There is increasing evidence to indicate that autoimmunity as well as inflammatory reactions occur systemically before development of any clinical sign of joint disease in patients with anti–citrullinated protein antibody (ACPA)–positive rheumatoid arthritis (RA) ([1, 2]). The fact that environmental agents such as smoking () contribute to the risk of developing ACPA-positive RA suggests that events in the lungs may occur early in the course of ACPA-positive RA and could contribute to the systemic autoimmunity that precedes the onset of RA.
There is, however, very little information available on whether changes in the lungs are present in the early stages of RA, and whether such changes might differ between ACPA-positive and ACPA-negative RA. Recently published data from a study of ACPA-positive healthy individuals at risk of RA suggested that structural pulmonary changes may indeed precede the onset of RA ().
In the present study, we investigated the structural and functional pulmonary manifestations in a group of patients with incident RA. We also studied ACPAs in the bronchoalveolar lavage (BAL) fluid of patients with early RA to investigate whether lung abnormalities and local anticitrulline immunity are already present in the early stages after the onset of the first symptoms of RA.
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- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
ACPA-positive RA is a complex disease. Signs of systemic immunity against citrullinated proteins are present before the onset of disease, in the absence of any clinical sign of joint inflammation. Our results demonstrated that lung abnormalities, increased protein citrullination, and ACPA enrichment in the lungs are present early after disease onset. Our observations strengthen the concept that the initiating event might be located outside the joint in patients with ACPA-positive RA.
The presence of lung abnormalities has been demonstrated in many previous studies of RA ([14-18]), but there are still many unresolved issues concerning the temporal relationships between various types of lung manifestations and various types of RA. A strength of our study is that it was performed in a population-based setting, where patients with suspected RA were referred directly from primary care to our rheumatology clinic early after the first symptoms of arthritis, and before receiving any disease-modifying drugs.
A further strength is that we were able to compare HRCT lung changes between patients with early, untreated RA and healthy controls and to account for smoking effects. One limitation is that our control population included only never and current smokers, but no former smokers, whereas the RA cohort included former smokers, which resulted in a much higher number of current smokers in the healthy population (67% of healthy individuals being current smokers, compared with 29% of RA patients). However, in the worst scenario, the bias introduced by this would result in detection of more HRCT findings in healthy individuals and a consequent underestimation of the differences between RA patients and controls.
The HRCT findings described herein do not necessarily represent clinically manifest lung disease, but could be an indirect sign of a subclinical inflammatory process. Preliminary results from our histologic analyses supported this hypothesis, despite the fact that the sample size of subjects with available peribronchial tissue was small, and despite the possibility of selection bias in the recruitment phase of volunteers for bronchoscopy. We did not observe any differences in lung function test results between the RA patients and healthy controls. This observation is consistent with previous studies in which pulmonary dysfunction was demonstrated to have no value in the prediction of RA development (), and in which only a modest correlation was demonstrated between pulmonary function test results and HRCT findings in DMARD-treated patients with early RA ().
A finding of particular interest in the present study was the presence of parenchymal changes at an early disease stage in patients with ACPA-positive RA, but not in those with ACPA-negative RA, compatible with a process in the lungs that precedes the symptoms in the joints. In contrast, the similar frequency of occurrence of airway disease in both ACPA-positive and ACPA-negative RA patients might point to a more general inflammation in the lungs during RA, rather than a specific feature associated with initiation/propagation of the ACPA-positive variant of the disease. In line with this hypothesis, a previous study demonstrated HRCT patterns indicative of a predominance of small airway disease in patients with longstanding RA. In contrast, interstitial abnormalities were frequently observed in early RA, even in the absence of respiratory symptoms ().
Taken together, the findings suggest that early lung injury is the initiating event leading to local molecular changes resulting in neoepitope formation (such as citrullinated proteins) and generation of an immune response in genetically susceptible individuals, which subsequently spreads into the general lymphoid system to ultimately target the joints. Our demonstration of parenchymal HRCT changes occurring mainly in ACPA-positive RA patients and the increased expression of citrullinated proteins in the bronchial biopsy tissue of ACPA-positive RA patients, together with local enrichment of IgG ACPAs and IgA ACPAs in the lungs, are all findings that support this hypothesis. Earlier studies similarly found that ACPAs were present in the blood of RA patients before disease onset ([1, 22]) and in the absence of obvious synovial changes (), while another study demonstrated evidence of antibody production in the lungs of RA patients with longstanding disease (). It still remains to be determined whether the origin of the detected citrullinated proteins is the lung, and whether the joints and lungs have the same citrullinated proteins in common. However, our identification of citrullinated proteins in the bronchial tissue of patients with early RA, using anti–CCP-2 antibodies derived from the synovial fluid of RA patients, gives indirect proof that common citrullinated targets exist in the lungs and joints of RA patients. It is also possible that early lung changes in RA may be due to the secondary immune injury of the lungs that is associated with the presence of ACPAs, in which an initial triggering event occurs at sites different from both the lungs and joints. These 2 different scenarios explaining the HRCT changes are complementary, and not mutually exclusive.
Previous studies, performed with methods and clinical materials different from those used in the present study, yielded results that were partly, but not entirely, in line with this suggested scenario. Pulmonary involvement was present in RA patients recruited within 3 years after diagnosis ([21, 25]). A recent report described an increased frequency of both interstitial and airway disease in a cohort consisting of patients with early RA and patients with longstanding RA (), with airway disease being more prominent in longstanding RA. Another study, in 60 patients with early RA, demonstrated that the presence of ACPAs was associated with bronchial wall thickening, and the presence of RF was associated with interstitial lung disease (). The major limitation of these studies is that a large majority of the included patients were already treated with DMARDs, including methotrexate. An elegant, but small, study of ACPA-positive and/or RF-positive healthy individuals at risk of developing RA demonstrated that there was a higher incidence of HRCT airway abnormalities, but not parenchymal abnormalities, in these patients as compared with ACPA-negative healthy individuals ().
In conclusion, the results from the present study in patients with newly diagnosed RA support the notion that early inflammatory events in the lungs may represent a critical initiating factor in the development of ACPA-positive RA. Thus, further studies on the relationships between inflammation in the lungs and inflammation in the joints are warranted, with the goals being to identify factors that may cause immune responses involved in joint-specific inflammation and to identify early events that can be targeted with preventive or therapeutic measures. Moreover, long-term followup studies to assess the potential clinical consequences of our findings are needed. Our current existing knowledge should nevertheless have direct consequences on the clinical management of the disease, such as underscoring the need for more active screening to identify lung disease in high-risk patients with RA (especially smokers with ACPA-positive RA), prompting implementation of antismoking strategies in the RA treatment program, and encouraging the development of interventional studies to suppress the local immune process in the lungs.
- Top of page
- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Catrina had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Reynisdottir, Karimi, Olsen, Grunewald, Nyren, Eklund, Klareskog, Sköld, Catrina.
Acquisition of data. Reynisdottir, Karimi, Joshua, Olsen, Hensvold, Harju, Engström, Grunewald, Nyren, Eklund, Klareskog, Catrina.
Analysis and interpretation of data. Reynisdottir, Karimi, Joshua, Olsen, Engström, Grunewald, Eklund, Klareskog, Sköld, Catrina.