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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 16  |  Issue : 5  |  Page : 109-115

Updates in the management of connective tissue disease-associated interstitial lung disease


1 Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
2 Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Date of Submission24-Aug-2021
Date of Acceptance26-Sep-2021
Date of Web Publication21-Dec-2021

Correspondence Address:
Dr. Chengappa Kavadichanda
Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-3698.332985

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  Abstract 


The occurrence of interstitial lung disease (ILD) in a setting of a well-defined autoimmune disease or in the presence of autoantibodies is being increasingly recognized. The traditional approach to the treatment of connective tissue disease-associated ILD (CTD-ILD) was a combination of glucocorticoids and cyclophosphamide or mycophenolate mofetil. Most of the evidence in treating these cases is limited to a few trials in scleroderma and idiopathic pulmonary fibrosis along with several observational studies in other CTDs. Insights into the pathology of these diseases and the associated lung involvement have resulted in the emergence of several immunosuppressive, antifibrotic, and small molecules as alternatives in CTD-ILD. In this review, we have attempted to summarize several emerging therapeutic options for CTD-ILD.

Keywords: Antifibrotic, biologicals, connective tissue disease–interstitial lung disease, treatment


How to cite this article:
Kavadichanda C, K Naidu G S. Updates in the management of connective tissue disease-associated interstitial lung disease. Indian J Rheumatol 2021;16, Suppl S1:109-15

How to cite this URL:
Kavadichanda C, K Naidu G S. Updates in the management of connective tissue disease-associated interstitial lung disease. Indian J Rheumatol [serial online] 2021 [cited 2023 Feb 1];16, Suppl S1:109-15. Available from: https://www.indianjrheumatol.com/text.asp?2021/16/5/109/332985




  Introduction Top


Involvement of the lungs is a common occurrence in various connective tissue diseases (CTDs). Although the most typical form of lung involvement in these diseases is pleurisy, interstitial lung disease (ILD) can occur in significant subgroups of CTDs. ILD in CTDs is a cause of diagnostic and therapeutic challenge and a major cause of morbidity and mortality. Another unique challenge in CTD-associated ILD (CTD-ILD) is the decision to treat lung disease. It is often not clear if the ILD detected using sensitive tools needs specific treatment or can be watchfully followed up. In current practice, the decision to treat ILD is made based on several factors such as clinical features, associated CTD, associated autoantibodies, anatomical extent of lung involvement, and the lung reserve detected by pulmonary function tests. Once the decision to treat is made, the choice of drugs available to treat CTD-ILD is limited. The physicians often choose from the usual conventional disease modifying agents such as cyclophosphamide (CYC), azathioprine, mycophenolate mofetil (MMF), methotrexate, cyclosporine, or tacrolimus.[1] The use of biological and synthetic target specific drugs is often limited to rituximab, mainly due to the lack of data supporting these drugs. In this review, we have attempted to present the available data on various new biological, synthetic, and target specific drugs being tried in various CTD-ILD. We have also summarized the various newer therapies that are being actively investigated for the treatment of ILD in CTDs.


  Rituximab Top


Rituximab is a chimeric monoclonal antibody directed against CD20. CD20 is a transmembrane protein present in most forms of B-cells. Following administration, rituximab results in depletion of B-cells by a combination of antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and apoptosis induction.[2] The use of rituximab for CTD-ILD has mostly been anecdotal case reports or case series with just a handful of trials.

In systemic sclerosis (SSc), rituximab use has been widely reported. A multicenter study from Greece included 51 patients with SSc-ILD. Thirty-three of them received four infusions rituximab at a dose of 375 mg per m2 of body surface area, once weekly and the course was repeated every 6 months. The other 18 were treated using conventional treatment. Rituximab showed improvement in forced vital capacity (FVC) from 80.60 ± 21.21 at baseline to 86.90 ± 20.56 at 2 years, with no such changes observed in the control group. A similar trend was also observed in five patients who were followed up for 7 years.[3] In a recent randomized, open-label, parallel group, trial from India, 30 patients each received rituximab and IV CYC for SSc-ILD. The FVC (percentage of predicted) improved from 61.30 (±11.28) to 67.52 (±13.59) in the rituximab group as compared to decrease from 59.25 (±12.96) to 58.06 (±11.23) in the CYC group at 6 months.[4] This finding was concordant with an earlier small, randomized trial of 14 SSc-ILD patients. The investigators found that among the 8 individuals who received rituximab for their ILD, percentage of FVC improvement over 1 year was 10.25%, opposed to 5.04% deterioration in the control group. The diffusing capacity of carbon monoxide (DLCO) also increased by 19.46% in the rituximab group, compared to 7.5% decline in the control group.[5] In contrast to these trials, a large observational cohort which included 146 SSc-ILD treated with rituximab found no difference in the pulmonary outcomes when compared to the controls. FVC at baseline was 76.3 (±19.3) and at follow-up was 77.7 (±20.2) with rituximab. Similar trend was observed in the controls (79.1 [±20.6] to 80.7 [±21.1]) (n = 497). The extent of fibrosis detected using computed tomography (CT) also remained stable (20.0 [±2.1] to 20.0 [±2.5]) in both the groups.[6] The two sets of evidence suggest that rituximab stabilizes established SSc-ILD and may improve ILD in early cases.

In rheumatoid arthritis-associated ILD (RA-ILD), rituximab is often used with a great deal of confidence in clinical practice. In a 10-year single-center observational study on RA-ILD from the United Kingdom, 16% had improvement in FVC and 52% stabilized while on rituximab.[7] Another retrospective study utilizing the British Society for Rheumatology Biologics Register for RA which included 352 patients showed almost 50% mortality benefit with rituximab in comparison to tumor necrosis factor inhibitor.[8] Data from the Spanish NEREA registry which included 68 patients with RA-ILD deduced that treatment with rituximab was associated with a lower risk of decline in FVC ≥5% (hazard ratio 0.51;95% confidence interval [CI]: 0.31, 0.85).[9]

Another autoimmune rheumatic disease which is associated with ILD and where rituximab is extensively being used is in idiopathic inflammatory myopathy (IIM), mainly in anti-synthetase syndrome (ASS). Data on 11 refractory patients with ASS-ILD from a Norwegian retrospective cohort showed a more than 10% improvement in FVC in six patients. Three of them had improvement in DLCO (>15%) along with improvement on imaging.[10] A follow-up study by the same group on a larger cohort of 34 ASS patients showed that there was a significant improvement in FVC, DLCO, and CT findings in 24 ASS-ILD individuals at 12 months post rituximab.[11] Similar results have emerged in other retrospective studies[12] where the benefits of rituximab for ILD seem to last up to 3 years.[13] Moreover, it is interesting to note that rituximab use in IIM-ILD has higher benefit than that seen with other CTD-ILDs, making it a viable and safe option in IIM.[14]


  Belimumab Top


BLyS or B-cell activating factor is required for B-cell activation, proliferation, and maturation. Belimumab is a recombinant antibody which inhibits the action of human BLyS by binding to the soluble form of the cytokine. Belimumab has been tried in a 52-week, double-blind, placebo-controlled, pilot study in diffuse SSc patients with a disease duration of less than 3 years. Among the nine patients who received belimumab, the mean change in FVC was +5% as opposed to −2% in those who received placebo.[15] This result is encouraging and will need larger well-designed trials for further confirmation. There is no evidence of belimumab use in other CTD-ILD.


  Tocilizumab Top


Tocilizumab (TCZ) is an interleukin (IL) - 6 receptor-inhibitor. IL-6 plays a major role in myofibroblast transformation and activation and differentiation of immune cells. In the bleomycin-induced SSc mouse model, use of monoclonal anti-IL-6R antibody showed improvement in fibrosis of skin.[16] The phase 2, randomized, double-blind, placebo-controlled trial investigating the safety and efficacy of subcutaneous TCZ (faSScinate trial) was conducted which included patients with a disease duration of ≤5 years. The trial found a smaller decline in FVC with TCZ (−34 mL) compared to placebo (−171 mL) at 24 weeks.[17]

The following phase III, randomized, double blind, placebo-controlled, multi-center trial of TCZ in diffuse systemic sclerosis confirmed the earlier findings. The trial showed a lesser drop in predicted percentages for FVC (−0.6%) with TCZ 162 mg/week compared to −3.9 with placebo over 48 weeks. In the meantime, 26% of those on TCZ had some improvement in FVC as compared to 29% on placebo.[18] These benefits paved way for the U.S. Food and Drug Administration (FDA) approval for TCZ use in SSc-ILD. Besides SSc, evidence for TCZ use in other CTD-ILD is lacking at present.


  Abatacept Top


Abatacept is a fusion protein that inhibits the T-cell co-stimulatory signal. The drug acts by binding to CD80 and CD86 which are essential for generating the second signal in a T-cell activation process. The role of abatacept in SSc was evaluated by the phase 2 safety and efficacy of abatacept in early diffuse cutaneous systemic sclerosis trial. The trial involved 88 individuals with SSc with a disease duration of <3 years. Abatacept was given to 44 and the other 44 received placebo. The primary endpoint assessed at 12 and 18 weeks was change in the modified Rodnan skin score. The change in predicted FVC was −2.7% in placebo as compared to −1.6% with abatacept at 12 months. There was an improvement in DLCO with abatacept, improvement of +0.7% as compared to decline of −2.1% in the placebo arm. The changes were maintained even at 18 months of the study.[19],[20]

The data for the use of abatacept in RA-ILD are limited to case series and a few observational studies. A systematic review of one case series and eight observational studies showed that abatacept resulted in improvement or stabilization of ILD on imaging in 76.6-92.7% of individuals. Moreover, during a follow-up of 17.4–47.8 months, the improvement in FVC or DLCO was more than 85%. The improvement was not dependent on the radiographic type of ILD but was observed in those with early ILD. Abatacept also showed 90% reduction in risk of ILD deterioration in comparison to TNFi during a 24-month follow-up.[21] A recent observational study from Italy evaluating 44 patients with RA-ILD showed that 11.4% had worsening, 16% had improvement, and 72.6% had stabilization of ILD on abatacept.[22] Based on this data, a trial, AbatacePt in RA-ILD (APRIL; NCT03084419), is in progress.[23]

Various ongoing trials currently investigating biological agents for various CTD-ILD are summarized in [Table 1].
Table 1: Details of various agents currently in trials for connective tissue disease-interstitial lung disease

Click here to view



  Janus Kinase inhibitors Top


The Janus Kinase (JAK)/STATs are intracellular downstream signaling molecules comprising JAKs 1, 2, 3, and tyrosine kinase 2 along with STATs 1, 2, 3, 4, 5A, 5B, and 6. These pathways are responsible for the biologic effects of several cytokines such as IL-2, IL-4, IL-6, IL-10, IL-13, IL-21, and interferons (IFNs).[27] In vitro studies with peficitinib (pan-JAKi) on peripheral blood mononuclear cells of SSc patients prevented the downstream phosphorylation of STAT1 and STAT3 and decreased secretion of IL-4, IL-13, IFN-γ, and TNF-α. The drug also stopped the dermal fibroblasts from being activated by IL-6 and IFN-α.[28] A study on bleomycin treated mice showed that early administration of tofacitinib reduced the STAT phosphorylation and the collagen deposition in lung.[29] A study targeting the JAK2 showed that by inhibiting the enzyme activity in human SSc fibroblasts, one could prevent TGF-β-mediated collagen deposition.[30] A recently concluded phase I/II trial of tofacitinib in SSc showed that the drug was well tolerated and the clinical parameters showed improvement with the treatment over a follow-up period of 6 months.[31] This finding has opened up a newer treatment option in SSc-ILD.


  Nintedanib Top


Nintedanib, a small molecule oral tyrosine kinase inhibitor, competitively blocks various receptor tyrosine kinases by binding to their adenosine triphosphate binding pockets.[32] It acts by inhibiting (a) proliferation and migration of lung fibroblasts resulting in decreased production of extracellular matrix proteins, (b) activity of Lck, required for T-cell proliferation and production of IL-2, IL-4, IL-5, IL-10, IL-12p70, IL-13, and interferon γ, and (c) production of CCL2 and M2 macrophage polarization.[33],[34] The efficacy of nintedanib in retarding the progression of lung disease in idiopathic pulmonary fibrosis (IPF) patients was studied in three randomized control studies, the TOMORROW and INPULSIS 1 and 2 trials.[35],[36] Based on these results, nintedanib was approved by the United States FDA (US-FDA) in 2014 for use in IPF patients. Subsequently, experimental studies on skin fibroblasts derived from mouse models of SSc and lung fibroblasts from SSc-ILD patients demonstrated the anti-fibroblast properties of nintedanib in skin and lung tissues in SSc.[37],[38]

SENSCIS trial was a double-blind, randomized, placebo-controlled trial that included 576 SSc patients with ILD involving more than 10% of the lung fields, FVC ≥40% of predicted, and diffusion capacity of the lungs for carbon monoxide (DLCO) between 30% and 89% of predicted.[39] Nintedanib group (n = 288) received 150 mg of nintedanib twice a day. At 52 weeks, there was significantly less decline of FVC with nintedanib (−52.4 ml/year) compared to placebo (−93.3 ml/year). However, minimal clinically important difference (MCID) for improvement, defined as increase in FVC by ≥3% of predicted, was noted in only 23% of patients on nintedanib, while 34.5% had MCID for worsening, defined as decrease in FVC by ≥3.3% of predicted.[40] The subsequently published subgroups analysis showed that there is no difference in the effect of nintedanib between Asians versus non-Asians, Japanese versus non-Japanese, and patients on MMF versus not on MMF.[41],[42],[43] Dose reduction or interruption was needed in 48.3% of patients on nintedanib compared to 12.2% of patients on placebo, and permanent discontinuation of drug due to adverse events was needed in 16% of patients on nintedanib compared to 8.7% on placebo.[44] Diarrhea was the most common adverse event with nintedanib, noted in 75.7% patients and it was the reason for permanent discontinuation of the drug in 6.9% of patients.

In the INBUILD study, 663 patients with progressive fibrosing ILD other than IPF, including 170 patients with autoimmune disease related ILD, were randomized to receive either nintedanib or placebo.[44] The autoimmune diseases included were RA (52.4%), SSc (22.9%), mixed connective tissue disease (MCTD, 11.2%), and others (13.5%). At 52 week, nintedanib use was associated with significantly reduced decline in FVC compared to placebo (−80.8 ml/year vs. −187.8 ml/year). Similar results were seen in the subgroup of patients with autoimmune ILDs, where the difference in the annual rate of decline in FVC favored nintedanib (104 ml/year; 95% CI: 21.1, 186.9).[45] In this study also, diarrhea was noted in 66.9% of patients in nintedanib group, and permanent discontinuation of drug due to adverse events was needed in 19.6% of patients.[44] Apart from the INBUILD study,[46] which included RA-ILD patients, and few case reports and animal studies, there is no good quality evidence on use of nintedanib in RA-ILD patients.[47],[48],[49] A dose modification to 100 mg twice a day is needed in patients with hepatic impairment (Child-Pugh A) and the drug is not to be used in patients with Child-Pugh B or C and severe renal impairment.[50]


  Hematopoietic Stem Cell Transplantation Top


Hematopoietic stem cell transplantation (HSCT) has been used in various treatment resistant autoimmune diseases including SSc. In the last one decade, three randomized controlled trials have evaluated the role of HSCT in rapidly progressive and conventional therapy resistant SSc.[51],[52],[53] The rationale behind the use of HSCT is that by use of high-dose CYC, anti-thymocyte globulin (ATG) with or without whole-body irradiation, there will be ablation of auto-reactive T- and B-cells and later, when autologous or allogenic hematopoietic stem cells are transplanted, there is reconstitution of tolerant immune system, which results in halting/improving the autoimmune process.

The ASSIST and the ASTIS trials were the earliest randomized trials to establish the role of HSCT in dcSSc patients with internal organ involvement, with majority of the included patients having ILD.[51],[52] In both these studies, the lymphoablative regimen was used which included IV CYC (200 mg/kg) and rabbit ATG (6.5 mg/kg). In the ASSIST trial, at 1 year after HSCT, the mean predicted FVC increased by 15% compared to a decline by 9% in patients who did not undergo HSCT. In the ASTIS trial, the mean predicted FVC increased by 6.3% at the end of 2 years from HSCT, while it decreased by 2.8% in the control arm. While there were no deaths in ASSIST trial during follow-up, in the ASTIS trial, 10% of patients died due to treatment related causes in the HSCT arm.

The recently published Short Course Oncology Treatment (SCOT) trial is different from the two previous studies with respect to the conditioning regimen used.[53] In the SCOT trial, myeloablative regimen was used, which included whole-body irradiation in addition to high-dose IV CYC and ATG. Seventy-five patients with dcSSC were included with 97% of the patients having ILD. The primary outcome was the global rank composite score (GRCS) at 54 months, an analytical tool that takes into account the various organ manifestations including FVC change for ILD apart from outcomes like death and even-free survival. At 54 months, the GRCS favored HSCT over IV CYC use. Among the 30 surviving patients in the HSCT arm, 4 (13.3%) had worsening of ILD, while the rest had improved or remained stable at 54 months. In the CYC arm, among the 28 surviving patients, 9 (32.1%) worsened and the remaining improved or remained stable. Over a follow-up of 72 months, 21 patients died, 7 in HSCT arm, and 14 in CYC arm. None of the transplant recipients died within the first year of transplant.


  Novel Agents for Connective Tissue Disease-Interstitial Lung Disease Top


There are various novel agents that are being studied in patients with CTD-ILD including the drugs targeting integrins, ubiquitin-proteasome pathway, IL-4/13 pathway, and endothelin 1 receptors. These various drugs are presently in preclinical or early phase I or II clinical trials stage and need further evaluation in various groups of CTD-ILD patients before being used in routine management. Table 1 summarizes the various novel agents being studied in CTD-ILD.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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