Therapeutic Options for the Treatment of Interstitial Lung Disease Related to Connective Tissue Diseases. A Narrative Review
Abstract
:1. Introduction
2. Systemic Sclerosis (SSc)
2.1. Glucocorticoids (GC)
2.2. Cyclophosphamide (CYC)
2.3. Mycophenolate Mofetil (MMF)
2.4. Azathioprine (AZA)
2.5. Rituximab (RTX)
2.6. Hematopoietic Stem Cell Transplantation (HSCT)
2.7. Lung Transplantation
2.8. Tyrosine Kinase Inhibitor
2.9. Pirfenidone
2.10. IL-6 Blockade
3. Idiopathic Inflammatory Myopathies (IIM)
3.1. Polymyositis (PM), Dermatomyositis (DM), Amyopathic Dermatomyositis
3.1.1. Glucocorticoids (GC)
3.1.2. Cyclophosphamide (CYC)
3.1.3. Mycophenolate Mofetil (MMF) and Azathioprine (AZA)
3.1.4. Calcineurin Inhibitors
3.1.5. Methotrexate (MTX)
3.2. Antisynthetase Syndrome (ASSD)
3.3. Others (Intravenous Immunoglobulins, Plasmapheresis, Lung Transplantation) in IIM and ASSD-ILD
4. Primary Sjogren Syndrome (pSS)
4.1. Glucocorticoids (GCs) and Conventional Immunosuppressive Agents
4.2. Rituximab (RTX)
4.3. IL-6 Blockade, Tocilizumab
5. Systemic Lupus Erythematosus (SLE)
6. Mixed Connective Tissue Disease (MCTD)
7. Undifferentiated Connective Tissue Disease (UCTD)
8. Acute Exacerbation (AE)
8.1. Pharmacological Treatment
8.2. Supportive Care
9. Non-Pharmacological Treatments
10. Ongoing Randomized Trials
11. Conclusions
12. Highlights
- The correct clinical and therapeutic management of CTDs-ILD needs a multidisciplinary approach including expert rheumatologist, pulmonologist, and thoracic radiologist;
- Treatment with conventional or biologic disease-modifying antirheumatic drug (DMARDs) is often based on expert-opinion and low-quality studies in CTD-ILD;
- Randomized controlled studies are available only for RTX, CYC, MMF, TCZ, and anti-fibrotics, mainly in SSc and sometimes without conclusive results;
- A possible role of antifibrotic treatment in CTDs-ILD has been supposed by some Authors; the INBUILD study demonstrated the efficacy of nintedanib in secondary form of ILD, including CTD;
- Further prospective studies are mandatory to investigate the efficacy and safety of the different treatment regimens in CTDs-ILD;
Author Contributions
Conflicts of Interest
References
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Systemic Sclerosis | ||||||||
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Trial | Year | Population | Phase | Follow-Up | Drug Investigated | Outcome | Results | |
SLS I [9] | 2006 | 145 SSc-ILD | Phase III | 12 Mo * | CYC | Oral CYC [72 pt] vs. PBO [73 pt] | I: FVC (%); II: TLC (%), PR-D, DLCO (%) | Oral CYC was associated with significant but modest improvement in FVC (%) compared with PBO and was associated with improvements in TLC (%), PR-D but not in DLCO (%). |
SLS I, FU extension [10] | 2007 | 145 SSc-ILD | Phase III | 24 Mo * | CYC | Oral CYC [72 pt] vs. PBO [73 pt] | I: FVC (%); II: TLC (%), PR-D, DLCO (%) | At a 24 month follow up, except for a sustained impact on dyspnea, the effects on FVC and TLC were no longer apparent. |
SLS I § [11] | 2009 | 98 SSc-ILD | Phase III | 12 Mo | CYC | Oral CYC [49 pt] vs. PBO [49 pt] | I: FVC (%), HRCT aspects (GGOs, FIB, Hcs scored on a scale of 0 to 4); II: TLC (%), DLCO (%) | At the end of FU, FIB was significantly worse in the PBO group than in the CYC group (p = 0.014) and these differences correlated significantly with FVC, TLC, and PR-D. No differences were noted in terms of GGOs and Hcs. |
FAST trial [12] | 2006 | 45 SSc-ILD | N.A. | 12 Mo | CYC-AZA | PDN + iv CYC + oral AZA as maintenance therapy [22 pt] or PBO [23pt]. | I: FVC (%), DLCO (%); II: HRCT (extent and pattern), PR-D | The improvement in terms of FVC (%) at the end of FU was modest but did not reach the statistical significance. Secondary outcome was not reached. |
SLS II [13] | 2016 | 126 SSc-ILD | Phase II | 24 Mo | MMF vs. CYC | MMF for 24 months [63 pt] vs. oral CYC for 12 months followed by PBO for 12 months [63 pt] | I: FVC (%); II: DLCO (%), PR-D, quantitative HRCT fibrosis scores. | Both MMF and CYC treatment resulted in significant improvements in FVC (%), DLCO (%), HRCT, PR-D. |
SLS I, II § [14] | 2017 | 122 SSc-ILD | N.A. | 24 Mo | MMF | SLS II-MMF (N = 61) and SLS I-PBO (N = 61) participants | I: FVC (%); II: DLCO (%), PR-D | MMF in comparison with PBO was associated with an improved course of FVC (%) (p < 0.0001), DLCO% (p < 0.001), and PR-D (p = 0.0112) after FU period. |
Nadashkevich et al. [15] | 2006 | 60 SSc° | N.A. | 18 Mo | CYC vs. AZA | Oral CYC [30 py] vs. oral AZA [30 pt]. PRD for the first 6 months. | I: FVC (%); DLCO (%), Chest X ray | FVC and DLCO did not change after treatment in the CYC-group, but statistically significantly worsened in the AZA-group. |
Daoussis et al. [16] | 2010 | 14 SSc-ILD | N.A. | 12 Mo | RTX | RTX [8 pt] vs. PBO [6 pt] | I: FVC (%), FEV1 (%), DLCO (%); II: HRCT score | There was a significant increase of FVC and DLCO in the RTX group compared with baseline (p = 0.0018 and p = 0.017). HRCT scores were identical at baseline and at 24 weeks in all patients in the RTX group, while in the control group, there was a modest nonsignificant increase. |
RECOVER trial [17] | 2013 | 22 SSc | Phase II/III | 12 Mo | RTX | RTX vs. PBO | II: Pulmonary functional tests | N.A. |
ASTIS trial [18] | 2014 | 156 SSc (n° SSc-ILD n.a.) | Phase II | 24 Mo | HSCT vs. CYC | HSCT [79 pt] vs. CYC [77 pt] | I: event-free survival. II: FVC (%), TLC (%); RV (%); DLCO (%) | HSCT therapy resulted in significant improvement in the FVC and total lung capacity (TLC) at a two-year follow-up |
ASSIST trial [19] | 2011 | 19 SSc-ILD | Phase II | 12 Mo | HSCT vs. CYC | HSCT [10 pt] vs. CYC [9 pt]. | FVC (%); DLCO (%); HRCT score | HSCT in comparison to CYC was more effective in improving FVC and decreasing diseased-lung volume. No effects on DLCO (%) was observed. |
SCOT trial [20] | 2018 | 73 Ssc-ILD | Phase II/III | 54 Mo | HSCT vs. CYC | HSCT [36 pt] vs. CYC [37 pt] | I: Global rank composite score including FVC (%) | HSCT achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival Data regarding pulmonary function were not available. |
SENSCIS trial [21] | 2019 | 576 Ssc-ILD | Phase III | 12 Mo | Nintedanib | Nintedanib [288 pt] vs. PBO [288 pt] | I:FVC (mL) ^; II: FVC (%) ^, FVC (mL) $, DLCO (%)$ PR-D | Nintedanib significantly reduced the annual rate of decline in FVC at the end pf FU (p = 0.04), even if the relative reduction in FVC decline was similar in the two groups. Additionally, other pulmonary secondary outcomes were not reached. |
Khanna et al. [22] | 2011 | 20 SSc-ILD | Phase I/IIa | 12 Mo | Imatinib | Imatinib [20 pt] | I: FVC (%), DLCO (%), HRCT, PR-D | Imatinib led to trends toward improvement of 1.74% in the estimated FVC %, TLC % and in the DLCO % predicted over a 1-year period (p not significant). PR-D improved statistically, but the improvement was not clinically meaningful. |
Fraticelli et al. [23] | 2014 | 30 SSc-ILD | Phase II | 6 Mo * | Imatinib | Imatinib [30 pt] for 6 months | I: FVC (%), DLCO (%), HRCT, PR-D | Three patients died and one pt was lost to follow-up. Four pt had a good response, seven worsened and 15 had a stabilized lung disease. Overall, 19 pt had an improved or stabilized lung disease. After a 6-month follow-up, 12 (54.5%) of the 22 pt showed an improved or stabilized lung disease. |
Martyanov et al. [24] | 2017 | 31 SSc-ILD | Phase IIa | 18 Mo * | Dasatinib | Dasatinib for 6 months | II: PFT, PR-D, HRCT, Serum KL-6, SP-D, APRIL and adiponectin. | No significant changes in clinical assessments or serum biomarkers were seen at the end of FU. By quantitative HRCT, 65% of patients showed no progression of FIB, 39% showed no progression of total ILD. Improvers showed stability in FVC and DLCO, while both measures showed a decline in non-improvers (p = 0.1289 and p = 0.0195, respectively). |
LOTUSS trial [25] | 2016 | 63 SSc-ILD | Phase II | 5 We * | PRF | 2-week titration [32 pt] vs. 4-week titration [31pt] from 801 mg/d to 2403 mg/d, for 16 weeks. | EE: FVC (%), DLCO (%) | FVC (%) and DLCO (%) remained largely unchanged at the end of FU. |
SLS III [26] | 2017 | Recruiting (estimated 150 SSc-ILD) | Phase II | 18 Mo | MMF, PRF | MMF +PBO vs. MMF + PRF | I: FVC (%); II: DLCO (%), PR-D, HRCT | N.A. |
FaSScinate trial [27] | 2016 | 87 SSc | Phase II | 48 We | TCZ | TCZ [43 pt] vs. PBO [44 pt] | EE: FVC (mL and %) $, DLCO (%) $ | FVC showed a not significant decrease in TCZ group than PBO group at the end of FU and fewer pt in the TCZ group than in the PBO group had worsening of percent predicted FVC (p = 0·037). The change from baseline in DLCO (%) did not differ significantly between PBO and TCZ. |
FocuSSced trial [28] | 2018 | 212 SSc | Phase III | 48 We | TCZ | TCZ vs. PBO | II: FVC (%) $ | The cumulative distribution of change from baseline to week 48 in FVC (%) favored TCZ over PBO (p = 0.0015). The difference in mean change from baseline in FVC at week 48 was in favor of TCZ. Preservation of lung function with TCZ was shown by change from baseline in FVC over time. |
Dermatomyositis and Polymyositis | ||||||||
Allenbach et al. [29] | 2015 | 12 ASSD | Phase II | 12 Mo | RTX | RTX | II: Improvement of ILD (increase of 10% in FVC or 15% of DLCO %). | Improvement of FVC was observed in four patients, stabilization in 5 five and worsening in one. Only 1 pt with increased FVC (%) also showed an improvement of DLCO (%). In addition, one patient had an improvement of DLCO without significant change for FVC (data not shown). Finally, five patients had improving ILD measured by PFT. |
ATtackMy-ILD [30] | 2017 | Recruiting (estimated 20 ASSD-ILD) | Phase II | 6 Mo | ABA | ABA vs. PBO | I: FVC (%) $; II: time to progression free survival, PR-D, time to improvement in FVC% (≥10 points) | N.A. |
Connective tissue diseases | ||||||||
RECITAL [31] | 2013 | Recruiting (estimated 116 CTD-ILD) | Phase II/III | 48 We | RTX, CYC | RTX vs. CYC | I: FVC (mL); II: DLCO $ | N.A. |
INBUILD trial [32] | 2019 | 663 pt with progressive fibrosing ILD other than IPF (including CTDs) | Phase III | 52 We | Nintedanib | Nintedanib vs. PBO | I: FVC ^; II: absolute change from baseline in the total score on the King’s Brief Interstitial Lung Disease (K-BILD) questionnaire; time until the first acute exacerbation of ILD or death; | In patients with progressive fibrosing interstitial lung diseases, the annual rate of decline in the FVC was significantly lower among patients who received nintedanib than among those who received placebo. Diarrhea was a common adverse event. |
Systemic Sclerosis | Idiopathic Inflammatory Myopathy | Primary Sjogren Syndrome | Systemic Lupus Erythematosus | |
---|---|---|---|---|
Glucocorticoids | Prospective [171] Nested case control [38] Retrospective [34] | Prospective [89] Retrospective [98,100,101,112] | ||
Cyclophosphamide | Randomized clinical trial [9,10,11,12,13,15,40] Prospective [171] Retrospective [34,41,50,52] | Prospective [89] Retrospective [79,88,91,115] | ||
Mycophenolate Mofetil | Randomized clinical trial [13,14] Prospective [45] Retrospective [34,43,44,46,47,48,51] | Retrospective [79,92,93] | ||
Azathioprine | Randomized clinical trial [12,15] Retrospective [34,50] | Prospective [89] Retrospective [79] | ||
Rituximab | Randomized clinical trial [16,17] Prospective [57,59] Nested case control [54] Retrospective [53,55,56,58] | Randomized clinical trial [29] Retrospective [119,120,121,122,123,125] Case report [109,115] | Prospective [143] Retrospective [145] Case report [136] | |
Hematopoietic stem cells transplantation | Randomized clinical trial [18,19,20] | |||
Tyrosine kinase inhibitors | Randomized clinical trial [21,22,23,24,72] | |||
Pirfenidone | Randomized clinical trial [25,26] Prospective [73] Retrospective [74] | Case report [150] | ||
Calcineurin inhibitors | Prospective [106] Retrospective [81,97,98,99,100,102,107,108,109,110,112,114,115,117] | |||
Lung transplantation | Retrospective [61,63,64,65,66,67,68,69,70] | Retrospective [133,134,135] Case report [131,132] | ||
Plasma exchange | Case report [129,130] | |||
Intravenous Immunoglobulins | Retrospective [126,128] Case report [127] | |||
IL-6 inhibitors | Randomized clinical trial [27,28] | Case report [146] | ||
Methotrexate | Prospective [89] |
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Vacchi, C.; Sebastiani, M.; Cassone, G.; Cerri, S.; Della Casa, G.; Salvarani, C.; Manfredi, A. Therapeutic Options for the Treatment of Interstitial Lung Disease Related to Connective Tissue Diseases. A Narrative Review. J. Clin. Med. 2020, 9, 407. https://doi.org/10.3390/jcm9020407
Vacchi C, Sebastiani M, Cassone G, Cerri S, Della Casa G, Salvarani C, Manfredi A. Therapeutic Options for the Treatment of Interstitial Lung Disease Related to Connective Tissue Diseases. A Narrative Review. Journal of Clinical Medicine. 2020; 9(2):407. https://doi.org/10.3390/jcm9020407
Chicago/Turabian StyleVacchi, Caterina, Marco Sebastiani, Giulia Cassone, Stefania Cerri, Giovanni Della Casa, Carlo Salvarani, and Andreina Manfredi. 2020. "Therapeutic Options for the Treatment of Interstitial Lung Disease Related to Connective Tissue Diseases. A Narrative Review" Journal of Clinical Medicine 9, no. 2: 407. https://doi.org/10.3390/jcm9020407