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Revista Americana de Medicina Respiratoria Vol 16 Nº 3 - Septiembre 2016
Factors associated with the
presentation of respiratory diseases in
patients with rheumatoid arthritis in a
Colombian institution between
Yeison Santamaria-Alza 2012 and 2015
Received: 01.04.2016 Accepted: 07.04.2016 Authors: Santamaria-Alza Yeison, Sánchez Robayo Kelly Johana
Industrial University of Santander. Medicine Directed towards Tobacco Intervention (MEDITA) Abstract
Introduction: Rheumatoid arthritis affects 1% of the world population, and up to 73%
of patients present respiratory disorders. In Colombia, there are no studies evaluating
the relationship between the presence of pulmonary disorders and rheumatoid arthritis.
Objective: To determine the factors associated with respiratory diseases in patients
with rheumatoid arthritis.
Methods: Case-control study (1:2) in 125 patients with rheumatoid arthritis. Descriptive,
bivariate and multivariate analysis.
Results: The mean age was 60.19 for cases and 53.15 years old for controls. 66.67%
of cases and 86.75% of controls were female. The respiratory rate (RR), Disease Activity
Score (DAS 28), smoking, exposure to biomass, dyspnea, weight loss and severe disease
activity were higher in cases. The use of nonsteroidal antiinflammatory drugs (NSAIDs)
and leflunomide predominated in controls. The bivariate analysis showed statistical
significance with positive correlation between respiratory disorders and age, sex, smok-
ing, exposure to biomass, dyspnea, weight loss, RR, DAS 28 and severe disease activity.
There was a statistically significant negative correlation with leflunomide and NSAIDs.
The multivariate analysis showed statistical significance in patients older than 65 years
old, exposure to biomass, cough, dyspnea, severe activity and use of NSAIDs.
Discussion: The results obtained are similar to those found in other studies. In addition,
the presence of exposure to biomass appears as a variable strongly associated with the
presentation of pulmonary disorders in patients with rheumatoid arthritis in our midst.
Key words: Rheumatoid arthritis, infection, pulmonary diseases
treatments that can increase the immunosup-pression process and generate high health-care Rheumatoid arthritis is a disease with high preva- system3 costs.
lence in the general population, representing 1% One of the most frequent complications occurs in Spain1. In 1998, Anaya J. M. et al calculated a at the respiratory system level, where different prevalence of rheumatoid arthritis of 0.4% in Co- diseases may affect the present structures, causing lombia; however, this study only includes African morphological and functional disorders and making Colombian patients; thus, such information does the system more susceptible to infectious processes. not represent the whole country2. The manifesta- Such infections, together with the underlying im- tions of this disease could have a strong impact munosuppression, may lead to sepsis and death3, 4.
on the quality of life of patients due to functional Some of the main pulmonary complications al- disability, affecting multiple systems and causing ready described are the interstitial pulmonary dis-chronic degenerative processes with biological ease5-7, the pleural disease (with findings of pleural Factors associated with respiratory diseases in patients with rheumatoid arthritis thickening in up to more than 73% of rheumatoid was to evaluate the full lung disease spectrum in arthritis [RA] patients on whom an autopsy had patients with rheumatoid arthritis. Subjects with been performed8), the airway disease, rheumatoid rheumatoid arthritis who, having received medi-nodules, and toxicity with pulmonary damage cal care at the same institution, did not show the caused by certain drugs such as methotrexate, already mentioned disorders at the chest X-ray cyclophosphamide and D-penicillamine9, 10.
were selected as controls. Data were collected At local level, there isn´t any study describing from magnetic clinical records of the Santander the current situation of pulmonary complications University Hospital. Diagnostic imaging reports of in patients suffering from this disease or their im- the radiology department of the same institution pact on the affected patients; thus, a case-control were also included.
study has been conducted. The main objective of
the study was to determine which variables are Measurements
associated with the presentation of respiratory The measured variables included identification
diseases in patients with rheumatoid arthritis. In data, personal history, respiratory system expo-
addition, the study searched for the prevalence of sure, used medication, symptoms, signs, labora-
such variables and described the general charac-
tory tests and disease activity (DAS28). Lab tests teristics of the affected population. requested at hospital admission and the signs and symptoms registered at first assessment were also Study Design
Sample Size Calculation
Analytical, observational, case-control study of pa- We calculated the sample size in accordance with tients with diagnosis of rheumatoid arthritis who the association reported by Wang J. X. and Du receive medical care at the Santander University C. G., who found an odds ratio (OR) of 3.72 of Hospital in the city of Bucaramanga, Colombia. presenting interstitial lung disorders in subjects Trained personnel gathered information from with positive rheumatoid factor4. 95% confidence institutional clinical records. The Medical Ethics level, 80% power and 2 controls per case ratio Committee of the Instituto Neumológico del Ori- were determined. 42 cases and 83 controls were ente approved the protocol. The study was consid- calculated through the Kelsey method, for 125 ered not to entail any risk, since data gathering had subjects in total.
been based on clinical records, in accordance with the 0084 Resolution of October 4th, 1993.
We performed the descriptive analysis of qualita- tive variables by means of relative and absolute The study included subjects diagnosed with rheu- frequencies. Quantitative variables were evalu- matoid arthritis by the rheumatology service, ated by means of the Shapiro-Wilk test in order to who received in-patient hospital care at the data define the normality of distribution and, depend-collection institution between 2012 and 2015. ing on the results, were expressed in mean and Patients who presented mixed connective tissue standard deviation or median and interquartile diseases, those younger than 18 years old and ranges. We made a group comparison through the ones with incomplete clinical records were Mann-Whitney or Fisher tests; we determined excluded. Patients who presented respiratory the association between each independent vari-disorders such as pleural effusion, pleuritis, adult able and the result calculating the OR, 95% respiratory distress syndrome, alveolar hemor- confidence intervals (95% CI) and p values. The rhage, interstitial pneumonitis, diaphragmatic selected variables were those with the greatest as-dysfunction, lung thromboembolism, pulmonary sociation, defined by p < 0.20, and we performed hypertension, upper airway disease, lower airway a logistic regression analysis in order to adjust disease, pneumothorax or lung infections were the raw OR to reduce confusion. Regarding lost considered as cases. Both acute and chronic dis- data, variables with more than 20% data loss were eases were included, since the purpose of the study excluded from the analysis.
Revista Americana de Medicina Respiratoria Vol 16 Nº 3 - Septiembre 2016
The most commonly used drugs both in cases and controls were corticosteroids, with predomi- nance in the group of controls. Other frequently 125 subjects with rheumatoid arthritis were in- used drugs in cases and controls were methotrex- cluded. 42 of the 125 subjects presented respiratory ate, chloroquine, nonsteroidal antiinflammatory disorders, with presence of infection and pulmo- drugs (NSAIDs) and leflunomide.
nary hypertension as the most frequent. Table 1 The most commonly found symptoms were summarizes the frequency of pulmonary disorders. dyspnea, cough, and fever in cases, and malaise, Mean age was greater in cases. Regarding the vital dyspnea, and cough in controls. The physical ex- signs, we found that the mean heart and respira- amination showed abnormal respiratory sounds, tory rates were much higher in cases, whereas predominant in cases.
the median for oxygen saturation was similar in The classification of the disease activity evalu- cases and controls. Additional tests to measure ated by DAS 28 showed greater remission and disease activity were altered in cases and controls, mild and moderate disease activity in controls. with higher erythrocyte sedimentation rate (ESR) The disease activity was mostly classified as severe and DAS 28 levels in cases. We observed a similar in cases.
behavior in the duration of rheumatoid arthritis, Table 2 summarizes the descriptive analysis the smoking index, heart rate, temperature, leu- of the evaluated quantitative and qualitative kocytes and reactive C-protein (RCP).
On the other hand, hemoglobin levels were We excluded the variables rheumatoid factor, lower in cases, with similar trends in the hemato- anti-citrulline antibodies, retraction, temperature, crit and platelet variables.
and blood pressure from the analysis due to a data Regarding qualitative variables, we found that loss of more than 20%. both in cases and controls, the female gender pre-
dominated. Most frequent co-morbidities in the Bivariate Analysis
group of cases were arterial hypertension (50%), 28 independent variables with p < 0.05 were found.
heart failure (30.95%), previous lung infections With regard to age older than 65 years old, we
(30.95%), gastroesophageal reflux (16.67%) and found an OR of 2.64, with statistical significance
hypothyroidism (16.67%). In the group of con-
given by p = 0.01, together with male gender show- trols, the most frequent medical records included ing an OR of 3.27 with p = 0.0096. arterial hypertension (30.13%), gastroesophageal History of heart failure, previous lung infections, reflux (15.66%) and hypothyroidism (16.67%).
arterial hypertension, chronic renal failure, smok- With regard to toxicology, wood smoke exposure, ing, alcohol use and wood smoke exposure is smoking, alcoholism and inhaled drug use were associated with the presentation of pulmonary greater in cases.
disorders, with an OR of 11.95 (p = 0.0000), 36.75 TABLE 1. Frequency of Found Pulmonary Disorders.
Pulmonary complication Pulmonary hypertension Interstitial pneumonitis Pleural effusion Lower airway disease Adult respiratory distress syndrome Lung thromboembolism Upper airway disease Alveolar hemorrhage Diaphragmatic dysfunction Factors associated with respiratory diseases in patients with rheumatoid arthritis TABLE 2. Descriptive Analysis. Quantitative and qualitative variables.
CASES (N= 42) CONTROLS (N=83) P value Age (n=125) (mean, SD [standard deviation]) Disease duration in months (n=125) (median, IQR [interquartile range]) Heart failure (n=125) Previous lung infections (n=125) Smoking index (n=22) (median, IQR) Wood smoke index (n=125) Corticosteroid (n=125) Methotrexate (n=125) Leflunomide (n=125) Symptoms and Signs Nonpurulent sputum (n=125) Hemoptisis (n=125) Heart rate (n=120) (median, IQR) Respiratory rate (n=118) (median, IQR) Oxygen saturation (n=110) (median, IQR) Abnormal respiratory sounds (n=125) Hemoglobin (n=115) (mean, SD) Hematocrit (n=115) (mean, SD) C-reactive protein (n=118) (median, IQR) Erythrocyte sedimentation rate (n=125) (median, IQR) DAS 28 (n=125) (mean, SD) Remitting disease (n=125) Low disease activity (n=125) Mild disease activity (n=125) Severe disease activity (n=125) (p = 0.0000), 2.32 (p = 0.0003), 11.08 (p = 0.0099), (p = 0.0000) and malaise, with an OR of 11.73 4.68 (p = 0.0014), 5.33 (p = 0.0140) and 5.20 (p = 0.0009).
(p = 0.0005), respectively. Vital signs associated with the presence of Regarding the use of drugs, treatment with respiratory disorders in patients with arthritis NSAIDs and leflunomide is found to be associated were heart rate of more than 90 beats per minute with a less frequent presentation of respiratory and respiratory rate of more than 17 breaths per disorders, with an OR of 0.36, an interval of 0.016 minute, with an OR of 7.26 (p = 0.0001) and 4.80 to 0.79 and p = 0.0091, and an OR of 0.42 with an (p = 0.0015), respectively. Oxygen saturation of interval of 0.18 - 0.94 with p = 0.0313, respectively. more than 94% was found as a protective factor Symptoms with a statistically significant given by an OR of 0.16 with 95% CI of 0.03 to 0.84 relationship were dyspnea, with an OR of and p = 0.0159.
32.17 (p = 0.0000); fever, with an OR of 18.13 Clinical findings with a strong statistical rela- (p = 0.0000), nonpurulent sputum, with an OR tionship were abnormal respiratory sounds, with of 5.33 (p = 0.0140); weight loss, with an OR of an OR of 80.99 (p = 0.0000), rhonchus, with an OR 11.04 (p = 0.0005); hemoptisis, with an OR of of 13.66 (p = 0.0032) and reduction of respiratory 8.63 (p = 0.0294); cough, with an OR of 13.36 sounds, with an OR of 49.02 (p = 0.0000).
Revista Americana de Medicina Respiratoria Vol 16 Nº 3 - Septiembre 2016
A statistically significant relationship was also diseases, since there isn´t any relevant study at found in the ESR higher than 22 with an OR of local level.
4.46 (p = 0.0039), hemoglobin higher than 10 with One of the main risk factors found in relation an OR of 0.22 (p = 0.0028), hematocrit higher than to the presentation of pulmonary disorders in 35 with an OR of 0.20 (p = 0.0031) and severe patients with RA was age older than 65 years old, disease activity (DAS 28 higher than 5.1) with an with a 3.98 times increased probability compared OR of 4.63 (p = 0.0001). Table 3 summarizes the to subjects of less than 65 years old. Similar stud-information of bivariate and multivariate analyses.
ies, such as the one conducted by . et al12, showed a higher risk of presenting pulmonary disorders with an OR of 1.06 when evaluating the For the multivariate analysis, we selected variables age of the subjects.
with a p value of less than 0.2 in the bivariate Pre-existing pulmonary diseases also show a analysis. We performed a multivariate logistic strong risk association. In a Japanese research13, regression, in which we discarded variables until an OR of 8.17 was found, whereas our study re-we got statistically significant variables. ported an almost three times higher risk of pre- In this analysis, we found 6 statistically signifi- senting lung infections with pre-existing RA, with cant variables, associated with the presentation an OR of 36.75. The difference in the magnitude of of respiratory disorders in patients with rheuma- the measurement could relate to the difference in toid arthritis. The variables were age older than sample size and the low prevalence of pre-existing 65 years old (p = 0.05), wood smoke exposure lung infections in the control subjects of our study.
(p = 0.02), use of NSAIDs (p = 0.038), presence of With regard to toxicology, as for example, smok- cough (p = 0.001), presence of dyspnea (p = 0.001) ing, different studies reported similar risk associa- and severe disease activity measured by the DAS tion findings. The already mentioned study con-28 scale (p = 0.001).
ducted by Sawada T et al13 showed an OR of 3.97, Table 3 summarizes the variables of the multi- and another research carried out by Mori S et al14 variate analysis with adjusted ORs.
determined an OR of 2.78. In our study, smoking was associated with a 4.68 times higher possibility of presenting the event in question, compared to subjects who never smoke. In Colombia, exposure Rheumatoid arthritis and its systemic complica- to biomass smoke is an important etiology that tions, mostly pulmonary disorders, represent one contributes to the development of multiple pulmo-of the main causes of disability in our environment, nary diseases; but there is no information about it and are the second cause of productive life year in the revised studies. However, in our study we loss in Colombia11.
did find a statistically significant association with The purpose of this study was to determine the the presence of pulmonary disorders, both in the variables associated with the presentation of these bivariate and in the multivariate analysis, thus diseases and contribute to early identification in indicating the strong association of the exposure patients at risk, thus taking timely preventive and with the result. Previous findings can relate to the therapeutic actions to reduce their impact. One physiopathological and respiratory mechanisms of its main objectives was to start a line of study already described in the literature of smoking of pulmonary disorders in patients with collagen and wood smoke, which cause similar disorders TABLE 3. Bivariate and Multivariate Analysis More than 65 years old Wood smoke exposure 13.36 5.26-33.89 9.31 2.54-34.07 23.17 8.73-61.47 7.39 2.27-24.05 Severe activity (DAS 28 higher than 5.1) Factors associated with respiratory diseases in patients with rheumatoid arthritis in patients with rheumatoid arthritis who have finding, we are able to suggest that the greater the a baseline-modified immune reaction, increas- inflammatory activity, the stronger the probability ingly compromising the respiratory system due to find pulmonary disorders in these patients. Lack to inflammation and remodeling of the pulmonary of association with the rheumatoid factor and anti- citrulline antibodies in our study has to do mainly The already mentioned study14 also reported a with the loss of data of those variables. DAS 28 5.18 times higher risk factor in patients who pre- and classification as severe activity show the sys- sented altered respiratory sounds. In our study, we temic compromise of rheumatoid arthritis, since found a stronger risk association with these vari- with our study we are able to state that subjects ables given by the presentation of rhonchus with who show a higher score in the DAS 28 scale and, an OR of 13.66 and reduced respiratory sounds thus, a higher classification of the disease, have an with an OR of 49.02. Although there is a similar increased risk of presenting pulmonary disorders.
association, the magnitude is different probably The main strength of this study is the fact because there are few controls in our study with that it is the first of its kind in the region, thus, altered respiratory sounds. it generates important information related to With regard to the drugs used to treat rheu- pulmonary disorders in patients with rheumatoid matoid arthritis, the work of Alarcon GS, et al15 arthritis in the northeastern region of Colombia. determined that the use of disease-modifying For that reason, also, we can generate hypotheses drugs increases the risk of presenting pulmonary and future studies. lesions. This information agrees with the study One disadvantage of the study is that, being a conducted by Sawada et al13, which concludes that case-control study, there may be selection bias, the use of leflunomide is associated with a greater and since it is a restrospective study, it could have probability of presenting interstitial pulmonary information bias. For that reason, an external disease. However, in our study we found statisti- evaluator has validated the data. In addition, the cal significance, with risk reduction, in the use of confusion generated in the study has been miti-leflunomide and NSAIDs. The other drugs did not gated after adjusting the OR in the multivariate present a statistical association. The discrepancy analysis. The classification bias was reduced by with leflunomide could relate to the presence of a reading the chest X-rays made by field specialists. small sample size, the study design or intrinsic dif- The multivariate analysis related to the in- ferences in the study populations. Association with creased risk of presenting pulmonary disorders the NSAIDs could relate to the fact that patients in patients with rheumatoid arthritis was statis-who control the symptoms with these drugs show tically significant for the age older than 65 years less inflammatory activity, thus showing fewer old, wood smoke exposure, presence of cough, systemic alterations. dyspnea and severe disease activity measured by Additional tests are important in patients with DAS 28 and presented a lower risk of developing arthritis and help predict the presence of pulmo- these complications with the use of NSAIDs. Tak- nary disorders in previous studies. Alarcon, G. S.15 ing into account the fact that the variables wood et al found an association with hypoalbuminemia; smoke exposure and use of NSAIDs as risk factor Yin Y. et al11 and Wang J. X. et al5 found a statisti- and protective factor, respectively, have not been cally significant relationship with the presence of described in the literature, it is imperative to con-anti-citrulline antibodies and rheumatoid factor duct future studies with epidemiological designs to levels. In our study, we found statistical signifi- mitigate the bias that have arisen and corroborate cance with hemoglobin, hematocrit and ESR. The the hypotheses presented in this original text.
hemoglobin and hematocrit findings could be similar to the findings of Alarcon GS et al, since Conflicts of Interest: The authors declare there is no
they do not physiologically explain the presence of conflict of interest related to the topic of this publication.
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