Connective Tissue Disease-ILD – Insights in ILD

 

Connective Tissue Diseases – Insights in ILD

Systemic Rheumatic ILD
 
Systemic Sclerosis
Rheumatoid Arthritis
Sjögren’s
Polymyositis/Dermatomyositis
Systemic Lupus Erythematosus (SLE)
Mixed Connective Tissue Disease (MCTD)
Ankylosing Spondylitis
Antisynthetase Syndrome
Interstitial Pneumonia with Autoimmune Features (IPAF)

Connective Tissue Diseases Overview – Insights in ILD

  • SRDsa are disorders that exhibit autoimmune-mediated damage due to circulating auto-antibodies that target various body organs and cause symptomatic presentation1
  • There are many SRDs:
    • Systemic Sclerosis (SSc)
    • Rheumatoid Arthritis (RA)
    • Systemic Lupus Erythematosus (SLE)
    • Sjögren’s
    • Interstitial Pneumonia with Autoimmune Features (IPAF)
    • Polymyositis/Dermatomyositis
    • Antisynthetase Syndrome
    • Ankylosing Spondylitis (AS)
    • Mixed Connective Tissue Disease
  • SRDs have various manifestations within each disease, as well as across all SRDs2,3
    • However, one potential manifestation that many SRDs have in common is ILD1,3
 
aSRD has also been referred to as connective tissue disease (CTD) and collagen-vascular disease (CVD).
ILD, interstitial lung disease; SRD, systemic rheumatic disease
1. Koo S-M et al. Kor J Intern Med. 2017;32(4):600-610. 2. Reddy B and Hantash B. Open Dermatol J. 2009; 3(1): 22-31. 3. Wallace B et al. Curr Opin Rheumatol. 2016;28(3):236-245.

CTD-ILD Overview – Insights in ILD

  • ILD is common among SRDs, and is associated with significant morbidity and mortality1,2 
  • Histologic presentation of SRD-ILD is variable, ranging from inflammatory to fibrotic1
  • Clinical manifestations of SRD-ILD also vary greatly, ranging from clinically insignificant or mild symptoms to respiratory failure1
  • A large percentage of patients with SRD will develop a progressive ILD resulting in irreversible damage to the lung parenchyma1
 
1. Koo S-M et al. Kor J Intern Med. 2017;32(4):600-610. 2. Wallace B et al. Curr Opin Rheumatol. 2016;28(3):236-245.

CTD Prevalence – Insights in ILD

CTD-ILD Prevalence – Insights in ILD

SRDs=systemic rheumatic diseases.

CTD-ILD Epidemiology – Insights in ILD

  • The overall rate of SRD-ILD is estimated to be 15%1,2
  • ILD has high incidence rates in several SRDs, including RA, SSc, PM/DM, and MCTD1
Rheumatoid arthritis, at an incidence rate of 0.5%-2% of the US population,  is considered the most common SRD1

MCTD, mixed connective tissue disease; PM/DM, polymyositis and dermatomyositis; RA, rheumatoid arthritis; SSc, systemic sclerosis.
1. Koo S-M et al. Kor J Intern Med. 2017;32(4):600-610. 2. Strange C and Highland K. Clin Chest Med. 2004; 549-559

CTD-ILD Symptoms and Clinical Features – Insights in ILD

  • The most common symptoms of ILDs are dyspnea and cough1
  • In newly identified cases of ILD without identified cause, patients should be screened for SRD, particularly when they exhibit rapidly progressive or chronic ILD2
    • Potential differential diagnoses in these cases include, but are not limited to: PM/DM, SLE, and RA2
 
1. Raghu G et al. Clin Chest Med 2004;25(3):409-419. 2. Bauer PR et al. Respir Med. 2015;109(3):397-405.

CTD-ILD Diagnosis – Insights in ILD

  • Patients with known or suspected SRD should undergo workup (eg, HRCT, PFTs)  when dyspnea, cough, or crackles on chest exam is present1
    • Patients with SRD-associated ILD may have subclinical or asymptomatic lung involvement but ILD can often be detected on HRCT or via PFTs2
  • Most SRD-ILDs commonly present as NSIP3
    • The primary exception is RA, which is characterized by a higher frequency of UIP3
 
HRCT, high-resolution computed tomography; NSIP, nonspecific interstitial pneumonia; PFT, pulmonary function test; UIP, usualinterstitial pneumonia.
1. Wallace B et al. Curr Opin Rheumatol. 2016;28(3):236-245. 2. Castelino FV et al. Arthritis Res Ther. 2010;12:213. 3. de Lauretis A et al. Chron Respir Dis. 2011;8(1):53-82.

CTD-ILD Prognosis – Insights in ILD

  • Patients with SRD-ILD overall show higher survival than patients with IIP
  • The predominant pattern in most SRD-ILDs is NSIP, which generally has a more favorable outcome than the UIP pattern
 
IIP, idiopathic interstitial pneumonia
1. Wallace B et al. Curr Opin Rheumatol. 2016;28(3):236-245.

Rheumatoid Arthritis-Related ILD – Insights in ILD

Rheumatoid Arthritis Overview – Insights in ILD

  • SSc, also known as scleroderma, is an autoimmune disease associated with immune activation, endothelial dysfunction resulting in a small-vessel vasculopathy, fibroblast dysfunction with resultant fibrosis, and other immunologic abnormalities1-3
    • SSc can target many organs including the lungs, heart, kidneys, and theGI tract3
  • The 3 subclassifications of SSc are determined by the extent of skin involvement and are1:
    • DcSSc
    • LcSSc
    • SSc sine scleroderma
 
DcSSc, diffuse cutaneous sclerosis; lcSSc, limited cutaneous sclerosis; SSc, systemic sclerosis.
1. Solomon JJ et al. Eur Respir Dis. 2013;22(127):6-19. 2. Ha Y-J et al. Biomed Res Int. 2018; doi:10.1155/2018/6930297. 3. Nevares A. Merck Manual-Systemic Sclerosis. 2018

Rheumatoid Arthritis Epidemiology – Insights in ILD

  • In the United States, an estimated 16,000-98,000 people are living with SSc, while 650-7,500 people will receive a new diagnosis this year 1
  • The typical patient with SSc is a woman between the age of 20 and 501,2
Risk Factors1:
  • Female Sex (3-14 times more likely to develop SSc than men)
  • Race (African American at higher risk)
  • Reported 5-year and 10-year survival of SSc patients were 75% and 63%, respectively3
 
1. Gabrielli A et al. NEJM. 2009;360(19):1989-2003 2. Nevarus A. Merck Manual-Systemic Sclerosis. 2018. 3. Ha Y-J et al. Biomed Res Int. 2018; doi:10.1155/2018/6930297.

Rheumatoid Arthritis Risk Factors – Insights in ILD

  • SSc may present with any of the following associated symptoms1,2:
    • Abnormalities of circulatory system (eg, Raynaud's phenomenon)
    • Polyarthralgia
    • Swelling
    • Dysphagia
    • Skin tightening
  • Some symptoms and involvement of specific organs are associated more regularly with a particular SSc subclassification2:
Limited cutaneous sclerosis
Esophageal dysmotility, Raynaud's phenomenon, skin tightening generally limited to face, knees, elbows. Commonly associated with pulmonary hypertension

Diffuse cutaneous sclerosis
Diffuse skin involvement, Raynaud’s phenomenon, rapidly evolves. Commonly associated with interstitial lung disease, and renal crisis

SSc sine scleroderma
Presence of SSc-associated circulating auto-antibodies and visceral manifestations. Absence of skin tightening 

1. Gabrielli A et al. NEJM. 2009;360(19):1989-2003. 2. Nevares A. Merck Manual-systemic sclerosis. 2018

Rheumatoid Arthritis Symptoms and Clinical Presentation – Insights in

  • Up to 90% of people with SSc will develop lung abnormalities1,2
    • SSc subclassification is a factor in developing ILD2
  • In a recent analysis of an SSc trial, 53% of patients with dcSSc and 35% of patients with lcSSc had ILD3
  • ILD accounts for approximately 33% of SSc-associated mortality1
  • Patients with SSc have almost a 3 times higher mortality risk when ILD is present compared with those without ILD1
1. Ha Y-J et al. Biomed Res Int. 2018; doi:10.1155/2018/6930297. 2. Solomon JJ et al. Eur Respir Dis. 2013;22(127):6-19. 3. Castelino FV et al. Arthritis Res Ther. 2010;12:213.

RA-ILD Overview – Insights in ILD

For SSc1-4
Established diagnosis of SSc
OR
Clinical history + physical exam + serologies (eg, anti-Scl70; anti-U3RNP, anti-Th/To)

For SSc-ILD2,5-8

PFTs
Restrictive defect (or mixed, if other comorbidities present)

HRCT
NSIP
UIP also seen but rarer

Lung Ultrasound
B-lines

Lung Biopsy
 NSIP (mostly)
Lung biopsy not used

1. Nevares A. Merck Manual-Systemic Sclerosis. 2018 2. Ha Y-J et al. Biomed Res Int. 2018; doi:10.1155/2018/6930297. 3. Castelino FV et al. Arthritis Res Ther. 2010;12:213. 4. Gabrielli A et al. NEJM. 2009;360(19):1989-2003. 5. Ranu H et al. Ulster Med J. 2011;80(2):84-90. 6. Gigante A et al. Intern Emerg Med. 2016;11(2):213-217.  7. Robles-Perez A et al. Respiration. 2015; 90(4):265-274. 8. Spagnolo P et al. Eur Respir J. 2016;47(5):1535-1558.

RA-ILD Risk Factors and Clinical Course – Insights in ILD

  • Although there are no standardized treatments, there are EULAR recommendations for SSc-ILD treatment1,2
    • Immunosuppressants are commonly used to treat SSc2
  • Symptomatic management of SSc-ILD often includes3:
    • Cough relief
    • Treatment of GERD
  • SSc-ILD Outcomes4:
    • 5-y survival: 82%-90% 
    • 10-y survival: 29%-69%
EULAR, European League Against Rheumatism; GERD, gastroesophageal reflux disease.
1. Castelino FV et al. Arthritis Res Ther. 2010;12:213. 2. Ha Y-J et al. Biomed Res Int. 2018; doi:10.1155/2018/6930297. 3. Robles-Perez A et al. Respiration. 2015; 90(4):265-274. 4. Solomon JJ et al. Eur Respir Dis. 2013;22(127):6-19.

RA-ILD Diagnosis – Insights in ILD

RA-ILD Comorbidities – Insights in ILD

  • RA is a systemic disease that causes pain and inflammation, tendon and ligament stretching, and erosion of cartilage and bone1,2
  • RA-induced inflammation that does not respond to therapy or is not treated results in joint destruction that reduces physical function and interferes with daily tasks of living and the ability to maintain employment2,3
  • RA has the highest prevalence of all connective tissue diseases4
 
RA, rheumatoid arthritis
1. Aletaha D et al. Ann Rheum Dis. 2010;69(9):1580-1588. 2. NCCIH. Rheumatoid Arthritis In Depth. Available at: https://nccih.nih.gov/health/RA/getthefacts.htm. Accessed on August 13, 2018. 3. CDC. Rheumatoid Arthritis Basics. Available at: https://www.cdc.gov/arthritis/basics/rheumatoid-arthritis.html. Accessed on August 13, 2018. 4. Robles-Perez A et al. Respiration. 2015; 90(4):265-274.

RA-ILD Treatment Recommendations – Insights in ILD

  • An estimated 1.3-1.5 million people in the United States are living with RA, and around 130,000 will receive a new diagnosis this year1,2
  • The typical patient with RA is a woman in her 60s3
  • Risk factors for RA3,4:
    • Not having children (females only)
    • Female sex (2-3:1 ratio affected vs men)
    • Male sex (tend to have later onset, more aggressive disease)
    • Smoking
    • Obesity
  • Protective factors:
    • Breastfeeding for 1+ year (females only)
 
1. NIH. Fact Sheet: Rheumatoid Arthritis. Available at: https://report.nih.gov/NIHfactsheets/ViewFactSheet.aspx?csid=63. Accessed on August 13, 2018. 2. Myasoedova E et al. Arthri Rheum. 2010;62(6):1576-1582. 3. CDC. Rheumatoid Arthritis. Available at: https://www.cdc.gov/arthritis/basics/rheumatoid-arthritis.html. Accessed on August 13, 2018. 4. Jawaheer D et al. Arthr Rheum. 2006; 54(10):3087-3094.

Sjogren’s Syndrome ILD – Insights in ILD

  • Patients with early disease may have joint manifestations that are difficult to distinguish from other forms of inflammatory polyarthritis1,2
  • The more distinctive signs of RA, such as joint erosions, rheumatoid nodules, and other extraarticular manifestations, are seen primarily in patients with long-standing, poorly controlled disease but are frequently absent on initial presentation1-3
  • Due to the systemic nature of the disease, lung tissue is often affected4-6
    • Parenchymal diseases (ILD, nodules)
    • Airway disease
    • Pleural disease
  • 20%of RA mortality is due to pulmonary manifestations7
 
1. Aletaha D et al. Ann Rheum Dis. 2010;69(9):1580-1588. 2. Heidari B. Caspian J Int Med. 2011;2(1):161-170. 3. Albrecht K et al. Arthr Res Ther. 2017;19:68. 4. Ha Y-J et al. Biomed Res Int. 2018; doi:10.1155/2018/6930297. 5. Castelino FV et al. Arthritis Res Ther. 2010;12:213. 6. Tanoue LT. Clin Chest Med. 1998;19(4):667-685. 7. Robles-Perez A et al. Respiration. 2015; 90(4):265-274.

Sjogren’s Syndrome Overview – Insights in ILD

  • Around 10% of patients with RA will have clinically significant ILD1
    • Higher numbers of patients will have asymptomatic pulmonary changes that can be found on HRCT1
    • Mostly associated with erosive joint disease2
  • Although ILD can occur anytime before or after RA diagnosis, 34% of ILD occurs within the first year1
 ILD Lifetime Risk (%)1
RA - 7.7
General Population - 0.9
  • ILD risk increases with duration of the disease1
  • Patients who develop RA-ILD have a 3-fold greater risk of death than RA patients without ILD1

While RA is more common in females, RA-ILD occurs more frequently in males (approximately 2:1)3

1. Ha Y-J et al. Biomed Res Int. 2018; doi:10.1155/2018/6930297 2. Perry E et al. Int J Rheum Dis. 2017;20(12):2003-2011. 3. Shaw M et al. Eur Respir Rev. 2015; 24:1–16.

Sjogren’s Syndrome Epidemiology – Insights in ILD

  • Risk factors for developing RA-ILD:
    • Male
    • Older age at onset
    • Smoking
    • High titer of Rheumatoid Factor/anti-citrullinated protein antibodies (ACPA)
There is high variability in the RA-ILD clinical course
Asymptomatic
Progressing Rapidly

ACPA, anti-citrullinated protein antibodies; RF, rheumatoid factor
1. Ha Y-J et al. Biomed Res Int. 2018; doi:10.1155/2018/6930297.

Sjogren’s Syndrome Risk Factors – Insights in ILD

For RA1
Established diagnosis of RA
OR
comprehensive medical history + synovitis + number of joints involved + serologies (RF, ACPA) + ESR + CRP

For RA-ILD2-4
PFTs
Restrictive defect (or mixed, if other comorbidities present)

HRCT and/or X-ray
UIP (mostly)

Lung Biopsy
Usually used if HRCT is not definitive

BAL
Usually used to identify other cause of diffuse lung diseases in case of acute onset; generally nonspecific

BAL, bronchoalveolar lavage; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; UIP, usual interstitial pneumonia.
1. Aletaha D et al. Ann Rheum Dis. 2010;69(9):1580-1588. 2. Shaw M et al. Eur Respir Rev. 2015; 24:1–16. 3. Akira M. Ann Am Thorac Soc. 2016;14(3):432-440. 4. Meyer KC et al. Eur Respir J. 2011;38:761-769.

Sjogren’s Syndrome Clinical Features – Insights in ILD

  • Many standard treatments for RA can lead to drug-induced ILD, which is often difficult to differentiate from RA-ILD1
  • Drug-induced ILD is relatively rare but should be suspected when clinical, functional, or radiological abnormalities appear in the first 6 months of treatment2
  • Other complicating factors include pulmonary infections, which can also occur in this population due to immunosuppression from standard RA therapies1
 
1. Robles-Perez A et al. Respiration. 2015; 90(4):265-274. 2. Iqbal K et al. Ther Adv Musculoskel Dis. 2015;7(6):247-267.

Sjogren’s Syndrome-ILD Epidemiology – Insights in ILD

  • Due to the absence of randomized, placebo-controlled trials, treatment strategies typically used for RA-ILD follow the recommendations associated with the type of ILD
  • Moderate- to high-dose steroids in combination with or without immunosuppressants are used to treat RA-ILD acute exacerbations
 
Ha Y-J et al. Biomed Res Int. 2018; doi:10.1155/2018/6930297

Sjogren’s Syndrome-ILD Diagnostics – Insights in ILD

 

Sjogren’s Syndrome-ILD Treatment Recommendations – Insights in ILD

  • SLE is an autoimmune disease of unknown etiology that has a wide array of organ involvement1,2
  • SLE commonly affects1:
    • Joints
    • Skin
    • Kidneys
    • Serous membrane
    • Vessels
    • Central nervous system
    • Respiratory system
SLE, systemic lupus erythematous
1. de Lauretis A et al. Chron Respir Dis. 2011; 8(1) 53–82. 2. Mondal S et al. J Case Reports. 2014;4(!):85-87.

Systemic Lupus Erythematosus-Related ILD – Insights in ILD

  • An estimated 161,000-322,000 people are living with SLE in the United States, while another 3,250-81,250 will receive a new diagnosis this year1-4
  • The typical patient with SLE is a woman between the ages of 15 and 445
  • Risk factors for developing SLE5:
    • African-American/African-Caribbean, Asian, or Hispanic ethnicity
    • Female sex (7:1-15:1)
  • Morbidity/mortality
    • Men have worse outcomes when they get SLE, including a higher 1-year mortality rate6
 
1. Helmick CG et al. Arthr Rheum. 2008;58(1):15-25. 2. Pons-Estel GJ et al. Semin Arthr Rheum. 2010;39(4):257-268. 3. Peschken C et al. Semin Arthr Rheum. 1999;28():368-391. 4. Danchenko N et al. Lupus. 2006;15:308-318.5. CDC. Lupus Detailed Fact Sheet. Available at: https://www.cdc.gov/lupus/facts/detailed.html. Accessed on August 14, 2018. 6. Tan TC et al. J Rheumatol. 2012;39(4):759-769.

SLE Overview – Insights in ILD

  • Malar rash, joint pain, and extreme fatigue are common presenting symptoms among men and women1
  • Some presenting symptoms are more commonly associated with a specific gender2-4:
More Common in Women
Raynaud's phenomenon
Photosensitivity
Mucosal ulceration
Malar rash

More Common in Men
Renal disease
Skin manifestations
Cytopenias
Serositis
Neurologic involvement
Thrombosis
Cardiovascular disease
Hypertension
Vasculitis


1. do Socorro M et al. Clin Pract. 2011;1(e103):266-267.  2. Tan TC et al. J Rheumatol. 2012;39(4):759-769. 3. Lu LJ et al. Lupus. 2010;19(2):119. 4. Cervera R et al. Medicine. 1993;72(2):113.

SLE Epidemiology – Insights in ILD

  • Symptomatic ILD typically occurs in ~3%-8% of patients with SLE1
    • Approximately 1 in 3 patients has interstitial abnormalities on HRCT2
  • Patients with SLE who have multiple end-organ manifestations are more likely to have ILD2
Common SLE-ILD Presenting Symptoms3
Acute dyspnea
Cough
Fever
Pleuritic pain
Occasionally pulmonary hemorrhage

ILD in SLE patients can have 2 differential diagnoses: alveolar hemorrhage (rare), and lupus pneumonitis, which occurs in 1%-10% of SLE patients1

1. de Lauretis A et al. Chron Respir Dis. 2011;8(1): 53–82. 2. Wallace B et al. Curr Opin Rheumatol. 2016;28(3):236-245.
3. Castelino FV et al. Arthritis Res Ther. 2010;12:213.

SLE Risk Factors and Mortality – Insights in ILD

ANA, antinuclear antibody; anti-Sm, autoantibodies to the nuclear Sm (Smith) proteins; DLCO, diffusing capacity of the lung for carbon monoxide; dsDNA, double stranded DNA; LIP, lymphoid interstitial pneumonia; OP, organizing pneumonia.
1. de Lauretis A et al. Chron Respir Dis. 2011;8(1): 53–82. 2. Wallace B et al. Curr Opin Rheumatol. 2016;28(3):236-245. 3. Mondal S et al. J Case Reports. 2014;4(!):85-87. 4. Meyer KC et al. Eur Respir J. 2011;38:761-769.
For SLE1
For SLE-ILD1-4
 
 
 
Established diagnosis of SLE
OR
medical history + thorough physical exam + serologies (ANA, anti-dsDNA, anti-Sm)
PFTs
HRCT
Lung Biopsy
BAL
 
Restrictive defect (or mixed, if other comorbidities present); reduced DLCO
NSIP
OP
LIP
UIP very rare
Rarely used
Primarily for exclusion of other causes
 

SLE Symptoms and Clinical Presentation – Insights in ILD

  • Nonsteroidal anti-inflammatory drugs (NSAIDs)
  • Corticosteroids
 
Robles-Perez A et al. Respiration. 2015; 90(4):265-274.

SLE-ILD Symptoms and Clinical Presentation – Insights in ILD

 

SLE-ILD Diagnostics – Insights in ILD

  • SjS is an autoimmune disease characterized by exocrine gland lymphocytic infiltration, which can be associated with neurologic, vascular, and other manifestations
 
SjS, Sjögren’s syndrome.
de Lauretis A et al. Chron Respir Dis 8(1) 53–82.
Secondary SjS
occurs in association with other SRDs
Primary SjSoccurs in isolation
There are 2 SjS subcategories:
Most commonly:
RA
SLE
SSc

SLE-ILD Treatment Recommendations – Insights in ILD

  • In the United States, approximately 1-4 million people are living with SjS1
  • The typical patient with Sjögren’s is a woman over 401
  • Symptoms of SjS include1,2:
–Objective dryness in ocular and/or oral cavities
–Well-established rheumatic disease
 
1. NINDS. Sjogren’s Syndrome. Available at: https://www.ninds.nih.gov/Disorders/All-Disorders/Sj%C3%B6grens-Syndrome-Information-Page. Accessed on August 14, 2018. 2. NIDCR. Sjogren’s Syndrome. Available at: https://www.nidcr.nih.gov/health-info/sjogrens-syndrome. Accessed on August 14, 2018.

Polymyositis/Dermatomyositis-Related ILD – Insights in ILD

  • 10%-25% of patients with SjS syndrome develop ILD
  • ILD tends to be mild and self-limited
 
Castelino FV et al. Arthritis Res Ther. 2010;12:213.

Polymyositis/Dermatomyositis-Related ILD

Anti-Ro, anti-Ro antibodies; anti-La, anti-La antibodies.
1. de Lauretis A et al. Chron Respir Dis. 2011;8(1):53–82. 2. Beckman KA et al. Clin Ophthalmol. 2016;10:43-53. 3. Meyer KC et al. Eur Respir J. 2011;38:761-769.
For SjS1,2
For SjS-ILD1,3
 
 
 
Established diagnosis of SjS
OR
serologies (eg, ANA, anti-Ro, anti-La, RF, ESR) + eye tests (Schirmer, Rose Bengal) + minor salivary gland biopsy
PFTs
HRCT
Lung Biopsy
BAL
 
Restrictive defect (or mixed, if other comorbidities present); reduced DLCO
NSIP
Ground glass
subpleural small nodules, nonseptal linear opacities, interlobular septal thickening, bronchiectasis, cysts
Not always necessary
Primarily for exclusion of other causes

PM/DM Overview – Insights in ILD

  • First-line therapy for SjS is often the use of corticosteroids, and is sometimes used in conjunction with immunosuppressive therapies
 
Robles-Perez A et al. Respiration. 2015; 90(4):265-274

PM/DM Clinical Features – Insights in ILD

Idiopathic Inflammatory Myopathies

 

PM/DM Epidemiology – Insights in ILD

 

PM/DM Risk Factors and Mortality – Insights in ILD

  • PM and DM are commonly associated with other SRDs1
Symptoms/presentation
  • PM presents with symmetric, proximal skeletal muscle weakness and muscle inflammation; dermatomyositis includes skin manifestations in addition to these symptoms1
–These skin manifestations include Gottron’s sign and heliotrope eruption1
–Both PM and DM can affect the lungs1
 
1. de Lauretis A et al. Chron Respir Dis. 2011;8(1):53–82. 2. Castelino FV et al. Arthritis Res Ther. 2010;12:213
 
Amyopathic dermatomyositis is a rare form of DM that has skin symptoms but no myositis; it is also associated with ILD and can have a poor prognosis1,2

PM/DM-ILD Epidemiology – Insights in ILD

  • In the United States, approximately 18,150 people have DM, while 4,500 will receive a new diagnosis this year1
  • The current US estimate of people with PM is 31,525, and 12,350 new cases will be diagnosed this year1
  • The typical patient with PM/DM is a woman in her 40s or 50s1,2
Morbidity/mortality
  • The 5-year survival range is 77%-95%3
  • ILD is a major cause of morbidity and mortality in PM/DM4
 
1. Malik A et al. Front Neurol. 2016; 7: 64. 2. Koler RA et al. Am Fam Physician. 2001; 64:1565-72. 3. Kawasumi H et al. Clinical Medicine Insights: Circulatory, Respiratory and Pulmonary Medicine 2015:9(S1) 9–17 4. Mira-Avendano et. al. Respiratory Medicine (2013) 107, 890e896

PM/DM-ILD Diagnostics – Insights in ILD

  • Between 20% and 66% of patients may get PM/DM-related ILD1,2
  • ILD usually manifests early in myositis, but can appear anytime before or after manifestations of skin or muscle3
  • 3 clinical patterns:
–Rapidly progressive (associated with high mortality of up to 50%)4
–The more common chronic form that has slowly progressive symptoms4
–Asymptomatic or subclinical form (up to 30% may fall in this category)3
  • Presence of amyopathic myositis-associated autoantibodies often accompanies rapidly progressive ILD1
 
1. de Lauretis A et al. Chron Respir Dis. 2011;8(1):53–82. 2. Castelino FV et al. Arthritis Res Ther. 2010;12:213 3. Ha Y-J et al. Biomed Res Int. 2018; doi:10.1155/2018/6930297 4. Robles-Perez A et al. Respiration. 2015; 90(4):265-274

PM/DM-ILD Treatment Recommendations – Insights in ILD

COP, cryptogenic organizing pneumonia; DAD, diffuse aveolar damage.
1. Mammen AL. Continuum (Minneap Minn). 2016;22(6):1852–1870. 2. Castelino FV et al. Arthritis Res Ther. 2010;12:213. 3. Ha Y-J et al. Biomed Res Int. 2018; doi:10.1155/2018/6930297 4. Ranu H et al. Ulster Med J. 2011;80(2):84-90. 5. de Lauretis A et al. Chron Respir Dis. 2011;8(1):53–82.
For PM/DM1
For PM/DM-related ILD2-5
 
 
 
Established diagnosis of PM/DM
OR
serologies + muscle biopsy
PFTs
HRCT,X-ray
Lung Biopsy
BAL
 
Restrictive defect (or mixed, if other comorbidities present); reduced DLCO
Cellular NSIP
Fibrotic NSIP
UIP
COP
DAD
Mixed histology
Not always necessary
Used to exclude infectious causes

Antisynthetase Syndrome-Related ILD – Insights in ILD

PM/DM-ILD:
  • High-dose steroid therapy and other immunosuppressants
  • Due to its association with high short-term mortality, intensive therapy and lung transplantation are options for acute ILD cases
 
1. Ha Y-J et al. Biomed Res Int. 2018; doi:10.1155/2018/6930297 2. Robles-Perez A et al. Respiration. 2015; 90(4):265-274 3. Castelino FV et al. Arthritis Res Ther. 2010;12:213 .
Patients with UIP pattern in PM/DM typically do not respond to glucocorticoids

Antisynthetase Syndrome Overview – Insights in ILD

 

Antisynthetase Syndrome Epidemiology – Insights in ILD

  • Antisynthetase syndrome is an autoimmune IIM characterized by autoantibodies against an aminoacyl transfer RNA (tRNA) synthetase
  • Clinical features may include:
–ILD (much higher prevalence than seen in PM or DM)
–Non-erosive arthritis
–Myositis
–Raynaud’s phenomenon
–unexplained fever
–Mechanic’s hands
 
IIM, idiopathic inflammatory myopathy
Witt LJ et al. Clin Pulm Med. 2016 September ; 23(5): 218–226

Antisynthetase Syndrome Risk Factors and Mortality – Insights in ILD

  • In the United States, approximately 3,250 people have antisynthetase syndrome1
  • The typical patient with antisynthetase syndrome is a woman around the age of 502
  • Risk factors for developing antisynthetase syndrome are similar to those of PM and DM2
 
1. Rare Genomics Institute. Antisynthetase Syndrome. Available at: https://www.raregenomics.org/antisynthetase-syndrome/. Accessed on August 15, 2018. 2. Solomon J et al. J Bras Pneumol. 2011 February ; 37(1): 100–109.

Antisynthetase Syndrome Clinical Features – Insights in ILD

  • Because antisynthetase syndrome is not commonly studied as a distinct entity from the other PM/DM, the prevalence of ILD in patients with antisynthetase syndrome is difficult to determine1
–One study found the prevalence of ILD in antisynthetase syndrome patients to be 86%1
  • ILD is often a presenting symptom in antisynthetase syndrome1,2
  • ILD in antisynthetase syndrome is associated with high morbidityand mortality1
1. Witt LJ et al. Clin Pulm Med. 2016 September ; 23(5): 218–226 2. Solomon J et al. J Bras Pneumol. 2011 February ; 37(1): 100–109.

Antisynthetase Syndrome-ILD Epidemiology – Insights in ILD

1. Witt LJ et al. Clin Pulm Med. 2016; 23(5): 218–226. 2. Ranu H et al. Ulster Med J. 2011;80(2):84-90.
For Antisynthetase Syndrome1
For Antisynthetase Syndrome-related ILD1,2
 
 
Established diagnosis of antisynthetase syndrome
or
comprehensive medical history + physical exam + serologies (anti-aminoacyl trna synthetase; anti-jo1) + muscle biopsy
PFTs
HRCT
Lung Biopsy
 
Restrictive defect
NSIP
OP
Most common signs:
Traction bronchiectasis, ground glass, reticulation
Not always necessary

Antisynthetase Syndrome-ILD Diagnostics – Insights in ILD

  • Corticosteroids
  • Other immunosuppressants
  • Studies suggest that antisynthetase syndrome-associated ILD may be severe, and may also be refractory to therapy
Witt LJ et al. Clin Pulm Med. 2016 September ; 23(5): 218–226

Antisynthetase Syndrome-ILD Treatment Recommendations – Insights in ILD

Mixed Connective Tissue-Related ILD – Insights in ILD

  • AS is a chronic inflammatory disease that primarily affects the axial skeleton, specifically the sacroiliac joints
  • Peripheral joints and extra-articular locations, including the lungs, kidneys, eyes, aorta, and heart may also become involved
 
AS, ankylosing spondylitis
1. Yuksekkaya R et al. Pol J Radiol. 2014;79:156-163.

MCTD Overview – Insights in ILD

AS: Epidemiology
aMale predominance may be artifactual.
1. Reveille JD. Am J Med Sci. 2011;341(4):284-286. 2. Reveille JD et al. Arthr Care Re. 2012;64(6):905-910. 3. Johns Hopkins Arthritis Center. Ankylosing Spondylitis. Available at: https://www.hopkinsarthritis.org/arthritis-info/ankylosing-spondylitis/. Accessed on August 14, 2018. 4. NIAMS. Ankylosing Spondylitis. Available at: https://www.niams.nih.gov/health-topics/ankylosing-spondylitis#tab-risk. Accessed on August 14, 2018.  5. Stolwijk C et al. Rheum Dis Clin North Am. 2012;38(3):441-476. 6. Deodhar A. Rheumatologists make progress defining spectrum of axial spondyloarthritis. Available at: https://www.the-rheumatologist.org/article/rheumatologists-make-progress-defining-spectrum-of-axial-spondyloarthritis/4/?singlepage=1. Accessed on August 14, 2018.
AS may be as prevalent as RA, but is not as frequently diagnosed6

MCTD Epidemiology – Insights in ILD

Symptoms:
  • Back stiffness, soreness, and pain
Symptoms may be caused by spinal inflammation
1. Johns Hopkins Arthritis Center. Ankylosing Spondylitis. Available at: https://www.hopkinsarthritis.org/arthritis-info/ankylosing-spondylitis/. Accessed on August 14, 2018.
Symptoms may be most prevalent in the early morning

MCTD Risk Factors and Mortality – Insights in ILD

  • The main characteristic of pulmonary abnormalities in AS was the high frequency of mild nonspecific interstitial abnormalities1
  • In one study, 30% of patients with AS had restrictive patterns on PFTs2
  • However, only 2% of patients have clinically significant ILD3
  • Most patients with pleuropulmonary involvement are males with long-standing disease4
1. El Maghraoui A et al. Pulm Med. 2012;.2012:965956. 2. Yuksekkaya R et al. Pol J Radiol. 2014;79:156-163. 3. Spagnolo P et al. Eur Respir J. 2016;47(5):1535-1558. 4. Lynch DA. J Thorac Imag. 2009;24(4):299-309.

MCTD Clinical Presentation and Symptoms – Insights in ILD

1. van der Linden S et al. Arthr Rheum. 1984;27(4):361-368. 2. Lynch DA. J Thorac Imag. 2009;24(4):299-309. 3. Ranu H et al. Ulster Med J 2011;80(2):84-90. 4. Spagnolo P et al. Eur Respir J. 2016;47(5):1535-1558.
For AS1
For AS-ILD2-4
 
 
Established diagnosis of AS
OR
comprehensive medical history + physical exam + laboratory tests (crp, hla-b27) + radiography
PFTs
X-ray and/or HRCT
Lung Biopsy
 
Restrictive defect
Upper zone fibrosis; nodular and linear opacities, and/or pleural thickening
Not always necessary

MCTD-ILD Epidemiology – Insights in ILD

  • While there is an approved therapy for AS, there are no approved therapies for the related ILD
  • AS-ILD – as in most other SRD-ILDs – is generally treated with corticosteroids and/or immunosuppressants1
 
1. Robles-Perez A et al. Respiration. 2015; 90(4):265-274.

MCTD-ILD Diagnostics – Insights in ILD

 

MCTD-ILD Treatment Recommendations – Insights in ILD

  • MCTD is an overlap syndrome including features of SLE, SSc, and PM1
  • Up to 80% of patients present with pulmonary manifestations, including ILD (sometimes fibrotic), pleural effusion and PAH2
  • The defining clinical feature of MCTD is the presence of high titers of anti-U1 ribonucleoprotein antibody1
 
MCTD, mixed connective tissue disease; PAH, pulmonary arterial hypertension
1. de Lauretis A et al. Chron Respir Dis. 2011;8(1):53-82. 2. Robles-Perez A et al. Respiration. 2015; 90(4):265-274.

Systemic Sclerosis-Related ILD – Insights in ILD

  • In the United States, approximately 32,000 people have MCTD, and around 6,500 will receive a new diagnosis this year1,2
  • The typical patient with MCTD is a woman under 303
  • Morbidity/mortality3
–10-year survival ~80%
–Prognosis is worse in patients with signs of SSc and/or PM
–Pulmonary hypertension is the most common MCTD-related cause of death
 
1. Ungprasert P et al. Arthr Care Res. 2016;68(12):1843-1848. 2. Orphanet. Mixed Connective Tissue Disease. Available at: . Accessed on August 14, 2018. 3. NIH. Mixed Connective Tissue Disease. Available at: https://rarediseases.info.nih.gov/diseases/7051/mixed-connective-tissue-disease. Accessed on August 14, 2018.

Systemic Sclerosis Overview – Insights in ILD

Symptoms of MCTD1,2: 
  • Raynaud’s phenomenon
  • Puffy or swollen fingers
  • Arthritis
  • Prone to developing PAH
 
1. NIH. Mixed Connective Tissue Disease. Available at: https://rarediseases.info.nih.gov/diseases/7051/mixed-connective-tissue-disease. Accessed on August 14, 2018. 2. de Lauretis A et al. Chron Respir Dis. 2011;8(1):53-82.
Many nonspecific symptoms may come before these more obvious signs – frequent fatigue, myalgias, arthralgias, low-grade fevers1
 

Systemic Sclerosis Overview (Continued) – Insights in ILD

  • Just as MCTD is underdiagnosed, the associated ILD is also likely underrecognized
  • An estimated 40% of people with MCTD have signs of ILD on HRCT
  • ILD affects survival of patients with MCTD
 
1. Graney BA et al. Rheumatol. 2018;57(2):204-205.

SSc Epidemiology – Insights in ILD

1. Bodolay E. et al. Rheumatology. 2005;44:656–661 2. de Lauretis A et al. Chron Respir Dis. 2011;8(1):53-82. 3. Castelino FV et al. Arthritis Res Ther. 2010;12:213. 4. Robles-Perez A et al. Respiration. 2015; 90(4):265-274. 5. Spagnolo P et al. Eur Respir J. 2016;47(5):1535-1558.
For MCTD1,2
For MCTD-related ILD3-5
 
 
Established diagnosis of MCTD
OR
comprehensive medical history + physical exam + serologies (anti-u1 rnp, ana, rf)
PFTs
HRCT
Lung Biopsy
 
Restrictive defect with reduced DLCO
Fibrotic NSIP
UIP
Not always necessary

SSc Risk Factors and Survival – Insights in ILD

  • MCTD-related ILD is generally treated similarly to other SRD-ILDs
  • One study reported a response to corticosteroids in 47% of patientswith MCTD
 
1. Castelino FV et al. Arthritis Res Ther. 2010;12:213.

SSc Symptoms and Clinical Presentation – Insights in ILD

 

SSc Can Affect Multiple Organs – Insights in ILD

  • An estimated 25% of patients with suspected systemic rheumatic disease have symptoms that point to underlying autoimmunity but do not have enough features that result in a clear diagnosis of SRD1,2
  • Patients with these types of indeterminate symptoms are labeled as having an UCTD3
  • However, patients in this category who have ILD should be considered to have IPAF4
 
IPAF, interstitial pneumonia with autoimmune features; UCTD, undifferentiated connective tissue disease.
1. Kelly A et al. Clin Rheumatol. 2017;36(6):1211-1214. 2. de Lauretis A et al. Chron Respir Dis. 2011;8(1):53-82. 3. Castelino FV et al. Arthritis Res Ther. 2010;12:213. 4. Fischer A et al. Eur Respir J. 2015;46:976-987

SSc-ILD Epidemiology and Mortality – Insights in ILD

  • In the United States, between 45,000-455,000 people will get an UCTD diagnosis this year1
–1% of UCTD patients will develop ILD (IPAF)2
  • Like most SRD-ILDs, there is lack of specificity for typical age and sexin IPAF3
1. Spinillo A et al. Am J Reprod Immunol. 2017;78(6):.12762. 2. Vij et al. Chest. 2011; 140(5):1292–1299 3. Fischer A et al. Eur Respir J. 2015;46:976-987.

SSc-ILD Diagnosis – Insights in ILD

IPAF: Symptoms
1. Fischer A et al. Eur Respir J. 2015;46:976-987. 2. Bonini and Fiorenzano. Eur Respir Rev.2017; 26: 160099
As with other ILDs, a common pulmonary symptom of IPAF is dyspnea2

SSc-ILD Management – Insights in ILD

1. Fischer A et al. Eur Respir J. 2015;46:976-987.
IPAF Diagnostic Domains1
 
 
Clinical
Serologic
Morphologic
Comprehensive medical history + physical exam
(example features: mechanics hands, inflammatory arthritis, Raynaud’s phenomenon)
 
Serologies (for example: anti-CCP, dsDNA, Ro, La, MDA-5)
 
HRCT/Lung Biopsy
NSIP
OP
LIP
 
UIP is not included in the morphological domain, but that does not exclude patients with this pattern being classified as IPAF; however, they must meet additional criteria from the other domains1

SSc-ILD Treatment Recommendations – Insights in ILD

  • Some patients have been treated with immunosuppressive therapies1
  • Current studies are investigating other treatment options2
1. Vij et al. Chest. 2011; 140(5):1292–1299. 2. Gutsche et al. Curr Respir Care Rep. 2012;1:224–232.

Interstitial Pneumonia with Autoimmune Features – Insights in ILD

  • Within IPAF, patients with UIP pattern have worse outcomes than those with NSIP
  • However, patients with UIP and IPAF have better outcomes than those with UIP and IPF
1. Kim HC at el. Chest. 2015 Jan;147(1):165-172.

IPAF Overview – Insights in ILD

IPAF Classification Criteria – Insights in ILD

IPAF Clinical Domain – Insights in ILD

IPAF Serologic Domain – Insights in ILD

IPAF Morphologic Domain – Insights in ILD

IPAF Diagnostics Review – Insights in ILD

IPAF Treatment Recommendations – Insights in ILD