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Revista americana de medicina respiratoria
On-line version ISSN 1852-236X
Rev. am. med. respir. vol.16 no.3 CABA Sept. 2016
ORIGINAL ARTICLE
Factors associated with the presentation of respiratory diseases in patients with rheumatoid arthritis in a Colombian institution between 2012 and 2015
Authors: Santamaria-Alza Yeison, Sánchez Robayo Kelly Johana
Industrial University of Santander. Medicine Directed towards Tobacco Intervention (MEDITA) Research Team
Correspondence: Yeison Santamaria-Alza e-mail: yeison-1807@hotmail.es
Received: 01.04.2016
Accepted: 07.04.2016
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 antiinfammatory drugs (NSAIDs)
and lefunomide predominated in controls. The bivariate analysis showed statistical
significance with positive correlation between respiratory disorders and age, sex, smoking, exposure to biomass, dyspnea, weight loss, RR, DAS 28 and severe disease activity.
There was a statistically significant negative correlation with lefunomide 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.
Introduction
Rheumatoid arthritis is a disease with high prevalence in the general population, representing 1%
in Spain1. In 1998, Anaya J. M. et al calculated a
prevalence of rheumatoid arthritis of 0.4% in Colombia; however, this study only includes African
Colombian patients; thus, such information does
not represent the whole country2. The manifestations of this disease could have a strong impact
on the quality of life of patients due to functional
disability, affecting multiple systems and causing
chronic degenerative processes with biological treatments that can increase the immunosuppression process and generate high health-care
system3 costs.
One of the most frequent complications occurs
at the respiratory system level, where different
diseases may affect the present structures, causing
morphological and functional disorders and making
the system more susceptible to infectious processes.
Such infections, together with the underlying immunosuppression, may lead to sepsis and death3, 4.
Some of the main pulmonary complications already described are the interstitial pulmonary disease5-7, the pleural disease (with findings of pleural thickening in up to more than 73% of rheumatoid
arthritis [RA] patients on whom an autopsy had
been performed8), the airway disease, rheumatoid
nodules, and toxicity with pulmonary damage
caused by certain drugs such as methotrexate,
cyclophosphamide and D-penicillamine9, 10.
At local level, there isn´t any study describing
the current situation of pulmonary complications
in patients suffering from this disease or their impact on the affected patients; thus, a case-control
study has been conducted. The main objective of
the study was to determine which variables are
associated with the presentation of respiratory
diseases in patients with rheumatoid arthritis. In
addition, the study searched for the prevalence of
such variables and described the general characteristics of the affected population.
Method
Study Design
Analytical, observational, case-control study of patients with diagnosis of rheumatoid arthritis who
receive medical care at the Santander University
Hospital in the city of Bucaramanga, Colombia.
Trained personnel gathered information from
institutional clinical records. The Medical Ethics
Committee of the Instituto Neumológico del Oriente approved the protocol. The study was considered not to entail any risk, since data gathering had
been based on clinical records, in accordance with
the 0084 Resolution of October 4th, 1993.
Patients
The study included subjects diagnosed with rheumatoid arthritis by the rheumatology service,
who received in-patient hospital care at the data
collection institution between 2012 and 2015.
Patients who presented mixed connective tissue
diseases, those younger than 18 years old and
the ones with incomplete clinical records were
excluded. Patients who presented respiratory
disorders such as pleural effusion, pleuritis, adult
respiratory distress syndrome, alveolar hemorrhage, interstitial pneumonitis, diaphragmatic
dysfunction, lung thromboembolism, pulmonary
hypertension, upper airway disease, lower airway
disease, pneumothorax or lung infections were
considered as cases. Both acute and chronic diseases were included, since the purpose of the study was to evaluate the full lung disease spectrum in
patients with rheumatoid arthritis. Subjects with
rheumatoid arthritis who, having received medical care at the same institution, did not show the
already mentioned disorders at the chest X-ray
were selected as controls. Data were collected
from magnetic clinical records of the Santander
University Hospital. Diagnostic imaging reports of
the radiology department of the same institution
were also included.
Measurements
The measured variables included identification
data, personal history, respiratory system exposure, used medication, symptoms, signs, laboratory tests and disease activity (DAS28). Lab tests
requested at hospital admission and the signs and
symptoms registered at first assessment were also
included.
Sample Size Calculation
We calculated the sample size in accordance with
the association reported by Wang J. X. and Du
C. G., who found an odds ratio (OR) of 3.72 of
presenting interstitial lung disorders in subjects
with positive rheumatoid factor4. 95% confidence
level, 80% power and 2 controls per case ratio
were determined. 42 cases and 83 controls were
calculated through the Kelsey method, for 125
subjects in total.
Statistical Analysis
We performed the descriptive analysis of qualitative variables by means of relative and absolute
frequencies. Quantitative variables were evaluated by means of the Shapiro-Wilk test in order to
define the normality of distribution and, depending on the results, were expressed in mean and
standard deviation or median and interquartile
ranges. We made a group comparison through
Mann-Whitney or Fisher tests; we determined
the association between each independent variable and the result calculating the OR, 95%
confidence intervals (95% CI) and p values. The
selected variables were those with the greatest association, defined by p < 0.20, and we performed
a logistic regression analysis in order to adjust
the raw OR to reduce confusion. Regarding lost
data, variables with more than 20% data loss were
excluded from the analysis.
Results
Descriptive Analysis
125 subjects with rheumatoid arthritis were included. 42 of the 125 subjects presented respiratory
disorders, with presence of infection and pulmonary hypertension as the most frequent. Table 1 summarizes the frequency of pulmonary disorders.
Mean age was greater in cases. Regarding the vital
signs, we found that the mean heart and respiratory rates were much higher in cases, whereas
the median for oxygen saturation was similar in
cases and controls. Additional tests to measure
disease activity were altered in cases and controls,
with higher erythrocyte sedimentation rate (ESR)
and DAS 28 levels in cases. We observed a similar
behavior in the duration of rheumatoid arthritis,
the smoking index, heart rate, temperature, leukocytes and reactive C-protein (RCP).
TABLE 1. Frequency of Found Pulmonary Disorders.
On the other hand, hemoglobin levels were
lower in cases, with similar trends in the hematocrit and platelet variables.
Regarding qualitative variables, we found that
both in cases and controls, the female gender predominated. Most frequent co-morbidities in the
group of cases were arterial hypertension (50%),
heart failure (30.95%), previous lung infections
(30.95%), gastroesophageal reflux (16.67%) and
hypothyroidism (16.67%). In the group of controls, the most frequent medical records included
arterial hypertension (30.13%), gastroesophageal
reflux (15.66%) and hypothyroidism (16.67%).
With regard to toxicology, wood smoke exposure,
smoking, alcoholism and inhaled drug use were
greater in cases.
The most commonly used drugs both in cases
and controls were corticosteroids, with predominance in the group of controls. Other frequently
used drugs in cases and controls were methotrexate, chloroquine, nonsteroidal antiinflammatory
drugs (NSAIDs) and leflunomide.
The most commonly found symptoms were
dyspnea, cough, and fever in cases, and malaise,
dyspnea, and cough in controls. The physical examination showed abnormal respiratory sounds,
predominant in cases.
The classification of the disease activity evaluated by DAS 28 showed greater remission and
mild and moderate disease activity in controls.
The disease activity was mostly classified as severe
in cases.
Table 2 summarizes the descriptive analysis
of the evaluated quantitative and qualitative
variables.
TABLE 2. Descriptive Analysis. Quantitative and qualitative variables.
We excluded the variables rheumatoid factor, anti-citrulline antibodies, retraction, temperature, and blood pressure from the analysis due to a data loss of more than 20%.
Bivariate Analysis
28 independent variables with p < 0.05 were found.
With regard to age older than 65 years old, we
found an OR of 2.64, with statistical significance
given by p = 0.01, together with male gender showing an OR of 3.27 with p = 0.0096.
History of heart failure, previous lung infections,
arterial hypertension, chronic renal failure, smoking, alcohol use and wood smoke exposure is
associated with the presentation of pulmonary
disorders, with an OR of 11.95 (p = 0.0000), 36.75 (p = 0.0000), 2.32 (p = 0.0003), 11.08 (p = 0.0099),
4.68 (p = 0.0014), 5.33 (p = 0.0140) and 5.20
(p = 0.0005), respectively.
Regarding the use of drugs, treatment with
NSAIDs and leflunomide is found to be associated
with a less frequent presentation of respiratory
disorders, with an OR of 0.36, an interval of 0.016
to 0.79 and p = 0.0091, and an OR of 0.42 with an
interval of 0.18 - 0.94 with p = 0.0313, respectively.
Symptoms with a statistically significant
relationship were dyspnea, with an OR of
32.17 (p = 0.0000); fever, with an OR of 18.13
(p = 0.0000), nonpurulent sputum, with an OR
of 5.33 (p = 0.0140); weight loss, with an OR of
11.04 (p = 0.0005); hemoptisis, with an OR of
8.63 (p = 0.0294); cough, with an OR of 13.36 (p = 0.0000) and malaise, with an OR of 11.73
(p = 0.0009).
Vital signs associated with the presence of
respiratory disorders in patients with arthritis
were heart rate of more than 90 beats per minute
and respiratory rate of more than 17 breaths per
minute, with an OR of 7.26 (p = 0.0001) and 4.80
(p = 0.0015), respectively. Oxygen saturation of
more than 94% was found as a protective factor
given by an OR of 0.16 with 95% CI of 0.03 to 0.84
and p = 0.0159.
Clinical findings with a strong statistical relationship were abnormal respiratory sounds, with
an OR of 80.99 (p = 0.0000), rhonchus, with an OR
of 13.66 (p = 0.0032) and reduction of respiratory
sounds, with an OR of 49.02 (p = 0.0000).
A statistically significant relationship was also
found in the ESR higher than 22 with an OR of
4.46 (p = 0.0039), hemoglobin higher than 10 with
an OR of 0.22 (p = 0.0028), hematocrit higher than
35 with an OR of 0.20 (p = 0.0031) and severe
disease activity (DAS 28 higher than 5.1) with an
OR of 4.63 (p = 0.0001). Table 3 summarizes the
information of bivariate and multivariate analyses.
TABLE 3. Bivariate and Multivariate Analysis
Multivariate Analysis
For the multivariate analysis, we selected variables
with a p value of less than 0.2 in the bivariate
analysis. We performed a multivariate logistic
regression, in which we discarded variables until
we got statistically significant variables.
In this analysis, we found 6 statistically significant variables, associated with the presentation
of respiratory disorders in patients with rheumatoid arthritis. The variables were age older than
65 years old (p = 0.05), wood smoke exposure
(p = 0.02), use of NSAIDs (p = 0.038), presence of
cough (p = 0.001), presence of dyspnea (p = 0.001)
and severe disease activity measured by the DAS
28 scale (p = 0.001).
Table 3 summarizes the variables of the multivariate analysis with adjusted ORs.
Discussion
Rheumatoid arthritis and its systemic complications, mostly pulmonary disorders, represent one
of the main causes of disability in our environment,
and are the second cause of productive life year
loss in Colombia11.
The purpose of this study was to determine the
variables associated with the presentation of these
diseases and contribute to early identification in
patients at risk, thus taking timely preventive and
therapeutic actions to reduce their impact. One
of its main objectives was to start a line of study
of pulmonary disorders in patients with collagen diseases, since there isn´t any relevant study at
local level.
One of the main risk factors found in relation
to the presentation of pulmonary disorders in
patients with RA was age older than 65 years old,
with a 3.98 times increased probability compared
to subjects of less than 65 years old. Similar studies, such as the one conducted by Yin Y.et al12,
showed a higher risk of presenting pulmonary
disorders with an OR of 1.06 when evaluating the
age of the subjects.
Pre-existing pulmonary diseases also show a
strong risk association. In a Japanese research13,
an OR of 8.17 was found, whereas our study reported an almost three times higher risk of presenting lung infections with pre-existing RA, with
an OR of 36.75. The difference in the magnitude of
the measurement could relate to the difference in
sample size and the low prevalence of pre-existing
lung infections in the control subjects of our study.
With regard to toxicology, as for example, smoking, different studies reported similar risk associa-
tion findings. The already mentioned study conducted by Sawada T et al13 showed an OR of 3.97,
and another research carried out by Mori S et al14 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
to biomass smoke is an important etiology that
contributes to the development of multiple pulmonary diseases; but there is no information about it
in the revised studies. However, in our study we
did find a statistically significant association with
the presence of pulmonary disorders, both in the
bivariate and in the multivariate analysis, thus
indicating the strong association of the exposure
with the result. Previous findings can relate to the
physiopathological and respiratory mechanisms
already described in the literature of smoking
and wood smoke, which cause similar disorders in patients with rheumatoid arthritis who have
a baseline-modified immune reaction, increasingly compromising the respiratory system due
to inflammation and remodeling of the pulmonary
structure.
The already mentioned study14 also reported a
5.18 times higher risk factor in patients who presented altered respiratory sounds. In our study, we
found a stronger risk association with these variables given by the presentation of rhonchus with
an OR of 13.66 and reduced respiratory sounds
with an OR of 49.02. Although there is a similar
association, the magnitude is different probably
because there are few controls in our study with
altered respiratory sounds.
With regard to the drugs used to treat rheumatoid arthritis, the work of Alarcon GS, et al15 determined that the use of disease-modifying
drugs increases the risk of presenting pulmonary
lesions. This information agrees with the study
conducted by Sawada et al13, which concludes that
the use of leflunomide is associated with a greater
probability of presenting interstitial pulmonary
disease. However, in our study we found statistical significance, with risk reduction, in the use of
leflunomide and NSAIDs. The other drugs did not
present a statistical association. The discrepancy
with leflunomide could relate to the presence of a
small sample size, the study design or intrinsic differences in the study populations. Association with
the NSAIDs could relate to the fact that patients
who control the symptoms with these drugs show
less inflammatory activity, thus showing fewer
systemic alterations.
Additional tests are important in patients with
arthritis and help predict the presence of pulmonary disorders in previous studies. Alarcon, G. S.15 et al found an association with hypoalbuminemia;
Yin Y. et al11 and Wang J. X. et al5 found a statistically significant relationship with the presence of
anti-citrulline antibodies and rheumatoid factor
levels. In our study, we found statistical significance with hemoglobin, hematocrit and ESR. The
hemoglobin and hematocrit findings could be
similar to the findings of Alarcon GS et al, since
they do not physiologically explain the presence of
pulmonary disorders but do indicate the presence
of a systemic disease.
With respect to the ESR, we believe it is a very
valuable finding, since it is one of the additional
tests used to determine disease activity. With this finding, we are able to suggest that the greater the
inflammatory activity, the stronger the probability
to find pulmonary disorders in these patients. Lack
of association with the rheumatoid factor and anticitrulline antibodies in our study has to do mainly
with the loss of data of those variables. DAS 28
and classification as severe activity show the systemic compromise of rheumatoid arthritis, since
with our study we are able to state that subjects
who show a higher score in the DAS 28 scale and,
thus, a higher classification of the disease, have an
increased risk of presenting pulmonary disorders.
The main strength of this study is the fact
that it is the first of its kind in the region, thus,
it generates important information related to
pulmonary disorders in patients with rheumatoid
arthritis in the northeastern region of Colombia.
For that reason, also, we can generate hypotheses
and future studies.
One disadvantage of the study is that, being a
case-control study, there may be selection bias,
and since it is a restrospective study, it could have
information bias. For that reason, an external
evaluator has validated the data. In addition, the
confusion generated in the study has been mitigated after adjusting the OR in the multivariate
analysis. The classification bias was reduced by
reading the chest X-rays made by field specialists.
The multivariate analysis related to the increased risk of presenting pulmonary disorders
in patients with rheumatoid arthritis was statistically significant for the age older than 65 years
old, wood smoke exposure, presence of cough,
dyspnea and severe disease activity measured by
DAS 28 and presented a lower risk of developing
these complications with the use of NSAIDs. Taking into account the fact that the variables wood
smoke exposure and use of NSAIDs as risk factor
and protective factor, respectively, have not been
described in the literature, it is imperative to conduct future studies with epidemiological designs to
mitigate the bias that have arisen and corroborate
the hypotheses presented in this original text.
Conflicts of Interest: The authors declare there is no conflict of interest related to the topic of this publication.
References
1. Gomez C, Bonilla H, Pulmonary Manifestations of Collagen Diseases, Archivos de bronconeumología 2013; 49: 249-60.
2. Anaya JM, Correa P, Mantilla RD. Prevalence and Severity of Rheumatoid Arthritis in African Colombians from Quibdó. Acta médica Colombiana 1998; 23(6): 322-33.
3. Gabriel SE, Michaud K. Epidemiological studies in incidence, prevalence, mortality, and comorbidity of the rheumatic diseases. Arthritis Res Ther 2009; 11(3): 229.
4. Assayag D, Ryerson C. Determining Respiratory Impairment in ConnectiveTissue Disease-Associated Interstitial Lung Disease. Rheum Dis Clin N Am, 2015: 1-11.
5. Wang JX, Du CG. A Retrospective Study of Clinical Characteristics of Interstitial Lung Disease Associated with Rheumatoid Arthritis in Chinese Patients. Med Sci Monit. 2015; 21: 708-715.
6. Antin-Ozerk D. Evans J, Rubinowitz A. Pulmonary manifestations of rheumatoid arthritis. Clin Chest Med 31 (2010) 451-478.
7. Fischer A, Bois R. Intertitial lung disease in connective tissue disorders. Lancet 2012; 380: 689-98.
8. Baggenstoss AH, Rosenberg EF. Visceral lesions associated with chronic infectious (rheumatoid) arthritis. Arch Pathol 1943; 35: 503.
9. Clements PJ, Furst DE, Wong WK, et al. High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis: analysis of a two-year, double-blind, randomized, controlled clinical trial. Arthritis Rheum 1999; 42(6): 1194-203.
10. Malik SW, Myers JL, DeRemee RA, et al. Lung toxicity associated with cyclophosphamide use. Two distinct patterns. Am J Respir Crit Care Med 1996; 154(6 Pt 1): 1851-6.
11. Clinical Practice Guideline for the early detection, diagnosis and treatment of rheumatoid arthritis. Ministry of Health and Social Protection - Colciencias, 2014: 26- 28.
12. Yin Y, Liang D, Zhao L, Li Y, Liu W, et al. (2014) Anti-Cyclic Citrullinated Peptide Antibody Is Associated with Interstitial Lung Disease in Patients with Rheumatoid Arthritis. PLoS ONE 9(4): e92449. doi:10.1371/journal. pone.0092449
13. Sawada T, Inokuma S, Sato T, Otsuka T, Saeki Y, et al. Leflunomide-induced interstitial lung disease: prevalence and risk factors in Japanese patients with rheumatoid arthritis. Rheumatology 2009; 48: 1069-1072.
14. Mori S, Koga Y, Sugimoto M. Small airway obstruction in patients with rheumatoid arthritis. Modern Rheumatology. 2011; 21(2): 164-173.
15. Alarcon GS, Kremer JM, Macaluso M, Weinblatt ME, Cannon GW, et al. Risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis. A multicenter, case-control study. Methotrexate-Lung Study Group. Ann Intern Med. 1997 Sep 1; 127(5): 356-64.
1. Gomez C, Bonilla H, Manifestaciones pulmonares de las enfermedades del colágeno, Archivos de bronconeumología 2013; 49: 249-60. [ Links ]
2. Anaya JM, Correa P, Mantilla RD. Prevalencia y severidad de la artritis reumatoidea en la población afrocolombiana de Quibdó. Acta médica Colombiana 1998; 23(6): 322-33. [ Links ]
3. Gabriel SE, Michaud K. Epidemiological studies in incidence, prevalence, mortality, and comorbidity of the rheumatic diseases. Arthritis Res Ther 2009; 11(3): 229. [ Links ]
4. Assayag D, Ryerson C. Determining Respiratory Impairment in ConnectiveTissue Disease-Associated Interstitial Lung Disease. Rheum Dis Clin N Am, 2015: 1-11. [ Links ]
5. Wang JX, Du CG. A Retrospective Study of Clinical Characteristics of Interstitial Lung Disease Associated with Rheumatoid Arthritis in Chinese Patients. Med Sci Monit. 2015; 21: 708-715. [ Links ]
6. Antin-Ozerk D. Evans J, Rubinowitz A. Pulmonary manifestations of rheumatoid arthritis. Clin Chest Med 31 (2010) 451-478. [ Links ]
7. Fischer A, Bois R. Intertitial lung disease in connective tissue disorders. Lancet 2012; 380: 689-98. [ Links ]
8. Baggenstoss AH, Rosenberg EF. Visceral lesions associated with chronic infectious (rheumatoid) arthritis. Arch Pathol 1943; 35: 503. [ Links ]
9. Clements PJ, Furst DE, Wong WK, et al. High-doseversus low-dose D-penicillamine in early diffuse systemic sclerosis: analysis of a two-year, doubleblind, randomized, controlled clinical trial. Arthritis Rheum 1999; 42(6): 1194-203. [ Links ]
10. Malik SW, Myers JL, DeRemee RA, et al. Lung toxicity associated with cyclophosphamide use. Two distinct patterns. Am J Respir Crit Care Med 1996; 154(6 Pt 1): 1851-6. [ Links ]
11. Guía de práctica clínica para la detección temprana, diagnóstico y tratamiento de la artritis reumatoidea . Ministerio de Salud y Protección Social - Colciencias, 2014: 26- 28. [ Links ]
12. Yin Y, Liang D, Zhao L, Li Y, Liu W, et al. (2014) AntiCyclic Citrullinated Peptide Antibody Is Associated with Interstitial Lung Disease in Patients with Rheumatoid Arthritis. PLoS ONE 9(4): e92449. doi:10.1371/journal. pone.0092449 [ Links ]
13. Sawada T, Inokuma S, Sato T, Otsuka T, Saeki Y, et al. Leflunomide-induced interstitial lung disease: prevalence and risk factors in Japanese patients with rheumatoid arthritis. Rheumatology 2009; 48: 1069-1072. [ Links ]
14. Mori S, Koga Y, Sugimoto M. Small airway obstruction in patients with rheumatoid arthritis. Modern Rheumatology. 2011; 21(2): 164-173. [ Links ]
15. Alarcon GS, Kremer JM, Macaluso M, Weinblatt ME, Cannon GW, et al. Risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis. A multicenter, case-control study. Methotrexate-Lung Study Group. Ann Intern Med. 1997 Sep 1; 127(5): 356-64. [ Links ]