digital tip ulcers | 21 (32) | 7 (47) | 14 (27) |
| Fingertip pitting scars | 10 (15) | 3 (20) | 7 (14) |
| Telangiectasia | 43 (65) | 8 (53) | 35 (69) |
| Calcinosis | 17 (26) | 3 (20) | 14 (27) |
| Pulmonary arterial hypertension f | 17/51 (33) | 5/12 (42) | 12/39 (31) |
| Interstitial lung disease g | 22/56 (40) | 4/12 (33) | 18/44 (41) |
| DLCO < 70% | 33/50 (66) | 7/10 (70) | 26/40 (65) |
| Esophageal dysmotility | 38/63 (60) | 10 (67) | 28/48 (58) |
| GERD or dyspepsia | 54/60 (90) | 12/14 (86) | 42/46 (91) |
| Pneumatosis | 3 (5) | 0 (0) | 3 (6) |
| Pseudo‐obstruction | 6 (9) | 0 (0) | 6 (12) |
| Small intestine bacterial overgrowth | 11 (17) | 2 (13) | 9 (18) |
| Scleroderma renal crisis | 1 (2) | 1 (7) | 0 (0) |
| Cancer diagnosis | 16 (24) | 4 (27) | 12 (24) |
| Cancer within 5 y of MCTD diagnosis h | 6 (9) | 3 (20) f | 3 (6) h |
Bold values indicate statistically significant differences (p values of 0.05 or lower). ANA, antinuclear autoantibody; CT, computed tomography; DLCO, diffusing lung capacity for carbon monoxide; GERD, gastroesophageal reflux disease; MCP, metacarpophalangeal; MCTD, mixed connective tissue disease; MFI, mean fluorescence intensity; mPAP, mean pulmonary arterial pressure; RNPC3, RNA‐binding region‐containing protein 3; SjD, Sjögren's disease; SLE, systematic lupus erythematosus; sPAP, systolic pulmonary arterial pressure; SSc, systemic sclerosis; TTE, transthoracic echocardiogram.
P = 0.006.
Definite SSc criteria: score of ≥9 (ACR/EULAR 2013). 14
Definite SLE criteria: score of ≥10 (ACR/EULAR 2019). 15
Definite SjD criteria: score of ≥4 (ACR/EULAR 2016). 16
P = 0.007.
Pulmonary arterial hypertension defined as sPAP 35 mm Hg on TTE or mPAP 25 mm Hg on right‐sided heart catheterization.
Interstitial lung disease based on thoracic CT scan.
Cancer diagnosis in anti‐RNPC3+ patients: two patients with pulmonary adenocarcinomas and one patient with colon adenocarcinoma. Cancer diagnosis in anti‐RNPC3− patients: one patient with breast cancer, one patient with squamous cell carcinoma of the esophagus, and one patient with cutaneous T cell lymphoma (non‐Hodgkin lymphoma) (see Supplemental Table 1).
Figure 1.
Kaplan–Meier curves of cancer risk stratified by anti‐RNPC3 autoantibody status. Log‐rank P = 0.07. RNPC3, RNA‐binding region‐containing protein 3.
Anti‐RNPC3 autoantibodies in MCTD are associated with SSc skin involvement
The presence of anti‐RNPC3 autoantibodies was associated with a higher frequency of sclerodactyly during the disease course (anti‐RNPC3+ vs anti‐RNPC3−: 100% vs 67%, P = 0.007) (Table 1). There was no significant association with other SSc features.
No association was found between the presence of anti‐RNPC3 autoantibodies and ILD or GI involvement
There was no association between the presence of anti‐RNPC3 autoantibodies and ILD (33% vs 41%, P = 0.75) or GI involvement (87% vs 84%, P = 1), including upper GI (defined as esophageal dysmotility and/or gastroesophageal reflux, 87% vs 86%, P = 1) and lower GI involvement (defined as pneumatosis, pseudo‐obstruction, and/or small intestinal bacterial overgrowth, 13% vs 18%, P = 1) (Table 1).
High‐titer anti‐RNPC3 autoantibodies may be associated with a higher risk of cancer in patients with MCTD
Cancer within five years of MCTD diagnosis was more common in anti‐RNPC3+ than in anti‐RNPC3− patients, although this was not statistically significant (20%, n = 3/15 vs 6%, n = 3/51, respectively; P = 0.13, odds ratio [OR] 4, 95% confidence interval [CI] 0.71–22.36). Numerically, more malignancy within five years was observed among patients with high‐titer anti‐RNPC3+ compared to anti‐RNPC3− patients (P = 0.07, unadjusted OR 16.00, 95% CI 0.54–484.28) (Table 2 and Supplemental Table 1). The time interval between MCTD and cancer diagnosis was shorter among anti‐RNPC3+ (log‐rank P = 0.07, hazard ratio [HR] 2.81, 95% CI 0.87–9.05; Figure 1) and high‐titer anti‐RNPC3+ patients (log‐rank P = 0.00002, HR 28.75, 95% CI 2.60–317.4).
Table 2.
Demographic and cumulative features of SSc in high‐titer anti‐RNPC3+ compared to anti‐RNPC3− patients with MCTD*
| Features | All patients (nCO = 66) | MCTD high‐titer anti‐RNPC3+ (n = 2) | MCTD anti‐RNPC3− (n = 51) |
|---|---|---|---|
| Female sex, n (%) | 58 (88) | 2 (100) | 43 (84) |
| Race, n (%) | |||
| White | 59 (89) | 2 (100) | 47 (92) |
| Black | 4 (6) | 0 (0) | 3 (6) |
| Other | 3 (5) | 0 (0) | 1 (2) |
| Smoker, n (%) | 30/60 (50) | 0 (0) | 25/47 (53) |
| Age at diagnosis, median [Q1, Q3], y | 40.6 [30.9, 53.4] | 35.8 [25.1, 46.4] | 38.9 [30.3, 51.3] |
| Duration of follow‐up from time of diagnosis, median [Q1, Q3], y | 10.5 [3.6, 18.9] | 13.2 [11.7, 14.6] | 14.1 [4.4, 22.2] |
| Speckled ANA ≥ 1:1,280, n (%) | 66 (100) | 2 (100) | 51 (100) |
| Median anti‐RNPC3 value (range), MFI | 300 (47–11,113) | 8,895 (6,676–11,113) | 176 (47–906) |
| MCTD classification, n (%) | |||
| Alarcón‐Segovia criteria | 57 (86) | 2 (100) | 45 (88) |
| Kahn criteria | 48 (73) | 1 (50) | 40 (78) |
| Kasukawa criteria | 64 (97) | 2 (100) | 49 (96) |
| Tanaka criteria | 65 (98) | 2 (100) | 50 (98) |
| Definite SSc, n (%) a | 47 (71) | 1 (50) | 43 (84) |
| Definite SLE, n (%) b | 54 (82) | 1 (50) | 23 (85) |
| Definite SjD, n (%) c | 8 (12) | 0/1 (0) | 8 (16) |
| SSc features, n (%) | |||
| Sine scleroderma | 17 (26) | 0 (0) | 17 (33) |
| Limited cutaneous scleroderma | 42 (64) | 2 (100) | 30 (59) |
| Diffuse cutaneous scleroderma | 7 (11) | 0 (0) | 4 (8) |
| Skin thickening proximal to MCP | 11 (17) | 0 (0) | 8 (16) |
| Sclerodactyly | 49 (74) | 2 (100) | 34 (67) |
| Raynaud phenomenon | 65 (98) | 2 (100) | 51 (100) |
| Abnormal nailfold capillaroscopy | 34/46 (74) | 1/1 (100) | 27/36 (75) |
| Puffy fingers | 43/64 (67) | 1/1 (100) | 32/50 (64) |
| Digital tip ulcers | 21 (32) | 0 (0) | 14 (27) |
| Fingertip pitting scars | 10 (15) | 0 (0) | 7 (14) |
| Telangiectasia | 43 (65) | 1 (50) | 35 (69) |
| Calcinosis | 17 (26) | 0 (0) | 14 (27) |
| Pulmonary arterial hypertension d | 17/51 (33) | 0/1 (0) | 12/39 (31) |
| Interstitial lung disease e | 22/56 (40) | 0 (0) | 18/44 (41) |
| DLCO < 70% | 33/50 (66) | 1/1 (100) | 26/40 (65) |
| Esophageal dysmotility | 38/63 (60) | 1 (50) | 28/48 (58) |
| GERD or dyspepsia | 54/60 (90) | 2 (100) | 42/46 (91) |
| Pneumatosis | 3 (5) | 0 (0) | 3 (6) |
| Pseudo‐obstruction | 6 (9) | 0 (0) | 6 (12) |
| Small intestine bacterial overgrowth | 11 (17) | 1 (50) | 9 (18) |
| Scleroderma renal crisis | 1 (2) | 0 (0) | 0 (0) |
| Cancer diagnosis | 16 (24) | 1 (50) | 12 (24) |
| Cancer within 5 y of MCTD diagnosis f | 6 (9) | 1 (50) f , g | 3 (6) f , g |
Bold values indicate a statistically significant difference (P values of 0.05 or lower). CI, confidence interval; ANA, antinuclear autoantibody; CT, computed tomography; DLCO, diffusing lung capacity for carbon monoxide; GERD, gastroesophageal reflux disease; MCP, metacarpophalangeal; MCTD, mixed connective tissue disease; MFI, mean fluorescence intensity; mPAP, mean pulmonary arterial pressure; OR, odds ratio; RNPC3, RNA‐binding region‐containing protein 3; SjD, Sjögren's disease; SLE, systematic lupus erythematosus; sPAP, systolic pulmonary arterial pressure; SSc, systemic sclerosis; TTE, transthoracic echocardiogram.
Definite SSc criteria: score of ≥9 (ACR/EULAR 2013). 14
Definite SLE criteria: score of ≥10 (ACR/EULAR 2019). 15
Definite SjD criteria: score of ≥4 (ACR/EULAR 2016). 16
Pulmonary arterial hypertension defined as sPAP 35 mm Hg on TTE or mPAP 25 mm Hg on right‐sided heart catheterization.
Interstitial lung disease based on thoracic CT scan.
Cancer diagnosis in high‐titer anti‐RNPC3+ patients: one patient with colon adenocarcinoma. Cancer diagnosis in anti‐RNPC3− patients: one patient with breast cancer, one patient with squamous cell carcinoma of the esophagus, and one patient with cutaneous T cell lymphoma (non‐Hodgkin lymphoma) (see Supplemental Table 1).
Numerically, more malignancy within 5 y was observed among patients with high‐titer anti‐RNPC3+ compared to anti‐RNPC3− patients (P = 0.07, unadjusted OR 16.00, 95% CI 0.54–484.28).
Anti‐RNPC3 autoantibodies are not associated with distinct SLE, SjD, or myositis features
No significant differences regarding SLE, SjD, or myositis features between anti‐RNPC3+ and anti‐RNPC3− patients with MCTD were observed (Supplemental Table 2). Myocarditis was found in none of the anti‐RNPC3+ patients compared to 6 (12%) anti‐RNPC3− patients, which were all anti‐SMN+. Over a median follow‐up of 10.5 (interquartile range [3.6, 18.9]) years, 71%, 82%, and 12% of patients fulfilled the ACR/EULAR criteria for SSc, SLE, and SjD, respectively.
DISCUSSION
Anti‐RNPC3 autoantibodies were found in a quarter of our patients with MCTD. To our knowledge, this is the largest cohort of anti‐RNPC3+ patients with MCTD reported to date and the first study evaluating the presence and clinical associations of anti‐RNPC3 autoantibodies in these patients.
MCTD is an SARD characterized by the presence of high‐titer anti‐U1RNP autoantibodies in combination with Raynaud phenomenon and clinical features of SSc, SLE, arthritis, and/or myositis. 12 Autoantibodies encountered in patients with autoimmune diseases are often useful biomarkers to help or predict diagnosis, clinical phenotype, prognosis, and treatment decision‐making. 18 For example, we recently reported that anti‐SMN autoantibodies in this same cohort of patients with MCTD were frequent and that their presence, especially in high titers, was associated with a severe SSc phenotype, myositis, myocarditis, and lower GI involvement. 7
In previous studies performed in SSc cohorts, the prevalence of anti‐RNPC3 autoantibodies was 3% to 4%, 2 , 4 and their presence was associated with an increased risk of severe ILD 2 , 3 and GI involvement. 5 Notably, in the largest study to date Fertig et al 3 have reported that anti‐RNPC3 autoantibodies were a marker for lung fibrosis which was often severe and at a higher risk of death in patients with SSc. In our cohort of patients with MCTD, anti‐RNPC3 was not associated with ILD or GI involvement. Interestingly, Casciola‐Rosen reported that anti‐RNPC3 autoantibodies are associated with an increased incidence of cancer in SSc and a shorter time interval between SSc diagnosis and cancer development. 4 , 6 , 19 , 20 In our patients with MCTD, the prevalence of cancer with anti‐RNPC3 was greater than in those without these autoantibodies (20% vs 5.9%, respectively), and the time interval between MCTD and cancer diagnosis was shorter among anti‐RNPC3+ patients. Moreover, numerically, more malignancy within five years of MCTD diagnosis was found in patients with high titers of anti‐RNPC3. Although these findings will need to be validated in other MCTD cohorts, this raises the question whether anti‐RNPC3 autoantibodies may be also a marker for an increased risk of cancer in early MCTD. This finding is of interest considering the proposal by Fiorentino et al 6 that autoantibody phenotypes will likely play an important role in the development of cancer screening guidelines in SSc and other SARDs.
Mechanistic insights for the pathogenesis of cancer‐associated autoimmunity include the possibility that cancers arise as a consequence of target tissue damage from the autoimmune disease, or because of a defective immune system that predisposes an individual to developing both autoimmunity and cancer. 5 More recently, Rosen et al proposed a possible role for genetically altered autoantigens in cancer as initiators of the autoimmune response in SSc. 19 , 20 , 21 , 22
Limitations of this study include its retrospective nature, the small number of patients which may have impacted the power to detect significant differences, and to adjust for potential confounders. This study did not find the same phenotypic associations regarding the presence of anti‐RNPC3 autoantibodies in patients with MCTD compared to patients with SSc. This may be due to true differences between the two patient populations or potential differences in assays and/or thresholds used. Median follow‐up duration was shorter in the anti‐RNPC3+ group compared to the anti‐RNPC3− group. This difference may have introduced a source of bias for clinical manifestations traditionally associated with later onset in SARD (eg, pulmonary arterial hypertension). Finally, there are currently no certified commercially available anti‐RNPC3 immunoassays available. Nonetheless, we studied a cohort of well‐defined patients with MCTD with a long follow‐up duration and provided novel results that may have significant impact on clinical care for patients with MCTD.
Anti‐RNPC3 autoantibodies were associated with a higher frequency of SSc skin involvement in patients with MCTD. Numerically, more malignancy within five years of MCTD diagnosis was found in patients with high levels of anti‐RNPC3. Further studies on larger MCTD cohorts are needed to verify whether patients with high‐titer anti‐RNPC3 autoantibodies are at higher risk of cancer.
AUTHOR CONTRIBUTIONS
All authors contributed to at least one of the following manuscript preparation roles: conceptualization AND/OR methodology, software, investigation, formal analysis, data curation, visualization, and validation AND drafting or reviewing/editing the final draft. As corresponding author, Dr Landon‐Cardinal confirms that all authors have provided the final approval of the version to be published and takes responsibility for the affirmations regarding article submission (eg, not under consideration by another journal), the integrity of the data presented, and the statements regarding compliance with institutional review board/Declaration of Helsinki requirements.
Supporting information
Disclosure form.
Supplemental Table 1: Features of patients with cancer within 5 years of MCTD diagnosis.
Supplemental Table 2: Cumulative features of SLE, SjD and myositis in anti‐RNPC3+ compared to anti‐RNPC3– MCTD patients.
Supplemental Figure 1: Flowchart.
Supported in part by the Université de Montréal Scleroderma Research Chair (to Drs Hoa and Senécal), a Université de Montréal Department of Medicine Clinician Researcher Award (to Dr Landon‐Cardinal) and grants from Sclérodermie Québec, Scleroderma Society of Ontario, Scleroderma Society of Canada, the Scleroderma Association of Saskatchewan, Scleroderma Manitoba, the Scleroderma Association of British Columbia (to Drs Hoa, Koenig, Senécal, and Landon‐Cardinal), and Myositis Canada (to Dr Landon‐Cardinal). Drs Hoa and Landon‐Cardinal's work was supported by Fonds de la recherche du Québec en Santé Clinical Research Scholar Junior 1 Awards.
1Division of Rheumatology, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada; 2Division of Rheumatology, Hôpital de la Cité‐de‐la‐Santé, Laval, Québec, Canada; 3Clinique Multidisciplinaire de Neuville, Neuville, Québec, Canada; 4Division of Internal Medicine, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada; 5Autoimmunity Research Laboratory, Centre Hospitalier de l'Université de Montréal Research Center, Montréal, Québec, Canada; 6Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; 7Division of Rheumatology, Hôpital du Sacré‐Cœur de Montréal, Montréal, Québec, Canada; 8Department of Medicine, Kitakyushu Yahata‐Higashi Hospital, Kitakyushu, Japan; 9Department of Human, Information and Life Sciences, University of Occupational and Environmental Health, Kitakyushu, Japan.
Additional supplementary information cited in this article can be found online in the Supporting Information section (https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/acr2.90035).
Author disclosures are available at https://onlinelibrary.wiley.com/doi/10.1002/acr2.90035.
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Supplementary Materials
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Supplemental Table 1: Features of patients with cancer within 5 years of MCTD diagnosis.
Supplemental Table 2: Cumulative features of SLE, SjD and myositis in anti‐RNPC3+ compared to anti‐RNPC3– MCTD patients.
Supplemental Figure 1: Flowchart.