Summary
Objective
We sought to characterize a novel cohort of patients with lung disease, anti-cyclic citrullinated peptide (CCP) antibody positivity, without rheumatoid arthritis (RA) or other connective tissue disease (CTD).
Methods
The study sample included 74 subjects with respiratory symptoms, evaluated January 2008–January 2010 and found to have a positive anti-CCP antibody but no evidence for RA or other CTD. Each underwent serologic testing, pulmonary physiology testing, and thoracic high-resolution computed tomography (HRCT) scan as part of routine clinical evaluation.
Results
The majority of subjects were women, and most were former cigarette smokers. Four distinct radiographic phenotypes were identified: isolated airways disease (54%), isolated interstitial lung disease (ILD) (14%), mixed airways disease and ILD (26%), and combined pulmonary fibrosis with emphysema (7%). This cohort had a predominance of airways disease, either in isolation or along with a usual interstitial pneumonia-pattern of ILD. Among subjects with high-titer anti-CCP positivity (n=33), three developed the articular manifestations of RA during a median follow-up of 449 days.
Conclusion
We have described a unique cohort of patients with anti-CCP antibody positivity and lung disease in the absence of existing RA or other CTD. The lung phenotypic characteristics of this cohort resemble those of established RA and a few of these patients have developed articular RA within a short period of follow-up. The implications of a positive anti-CCP antibody among patients with lung disease but not RA are not yet known, but we believe requires further investigation.
Keywords: Anti-cyclic citrullinated peptide, Rheumatoid arthritis, Interstitial lung disease, Lung diseases
Introduction
Connective tissue diseases (CTDs) are often associated with lung disease,1 and as a result, pulmonologists frequently undertake screening for CTDs as a component of their evaluation of patients presenting with respiratory symptoms of unknown cause; however, there is no standardized approach to the assessment for CTD. Anti-cyclic citrullinated peptide (CCP) antibodies, often a component of such an assessment, are highly specific for rheumatoid arthritis (RA) and are identified in majority of patients with RA.2 Anti-CCP positivity can predate the development of clinically apparent joint inflammation in patients ultimately diagnosed with RA.3,4 Likewise, lung disorders, particularly interstitial lung disease (ILD) or certain airways diseases (e.g., bronchiolitis or bronchiectasis), are common in patients with RA and may also predate the articular manifestations of RA.5
Data on whether there is an association between anti-CCP positivity and lung disease among patients with RA are extremely limited and conflicting. In one study, there was no difference in serum levels of anti-CCP antibodies between RA patients with or without lung disease.6 In another study, investigators found that high anti-CCP antibody levels were associated with RA-related lung disease.7 Far less well studied is the question of whether there is a relationship between anti-CCP positivity and lung disease in patients without RA (clinically apparent synovial disease). We and others have proposed that anti-CCP is a useful auto-antibody to assess in a patient presenting with an idiopathic interstitial pneumonia, because the presence of anti-CCP identifies ILD patients at risk for developing RA.8,9 For those patients who do, the pulmonary diagnosis changes from idiopathic ILD to RA-related ILD, and with that comes arguably a change in management strategies and prognosis.10 Primarily for research purposes, we have proposed to identify ILD patients with anti-CCP as having a “lung-dominant” form of connective tissue disease (CTD),8 even in the absence of clinically apparent inflammatory joint disease.
In the current study, our goal was to characterize a novel cohort of patients who presented with lung disease in the absence of RA or other CTD and were found to have a positive anti-CCP antibody on serologic screening. We hypothesized that the lung manifestations in such patients would resemble those found in RA-related lung disease – in particular, airways or fibrosing ILD or pleural disease. Furthermore, we hypothesized that some of our patients, despite a limited study duration, would go on to develop articular RA, suggesting that in some cases, lung disease with a positive anti-CCP antibody may represent a forme fruste presentation of RA.
Methods
Cohort development
The cohort in this retrospective study was comprised of patients who presented to our center between January 2008 and January 2010 for evaluation of unexplained respiratory symptoms and who met the following inclusion criteria: (1) age >18 years; (2) anti-CCP ≥20 international units (IU) in our laboratory; (3) absence of RA or other CTD; (4) absence of a history of (or currently present) joint symptoms or signs suggestive of inflammatory arthritis; (5) clinical evidence of lung disease (respiratory symptoms or pulmonary physiologic, gas exchange, or chest imaging abnormalities); and (6) thoracic high-resolution computed tomography (HRCT) scan available for review. Each subject underwent pulmonary physiology testing [based on current accepted methodology11–13 and with results expressed as a percentage of the predicted value for age, gender, and height], and thoracic HRCT as part of their routine clinical evaluation. This study was approved by the National Jewish Health Institutional Review Board (IRB) (protocol HS #2454) and due to the retrospective nature of the study; the requirement for informed consent was waived.
Autoantibody testing
Pulmonologists at our center typically order a broad panel of autoantibodies to screen for CTD in patients with unexplained respiratory problems. In this study, the decision to check for autoantibodies – including the anti-CCP antibody – was made by the evaluating pulmonologist.
Anti-CCP testing
Anti-CCP was tested using the INOVA Diagnostics QUANTA Lite™ CCP3.1 IgG/IgA ELISA kit (San Diego, CA, USA) wherein a positive result is defined by an anti-CCP titer of >20 IU. A positive result with this kit is defined by an anti-CCP titer of >20 IU. A low-positive titer is defined as 21–39 IU, a moderate-positive titer as 40–59 IU, and a high-titer positive as ≥60 IU.
Radiographic and histopathological data analyses
The thoracic HRCT scan for each subject was reviewed and scored in a standardized manner by expert thoracic radiologists (DAL, DAB, ISP) blinded to clinical data. The HRCT scan was considered as demonstrating “airways disease” if there was evidence of mosaic attenuation on inspiratory images, air-trapping on expiratory images, cylindrical bronchiectasis, or bronchiolitis (centrilobular nodularity). The HRCT scan was considered as demonstrating “ILD” if there was evidence of reticular and/or ground-glass opacities, with or without traction bronchiectasis or honeycombing, in a pattern consistent with diffuse parenchymal lung disease. Available lung histopathologic specimens were reviewed and scored in a standardized manner by expert lung pathologists (RDAD, SDG) blinded to clinical data.
Statistical analysis
Baseline data were tabulated using proportions, counts, or medians with measures of central tendency. We compared anti-CCP titer between subgroups defined by HRCT pattern by using the Kruskal–Wallis Test (non-parametric equivalent to one-way analysis of variance) and between former and never smokers by using the Mann–Whitney U test. We compared HRCT patterns between subgroups stratified on anti-CCP titer (low vs. non-low) by using the Chi-square statistic. We used Spearman’s rank correlation to examine the relationships between anti-CCP titer and other continuous variables. We considered p < 0.05 to represent statistical significance. All statistics were run using SAS, Version 9.2 (SAS Inc.; Cary, NC).
Results
We identified 74 subjects who met our inclusion criteria. The majority were women, and most were former cigarette smokers (Table 1). Each subject presented with unexplained respiratory symptoms (dyspnea n=15 [20%], cough n=17 [23%], or both n=42 [57%]). Based on a comprehensive symptom review and clinical assessment by the treating physician, no subject had a history of or current symptoms or signs of joint inflammation (or non-articular symptoms or signs of RA or other CTD). Nearly half (n=36) of the subjects had rheumatologic evaluation within the context of the positive anti-CCP and none of these subjects had features to suggest RA or other CTD. The remainder of the cohort (n=38) did not have specific consultation with a rheumatologist, but on medical record review, none had features to suggest RA or other CTD as determined by their treating physician.
Table 1.
Characteristics of subjects after stratification on anti-CCP titer.
| Low-titer anti-CCP (n =28) | Moderate-high titer anti-CCP (n =46) | |
|---|---|---|
| Median age (range) | 67 (20–85) | 68 (36–84) |
| Female gender | 18 (64%) | 27 (59%) |
| History of cigarette smoking | 16 (57%) | 27 (59%) |
| Current cigarette smokers | 3 (11%) | 0 |
| First degree relative with RA | 3 (11%) | 7 (15%) |
| RF positive | 6 (21%) | 16 (35%) |
| Median RF (range) | 138 (25–1580) | 148 (31–3650) |
| ANA ≥ 1:320 | 0 | 4 (9%) |
| Median anti-CCP (range) | 24 (21–37) | 100 (40–235) |
| Isolated airways disease | 17 (61%) | 23 (50%) |
| Isolated ILD | 5 (18%) | 5 (11%) |
| Airways disease and ILD | 5 (18%) | 14 (30%) |
| Combined pulmonary fibrosis with emphysema | 1 (4%) | 4 (1%) |
ANA=anti-nuclear antibody, CCP=cyclic citrullinated peptide, RF=rheumatoid factor, and ILD=interstitial lung disease.
Twenty-eight (38%) subjects had a low-titer anti-CCP (median 24 IU, range 21–37), 13 (18%) had a moderate-titer anti-CCP (median 47 IU, range 40–58) and 33 (45%) had a high-titer anti-CCP (median 124 IU, range 60–235). Twenty-two (30%) subjects had an elevated rheumatoid factor (RF) antibody (median 148 IU, range 25–3650), and four (5%) subjects had a positive anti-nuclear antibody (ANA) of >1:320 titer. No other auto-antibodies were identified.
HRCT patterns
Four distinct radiographic phenotypes were identified (Tables 2–4): isolated airways disease, isolated ILD, mixed airways disease and ILD, and combined pulmonary fibrosis with emphysema (CPFE).14 Isolated airways disease was the most common pattern identified (n=40, 54%). Twenty-one subjects (28%) had a HRCT pattern consistent with obliterative bronchiolitis; 11 (15%) with cellular bronchiolitis; and 26 (35%) with cylindrical bronchiectasis. Among the 29 subjects with ILD, 19 had a HRCT scan pattern consistent with an underlying histologic pattern of UIP.
Table 2.
Subgroup characteristics after stratification on HRCT pattern.
| Age | Female gender | Smoking history | RF positive | Median anti-CCP titer | |
|---|---|---|---|---|---|
| Isolated airways disease (n =40) | 67 (36–85) | 28 (70%) | 19 (48%) | 15 (38%) | 44 IU (21–235) |
| Isolated ILD (n =10) | 66 (63–78) | 3 (30%) | 7 (70%) | 2 (20%) | 54 IU (22–103) |
| Airways disease and ILD (n =19) | 69 (53–84) | 12 (63%) | 12 (63%) | 3 (16%) | 81 IU (21–219) |
| Combined pulmonary fibrosis with emphysema (n =5) | 75 (66–84) | 2 (40%) | 5 (100%) | 2 (40%) | 81 IU (24–217) |
ILD=interstitial lung disease, HRCT=high resolution computed tomography, RF=rheumatoid factor, and CCP=cyclic citrullinated peptide.
Table 4.
Pulmonary function testing after stratification on HRCT pattern.
| TLC% | RV% | FVC% | FEV-1% | FEV-1/FVC | DLCO% | |
|---|---|---|---|---|---|---|
| Isolated airways disease (n =40) | 112 (59–165) | 218 (79–340) | 75 (45–126) | 66 (19–115) | 72 | 74 (37–100) |
| Isolated ILD (n =10) | 88 (66–100) | 111 (99–166) | 72 (46–88) | 76 (46–96) | 85 | 43 (25–67) |
| Airways disease and ILD (n =19) | 80 (59–142) | 145 (84–236) | 61 (46–100) | 69 (53–105) | 84 | 46 (21–92) |
| Combined pulmonary fibrosis with emphysema (n =5) | 94 (88–98) | 104 (90–143) | 88 (77–109) | 92 (83–112) | 76 | 27 (22–56) |
TLC=total lung capacity, RV=residual volume, FVC=forced vital capacity, FEV-1=forced expiratory volume in 1 s, DLco=diffusing capacity for carbon monoxide, ILD=interstitial lung disease, and HRCT=high resolution computed tomography.
Histopathology findings
Ten subjects had endobronchial (n=6) or transbronchial (n=4) biopsy specimens for review. All but one of the subjects had evidence of airway inflammation; four had evidence of lymphoplasmacytic or eosinophilic inflammation in the airways (Table 5 and Fig. 1). Fourteen subjects had surgical lung biopsy specimens available for review: UIP was the predominant pattern among those with ILD (7 of 11 cases) (Table 6 and Fig. 2). There was one case each with non-specific interstitial pneumonia (NSIP), diffuse alveolar damage, organizing pneumonia, and desquamative interstitial pneumonia. In each of the ILD cases, along with the primary histologic pattern, the pathologist identified areas of interstitial lymphoplasmacytic inflammation (Fig. 2). The three biopsy specimens from subjects whose HRCT scans were categorized as having isolated airways disease all showed evidence of airways inflammation. Seventeen subjects underwent bronchoalveolar lavage (BAL): median (interquartile range) number of cells per microliter for macrophages was 80 (23–86), neutrophils was 6 (1–31), lymphocytes was 8 (3–14), and eosinophils was 1 (0–1).
Table 5.
Histopathologic findings of bronchoscopic biopsy specimens after stratification on HRCT pattern.
| HRCT pattern | Histopathology by bronchial biopsy |
|---|---|
| Isolated airways disease (n =4) | Lymphoplasmacytic inflammation with bronchial inflammation Lymphoplasmacytic inflammation (transbronchial) Granulomata (transbronchial) Inflammation with eosinophils |
| Isolated ILD (n =2) | Cellular bronchiolitis with granulomata (transbronchial) |
| Minimal chronic inflammation | |
| Airways disease and ILD (n =4) | Eosinophilic and lymphoplasmacytic inflammation Chronic inflammation (transbronchial) Chronic inflammation Chronic inflammation |
HRCT=high resolution computed tomography, and ILD=interstitial lung disease.
Figure 1.
Photomicrograph (10×) of histopathology from transbronchial biopsy demonstrating airways disease with lymphoplasmacytic inflammation in a subject with anti-CCP positivity without RA.
Table 6.
Histopathologic findings of surgical lung biopsy specimens after stratification on HRCT pattern.
| HRCT pattern | Histopathology by surgical lung biopsy |
|---|---|
| Isolated airways disease (n =3) | Cellular bronchiolitis with lymphoplasmacytic inflammation, organizing pneumonia, increased perivascular collagen Organizing pneumonia with granulomata and fibrosis Cellular bronchiolitis with lymphoplasmacytic inflammation and patchy cellular interstitial inflammation |
| Isolated ILD (n =4) | UIP with lymphoplasmacytic inflammation, pleuritis, increased perivascular collagen UIP with lymphoplasmacytic inflammation, DIP-like macrophages UIP with lymphoplasmacytic inflammation DIP with lymphoplasmacytic inflammation, pleuritis |
| Airways disease and ILD (n =6) | Bronchiolitis with UIP with granulomata, lymphoplasmacytic inflammation, germinal centers, increased perivascular collagen, DIP-like macrophages UIP with lymphoplasmacytic inflammation, DIP-like macrophages AIP, with DIP-like macrophages, lymphoplasmacytic inflammation, organizing pneumonia NSIP with lymphoplasmacytic inflammation Bronchiolitis and organizing pneumonia with lymphoplasmacytic and eosinophilic inflammation UIP with lymphoplasmacytic inflammation, DIP-like macrophages |
| Combined pulmonary fibrosis with emphysema (n =1) | UIP with lymphoplasmacytic inflammation and emphysema |
AIP=acute interstitial pneumonia, DIP=desquamative interstitial pneumonia, NSIP=non-specific interstitial pneumonia, UIP=usual interstitial pneumonia, and ILD=interstitial lung disease.
Figure 2.
Photomicrograph (20×) of histopathology from surgical lung biopsy demonstrating UIP with lymphoid aggregates and germinal center formation in a subject with anti-CCP positivity without RA.
Associations between anti-CCP and type of lung disease
There was no difference in anti-CCP titer between subjects stratified on HRCT pattern (p=0.5), nor between never and former smokers (p=0.8). Similarly, the clinical features and types of lung disease identified were no different between subgroups stratified on anti-CCP titer (p=0.4). Anti-CCP titer did not correlate with any measure of pulmonary physiology.
Evolution to RA
None of the subjects with low- or moderate-titer anti-CCP developed articular RA during the study period. Three (9%) of the 33 subjects with high-titer anti-CCP developed the articular manifestations of RA during a median follow-up period of 449 days (interquartile range 328–579 days) (Table 7). Only one of the three ever smoked; he was a 70-year-old man with an anti-CCP titer of 175 IU and a RF titer of 366 IU assessed ~1 year prior to onset of symptoms of inflammatory arthritis. He had findings of obstructive airways disease and decreased diffusion capacity by PFTs, and HRCT imaging of isolated airways disease (bronchiectasis and air trapping). The second was a 36-year-old man with an anti-CCP titer of 136 IU and negative RF at the time of lung evaluation, who developed articular RA ~1.5 years later with an anti-CCP titer of 136 IU and a negative RF. He had severe airflow limitation on PFTs, and HRCT imaging evidence of isolated airways disease (bronchiectasis, air trapping). The third subject developed RA within 0.75 years after her lung evaluation. She was 67 years old and had an anti-CCP titer of 92 IU and a RF titer of 718 IU at time of her lung evaluation. She had both obstructive and restrictive findings on PFTs, and HRCT scan evidence of airways disease (air trapping) and ILD (ground-glass and reticular opacities in a pattern suggesting an NSIP-pattern of lung injury).
Table 7.
Characteristics of subjects who developed articular RA during follow-up.
| Subject 1 | Subject 2 | Subject 3 | |
|---|---|---|---|
| Age in years | 70 | 36 | 67 |
| Gender | Male | Male | Female |
| Smoking history | 13 pack years | None | None |
| Current smoker | No | No | No |
| Anti-CCP titer | 175 IU | 136 IU | 92 IU |
| RF titer | 366 IU | Negative | 718 IU |
| HRCT pattern | Isolated airways disease | Isolated airways disease | Airways disease & ILD |
| Histopathology (TBBx) | None | Lymphoplasmacytic inflammation | Lymphoplasmacytic and eosinophilic inflammation |
| Time to development of articular RA | 234 days | 561 days | 261 days |
RF=rheumatoid factor, RA=rheumatoid arthritis, CCP=cyclic-citrullinated peptide, IU=international units, ILD=interstitial lung disease, HRCT=high resolution computed tomography, and TBBx=transbronchial biopsy.
Discussion
In this study, we characterize the lung phenotype of a novel cohort of patients that presented with unexplained respiratory symptoms and abnormal thoracic imaging without RA or other CTD that had a positive anti-CCP antibody on screening serologic assessment.
The HRCT scan patterns and histopathologic features we observed were similar to what one would expect to find in patients with RA-related lung disease,5 thus raising our suspicion that the lung disease in the subjects in our cohort may represent a forme fruste of RA – or perhaps a “pre-arthritis” phenotype in the natural history of RA development. Consider our subjects who underwent surgical lung biopsy; like patients with RA-related ILD, UIP was the most common interstitial injury pattern. Likewise, in the majority of airways specimens (and in all specimens from subjects with ILD), there was lymphoplasmacytic inflammation, a frequent finding in RA-related lung disease.8,15 And finally, as is typically seen in any CTD-related lung disease, we commonly observed multi-compartment lung involvement (e.g., airways and parenchymal disease within the same subject).5,15
We also observed that 3 of 33 subjects (9%) with a high-titer anti-CCP antibody developed the peripheral synovitis of RA within 1.5 years of their pulmonary evaluation and identification of elevated RA-related autoantibodies. The remaining subjects, despite having a circulating autoantibody known to be highly-specific for RA, have not yet developed RA or other definable CTD.
Recent evidence suggests that protein citrullination, a process well-known to occur in the lung,16 is a key component in the pathogenesis of RA. In fact, some investigators speculate that the immune dysregulation of RA originates in the lungs, not the joints.7,16,17 Cigarette smoking may play a role: it is a well-established risk factor for RA and also leads to an increased level of citrullinated proteins in cells obtained from bronchoalveolar lavage.16 Researchers theorize that once immune dysregulation is established in the lungs (possibly through protein citrullination within airway mucosa) a cascade of events ensues. Depending on an intricate interplay of genetics, environmental exposures, and other factors, potential results include articular RA with or without clinically apparent RA-related lung disease.7,16,17 Our observation that 3 subjects with high-titer anti-CCP antibody levels – all with airways disease at baseline – had developed the articular manifestations of RA by a median 449 days of follow-up would seem to bolster this theory. Interestingly, only one of these subjects had ever smoked cigarettes.
Another plausible linkage between the airways and the development of RA has been put forth by Rangel-Moreno and colleagues.18 Rangel-Moreno and colleagues showed that bronchus associated lymphoid tissue (BALT) can be induced by respiratory infection and is identified in some patients with pulmonary manifestations of systemic autoimmune diseases, such as RA. Among their subjects, inducible BALT was associated with the expression of chemokines and cytokines involved in the pathology of RA. Interestingly, and perhaps supportive of a pathologic link, patients with well-developed BALT exhibited higher levels of anti-CCP antibodies in BAL fluid. Thus, the authors conclude that inducible BALT may play a role in the pulmonary manifestations of RA.18
The clinical implications of a positive anti-CCP in patients without RA but with lung disease remain to be determined. It is possible that these patients represent a pre-RA state and the lung disease reflects a forme fruste presentation of RA. Recently, Gizinski and colleagues described four patients with ILD and no articular manifestations of RA, who were RF and anti-CCP positive; all were male smokers, and within 18 months of follow-up, one had developed RA.17
The significance of the positive anti-CCP antibody among subjects in our cohort who have not developed RA is not known. We believe that there are several distinct possibilities: The first is that these individuals are in a pre-RA state. They already possess a “RA-related lung disease” phenotype, and those with the “right” combination of genetics and environmental factors will ultimately develop articular RA. Multiple studies have shown that RA-specific autoantibodies may be present years prior to the articular manifestations of RA, and anti-CCP antibodies are reported to be 98% specific for RA.2–4,19–21 An alternative explanation is that anti-CCP generation in our subjects is a non-specific, non-RA inflammatory response to lung injury. Indeed, none of the subjects with low-titer or moderate-titer anti-CCP antibodies have developed the articular features of RA. Anti-CCP positivity in these subjects may be a false-positive reaction. Such a finding has been described by Elkayam and colleagues in patients with active pulmonary tuberculosis, with later testing identifying that anti-CCP reactivity was in reality binding to non-citrullinated residues on the antigen plate.22 The final, and we believe least likely, possibility is that the assay used to detect anti-CCP at our center has a high-degree of false positives. Our clinical laboratory uses the INOVA Diagnostics QUANTA Lite™ CCP3.1 IgG/IgA ELISA kit (San Diego, CA, USA). This commercially available, third-generation CCP ELISA kit, is used worldwide, and is reported to be 70% sensitive and 98% specific for RA.2,21 Because there was a question about whether the initial anti-CCP result was a “true” positive (most likely because the subject had no articular manifestations of RA), 15 subjects had a repeat anti-CCP test performed; 12 of whom had a high-titer positive anti-CCP on repeat testing. The three that were negative on retest had initial low-titer anti-CCP. Because repeat testing was not uniformly performed, and alternative CCP kits were not used to further confirm antibody positivity, it is possible that other subjects may have had a false-positive result.
This study has other limitations. The retrospective design means that data were not systematically collected, and results should be viewed as hypothesis generating. Only half of the subjects were evaluated by a rheumatologist, so it is possible that in the other half of subjects subtle synovitis or the presence of other subtle extra-thoracic CTD features may have been missed at the time the anti-CCP antibody level was determined. We believe that because we excluded any potential subject who admitted to joint pain or stiffness on systems review, and because we excluded any patient with pre-existing diagnoses of RA or other CTD, we were unlikely to include a large number of subjects with RA at baseline. The short-term follow-up limits the potential to draw definite conclusions about the evolution to RA. Another important limitation of this study is the lack of a control group. The cohort was formed by identifying individuals with a positive anti-CCP, without prior history or current features of RA or other CTD. The anti-CCP test was ordered by the evaluating clinician as part of a screening assessment for occult CTD. Obviously, not every patient with respiratory symptoms at our center was tested for anti-CCP antibodies. Thus, although we have characterized the lung phenotype in this hypothesis-generating study, additional research is needed to answer some important questions about anti-CCP antibodies in patients with respiratory symptoms. Does anti-CCP influence the pulmonary phenotype? Does it impact on the natural history of lung disease? How well does it predict the later development of RA in such patients? Does it lend support for theories favoring the lungs as the initial site of RA-associated immune dysregulation?
In conclusion, we have described a cohort of patients with lung disease and anti-CCP antibody positivity but without evidence of RA or other CTD. We found that these subjects have pulmonary phenotypic features that are similar to those seen in patients with established RA. Although we do not know whether this autoantibody impacts the natural history of the lung diseases we identified, our findings do support the concept that the combination of elevated anti-CCP antibody levels and lung disease, in patients without RA, may represent a pre-RA phenotype, and these patients should be followed for the development of synovitis. Our results also lend support for the hypothesis that the lungs may be an initial site of RA-related immune dysregulation – or of RA itself. Finally, we believe that prospective study is needed and will help answer questions about the etiopathogenesis of RA, the role of protein citrullination in the lungs, and the clinical impact of anti-CCP positivity on the natural history of airway and parenchymal lung disease.
Table 3.
Subgroup characteristics after stratification by smoking status.
| Age | Female gender | Median Pack Years (range) | Isolated airways disease | Isolated ILD | Airways disease and ILD | CPFE | |
|---|---|---|---|---|---|---|---|
| Never smokers (n =31) | 66 (20–80) | 22 (71%) | NA | 21 (68%) | 3 (10%) | 7 (23%) | 0 |
| Smokers (n =40 past, 3 active) | 70 (41–85) | 23 (53%) | 18 (1.3–70) | 19 (44%) | 7 (16%) | 12 (28%) | 5 (12%) |
CPFE=combined pulmonary fibrosis with emphysema, and ILD=interstitial lung disease.
Acknowledgments
Funding
This research was not supported by any grant or other source of funding.
The authors thank Jennifer Brandorff for her assistance with the regulatory components of this study.
Footnotes
Author contribution
All of the authors had meaningful contributions on this research project and manuscript.
Conception and design: AF, JJS, JJS, RMdB, KKB, ALO, TJH, ERFP, KDD. Analysis and interpretation: AF, RMdB, RJM, DAL, DAB, IRP, SDG, RDDA, JJS, JJS, KDD, KKB, ADS, MG, AMR. Drafting the manuscript for important intellectual content: AF, RMdB, RJM, JJS, KKB, KDD, JJS, and RJM.
Aryeh Fischer serves as the corresponding author and is the guarantor of the paper, taking responsibility for the integrity of the work as a whole, from inception to published article.
Conflict of interest
None of the authors have any conflicts of interest pertinent to this research to disclose.
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