Interstitial Lung Disease in Systemic Lupus Erythematosus and Systemic Sclerosis: How Can We Manage the Challenge?
Abstract
:1. Introduction
2. Systemic Lupus Erythematosus
2.1. ILD in SLE
2.2. Management of ILD in SLE
Author | Year | Patients | Endpoint | Clinical Results |
---|---|---|---|---|
Weinrib et al. [53] | 1990 | 14 SLE patients with ILD | Evaluation of the clinical course of ILD in SLE patients after CS therapy | High doses of oral prednisolone showed significant improvement in 3 patients. |
Improvement of respiratory symptoms in 6 patients when systemic steroids were used | ||||
Eiser et Shanies [57] | 1994 | 2 SLE patients with ILD | The efficacy of the early use of IPC for SLE-associated ILD | VC showed significant improvement after intravenous CYC treatment |
Fink et al. [58] | 1995 | 1 SLE patient with ILD | The outcomes of methotrexate treatment in one case of SLE-associated ILD | Notable improvement in lung function after oral methotrexate |
Swigris et al. [59] | 2006 | 28 CTD patients with ILD | Safety and tolerability of MMF in CTD-ILD patients and its impact on lung function | MMF was highly safe and well tolerated in this cohort |
Lim et al. [60] | 2006 | 1 SLE patient with ILD | The evolution of the first patient with SLE-pneumonitis refractory to conventional medication treated with rituximab | Improvement in clinical parameters, disease activity and spirometry values post rituximab therapy |
Okada et al. [61] | 2007 | 17 CVD patients with ILD | The efficacy and safety of the administration of CYC infusion for CVD-associated ILD | CYC pulse therapy ameliorated pulmonary symptoms in all patients; |
Beneficial effects also on VC and DLCO | ||||
Sumida et al. [62] | 2014 | 1 Overlap case (SLE and SSc) with ILD | The follow-up at baseline and 6 months later after two cycles of rituximab | Treatment with rituximab showed an improvement in respiratory symptoms, reduction in FVC and DLCO functional tests; |
Improvement in SLE activity | ||||
Yang et al. [63] | 2017 | 1 SLE patient with ILD | The effect of an oral antifibrotic agent -pirfenidone combined with corticosteroids | One year treatment with pirfenidone and corticosteroids showed a positive effect on malar rash, respiratory symptoms, DLCO, FCV and HRCT aspect |
Nawata et al. [64] | 2020 | 1 SLE patient with IP | The efficacy of MMF in a SLE complicated by PAH/IP | Improvement of SLE activity score and PAH/IP following MMF treatment |
Robles-Perez et al. [56] | 2020 | 18 CTD-related pulmonary disease | The effect of rituximab in CTD-associated lung conditions patients who were eligible for a lung transplant | Following a two-year rituximab treatment, DLCO considerably improved |
Mwagni et al. [54] | 2021 | 1 Overlap syndrome (SLE and Scleroderma) with ILD | The effect of belimumab | Total lung capacity, chest CT opacities improved, right ventricular systolic pressure normalized during two years treatment with belimumab |
Jordan et al. [39] | 2021 | 1 SLE patient with ILD | The evolution on a SLE associated-ILD patient treated with Intravenous Immunoglobulin | Successful response at Intravenous Immunoglobulin |
3. Systemic Sclerosis
3.1. ILD in SSc
3.2. Management of ILD in SSc
4. Comparison between ILD SLE and SSc
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Author | Year | Patients | Endpoint | Clinical Results |
---|---|---|---|---|
Flaherty et al. [81] | 2019 | The INBUILD study included 663 patients of which 39 had SSc (23 received nintedanib vs. 16 placebo) | Primary: annual decline in FVC (mL/year) after 52 weeks of treatment | The annual decline rate of FVC was significantly lower in the nintedanib group in patients with UIP-like fibrotic pattern. |
Secondary: change in the total score of K-BLID questionnaire and the time until the first acute exacerbation of ILD or death within 52 weeks. | ||||
Kuwana et al. [82] | 2020 | The study included Japanese patients (n = 70) from SENSCIS trial: | Primary: annual decline in FVC (mL/year) after 52 weeks of treatment | 17.6% of the nintedanib group and 5.6% of the placebo group discontinued the treatment due to adverse effects. |
36 patients received placebo vs. 34 nintedanib. | Secondary: changes from baseline in mRSS and SGRQ scores after 52 weeks. | The decline in FVC from baseline was smaller for patients in the nintedanib group compared to placebo at 52 weeks and the effect persisted up to 100 weeks, similar between Japanese and non-Japanese participants. | ||
The mRSS and SGRQ scores and the rate of adverse effects were similar between Japanese and non-Japanese patients. | ||||
Seibold et al. [83] | 2020 | The study included the same patients (n = 576) from the SENSCIS trial. | Primary: data about possible digestive (diarrhea, liver enzyme, and bilirubin elevation) and cardiovascular adverse effects. | The most common adverse effect was diarrhea in both groups (75.7% in the nintedanib group and 31.6% in the placebo group). |
Almost half of these patients had the first episode in the first 30 days of treatment. | ||||
70.2% of them had one or two diarrhea episodes 94% of the cases being described as mild or moderate. | ||||
288 received placebo and 288 nintedanib. | Secondary: the predisposition to develop intestinal side effect. | Antidiarrheal medication was prescribed in 48% of nintedanib patients and in 9% of placebo group. | ||
Dose reduction was considered in order to maintain the continuity of the treatment in 40.6% of the nintedanib group participants. | ||||
Other digestive adverse events (nausea, vomiting, abdominal pain) or weight loss were more common in patients treated with nintedanib. | ||||
Azuma et al. [84] | 2021 | The study included Asian patients (n = 143) from the SENSCIS trial. | Primary: the annual decline in FVC rate (mL/year), the baseline changes in mRSS and SGRQ scores after 52 weeks | Fewer Asian participants received MMF and methotrexate compared to non-Asian patients. |
62 were from nintedanib group. | Secondary: adverse events developed over 52 weeks of treatment. | The benefit of slowing the FVC decline and the adverse events described were similar between Asian and non-Asian patients throughout the entire study. | ||
Highland et al. [85] | 2021 | The study included the patients from the SENSCIS trial (n = 576). | Primary: the annual decline in FVC (mL/year) after 52 weeks of treatment | More than 90% of cases continued MMF treatment until week 52. |
They were divided based on the treatment with MMF at baseline (median dose of 2000 mg): 139 from nintedanib group and 140 from placebo group. | Secondary: changes from baseline in mRSS and SGRQ scores after 52 weeks. The annual percentage rate of FVC decline, the absolute change in mL of FVC baseline the absolute and relative decrease in FVC of more than 5% predicted and more than 10% predicted were also evaluated. | Nintedanib usage was associated with a reduced rate of decline in FVC regardless of the association with MMF | ||
MMF association did not improve skin fibrosis or quality of life in both nintedanib and placebo groups and had a similar adverse event profile. | ||||
Maher et al. [86] | 2021 | The study included the same patients (n = 576) from the SENSCIS trial. | Primary: the absolute decrease/increase in FVC | A decline in FVC% predicted was described in 55.7% of participants in nintedanib group and in 66.3% of participants in placebo group. |
After 52 weeks, 13.6% of nintedanib group had an absolute decline in FVC between 5–10% predicted, while only 3.5% had an absolute decline in FVC between 10 and 15% predicted. In placebo group, the absolute decline in FVC and death were present in a higher proportion. | ||||
Secondary: The MCID for improvement, worsening or stability in FVC. | The absolute decrease in FVC at 52 weeks of ≥3.3% (the proposed MCID) was 34.5% in nintedanib group versus 43.8% in placebo group. | |||
The absolute increase in FVC at 52 weeks of ≥3.3%(the proposed MCID) was 23% versus 14.9% in nintedanib vs. placebo groups. | ||||
Allanore et al. [87] | 2022 | The study included patients from the SENSCIS-ON trial who completed the 52 weeks of the SENSCIS trial. | Primary: reported adverse events from the first day of treatment until 52 weeks or to the last drug intake plus 7 days for those who prematurely discontinued treatment. | Diarrhea was reported in 68% of the cases who continued nintedanib and in 68.8% in the group of patients who initiated nintedanib as the most frequent adverse effect, having a mild or moderate intensity. |
It included n = 444 patients, 197 who continued nintedanib and other 247 who initiated the treatment. | Secondary: absolute increase and decrease in FVC, changes in mRSS, SGRQ total score, UCLA SCTC GIT 2.0 score. | Serious adverse events were documented in approximately 20% of the cases from both groups, the most important being pneumonia. | ||
Almost half of the patients from both groups were taking MMF. | The frequency of adverse events did not differ in SENSCIS-ON as compared to SENSCIS trial. | |||
Fewer patients discontinued the treatment in SENSCIS-ON group. | ||||
The progression of FVC over 52 weeks was similar. | ||||
Assassi et al. [88] | 2022 | The study included the same patients (n = 576) from SENSCIS trial. | Primary: the annual decline in FVC (mL/year) after 100 weeks | In both intent-to-treat and on-treatment analysis, the adjusted mean annual rate of decline in FVC after 100 weeks was slower in patients with nintedanib compared to placebo. |
Secondary: the effect of nintedanib in patients who followed the treatment until the end of the study | ||||
Denton et al. [89] | 2022 | The study included the same patients (n = 576) from SENSCIS trial. | Primary: the relationship between the degree of fibrotic ILD and the absolute rate of FVC decline in 52 weeks. | The degree of fibrotic ILD on HRCT at baseline and the decline in FVC predicted at 52 weeks were not related with the overall population or with subgroups of participants. |
the extent of fibrotic ILD at baseline was not associated with the rate of decline in FVC over 52 weeks. | ||||
Secondary: the extent of fibrotic ILD and predicted FVC at baseline | the higher the FVC predicted values at baseline the greater the decline in FVC during the trial, suggesting that a greater respiratory reserve leads to a higher decline in FVC. | |||
nintedanib is beneficial irrespective of the fibrotic ILD extent on HRCT. | ||||
Kreuter et al. [90] | 2022 | The study included the same patients (n = 576) from the SENSCIS trial. | Primary: annual decline in FVC (mL/year) over 52 weeks. | Baseline PRO measures scores were worse in dcSSc and correlated with a lower FVC, greater extent of fibrosis on HRCT, higher mRSS, presence of GERD, and other upper gastrointestinal symptoms in patients receiving MMF. Additionally, it was linked with hospitalization during the study and with supplemental oxygen usage. |
Secondary: changes from baseline in PRO measures questionnaires: SGRQ, FACIT-dyspnea, and HAQ-DI after 52 weeks. | After 52 weeks, in patients with FVC ≥ 70% predicted, PRO measures scores had better results compared with FVC ˂ 70% predicted. | |||
Kreuter et al. [91] | 2022 | The study included the same patients (n = 576) from the SENSCIS trial. | FVC decline rate in patients who were hospitalized for an all-cause event or SSc-related causes. | After 52 weeks, 13.7% of the participants experienced an all-cause hospitalization event or died, of which 7.4% were related to SSc. |
FVC decline and time to first all-cause hospitalization or death were linked with statistically significant results after 52 weeks. | ||||
78 were hospitalized for all-cause events, 42 for SSc causes and 75 were admitted in ER or hospital followed by admission to ICU. | The risk of first hospitalization events related to FVC decline rate. | FVC decline was also correlated with time to first SSc-related hospitalization or death, yet no relationship was found between FVC decline and risk of hospitalization or death of any cause. | ||
The reduction in FVC decline resulting after nintedanib treatment may reduce the risk of hospitalization. | ||||
Kuwana et al. [92] | 2022 | The study included the same patients (n = 576) from the SENSCIS trial divided after ATA status, baseline MRSS and SSc subtype. | Primary: the annual decline in FVC over 52 weeks in the 3 groups. | Almost 60% of the patients were ATA-positive in both groups. Patients in the placebo group who were ATA-positive or negative had the same adjusted yearly rate of reduction in FVC. |
In the nintedanib group there were 173 ATA positive patients versus 177 in the placebo group. | Compared to ATA-positive patients, nintedanib’s effect on lowering the annual rate of decline in FVC was more pronounced in the ATA-negative patients. | |||
There were 218 patients with mRSS < 18 in the nintedanib group and 226 in the placebo group. | Secondary: the correlations between FVC and MRSS at baseline versus week 52 and the decline rate of FVC considering MRSS at baseline a continuous variable. | The reduction in mRSS was similar between nintedanib and placebo groups regardless of the ATA status. | ||
In the placebo group, the rate of decline in FVC over 52 weeks was similar in ATA positive and negative patients, higher in patients with a mRSS ≥ 18 at baseline compared to those with a mRSS ˂ 18 and higher in patients with dcSSc compared to lcSSc. Nintedanib had no effect on reducing the mRSS in any of the subgroups. | ||||
Maher et al. [93] | 2022 | The study included the same patients (n = 576) from the SENSCIS trial. | Primary: the decline in FVC at baseline and over 52 weeks in the two groups | Participants from SENSCIS trial had a substantial impairment in FVC at baseline, with an FVC (mL) over 25% (around 950 mL) lower than it would be anticipated in those without lung disease. As the average duration of SSc in the SENSCIS study was about 3.4 years, the predicted loss of lung function was about 280 mL/year since the onset of SSc. |
They were compared to a matched population for age, sex, ethnicity and height. | Secondary: to estimate the „effective lung age” and compare the results to the real age | After 52 weeks, the decline in FVC was four-fold greater in the placebo group, while in the nintedanib group it was only two-fold greater compared to hypothetical healthy references. | ||
Volkmann et al. [94] | 2022 | The study included 574 patients from the SENSCIS trial with information on cough and dyspnea. 353 had both cough and dyspnea, 156 had only cough or dyspnea, 65 no complaints. | Primary: the annual decline of FVC over 52 weeks; the proportion of patients with relative/absolute decline in FVC > 5% and >10% at week 52; time to absolute decline in FVC >10% or death over 52 weeks in all the subgroups based on cough and/or dyspnea. | Most of cases reported coughing (76.6%) several days a week and some (23.4%) reported coughing a few days a month. |
Cough was described in 229 patients from the nintedanib group and in 232 of the placebo group. | Secondary: changes in SGRQ scores at week 52. | In the dyspnea group, 70% reported it several days a week and 29.6% described dyspnea a few days a month. | ||
Dyspnea was present in 209 of the nintedanib participants and 193 of the placebo participants. | Both cough and dyspnea were associated with a greater extent of fibrotic ILD, a lower FVC % predicted and a lower DLCO% predicted at baseline. | |||
The rate of FVC decline after 52 weeks was similar in placebo patients regardless of the presence of cough or dyspnea. | ||||
In the nintedanib group, the effect of reducing FVC decline was more pronounced in those without cough or dyspnea, although no heterogeneity was observed between the subgroups. |
SLE | SSc | |
---|---|---|
Frequency | 2–4% | 75% |
Risk factors | Older age Longstanding disease | dcSSc male sex African American race Nailfold capillary abnormalities Digital ulcers Longer disease duration Pulmonary hypertension |
Genetics | - | HLA-DRB1*11 HLA-DRB1*301 |
Antibodies | Anti-dsDNA Anti-La Anti-Scl-70 Anti-U1RNP Anti-Sm lupus anticoagulant | Anti-topoisomerase I Anti-neutrophil cytoplasmic antibody Anticardiolipin Anti-Ro52 Anti-NOR90 Anti-U11/U12 Anti-Th/To Anti-polymyositis-scleroderma |
Type | NSIP organizing pneumonia follicular bronchitis | NSIP UIP PPFE |
Onset | Within an average of 7.7 years of SLE onset | Within 5 years of the first non-Raynaud phenomenon symptom. |
Pathology | An aberrant inflammatory response due to cytokine release; The impaired apoptosis and abnormal fibroblast proliferation leading to alveolar injury was described. | An injury to the alveolar epithelium, the vasculature, or both have been proposed as the initial event, followed by an aberrant immune response with fibroblast recruitment and activation. Extracellular matrix overproduction and an important scarring process replace the standard pulmonary architecture. The fibrotic variant of NSIP is more frequent than the cellular variant. Survival is not different between the two types of NSIP variants. |
Clinical | May be asymptomatic Dyspnoea Tachypnea Cough Possible evidence of scleroderma | Dyspnoea Non-productive cough fatigue Velcro-like crackles on auscultation |
Treatment | Hydroxycholoquine Glucocorticoids CYC MMF Belimumab/Rituximab IVIg Antifibrotic treatments Lung transplantation | CYC MMF Rituximab Nintedanib Bone marrow or lung transplantantion |
Diagnosis | HRCT Pulmonary function tests | HRCT Pulmonary function tests |
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Richter, P.; Cardoneanu, A.; Dima, N.; Bratoiu, I.; Rezus, C.; Burlui, A.M.; Costin, D.; Macovei, L.A.; Rezus, E. Interstitial Lung Disease in Systemic Lupus Erythematosus and Systemic Sclerosis: How Can We Manage the Challenge? Int. J. Mol. Sci. 2023, 24, 9388. https://doi.org/10.3390/ijms24119388
Richter P, Cardoneanu A, Dima N, Bratoiu I, Rezus C, Burlui AM, Costin D, Macovei LA, Rezus E. Interstitial Lung Disease in Systemic Lupus Erythematosus and Systemic Sclerosis: How Can We Manage the Challenge? International Journal of Molecular Sciences. 2023; 24(11):9388. https://doi.org/10.3390/ijms24119388
Chicago/Turabian StyleRichter, Patricia, Anca Cardoneanu, Nicoleta Dima, Ioana Bratoiu, Ciprian Rezus, Alexandra Maria Burlui, Damiana Costin, Luana Andreea Macovei, and Elena Rezus. 2023. "Interstitial Lung Disease in Systemic Lupus Erythematosus and Systemic Sclerosis: How Can We Manage the Challenge?" International Journal of Molecular Sciences 24, no. 11: 9388. https://doi.org/10.3390/ijms24119388