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Current approach to connective tissue disease-associated interstitial lung disease

Solomon, Joshua J.a; Chartrand, Sandraa,b; Fischer, Aryeha

Current Opinion in Pulmonary Medicine: September 2014 - Volume 20 - Issue 5 - p 449–456
doi: 10.1097/MCP.0000000000000081
INTERSTITIAL LUNG DISEASE: Edited by Francesco Bonella and Steven D. Nathan
Free

Purpose of review To review current approaches to the complex intersection of interstitial lung disease (ILD) with the spectrum of connective tissue disease (CTD).

Recent findings There is a growing appreciation that the approach to CTD-associated ILD (CTD-ILD) can be enhanced by a multidisciplinary evaluation that often incorporates the rheumatologist. Determining that ILD is associated with an established CTD requires the exclusion of alternative causes and thorough assessments of the clinical features of both the CTD and ILD. The detection of occult CTD in patients with presumed ‘idiopathic’ disease requires careful attention to the demographic profile, historical clues, subtle physical examination findings, specific autoantibody positivity, radiologic, and histopathologic features. A comprehensive treatment program for CTD-ILD should address comorbid conditions and consider implementation of adjunctive therapeutic strategies. Pharmacologic intervention for CTD-ILD is reserved for those with progressive, clinically significant disease and typically involves use of immunosuppressive therapies.

Summary A multidisciplinary approach can be helpful for CTD-ILD. Further research and controlled trials are needed to determine how to best manage the diverse spectrum of CTD-ILD.

aDepartment of Medicine, National Jewish Health, Denver, Colorado, USA

bRheumatology Research Fellow, University of Colorado School of Medicine, Hôpital Maisonneuve-Rosemont affiliated to Université de Montréal, Department of Medicine, Montréal, Québec, Canada

Correspondence to Aryeh Fischer, MD, Associate Professor of Medicine, Department of Medicine, National Jewish Health, University of Colorado School of Medicine, 1400 Jackson Street, G07, Denver, CO 80206, USA. Tel: +1 303 398 1703; fax: +1 303 398 1040; e-mail: fischera@njhealth.org

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INTRODUCTION

The idiopathic interstitial pneumonias (IIPs) are a group of diffuse parenchymal lung disorders grouped together on the basis of similar clinical, radiologic, and histopathologic features (Table 1) [1]. Before determining that an interstitial pneumonia is ‘idiopathic’ in nature, the clinician must exclude an exhaustive list of known causes, including underlying systemic autoimmune disease – most commonly referred to as ‘connective tissue disease’ (CTD) [1,2].

Table 1

Table 1

Lung involvement is common within the spectrum of CTD, and interstitial lung disease (ILD) is a particularly challenging and potentially devastating manifestation. The CTDs are as follows:

  1. rheumatoid arthritis (RA),
  2. systemic sclerosis (SSc),
  3. systemic lupus erythematosus,
  4. polymyositis/dermatomyositis (PM/DM),
  5. primary Sjögren's syndrome,
  6. mixed connective-tissue disease,
  7. undifferentiated connective tissue disease (UCTD).

The intersection of CTD and ILD is often complex because of the variety of interstitial pneumonia patterns encountered in CTD, and in particular, because the presentation of CTD-associated ILD (CTD-ILD) can vary by time of onset, order of organ manifestation, and degree of disease severity. ILD may be ‘subclinical’ in nature, chronically progressive, or may present in a fulminant, life-threatening manner. ILD may be the initial manifestation of a CTD [3,4▪,5–15] or may be identified in individuals with long-standing CTD.

Although ‘CTD-ILD’ is sometimes considered a homogeneous entity, the spectrum of CTD-ILD actually reflects a heterogeneous category of diseases composed of the different CTDs along with the various interstitial pneumonia patterns. It remains to be determined whether the approach to one type of CTD-ILD can be applied to other forms.

Box 1

Box 1

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Interstitial lung disease occurring in established connective tissue disease

ILD is commonly identified in patients with established CTD; recent studies have shown radiographic prevalence rates of subclinical ILD of 33–57% in various CTD cohorts [16▪]. However, just because a patient with CTD is identified to have diffuse lung disease does not mean the two are necessarily related. Because CTD patients are often on immunosuppressive medications, the finding of new pulmonary infiltrates in these patients should raise strong suspicions for respiratory infection – with either typical or atypical pathogens. Consideration for medication-induced lung toxicity is also warranted because many of the immunomodulatory therapies are associated with drug-induced pneumonitis [17]. A comprehensive evaluation is needed to explore all potential causes, and determining that the ILD is associated with the CTD is usually determined through a process of elimination.

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Identifying occult connective tissue disease in ‘idiopathic’ interstitial lung disease

A thorough evaluation for subtle extrathoracic features of CTD, assessing a broader array of specific autoantibodies, and consideration of radiographic and histopathologic features are all important components of an evaluation for occult CTD. A multidisciplinary evaluation that includes rheumatologic consultation may also be useful [18]. Mittoo et al. [19] retrospectively evaluated a cohort of 114 consecutive patients referred to a tertiary referral center for ILD evaluation. Thirty-four (30%) were found to have CTD-ILD, and of these only half had presented with pre-existing CTD. They found that younger age, high-titer anti-nuclear antibody (ANA), and elevated muscle enzymes were associated with underlying CTD [19]. Castelino et al.[20] described a cohort of 50 patients with ILD evaluated over a 1-year period at a tertiary referral center. Of the 25 patients with a final diagnosis of CTD-ILD, 28% had been initially referred with a diagnosis of idiopathic pulmonary fibrosis (IPF). Among those referred with CTD-ILD, 36% had their diagnosis changed to an alternate CTD. In total, the diagnosis was changed in 54% of the cohort [21].

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Clues to distinguish idiopathic interstitial pneumonia from connective tissue disease-associated interstitial lung disease

In the following section, we discuss clues to distinguish idiopathic interstitial pneumonia from connective tissue disease-associated interstitial lung disease.

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Demographics and clinical features

Demographic features may help distinguish the patient with an underlying CTD. In comparison with IPF, patients with CTD-ILD are more likely to be younger and female [22▪▪]. Certain specific clinical features lend more support for underlying CTD than others. The presence of Raynaud's phenomenon is associated with a pattern of nonspecific interstitial pneumonia (NSIP) [22▪▪] and when identified in a patient with ILD should raise strong suspicions for underlying CTD in general, and SSc in particular [8]. Raynaud's phenomenon is encountered in nearly all patients with SSc and is a common finding in patients with other forms of CTD. As part of the evaluation of Raynaud's phenomenon, clinicians should consider utilizing nailfold capillaroscopy as a relatively simple, inexpensive, and noninvasive diagnostic tool that may be useful to distinguish individuals with early SSc, inflammatory myopathy, or other CTD from those with an IIP [23]. The reporting of symmetric joint swelling or stiffness, or identifying synovitis on physical examination, often suggests underlying CTD. Other clinical features of particular importance include digital edema, ‘mechanic hands’, palmar telangiectasia, and Gottron's sign as they suggest underlying SSc, PM/DM, or the antisynthetase syndrome [24,25]. In contrast, nonspecific symptoms (such as gastroesophageal reflux, pain, and fatigue) are not nearly as helpful because they are ubiquitous and not specific for CTD.

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Autoantibodies

Autoantibody assessment can be an important component of the evaluation of patients with IIP. In the most recent guidelines for the diagnosis of IPF, a panel of screening serologies that include ANA, rheumatoid factor, and anti-cyclic citrullinated peptide (CCP) antibody testing is recommended [2]. In addition to these autoantibodies, a broader panel of screening serologies should be considered in certain circumstances – such as in patients with NSIP. Autoantibodies to consider in patients with features suspicious for CTD include the ANA (with pattern and titer), anti-Smith, anti-RNP, anti-dsDNA, anti-Ro (SS-A), anti-La (SS-B), anti-Scl-70, anti-tRNA synthetase antibodies (e.g., Jo-1, PL-7, PL-12, and others), and anti-CCP.

Autoantibodies can also be useful in those with established CTD as biomarkers to predict the development of progressive ILD. Specifically, anti-Scl-70 is a strong predictor of progressive SSc-ILD, certain anti-tRNA synthetase autoantibodies (e.g., Jo-1, PL-7, and PL-12) are associated with progressive ILD in PM/DM, and there is evidence to suggest that anti-CCP positivity is associated with an increased risk of RA-ILD [26].

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Radiologic features

Thoracic high-resolution computed tomography (HRCT) imaging plays a central role in the evaluation of ILD by providing detailed information on the pattern, distribution and extent of the ILD, assessment of disease severity, and the presence of extraparenchymal abnormalities [27,28]. In contrast to IIP, patients with CTD-ILD are more likely to have ground glass abnormalities, pleural effusions, pericardial effusions, pericardial thickening, and esophageal dilatation and less likely to have honeycombing [27,28]. Individuals with CTD are also more likely to have a HRCT pattern suggestive of NSIP when compared with those without CTD.

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Histopathologic features

The role of surgical lung biopsy in CTD-ILD remains controversial because it is not certain that the interstitial pneumonia lung injury pattern impacts prognosis or management decisions in this population. The distinction between the specific ILD subtypes [e.g., usual interstitial pneumonia (UIP) versus NSIP] is known to have baseline prognostic significance among patients with IIP but does not appear to be as prognostically significant in patients with CTD. In the largest series of biopsied patients with SSc-ILD (n = 80), Bouros et al.[29] showed that changes in diffusing capacity over time – but not baseline histopathologic pattern – predicted prognosis. In the largest series of biopsied CTD-ILD (n = 93), Park et al.[30] demonstrated that age, pulmonary function, and degree of dyspnea were of prognostic importance – but differences in pattern of lung injury did not impact survival. The relatively small study cohort sizes and the impact of selection and referral bias cannot be discounted, and therefore the predictive power of different patterns of lung histopathology remains uncertain in CTD-ILD. Furthermore, CTD-ILD patients tend to be treated with immunosuppressive therapies – targeting both progressive ILD and the extrathoracic inflammatory features – irrespective of specific ILD pattern. In this context, because the biopsy finding may not impact on treatment decisions, when the HRCT provides a strongly suggestive pattern that is consistent with what would be expected under the clinical conditions, clinicians often elect not to proceed with a surgical biopsy [18].

Several histopathologic features may be useful when trying to distinguish an IIP from CTD-ILD. An initial clue to an underlying CTD is the presence of multicompartment involvement on the biopsy; in addition to parenchymal lung injury, there may be components of airways, vascular, or pleural disease [31]. Additional histopathologic features that lend support for the presence of underlying CTD include the presence of lymphoid aggregates, germinal centers, increased perivascular collagen, lymphoplasmacytic inflammation, eosinophil infiltration, or pleural inflammation [31]. When compared with IPF, CTD-associated UIP is characterized by fewer fibroblastic foci, lower fibrosis scores, less honeycombing, and less alveolar cellularity [32]. Flaherty et al.[33] compared the histopathologic features of nine patients with CTD-UIP to that of 99 patients with IPF. Those with CTD-UIP were younger, had better lung function, and shorter duration of symptoms. They found that those with IPF had significantly higher fibroblast focus scores than CTD-UIP and that the fibroblast focus score was the most discriminative feature between these groups. Song et al.[32] compared histopathologic features in 39 patients with CTD-UIP compared with 61 patients with IPF and found that CTD-UIP patients had fewer fibroblastic foci and smaller honeycombing spaces with higher germinal centers and total inflammation scores than IPF patients. Furthermore, the germinal centers score was the best distinguishing feature between CTD-UIP and IPF [32].

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Interstitial lung disease in suggestive forms of connective tissue disease-associated interstitial lung disease

There is a growing appreciation that many patients with IIP have subtle features suggestive of an autoimmune cause and these individuals often do not meet classification criteria for a specific CTD [13,34,35]. Because of the better prognosis associated with CTD-ILD, there may be an inherent desire to define these cases as CTD-ILD. Sometimes these subtle symptoms or signs occur in the absence of serologic abnormalities, or a circulating autoantibody known to be highly specific for a certain CTD (such as anti-Scl-70 with SSc) may be present without typical extrathoracic features. Other scenarios exist whereby specific radiologic or histopathologic features are suggestive of an underlying CTD, and yet the absence of extrathoracic or serologic findings precludes reliable classification as CTD-ILD. The terms ‘undifferentiated CTD’ [34], ‘lung-dominant CTD’ [13], or ‘autoimmune-featured ILD’ [35] have all been used to describe such patients with suggestive forms of CTD-ILD. Each of these categories has a unique set of proposed criteria, represents the ideas of investigative teams from distinct ILD referral centers, and has yet to be prospectively validated. An American Thoracic Society/European Respiratory Society Task Force – An International Working Group on Undifferentiated forms of CTD-ILD’ – is in the process of developing consensus regarding the nomenclature and criteria for the classification of suggestive forms of CTD-ILD. Once there is international and multidisciplinary consensus surrounding the nomenclature and classification criteria of these suggestive forms of CTD-ILD, the requisite platform will be in place to enable the much-needed prospective, multicenter, and multidisciplinary studies to further our understanding of this important subgroup of ILD [6].

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Management considerations

Not all patients with CTD-ILD require treatment. Therapy is typically composed of immunosuppressive medications and is usually reserved for those patients with clinically significant, progressive disease. Furthermore, when considering immunomodulatory therapy options for CTD-ILD, both intrathoracic and extrathoracic disease aspects and degrees of activity need to be considered. Unfortunately, we are left with few data to guide choice of specific therapeutic agents because other than for SSc-ILD and cyclophosphamide (CYC), there are no controlled clinical trial data to provide an evidence base to guide management decisions. Other challenges relate to the paucity of available therapeutic options and that those therapies that are available carry the risk of potentially significant toxicity, the heterogeneity of disease within the CTD-ILD spectrum, and the lack of well defined and validated outcome measures.

As part of a comprehensive management approach in CTD-ILD, it is also important to consider and assess for common comorbid conditions, including gastro-esophageal reflux disease, sleep apnea, and pulmonary hypertension. Furthermore, a comprehensive treatment approach should consider adjunctive therapeutic modalities, such as supplemental oxygen use, formal exercise, and cardiopulmonary rehabilitation.

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Corticosteroids

Corticosteroids have served as an initial and mainstay of therapy for CTD-ILD. There are some small case series supporting the use of corticosteroids for CTD-ILD [36,37] but no controlled studies. In general, we would not advocate for corticosteroids as monotherapy for CTD-ILD. Rather, our approach is to initiate treatment with corticosteroids and either concomitantly or shortly thereafter to initiate a secondary agent [(e.g., azathioprine (AZA), mycophenolate mofetil (MMF), or cyclophosphamide (CYC)] to serve as a steroid-sparing therapy.

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Cyclophosphamide

Small prospective [38–40] and retrospective studies [41,42] have suggested that the use of CYC in CTD-ILD, and SSc-ILD in particular, may lead to stabilization or improvement in lung function. In practice, CYC is often considered the first line of therapy for the more severe forms of CTD-ILD. CYC is the only agent for which we have controlled clinical trial data in support of its use for CTD-ILD, but those data are limited to SSc-ILD and these findings only lend modest support for this agent. Furthermore, it remains to be determined to what extent, data from SSc-ILD can be applied to other forms of CTD-ILD.

The Scleroderma Lung Study (SLS) provided some insights into the treatment of SSc-ILD [43]. In SLS, 158 patients were randomized to either oral CYC at least 2 mg/kg/day or placebo for a 12-month period. The primary endpoint was change in forced vital capacity (FVC). The study cohort was composed of SSc patients with evidence of active ILD by bronchoalveolar lavage or via thoracic HRCT, ‘early disease’ (first non-Raynaud's symptom within 7 years), an FVC between 45 and 85% and at least moderate exertional dyspnea on the Mahler Dyspnea Index. A majority of the patients were women (70.3%) with a mean age of 47.9±1.0 years and 59.5% had diffuse cutaneous SSc. The baseline mean FVC was 68.1 ± 1.0% of predicted and diffusing capacity for carbon monoxide (DLco) was 47.2 ± 1.1% of predicted. The FVC difference at 12 months was +2.53% of predicted (P < 0.03) in favor of the CYC group. The difference remained significant at 18 months from study onset but was lost by 24 months [44], thus reinforcing the notion that longer term immunosuppression is needed in SSc-ILD. Secondary endpoints achieved with CYC treatment included less radiographic progression of fibrosis [45], improved quality of life, and improvements in degree of skin thickening. Patients with more restrictive disease (FVC < 70%) [44], or higher fibrosis scores on thoracic HRCT, or more skin thickening had a more robust response to CYC, with improvement of their FVC instead of deterioration [ΔFVC at 18 months from baseline: +5.10% of predicted with CYC versus −4.71% of predicted with placebo; average treatment effect of 9.81% (P < 0.001)] [46]. Treatment with oral CYC was associated with significant toxicities. There were statistically significant increases in the incidence of leukopenia and neutropenia and trends toward significantly higher prevalence rates of hematuria, pneumonia, and anemia, among those treated with CYC. The Fibrosing Alveolitis in Scleroderma Trial (FAST) [47] randomized 45 patients to active treatment (n = 22) with intravenous CYC 600 mg/m2 monthly for the first 6 months followed by AZA 2.5 mg/kg/day as maintenance therapy with background oral prednisolone 20 mg on alternate days, compared with placebo (n = 23). The majority of the patients were women and most had limited cutaneous SSc. The difference in the change in FVC in the active treatment group (FVC0 80.1 ± 10.3% of predicted and FVC12 82.5 ± 11.3% of predicted) versus the placebo group (FVC0 81.0 ± 18.8% of predicted and FVC12 78.0 ± 21.6% of predicted) showed a trend toward statistical significance [ΔFVC, after adjustment for baseline FVC, was 4.19% (P = 0.08)]. In fact, the ΔFVC was more favorable in FAST than in SLS (+4.2 versus +2.5% respectively), but the smaller number of patients in FAST (n = 45) compared with SLS (n = 158) impacted the ability to achieve statistical significance. Contrary to SLS, adverse events were few, without any bone marrow toxicity and fewer cases of hematuria. Respiratory tract infections occurred more frequently in the placebo group than with the actively treated group (17.4 versus 13.6%).

Taken together, in our opinion, the results from SLS and FAST have dampened enthusiasm for the use of CYC. Although improvements were noted in FVC, they were quite modest in nature. This, along with the substantial toxicity (bone marrow suppression, infection risk, and malignancy risk) associated with CYC, has continued to temper its short-term and long-term use in SSc-ILD and in all forms of CTD-ILD. Although CYC continues to be used in severe forms of CTD-ILD, there remains a desperate need to identify less toxic and more effective therapies for CTD-ILD.

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Mycophenolate mofetil

Mycophenolate mofetil (MMF) has become an increasingly popular treatment in CTD-ILD. The first series advocating for MMF in CTD-ILD was composed of 28 patients and demonstrated that MMF was well tolerated and associated with preservation of lung function among a diverse spectrum of CTD-ILD [48]. Several other retrospective studies report the use of MMF in SSc-ILD, showing trends toward significant improvement of pulmonary function testing parameters and thoracic HRCT findings [48–51]. The largest study of MMF use for CTD-ILD was recently published [52▪] and included a heterogeneous cohort composed of 125 CTD-ILD patients (including 44 SSc-ILD, 32 PM/DM-ILD, 18 RA-ILD). The mean age was 60.4 ± 11.6 years, 42% were women, and most were treated with MMF 3000 mg/day over a 3-year period. In this large and diverse CTD-ILD retrospective cohort, MMF treatment was associated with effective corticosteroids dose tapering [at MMF initiation, median prednisone dose was 20 mg/day and at 12 months from MMF initiation, median prednisone dose was 5 mg/day (P < 0.0001)]. Along with its steroid-sparing effects, treatment with MMF was also associated with longitudinal improvements in FVC and DLco and was found to be a very well tolerated therapy (∼90% adherence rate).

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Azathioprine

AZA is commonly used to treat CTD-ILD; however, other than as used in FAST, the data for AZA are limited to small and retrospective series [47,53]. There are numerous other case series or small retrospective reports demonstrating variable degrees of efficacy of AZA in CTD-ILD [54], and it is a commonly employed therapy without controlled data to guide its use.

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Cyclosporine and tacrolimus

Cyclosporine and tacrolimus are two other commonly used immunosuppressive medications for CTD-ILD. No controlled data exist to guide their use, but retrospective studies lend support for their efficacy [55–57].

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Rituximab

Small series and case reports suggest that rituximab (RTX) may be considered in more refractory cases of CTD-ILD or as rescue therapy. Keir et al.[58▪] recently reported their experience with RTX infusions in 50 cases of severe and refractory ILD; 33 of these cases had CTD-ILD (10 PM/DM, eight SSc, nine UCTD). This was a very severely impacted cohort: 49 out of 50 had received prior immunosuppression with cytotoxic medications, four required mechanical ventilation, mean DLco was 24.5% of predicted and mean FVC was 44.0% of predicted. In the CTD-ILD subgroup, 85% of the patients (most with idiopathic inflammatory myopathy) were classified as responders. In the 6–12-month period prior to RTX, a median decline in FVC of 13.3% of predicted and in DLco of 18.8% of predicted was noted, compared with the 6–12-month period after RTX therapy, in which an improvement of 8.9% of the FVC in percentage of predicted (P < 0.01) and a stabilization of the DLco (P < 0.01) was noted.

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Lung transplantation

Lung transplantation is the last resort in the management of CTD-ILD. Careful selection of suitable CTD-ILD patients for lung transplantation is a complex and tedious process, and thorough evaluations are needed. Studies of carefully selected patients do show that mortality in SSc-ILD transplanted patients is comparable with IPF at 2 years (38 in SSc versus 33% in IPF) [59]. Another study showed no survival difference at 1 year between SSc and IPF patients, but rates of acute graft rejection were significantly increased for the SSc compared with the IPF group (hazard ratio 2.91, P < 0.007) contrary to other adverse effects such as chronic graft rejection, infection, and pulmonary function for which there was no difference [60].

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CONCLUSION

ILD is a common manifestation of CTD and is associated with significant morbidity and mortality. The evaluation of ILD in patients with CTD is complex because of the heterogeneity of the CTDs, the varied types and degrees of severity of ILD encountered, and because ILD can be identified at any point in time in these patients. A thorough – and often multidisciplinary – evaluation is needed when CTD patients develop ILD or when evaluating ILD patients for the presence of occult CTD. Determining that ILD is associated with an established CTD requires the exclusion of alternative causes and thorough assessments of the clinical features of both the CTD and ILD. The detection of occult CTD in patients with presumed ‘idiopathic’ disease requires careful attention to the demographic profile, historical clues, subtle physical examination findings, specific autoantibody positivity, radiologic, and histopathologic features and can be optimized by a multidisciplinary approach that includes rheumatologic collaboration. A comprehensive treatment program for CTD-ILD should consider and address comorbid conditions and implement adjunctive therapeutic strategies. Pharmacologic intervention with immunosuppressive therapies in CTD-ILD should be reserved for those with progressive, clinically significant disease, and is unfortunately not evidence based. Further research and controlled trials are needed to determine how to best manage the diverse spectrum of CTD-ILD.

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Acknowledgements

Aryeh Fischer serves as a paid consultant for Actelion Pharmaceuticals, Gilead Sciences, and InterMune.

Sandra Chartrand received bursary funding from Fondation de l’Hôpital Maisonneuve-Rosemont and Bourse de perfectionnement du Programme de rhumatologie de l’Université de Montréal - Abbvie.

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Conflicts of interest

None declared.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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This study is the largest study to date to evaluate the role of MMF in patients with ILD. The cohort evaluated is 125 patients with a diverse spectrum of CTD-ILD.

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This study evaluates the role of RTX as rescue therapy in a diverse cohort of patients with ILD from several centers.

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Keywords:

collagen vascular disease; connective tissue disease; interstitial lung disease; interstitial pneumonia; pulmonary fibrosis

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