How can scleroderma-related interstitial lung disease (ILD) affect my body and lifestyle?

Scleroderma Overview

Scleroderma or systemic sclerosis (SSc) is a rare systemic autoimmune disease that is characterized by vasculopathy, immune dysregulation, autoantibody formation and fibroblast dysfunction, which can result in fibrosis in various organ systems.¹ SSc is broadly categorized into two main subsets: diffuse cutaneous SSc and limited cutaneous SSc. Diffuse cutaneous SSc is characterized by extensive fibrosis, with skin thickening proximal to the elbows, knees and neck, as well as a high prevalence of interstitial lung disease (ILD. Limited cutaneous SSc manifests as a largely vascular disease, resulting in Raynaud phenomenon, pulmonary arterial hypertension and skin sclerosis confined to the distal extremities.

The degree of skin and organ involvement varies among patients with SSc, and virtually all organs can be affected by SSc, so clinical presentation and symptom load can vary widely.¹ According to 2013 American College of Rheumatology and European Alliance of Associations for Rheumatology (ACR/EULAR) guidelines, SSc major classification criteria is proximal scleroderma and minor diagnostic criteria include skin thickening (puffy fingers or sclerodactyly), fingertip lesions (digital tip ulcers or fingertip pitting scars), telangiectasia, abnormal nailfold capillaries, pulmonary involvement (pulmonary arterial hypertension or ILD), Raynaud’s phenomenon, and presence of SSc-related antibodies.²

Scleroderma Symptoms

A 2010 survey of 464 patients with SSc found that the chief complaints in terms of both frequency and impact on daily activity were fatigue (89% reported frequency greater than sometimes, 72% reported moderate to severe impact on activities), Raynaud phenomenon (86% and 67%), hand stiffness (81% and 59%), joint pain (81% and 64%), and difficulty sleeping (76% and 59%).³ Other symptoms that were reported as having a frequency greater than sometimes included skin tightening (72%), muscle pain (71%), tender joints (71%), itching (69%), sexual dysfunction (69% for men, 52% for women), dry mouth (66%), heartburn (66%), shortness of breath (63%), difficulty with physical activity such as climbing a flight of stairs (63%), difficulty concentrating (62%), dysphasia (58%), dry or burning eyes (55% and 41%), skin pain (53%), numbness (52%), diarrhea (50%), constipation (50%), calcium deposits (42%), persistent cough (40%), skin rashes (36%), nausea (36%), chest pain (34%), rapid or irregular heart rate (33% and 25%), migraines (25%), and weight loss (21%).

Just as clinical presentation of SSc varies, so does SSc-ILD. The most common symptoms of SSc-ILD include exertional dyspnea, fatigue, reduced exercise tolerance, and cough. A 2018 prospective study of 448 individuals with SSc in the European Alliance of Associations for Rheumatology Scleroderma Trial Research (EUSTAR) database and Chinese Rheumatism Data Center—of whom 86% had ILD--found that 60.5% of patients had respiratory symptoms, with shortness of breath after exercise being the most common (55.8%), followed by cough (23.7%) and dyspnea (8.5%).⁶ However, pulmonary involvement can remain asymptomatic until it is advanced. A study that surveyed 890 patients with SSc from 1972-1989 found that dyspnea and dyspnea at rest were reported in 52% and 8% of those with minimal disease (Forced vital capacity [FVC] >75% predicted), 77% and 17% of those with moderate disease (FVC 50-75% predicted), and 94% and 41% of those with severe disease (FVC <50% predicted

Disease Progression and Prognosis

SSc-ILD has a variable course; some patients have stable lung involvement whereas others have highly progressive lung involvement. A 2021 study using the EUSTAR database showed that among patients with SSc-ILD (n=826) 33% of patients had stable lung function during five years of follow-up, 58% had a pattern of slow lung function decline with more periods of stability or improvement than decline, and 8% had a rapid continuous decline.⁴ FVC decline over the five-year follow-up period was predicted by male sex (17% of patients with significant progression were male vs 20% were male out of those who were stable), reflux (present in 76% of those with progression vs 66% for stable), and higher baseline modified Rodnan skin score (mRss), which is a clinical score measuring skin thickness and ranges from 0 to 40, with higher scores indicating greater thickening and more extensive body surface area involvement (mRSS mean of 11 among those with progression and 10 for stable). The relationship between male sex, reflux, and baseline mRSS and FVC decline was associated with time. There was no significant difference in mortality between patients with significant ILD progression (12%), moderate progression (15%), or stable ILD (9%).

Quality of Life

The progression of scleroderma-related interstitial lung disease (SSc-ILD) and its effect on health-related quality of life (QOL) depends on different clinical features.

A 2022 study of 89 patients with SSc-ILD explored the effect of their condition on QOL using a variety of questionnaires.⁷ The average score of the King’s Brief Interstitial Lung Disease (KBILD, scores 0-100, where higher scores indicate better health status) was 58.4, with only 9.4% of patients scoring ≥75. When broken out into the three parts of the KBILD questionnaire, average scores were 63.8 for psychology, 48.5 for breathlessness and activities, and 75.2 for chest symptoms. When ranking symptoms on a five-point scale, patients reported that fatigue was their most severe symptom with a mean score of 4.4. The average score of the EQ-5D-5L QOL questionnaire (scores -0.525-1) was 0.793. Patients with a lower FVC (<80%) had significantly lower scores compared to those with a higher FVC (-0.109, p=0.026).

A 2020 cross-sectional study with adults (≥18 years) with idiopathic pulmonary fibrosis (IPF) (n=57) and SSc-ILD (n=29) used the KBILD survey (scores 0-100) to measure QOL.⁸ Patients with SSc-ILD had a better mean KBILD score compared to patients with IPF (63.1 vs 54.7, p=0.005). Patients with SSc-ILD scored higher on all domains of the KBILD questionnaire (breathlessness, chest symptoms, and psychological), although the difference was only significant for psychological quality of life (71.9 vs 55.5, p=0.003). Participants with IPF also had lower pulmonary function than those with SSc-ILD (FVC 73% vs 92%, DL_CO 45% vs 57%), which could contribute to poor QOL.

Social and Work Life

Changes to social life are common for patients with SSc-ILD. The evolving social landscape can contribute to changes in patients’ routines and corresponding psychosocial behavior. In a 2021 qualitative study looking at impacts of SSc on patients and caregivers, questionnaires were distributed to 260 patients (70 of whom had pulmonary fibrosis) and 47 caregivers.⁹ Significantly more patients with SSc-ILD reported job loss or changes in work roles due to the impacts of the disease compared to those with SSc without ILD (85.3% vs 54%, p=0.004). Pulmonary complications had a considerable impact on patients’ working lives regardless of job type. Patients reported difficulty with common activities such as object manipulation (61.1%), running (73.6%), doing small manual jobs (44.0%), moving their arms (42.6%), writing (38.9%), and eating-related activities such as cutting meat, opening a jar, or raising a full cup (50.0%).

These limitations influence patients’ ability to take care of themselves, especially for those with pulmonary involvement.⁹ The support of a caregiver was necessary for 52.9% of patients with SSc-ILD compared to 39.8% of those with SSc but not ILD. Patients with SSc-ILD also needed to visit the doctor more often, with 90.0% reporting at least three visits per year compared to 71.1% of those with no pulmonary complications (p=0.001).

Challenges of SSc also had an impact on interpersonal relationships, with 65.5% of patients reporting that it changed their family habits and 48.6% reporting a change in their family social life.⁹ Most patients reported difficulty coping with stressful situations (57.4%) or responsibility (44.0%), and these numbers were higher among those with lung involvement (43.8% and 37.5%). There was also a reported effect on patients’ sexual relationships, with 41.2% with hand/feet/joint involvement, 42.9% with pulmonary fibrosis, and 46.3% with both reporting challenges.

Negative impacts to social life were also corroborated by another 2021 Delphi survey-based study of physicians (n=138) caring for patients with SSc-ILD (n=805) in Europe.¹⁰ Due to symptoms, 40.4% of patients retired early (average of 11.9 years before usual retirement age) and 17.2% lost their job due to SSc-ILD. While only 2% of patients required a paid caregiver, 37.7% needed an unpaid caregiver, such as a family member. The study also sought to estimate the annual costs of diagnosis, follow-up, and exacerbation management in each participating country, finding that costs ranged from €6191 in Greece to €25,354 in Sweden. The main driver of cost was follow-up procedures which accounted for 80% of total annual costs.

Malnutrition

A 2023 analysis of the SENSCIS data (a randomized controlled trial of nintedanib in SSc-ILD) examined the risk for malnutrition in patients with SSc-ILD using the Malnutrition Universal Screening Tool (MUST, scored 0-6 with 6 being highest risk of malnutrition).¹² Baseline scores indicated that in the nintedanib group, 2.4% of patients were at high risk of malnutrition and in the placebo group, 4.9% were at high risk. At 52 weeks, while most patients in both the nintedanib and placebo groups were still at low risk of developing malnutrition, more patients in the nintedanib group (9.6%) were at risk than those in the placebo group (5.4%).

A 2019 study used the MUST to look at malnutrition in 98 patients with SSc, where 89 patients also had ILD.¹³ Patients with SSc-ILD were more likely to be at high risk of malnutrition compared to patients with SSc but without ILD (24.7% vs 20.0%, p=0.044). There were no associations between MUST scores and FVC (p=0.189) or diffusing capacity for carbon monoxide (DL_CO) (p=0.158). High MUST scores were associated with symptoms of depression as assessed by the Beck Depression Inventory (82% of those at high risk had borderline depression or higher vs 46% of those at low risk, p=0.012). The authors suggest that malnourishment may lead to or result from depression in patients with SSc, though a limitation of this finding is that the authors did not note specific applicability to patients who also have ILD. 

Sleep

Other impacts to the body related to ILD include changes in sleep. One 2013 prospective study looked at obstructive sleep apnea (OSA) in 62 patients with ILD of which 18 had scleroderma.¹⁴ There was a 55% prevalence of OSA in patients with scleroderma and ILD compared to an estimated 2-4% of the general population. Disease severity as assessed by FVC and DL_CO was correlated with sleep efficiency (ratio between time spent asleep and total time dedicated to sleep, 72.35% for all patients vs 71.04% for those with SSc, r=-0.586, p=0.01), mean oxygen saturation (93.5% vs 94.72%, r=-0.705, p=0.001), and time with an oxygen saturation <90% (5.96 vs 4.13 hours, r=0.665, p=0.003). 

Another 2001 study of 27 patients with SSc, 13 of whom had abnormal pulmonary function, found that 77.8% had decreased rapid eye movement (REM) sleep compared to age-adjusted norms (average 13.1%, median 12.3%), and 70.4% had reduced sleep efficiency (average 82%, median 87.1%).¹⁵ When surveyed for sleep complaints, six patients (21.4%) reported insomnia and six reported excessive daytime sleepiness.

Medication

American Thoracic Society clinical practice guidelines recommend the use of the immunosuppressants mycophenolate mofetil and conditionally recommend cyclophosphamide, rituximab, tocilizumab, nintedanib, and nintedanib in combination with mycophenolate for the treatment of SSc-ILD.¹⁶ Many of these medications are associated with significant side effects, particularly gastrointestinal (GI), which can be especially challenging in a disease characterized by extensive GI complications. The Safety and Efficacy of Nintedanib in Systemic Sclerosis (SENSCIS) placebo-controlled clinical trial conducted from 2015-2017 evaluated the safety and tolerability of nintedanib in 576 patients with SSc-ILD.¹⁷ Most patients receiving nintedanib in the trial experienced mild or moderate GI effects (94.5%) with the most common being diarrhea (75.7%). Patients taking nintedanib and predisposed to GI problems were not more likely to experience them compared to those without such predispositions. Weight loss was reported in 11.8% of patients taking nintedanib compared to 4.5% of patients in the placebo arm. Around half of the patients were also taking mycophenolate, which could have contributed to the GI effects observed in this study.

Depression

Depression is more common among those with SSc than the general population. A 2018 population-based study that compared 2,500 patients with SSc to matched controls found that depression was significantly more common among SSc patients (16.2% vs 10.9%).¹⁸ This proportion was even higher in patients of low socioeconomic status (47.1% vs 40.4%).

A 2005 cross-sectional study with 42 patients with SSc, of which 22 had pulmonary fibrosis (PF), measured the prevalence of depression and anxiety using the Montgomery and Asberg Depression Rating Scale (MADRS, scored 0-60 with ≥15 indicating depression).¹⁹ A significantly higher MADRS score was reported in patients with pulmonary diseases (FVC<80%) compared to patients without pulmonary diseases (19.5 vs 12.2, p=0.009). Scores for anxiety were measured by the Hamilton Anxiety Rating Scale (HARS), but these scores were not associated with any organ involvement or functional impairment.

References

1. Varga J. Systemic Sclerosis (Scleroderma) and Related Disorders. In: Jameson J, Fauci A, Kasper D, Hauser S, Longo D, Loscalzo J, eds. Harrison's Principles of Internal Medicine. 20 ed. McGraw-Hill Education; 2018.
2. van den Hoogen F, Khanna D, Fransen J, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum. Nov 2013;65(11):2737-47. doi:10.1002/art.38098
3. Bassel M, Hudson M, Taillefer SS, Schieir O, Baron M, Thombs BD. Frequency and impact of symptoms experienced by patients with systemic sclerosis: results from a Canadian National Survey. Rheumatology (Oxford). Apr 2011;50(4):762-7. doi:10.1093/rheumatology/keq310
4. Hoffmann-Vold A-M, Allanore Y, Alves M, et al. Progressive interstitial lung disease in patients with systemic sclerosis-associated interstitial lung disease in the EUSTAR database. Annals of the Rheumatic Diseases. 2021;80(2):219-227. doi:10.1136/annrheumdis-2020-217455
5. Steen VD, Conte C, Owens GR, Medsger TA, Jr. Severe restrictive lung disease in systemic sclerosis. Arthritis Rheum. Sep 1994;37(9):1283-9. doi:10.1002/art.1780370903
6. Hu S, Hou Y, Wang Q, Li M, Xu D, Zeng X. Prognostic profile of systemic sclerosis: analysis of the clinical EUSTAR cohort in China. Arthritis Res Ther. Oct 22 2018;20(1):235. doi:10.1186/s13075-018-1735-4
7. Allanore Y, Constans J, Godard D, et al. Quality of life in SSc-ILD patients: Understanding the impact of the ILD and the needs of the SSc-ILD patients and their need for caregivers in France. Journal of Scleroderma and Related Disorders. 2021;7(1):49-56. doi:10.1177/23971983211013979
8. Durheim MT, Hoffmann-Vold A-M, Eagan TM, et al. ILD-specific health-related quality of life in systemic sclerosis-associated ILD compared with IPF. BMJ Open Respiratory Research. 2020;7(1)doi:10.1136/bmjresp-2020-000598
9. Galetti I, Nunzio Sd, Brogelli L, Mirisola V, Garbagnati C. How do systemic sclerosis manifestations influence patients’ lives? Results from a survey on patients and caregivers. Current Medical Research and Opinion. 2021;37(sup2):5-15. doi:10.1080/03007995.2021.1992371
10. Davidsen JR, Miedema J, Wuyts W, et al. Economic Burden and Management of Systemic Sclerosis-Associated Interstitial Lung Disease in 8 European Countries: The BUILDup Delphi Consensus Study. Advances in Therapy. 2020;38(1):521-540. doi:10.1007/s12325-020-01541-5
11. Caminati A, Vigone B, Cozzaglio S, et al. Expert opinion and patients’ in-depth interviews on the impact of pulmonary complications in systemic sclerosis. Current Medical Research and Opinion. 2021;37(sup2):17-26. doi:10.1080/03007995.2021.1992370
12. Volkmann ER, McMahan ZH, Smith V, et al. Risk of Malnutrition in Patients With Systemic Sclerosis-Associated Interstitial Lung Disease Treated With Nintedanib in the Randomized, Placebo-Controlled SENSCIS Trial. Arthritis Care Res (Hoboken). Dec 2023;75(12):2501-2507. doi:10.1002/acr.25176
13. Türk İ, Cüzdan N, Çiftçi V, Arslan D, Doğan MC, Unal İ. Malnutrition, associated clinical factors, and depression in systemic sclerosis: a cross-sectional study. Clinical Rheumatology. 2019;39(1):57-67. doi:10.1007/s10067-019-04598-y
14. Pihtili A, Bingol Z, Kiyan E, Cuhadaroglu C, Issever H, Gulbaran Z. Obstructive sleep apnea is common in patients with interstitial lung disease. Sleep and Breathing. 2013;17(4):1281-1288. doi:10.1007/s11325-013-0834-3
15. Prado GF, Allen RP, Trevisani VnMF, Toscano VG, Earley CJ. Sleep disruption in systemic sclerosis (scleroderma) patients: clinical and polysomnographic findings. Sleep Medicine. 2002;3(4):341-345. doi:10.1016/s1389-9457(02)00013-8
16. Raghu G, Montesi SB, Silver RM, et al. Treatment of Systemic Sclerosis-associated Interstitial Lung Disease: Evidence-based Recommendations. An Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med. Sep 29 2023;doi:10.1164/rccm.202306-1113ST
17. Seibold JR, Maher TM, Highland KB, et al. Safety and tolerability of nintedanib in patients with systemic sclerosis-associated interstitial lung disease: data from the SENSCIS trial. Annals of the Rheumatic Diseases. 2020;79(11):1478-1484. doi:10.1136/annrheumdis-2020-217331
18. Bragazzi NL, Watad A, Gizunterman A, et al. The burden of depression in systemic sclerosis patients: a nationwide population-based study. J Affect Disord. Jan 15 2019;243:427-431. doi:10.1016/j.jad.2018.09.075
19. Legendre C, Allanore Y, Ferrand I, Kahan A. Evaluation of depression and anxiety in patients with systemic sclerosis. Joint Bone Spine. 2005;72(5):408-411. doi:10.1016/j.jbspin.2003.11.008