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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 16  |  Issue : 5  |  Page : 10-19

Connective tissue disease-associated interstitial lung disease – A multicenter observational study from India


1 Department of Rheumatology, Gleneagles Global Health City, Chennai, Tamil Nadu, India
2 Apex Centre of Rheumatology, Pune, Maharashtra, India
3 Department of Medicine and Rheumatology Unit, Ananta Institute of Medical Sciences, Nathdwara; CARE Pain and Arthritis Centre, Udaipur, Rajasthan, India
4 Department of Clinical Immunology and Rheumatology, Amrita Institute of Medical Sciences, Kochi, Kerala, India
5 Department of Rheumatology, Apollo Gleneagles Hospital; Department of Rheumatology, Vivekananda Institute of Medical Sciences, Kolkata, West Bengal, India
6 Department of Rheumatology, Saveetha Medical College Hospital, Chennai, Tamil Nadu, India
7 Department of Rheumatology and Clinical Immunology, Sir Ganga Ram Hospital, New Delhi, India
8 Department of Rheumatology, Krishna Institute of Medical Sciences, Secunderabad, Telangana, India
9 Department of Rheumatology, Yashoda Hospitals, Secunderabad, Telangana, India
10 Department of Rheumatology, Tricolour Hospitals, Vadodara, Gujarat, India
11 Punjab Rheumatology and Immunology Clinic, Ludhiana, Punjab, India
12 OPTIMA Arthritis and Rheumatology Clinics, Bengaluru, Karnataka, India

Date of Submission06-Nov-2021
Date of Acceptance17-Nov-2021
Date of Web Publication21-Dec-2021

Correspondence Address:
Dr. Sham Santhanam
344/107, Lakshmanaswamy Salai, KK Nagar West, Chennai - 600 078, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-3698.332974

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  Abstract 


Objectives: The objectives of the study were to study the demographic, clinical, serological, and imaging characteristics of connective tissue disease-associated interstitial lung disease (CTD-ILD) patients seen at rheumatology centers across India.
Methods: Adult outpatients with CTD-ILD and interstitial pneumonia with autoimmune features (IPAF), who were seen at the 12 participating rheumatology centers at least once in the preceding 6 months, were recruited and information was retrieved from their medical records. Information on demographics, duration of symptoms, diagnosis, comorbidities, autoantibodies, lung imaging, pulmonary function testing (PFT), echocardiography (ECHO), treatment, immunization, and admissions for exacerbations was obtained.
Results: A total of 620 patients (505 women) were recruited. Rheumatoid arthritis (RA) was the most common CTD associated with ILD followed by systemic sclerosis and mixed connective tissue disorder. In our cohort, 372 (60%) patients had not received a diagnosis of their rheumatic disease or the ILD before seeing their rheumatologist. High-resolution computed tomography of the chest was available for 551 (88.9%) of the patients, and 327 (59.3%) had a nonspecific interstitial pneumonitis (NSIP) pattern. PFT and ECHO data were available for 437 (70.5%) and 453 (73.1%) patients, respectively. The mean forced vital capacity was 61.89% ± 14.8% of the predicted. Pulmonary hypertension (PH) was detected in 162 (35.8%) patients. The most common immunosuppressive used for lung disease was mycophenolate mofetil (54.0%) followed by azathioprine (19.5%). Medical records of these patients showed that after a diagnosis of ILD, in 79 patients, methotrexate (MTX) was changed to an alternative drug, whereas in 11 patients, MTX was added by the rheumatologist after diagnosing the CTD-ILD. There were 28 patients with IPAF. Mycophenolate and rituximab were the common drugs used in IPAF patients. Only 36 (5.8%) of the 620 patients were vaccinated with influenza as well as both the conjugate and the polysaccharide pneumococcal vaccines. Seventy-four (12.25%) patients had a history of one or more admissions for acute exacerbations or complications of ILD.
Conclusion: In this study, RA-ILD was the most common CTD and NSIP was the predominant ILD pattern on high-resolution computerized tomography. More than a third of the patients had PH. In the real-life scenario, we noticed hesitancy among the treating doctors in using MTX in RA-ILD. The number of patients with complete influenza and pneumococcal vaccination was low and this issue needs to be specifically addressed. Larger prospective registry-based data are needed to understand CTD-ILD and the unmet needs in the Indian context.

Keywords: Connective tissue disease, connective tissue disease-associated interstitial lung disease, interstitial lung disease, interstitial pneumonia with autoimmune features


How to cite this article:
Santhanam S, Patil P, Goyal M, Mithun C B, Das P, Mohanasundaram K, Jain N, Prasanna V, Talari K, Pathak H, Aggarwal P, Ponnuru D, Jain VR, Kumar S. Connective tissue disease-associated interstitial lung disease – A multicenter observational study from India. Indian J Rheumatol 2021;16, Suppl S1:10-9

How to cite this URL:
Santhanam S, Patil P, Goyal M, Mithun C B, Das P, Mohanasundaram K, Jain N, Prasanna V, Talari K, Pathak H, Aggarwal P, Ponnuru D, Jain VR, Kumar S. Connective tissue disease-associated interstitial lung disease – A multicenter observational study from India. Indian J Rheumatol [serial online] 2021 [cited 2022 May 28];16, Suppl S1:10-9. Available from: https://www.indianjrheumatol.com/text.asp?2021/16/5/10/332974




  Introduction Top


Interstitial lung disease (ILD) is a common extra-articular manifestation of various connective tissue diseases (CTDs). If not diagnosed in time, it leads to significant morbidity and mortality. There is a paucity of data on CTD-associated ILD (CTD-ILD) in India. There have been few studies on the overall prevalence of ILD in India, mainly from the pulmonology centers, in which CTD-ILD has also been included. A study by Singh et al.[1] across 27 centers in India had a total of 1084 patients, of which 151 had CTD-ILD. In a single-center study by Dhooria et al., of the 803 total patients with ILD, 102 (12.7%) had CTD-ILD.[2] In another retrospective study by Kumar et al., of the 289 patients with ILD, 108 (37.37%) had sarcoidosis and only 13 had CTD-ILD.[3]

The percentage of CTD-ILD among patients with ILD varies widely depending on the departments and the centers participating in the study. There is a paucity of published data on CTD-ILD from rheumatology centres in India. The few available studies are on systemic sclerosis-associated ILD (SSc-ILD), mainly focusing on the treatment responses to various immunosuppressives.[4],[5],[6],[7],[8],[9] Given a lack of Indian data on CTD-ILD, we planned for this large-scale observational study covering multiple geographic territories across India.

The objective of this study was to analyze the clinical, serological, and imaging characteristics of CTD-ILD patients seen at rheumatology units across India.


  Methods Top


Twelve rheumatology centers across 10 states of India participated in this retrospective study [Figure 1]. Adult patients who received a diagnosis of a CTD-ILD or interstitial pneumonia with autoimmune features (IPAF) from their rheumatologist and had visited one of the participating centers at least once in the preceding 6 months (April 2021–September 2021) were recruited. Information was also retrieved from medical records. Patients who had received a diagnosis of CTD-ILD or IPAF from their treating rheumatologist were included in the study.
Figure 1: Rheumatology centers from the north, west, south, and eastern parts of India participated in the study

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Patients with diagnoses of sarcoidosis, antineutrophil cytoplasmic antibody-associated vasculitis, idiopathic pulmonary fibrosis (IPF), and other idiopathic interstitial pneumonia were excluded as they cannot be categorized as CTDs. Information on demographics, duration of symptoms, clinical assessment, diagnosis, blood investigations including autoantibodies, high-resolution computerized tomography (HRCT), two-dimensional echocardiography (ECHO), and pulmonary function testing (PFT) was retrieved. Furthermore, information on treatment, comorbidities, vaccination, and admissions for exacerbations was obtained. We collected the information on drugs used for various CTDs associated with ILD and looked at the patient records to note the changes in prescription patterns after the diagnosis of ILD in patients with an already diagnosed CTD. The diagnosis of ILD in these patients had been confirmed with an HRCT chest and/or PFT. The radiological pattern was identified with the help of printed reports or by going through the clinical notes of the treating physicians at the participating centers. The severity of restriction of ILD on spirometry was graded (adapted from the staging for IPF[10]) using the percentage of predicted forced vital capacity (FVC) (mild – more than 70; moderate – 50–69; severe – 35–49; and very severe – <35). ECHO reports were screened for assessing the presence and severity of pulmonary hypertension (PH).

Ethics statement

The study was approved by the Institutional Ethics Committee for Biomedical Health and Research, Gleneagles Global Health City vide letter number EC/NEW/INST–BMHR/2021/018 and the study was conducted in accordance with the Declaration of Helsinki. Waiver of informed consent was obtained.

Statistical analysis

For normally distributed continuous data, mean and standard deviation (SD) were used and for nonnormal data, median and interquartile range were used. For categorical data, percentages and proportions were calculated. The data were managed and analyzed using IBM SPSS Statistics for Windows (version 25, Armonk, New York, USA).


  Results Top


A total of 620 patients (505 women) with CTD-ILD were found eligible and included. Rheumatoid arthritis (RA) (n = 252, 40.32%) was the most common CTD associated with ILD followed by SSc (n = 159, 25.65%), mixed connective tissue disorder (MCTD) (n = 45, 7.26%), and others. The frequency of the CTDs, demographics, and other baseline characteristics is depicted are [Table 1].
Table 1: Baseline demographic characteristics of patients with connective tissue disease-associated interstitial lung disease

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In our cohort, 372 (60%) of the patients were not diagnosed with either a rheumatic disease or an ILD before seeing a rheumatologist. Of the remaining, 205 (33.1%) patients had only their rheumatic disease diagnosed, 28 (4.5%) had only the ILD diagnosed, and only 15 (2.4%) had both their rheumatic disease and the ILD diagnosed before they were seen by a rheumatologist. Among the 205 patients who had their rheumatic disease diagnosed before seeing a rheumatologist, 142 (69.2%) were diagnosed with RA and 28 (13.6%) with SSc. While screening the patients for eligibility, the electronic medical records at many centers interestingly showed that many patients with ILD had been labeled as CTD-ILD before seeing a rheumatologist, based on a low titer of rheumatoid factor (RF) or anti-nuclear antibody (ANA) positivity. These were later found to have IPF and such patients were not recruited for this study.

An HRCT chest report was available for 551 (88.9%) of the patients. Of these, a majority (n = 327, 59.3%) had a nonspecific interstitial pneumonitis (NSIP) pattern of ILD followed by usual interstitial pneumonia (UIP) pattern (n = 179, 32.5%). PFT data were available for 437 (70.5%) patients and ECHO results for 453 (73.1%) patients. The findings of HRCT chest, PFT, and ECHO are discussed in [Table 1]. The frequency of various autoantibodies in these patients is shown in [Table 2]. In our RA-ILD cohort, 59 percent were positive for both RF and anti-CCP and 30 percent for either one of the autoantibodies. In SSc-ILD, 57 percent were positive for anti-Scl-70 antibody.
Table 2: Autoantibodies in various connective tissues disease-associated interstitial lung disease

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The frequency of NSIP was higher than UIP in all the well-defined CTDs such as SSc and MCTD except for RA where both were nearly equally frequent. Among patients classified as IPAF, 11 had NSIP and nine had UIP patterns on HRCT. The individual radiological patterns in each CTD are discussed in [Table 3].
Table 3: Radiological pattern of interstitial lung disease in well-defined connective tissue diseases*

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ECHO data were available for 453 patients, of which 162 (35.8%) had PH. Among the well-defined CTDs, 145 of the 399 (36.3%) patients had PH. Of them, half had mild PH and the other half had moderate-to-severe PH. The prevalence of PH was more in SSc (48.7%) followed by MCTD (47.6%). We have discussed the prevalence of PH and its severity in various CTDs as shown in [Table 4]. We tried to study the relationship between the severity of PH with the severity of restriction on PFT [Supplementary Table] but did not find a strong correlation between the two.
Table 4: Prevalence and severity of pulmonary hypertension in well-defined connective tissue diseases*

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The most common immunosuppressive used in the management of ILD was mycophenolate mofetil (54%), followed by azathioprine (19.5%), rituximab (18.8%), and cyclophosphamide (10.3%). Among the antifibrotics, pirfenidone was used in 7.6 percent and nintedanib in 3.4 percent. Methotrexate (MTX) was used in 165 patients with CTD-ILD of which 99 had RA-ILD, 28 had SSc-ILD, and 14 had MCTD-ILD. In 79 patients, there was a history of switching from MTX to another drug after a diagnosis of ILD was confirmed, whereas in 11 patients, MTX was added by the rheumatologist on the diagnosis of the CTD-ILD. The other synthetic disease-modifying anti-rheumatic drugs used in RA after the diagnosis of ILD were hydroxychloroquine (n = 127, 50.4%), sulfasalazine (n = 98, 38.9%), and leflunomide (n = 5, 1.9%). Similarly in MCTD, 39 (86.7%) patients were on hydroxychloroquine, 14 (31.1%) on MTX, and 2 (4.4%) on sulfasalazine. In our cohort, nearly three-fourths (457/620) of the patients were on oral glucocorticoids (GC). The mean dose of oral GC was 13.64 (±15.29) mg of prednisolone equivalent per day.

The clinical characteristics of the patients with IPAF are summarized in [Table 5]. In patients labeled as IPAF, the most common pattern of ILD was NSIP and the immunosuppressives used were mycophenolate mofetil and rituximab.
Table 5: Clinical, serological, and imaging characteristics of the patients with interstitial pneumonia with autoimmune features

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In this cohort, 288 (46.4%) patients had received either one, two, or all three of the influenza, pneumococcal conjugate, and polysaccharide vaccines. Out of these, only 36 (5.8%) had received all three vaccines. There were 74 (12.2%) patients who had admissions for ILD exacerbations.


  Discussion Top


Our study was a large observational study involving rheumatology centers from across India. We had a total of 620 patients, with over three quarters being women. RA was the most common CTD followed by SSc. Mycophenolate mofetil was the most common immunosuppressive used for ILD and the most common conventional DMARD used was hydroxychloroquine. Seventy-three percent of the patients were on GCs at the recruitment time point.

The data in our cohort were compared with two other Indian and two Western studies [Table 6]. Both the Indian studies were from pulmonology groups on ILD, with 12-13 percent of the cohort being patients with CTD-ILD. Unlike the Indian studies, the two Western studies from Canada and Portugal included only CTD-ILD patients and they were managed by a multidisciplinary team.[11],[12] In our study, some of the centers had a multidisciplinary team (MDT) involved in managing CTD-ILD patients, whereas others did not, and the practice was not uniform even at the level of each center.
Table 6: Comparison of the clinical characteristics of patients with connective tissue disease-associated interstitial lung disease in the present study with other Indian and Western studies

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In our cohort, RA-ILD was most frequent followed by SSc-ILD and then by MCTD associated ILD. The two Indian studies had similar frequencies of various CTD-ILDs unlike the study by Chan et al. which had SSc-ILD constituting more than 50% of the cohort.[11] The mean age was almost similar (varying between 49 and 56 years) in all the studies. All studies had a much higher percentage of women as expected, and our study had comparatively an even higher proportion of women. All the studies had NSIP as the most common (around 60%) radiographic ILD pattern. The mean FVC in our study was similar to other Indian studies with a moderate restriction being most frequent, unlike the Western studies where a normal FVC or mild restriction was the most frequent. This difference may be due to late referrals and the lack of an MDT approach in the management of these patients.

Takahashi et al. studied the mean pulmonary arterial pressure (MPAP) as an indicator of survival in CTD-ILD. They studied around 74 patients and found that six patients had MPAP >25 mmHg and 16 patients had MPAP >20 mmHg. They found that MPAP was a significant predictor of survival in CTD-ILD patients.[13] In our study, nearly a third of the patients had PH on echocardiogram. Further details to enable the classification of PH as per the World Health Organization criteria were not available. In a study by Hyldgaard et al., among the 11,731 patients, 637 (5.4%) had a diagnosis of CTD-ILD; SSc-ILD (13.4%) was the most common followed by MCTD associated ILD (9.1%). Among patients with CTD, the prevalence of PH was 2.2 percent, which rose to 14.8 percent in patients with CTD-ILD. PH was more common in SSc-ILD (24.1%) followed by MCTD-ILD (20.8%).[14]

In our cohort, 60 percent of the patients had neither a diagnosis of their rheumatic disease nor their ILD before seeing a rheumatologist. This may be attributed to the lack of awareness and delay in referral to the concerned specialist (s). In the study by Tirelli et al., they tried to evaluate a MDT approach for the early detection of CTD-ILD. They found that 33 percent of the referred ILD patients had IPAF, 15 percent had an associated CTD, and the remaining had no evidence of associated CTD. They concluded that a standardized screening questionnaire, autoimmune serological tests, and nail-fold video capillaroscopy helped in establishing the correct diagnosis. The study also emphasized the importance of having a rheumatologist in the MDT, considering a significant percentage of autoimmune disease-related ILD.[15]

In our cohort, only 39.1 percent of the 253 patients with RA-ILD were on MTX. A review of the medical records of patients showed that after the diagnosis of ILD, MTX was switched to another drug in many patients after the diagnosis of their ILD. In the study by Oliveira et al., 23 patients were on MTX before they were diagnosed with ILD, and later, it was switched in all but two patients.[12] In the early RA study and network studies, it was clearly shown that MTX did not increase the risk of ILD and rather delayed the onset of ILD.[16] However, in a meta-analysis by Conway et al., it was demonstrated that MTX results in a small but clinically significant increase in the risk of adverse respiratory events and respiratory infections in RA-ILD.[17] The protective effect of MTX against the development of RA-ILD was demonstrated in another case–control study.[18] Although MTX does not increase the risk for ILD (rather helps in delaying the onset of ILD), in our study, we observed some reluctance among treating clinicians toward using MTX in patients with RA-ILD.[16]

Of the 620 patients, 74 (12.25%) had a history of one or more admissions for exacerbation (s) or complications of their respiratory disease. In a study by Singh et al., the majority of patients with acute exacerbations had SSc and five of the mechanically ventilated patients died. They also found increased mortality in patients with a shorter duration between ILD onset and an acute exacerbation.[19]

We had 28 patients with IPAF in our cohort. The ratio of NSIP to UIP pattern was almost equal. Recently, Hazarika et al. from India studied the clinical characteristics of IPAF in 35 patients.[20] Their study showed a predominance of NSIP radiographic pattern. Sixty percent of the cohort had PH, though 43 percent of them had only mild PH. In our study, we had two patients of IPAF with PH. Cyclophosphamide and MMF were the most common drugs used in the study by these authors, unlike MMF and rituximab in our cohort. Chaurasia et al. studied about 24 patients with IPAF. They had an almost equal distribution of NSIP and UIP patterns with around 96 percent testing positive for ANA.[21] The mean age was 47.8 (±10.7) years and the mean FVC was 44.2 (±24.1) percent of predicted.

In the study by Chan et al. and Oliveira et al., the mortality was 24 percent and 20 percent, respectively.[11],[12] Our study was not designed to assess mortality. Recently, Hyldgaard et al. prospectively studied the survival patterns in patients with CTD-ILD based on a population-based database in Denmark.[14] The survival of patients with CTD-ILD was reduced in comparison to patients with only CTD, although there was no significant difference in survival between individual CTD-ILD subtypes. The 5-year survival varied between 73 percent and 85 percent among the various CTD-ILD.[14]

In our cohort, only 12.5 percent of patients had received all three, i.e., influenza, pneumococcal conjugate, and pneumococcal polysaccharide vaccines. In a study by Malaviya et al. in 2010, nearly 50% of patients complied with the vaccination advice.[22] The same group later in 2017 emphasized the role of a specialist nurse in counseling the patients for vaccination and the compliance rate in this study was 85-90 percent.[23]

There is a paucity of published data on CTD-ILD from India and to the best of our knowledge, this is the first large study on CTD-ILD involving multiple rheumatology centers in India. There were a fair number of patients for each type of CTD-ILD. RA-ILD was the most frequent, and the frequency of others was in line with the prevalence of the various CTDs. The participating centers included medical colleges, corporate hospitals, and private clinics, hence nullifying the referral bias. Thus, the sample can be considered as a fair representation of the CTD-ILD population across the country and also representative of the real-world (usual clinical setting) data.

Our study although has certain limitations. Since it was a retrospective study, we had missing data, and hence, certain data such as the 6 min walk test, diffusing capacity of the lung for carbon monoxide, etc., were not included for the analysis. The diagnostic and treatment algorithm may not have been uniform and would have varied across the centers. Some of them were teaching centers or referral hospitals with a MDT involved in the management of CTD-ILD, unlike others which were single doctor clinics or small group practice hospitals. We did not do a follow-up study and could not assess the response to treatment, mortality rate, or factors predicting mortality. Similarly, we could not study in detail the factors responsible for ILD exacerbations. We could not assess in detail the type of PH in each individual with CTD-ILD. The gold standard for the assessment of pulmonary artery hypertension is right heart catheterization and it was not available at any of the participating centers.


  Conclusion Top


In our cohort, RA-ILD was the most common CTD and NSIP was the predominant ILD pattern on HRCT. Surprisingly, more than a third of the patients had PH. In the real-life scenario, we noticed hesitancy in the use of MTX in RA-ILD. The vaccination coverage was poor and needs to be improved. Larger prospective registry-based data are needed to understand CTD-ILD and the unmet needs in the Indian context.

Acknowledgment

The authors would like to thank Dr. Neha Goyal, Mr. Rahul Jain, and Ms. Divya Sharma for their help in organizing and analyzing the data.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Shenoy PD, Bavaliya M, Sashidharan S, Nalianda K, Sreenath S. Cyclophosphamide versus mycophenolate mofetil in scleroderma interstitial lung disease (SSc-ILD) as induction therapy: A single-centre, retrospective analysis. Arthritis Res Ther 2016;18:123.  Back to cited text no. 4
    
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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