Ppt presentation on connective tissue disease associated interstitial lund disease explaining different subtypes.

1. Dr. Emil Mohan
III Year Post Graduate Student
Dept of Resp. medicine
Moderator: Dr Mukesh Goyal sir
Assistant professor
Dept of Resp. medicine

2. Introduction of CTD-ILDs
• Connective tissue disease (CTD) are multisystemic disorders
characterized by autoimmune-mediated tissue damage & presence of
circulating auto-antibodies that target various body organs with
autoimmune-mediated chronic inflammation
• Interstitial lung disease (ILD) represents a broad group of diseases
characterized by diffuse parenchymal lung injury patterns & varying
degrees of inflammation and fibrosis
• The lung is a frequent target in many CTDs and all components of the
respiratory system are at risk.
• CTDs cause ILDs when they establish an autoimmune mediated
chronic inflammation in the pulmonary interstitium

3. ATS/ERS CLASSIFICATION

4. ⚫Collagen-vascular diseases (CVDs) area heterogeneous
group of autoimmune disorders characterized by the
presenceof autoantibodies.
⚫Include-
Progressive systemic sclerosis (PSS),
Rheumatoid arthritis
Dermatomyositis (DM)/ Polymyositis (PM),
Sjögren syndrome (SS)
Systemic lupuserythematosus
Ankylosing spondylitis (AS),
Mixed connective-tissue disease (MCTD)

6. Pathogenesis of CTD-ILDs
• Environmental factors: Exposure to environmental
factors which worsens the primary CTDs e.g. exposure
to UV light & drugs like hydralazine, procainamide,
D- penicillamine can exacerbate or induce SLE-like
responses
• UV induces keratinocytes to produce IL-1, a
factor known to influence immune response
• Inflammatory mediators: A wide variety of cytokines
identified in BAL fluid have been found to contribute to
the cascade of inflammation in the lungs

7. Pathogenesis of CTD-ILDs
The most striking of these are:
• IL-8 (a neutrophil chemoattractant & activator
• TNF-α (an early cytokine involved in many
pathologic processes)
• Macrophage inflammatory protein-1a (a cytokine that
is important in neutrophil chemotaxis)
• RANTES (regulated on activation normal T cell
expressed and secreted, a cytokine that is important in
T-cell & eosinophil recruitment & activation)
• TGF-β
• Endothelin-1

8. ⚫Histological subtypes in ILD associated with
CTD including-
 Usual interstitial pneumonia (UIP),
 Nonspecific interstitial pneumonia (NSIP),
 Organizing pneumonia,
 Diffusealveolardamage,
 Lymphoid interstitial pneumonia (LIP),
⚫ILD related to CTD may beassociated with pulmonary
hypertension.

9. Pathology
• NSIP refer to a spectrum of histologic features with varying degress of lymphoplasmacytic
infiltration of interstium and collagen deposition.NSIP is most frequently seen in RA,
polymyositis-dermatomyositis, MCTD, and scleroderma.
• Lymphocytic interstitial pneumonia refers to a monotonous infiltration of the
interstitium by mature lympho cytes . Other feature are macrophage giant cells ,
granuloma formation and amyloid deposition. This pneumonitis accompanies primary
Sjogren syndrome and rheumatoid artirits.
• UIP is the underlying lesion of IPF and also appear in CTD-ILD. varying degree of mono
nuclear cell infiltration and fibroblastic proliferation leading to collagen deposition within
alveolar intersitium and seen especially in RA.
• Diffuse alveolardamage consists of a mixed interstitial inflammatory infiltrate ,
interstitial edema and fibrin deposition. (a/c lupus pneumonitis , PM-DM)

10. Source; Fishman’s Textbook
of Pul. Diseases

11. Source; Fishman’s Textbook
of Pul. Diseases

12. Pattern of ILD in connective tissue disease
CTD ILD ILD PATTERN
SSc ++++ NSIP>>>UIP
RA ++ UIP>NSIP>OP=DAD
PM-DM +++ NSIP=OP>DAD>UIP
Sjo¨ gren’s ++ NSIP>LIP>OP=UIP=DAD
SLE + NSIP>DAD=LIP=OP=UIP

13. Workup
⚫A thorough history is key for thediagnosisof collagen-
vasculardiseases (CVDs).
⚫Historyof occupation, environmental exposures,
radiation exposure, and drug use
⚫ Historyof smoking
⚫Detailed family history- like SLE
⚫Physical Examination

14. Systemic
symptoms
CTD
Dermatological Heliotrope rash, Gattron’s papule,
mechanic’s hand.
history of skin tightness and thickening,
telangiectasias, Raynaud’s phenomenon, or
digital pitting.
Malar rash, photosensitivity skin reaction,
or hair loss.
Dermatomyositis
Systemic sclerosis
(scleroderma)
SLE
Gastrointestinal Esophageal motility problems as acid
reflux (chest burning or pressure, cough
after meals, regurgitation of food)
Systemic sclerosis and
polymyositis,
Musculoskeletal Arthralgias,morning stiffness, joint
swelling and erythema, and deformities
Swollen fingers (“sausage digits”)
Rheumatoid arthritis,
Sjögren syndrome, or
mixed connective
tissue disorder.
systemic sclerosis
and polymyositis
Ophthalmologic Dry eyes or the use of eye drops may
uncover sicca syndrome,
history of uveitis
Sjögren syndrome
SLE or sarcoidosis

15. Digital tip infarction
cutaneous calcium deposits
(calcinosis cutis)
Salt & Pepper Skin - Hyperand
hypopigmentattion seen in systemic
sclerosis.
Matted telangiectasia common in
scleroderma. (Image courtesy of
Dr. Lorinda Chung.)
sclerodactyly, a thickening of
theskin
Courtesy of Vandana Mehta Rai MD, and C Balachandran MD via Derma tology
Online Journal

16. Heliotrope rash in woman with
dermatomyositis.
Gottron papules and nail-fold
telangiectasia in patient with
dermatomyositis.
Classic malar rash
(butterfly rash) in SLE
mechanic’s hand.
Swollen fingers (“sausage
digits)

17. Investigations
⚫Chestx-ray - either normal or Diffuse bilateral
infiltrates
⚫Physiological testing
Restriction
reduced FVC
reduced DLCO
⚫HRCT
⚫6MWT

18. ref.. Murray & nadel’s textbook of respiratory medicine

19. The role of lung ultrasound in the
diagnosis of interstitial lung disease
⚫ Currentdata have shown that lung ultrasound (LUS) is an
emerging tool in the diagnosis of interstitial lung disease
(ILD) by evaluating numbers of B-lines, pleural
irregularities and nodules or consolidations.
⚫These features can distinguish between ILD and others
different pulmonaryconditions (i.e., patients with heart
failureor end-stage renal disease accompanied by
pulmonary congestion).
⚫Number of B lines had a good correlation with HRCT
fibrosis pattern, and good diagnostic sensitivity(Wang et al)

20. Sonographic interstitial syndrome.
Multiple, separated B-lines
Black arrow indicates the pleuraand
whitearrowsshow lung comets
associated with thickened irregular
pleural lines.
Falcetta A, Leccardi S, Testa E, et al. Theroleof lung ultrasound in thediagnosis of
interstitial lung disease. Shanghai Chest. 2018 May 28;2(5).

21. SSc-ILD
• SSc is a heterogeneous systemic disorder
characterized by excessive collagen deposition
• SSc is the CTD with the largest percentage of
patients afflicted with ILD (40-80%)
• Along with pulmonary hypertension (PH), ILD is a
major cause of death in this disease.
• The development of ILD is considered more likely in
those with diffuse SSc although autoantibody pattern
& ethnicity are also important

22. SSc-ILD
• However, Scleroderma Lung Study*, reported no significant
differences in the frequency of alveolitis on HRCT scan between lcSSc
and dcSSc, suggesting that all patients with SSc are at risk for ILD
• Most patients with SSc have high titers of antinuclear antibodies
(ANA)—most often in a nucleolar pattern
• Three antibodies with the highest specificity for SSc include
antibodies against anti-RNA polymerase III (Pol3), anticentromere
antibodies (ACA) and antibodies against topoisomerase (anti-Scl70)
• Anti-Scl70 antibodies are strongly associated with ILD
* Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE, et al.
Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006

23. SSc-ILD
• The majority of patients with SSc-ILD have NSIP-
pattern injury. Less commonly a UIP pattern is
observed, and other histopathological patterns
(e.g., OP or DAD) are very rare
• The median survival for patients with SSc-ILD is 5
to 8 years
• The most common radiographic findings for these
patients are ground glass opacities and fibrosis
• Patients with lung involvement greater than 20%
on HRCT and a FVC <70% of predicted were most
likely to progress without therapy

24. SSc-ILD
• The development of pulmonary hypertension is a
well-described complication of in SSc-ILD
• Pulmonary hypertension in SSc-ILD portends a poorer
prognosis. The 1-, 2-, and 3-year survival for these
patients is 71%, 39%, and 21%, respectively

26. TREATMENT
Traditional immunosuppressive therapy, mycophenolate mofetil (MMF) or
cyclophosphamide (CYC) have been used as initial treatment for SSc-ILD.
Dose of MMF: 2000-3000mg/ daily given in divided doses twice daily
Dose of CYC: oral: 1.5 – 2.5 mg/ kg/day
The use of systemic steroids in the treatment of SSc-ILD is debated.
 Data on the use of high dose steroids in SSc-ILD is limited.
 Steroids need to be weighed with the risk of renal crisis as this is typically associated
with doses of prednisone > 15mg daily.
 Nintedanib, an oral tyrosine kinase inhibitor was recently approved for the treatment
of SSc-ILD based on the results of the SENSCIS Trial .
 Dose: 150 mg PO twice daily
 > Annual rate of decline in FVC was lower in nintedanib treated patients by 44%
compared to placebo.
 The most common adverse event was diarrhea.
 Tocilizumab is an anti-IL-6 inhibitor that has been recently approved for the treatment
of SSc-ILD.

27. RA-ILDs
• RA is the most common CTD and is characterized by
an erosive inflammatory polyarthropathy with
symmetrical arthritis and a range of pulmonary
manifestations
• While RA occurs more commonly in females (F/M,
3:1), RA-ILD is more frequent in males
• The prevalence of RA-ILD varies from 5–58%,
depending on the case definition for ILD

28. RA-ILD
• RA-ILD manifests most commonly in the UIP-
pattern, and less commonly with NSIP pattern injury
• Patients with RA with a usual interstitial pneumonia (UIP)
pattern on HRCT scan have worsened survival compared
with those with nonspecific interstitial pneumonia (NSIP)
• Drug-induced pneumonitis is an important consideration
in the differential diagnosis of patients with suspected RA-
ILD

31. Management –Immunosuppression
Steroids 
• A retrospective study by SONG et al. demonstrated that in patients with RA-UIP,
treatment with glucocorticoids alone or in combination with immunosuppressive
medications improved or stabilised the disease in about 50% of 84 patients, but
without significant difference in survival with the untreated group
• 0.5 mg/kg , wait for 1-3 months , taper to 10mg per day .
• In a recent retrospective case series(Yamano Y et al) including 11 RA patients,
therapy with pulse intravenous methylprednisolone followed by oral prednisone
and tacrolimus appeared to be effective and well-tolerated
Song JW, Lee HK, Lee CK, Chae EJ, Jang SJ, Colby TV, Kim DS. Clinical course and outcome of rheumatoid arthritis-
related usual interstitial pneumonia. Sarcoidosis Vasc Diffuse Lung Dis. 2013 Aug 1;30(2):103-12. PMID: 24071881.

32. Management –Immunosuppression
.
MMF and azathioprine 
Smaller study on CTD ILD ,MMF improves(NSIP) or stabilises(UIP) FVC .
Dose of MMF:2000-3000mg/ daily given in divided doses twice daily
Dose of azathioprine:2-3 mg/kg/daily
Cyclophosphamide
Mean survival time better in retrospective study on 25 pts with RA-ILD
Fulminant disease
Limited long term use due to toxicity
Dose:oral: 1.5 – 2.5 mg/ kg/day

33. Biologics
TNF inhibitors have both profibrotic( worsen ILD) and antifibrotic effects
Improvement or stability of lung functions
• Rituximab better survival compared to TNF inhibitors
• Dose:1000mg IV 0, 2 weeks then q6 months
• Tocilizumab
DOSE:4 mg/kg IV q4Weeks initially; may increase to 8 mg/kg q4Weeks
• Abatacept
• JAK inhibitors –tofacitinib , baricitinib
There are limited reports of successful treatment with methotrexate, azathioprine,
cyclosporine, mycophenolate, TNF-alpha inhibitors, and rituximab

34. Antifibrotics
The only Food and Drug Administration-approved therapy is nintedanib which is
approved for progressive fibrotic ILD regardless of etiology.
Dose:150 mg PO twice daily
INBUILD trial  Nintedanib in progressive fibrotic disease(13% pt had RA-ILD ), slower
decline of FVC (107 ml/year)
ADR:Nausea and diarrhea are the most common adverse effect, Hepatotoxicity

35. DM/PM-ILDs
• Both PM and DM share the diagnostic criteria of
symmetrical proximal muscle weakness, raised serum
muscle enzymes, and muscle biopsy and EMG results
consistent with myositis
• DM/PM are common in women and black patients
• In addition, DM requires the presence of certain skin
manifestations (e.g., heliotrope rash , Gottron’s sign & V or
shawl sign) to fulfill diagnostic criteria
• ILD is common in DM/PM (35%-45%) and presents prior to
the onset of myositis in 18% to 20% of patients

36. DM/PM-ILDs
• Most patients with DM/PM-ILD have a chronic, slowly
progressive course, but subacute worsening may occur.
• This patients usually have a combined pattern of NSIP and
OP observed on HRCT and in histopathological specimens
• DM/PM-ILDs usually have myositis-associated
autoantibodies, such as positive ANA titer or anti-Ro
antibody (anti-SSA) & several myositis-specific
autoantibodies, such as the tRNA synthetase antibodies
such as anti-PL-12 (anti-alanyl-tRNA synthetase)
autoantibodies, which in one series was associated with
ILD in 90% of the patients.

37. DM/PM-ILDs
• Radiographic and pathologic findings in patients with ILD
secondary to DM/PM are the most varied of all the CTD-
ILD
• Radiographic study of patients with DM/PM showed that
all patients with fatal ILD had ground glass opacities on
HRCT scan, with consolidation being the principal finding in
most nonfatal cases
• Poor outcome was associated with a rapidly progressive
respiratory failure and DM-ILDs

39. Treatment
• There is no standard systemic steroid regimen specified for dermatomyositis,.
• Initially, prednisolone is given at high doses for the first few months until the muscle
enzyme levels decline, and muscle strength improves.
• Once an adequate response occurs, the administration of systemic steroids is gradually
tapered off over time.
• The total duration of therapy with systemic steroids usually spans between nine and
twelve months.
• It is important to note that administering high dose glucocorticoids for more than six
weeks may lead to glucocorticoid myopathy.

40. SjS-ILDs
• Sjogren’s syndrome (SjS) is a chronic inflammatory
condition characterized by lymphocytic infiltration of
exocrine glands (including salivary and lacrimal glands) –
and other structures, including the lungs
• It can occur either in isolation, (primary SjS) or as a
secondary phenomenon in the setting of another
established CTD (secondary SjS)
• In the absence of a salivary gland biopsy demonstrating
focal lymphocytic sialoadenitis, the presence of
“keratoconjunctivitis sicca” and anti-nuclear antibodies
against ribonucleoproteins Ro/SSA and La/SSB is required
to fulfill diagnostic criteria in both primary and secondary
SjS

41. SjS-ILDs
• Several histopathologic patterns have been described,
including NSIP, UIP, OP, and LIP
• LIP was considered one of the most common pulmonary
manifestations, but studies have demonstrated a much lower
prevalence. Its typical radiographic appearance is ground glass
opacities with thin-walled cysts
• Patients with SjS are at increased risk for pulmonary lymphomas
but clinically significant ILD is rare, and in most cases SjS-ILD
follows a mild and self-limited course
• Restrictive PFT and reduced DLCO have been found in 17%–
37.5% of patients with SjS

42. SjS-ILDs
• In patients with SjS-ILD, HRCT and histopathological
findings correlate well with each other, so SLBx is usually
not recommended
• Five-year survival for patients with Sjögren-ILD is 84%
• Common radiographic findings are ground glass opacities
(45%-92%) and fibrotic honeycomb cysts (13%-43%)
• The presence of multifocal cysts on HRCT scan should
raise clinical suspicion for Sjögren-ILD

43. 40yr old woman with Primary Sjoren syndrome. Note the multiple cystic air spaces

45. Treatment
Hydroxy cloroquine 200-400 mg/d
Or
Methotrexate 0.2-0.3mg/kg body wt weekly plus
Prednisolone <10 mg daily orally
Rituximab may be beneficial but further studies are required
Cyclosporin has also been recommended in steroid resistant cases

46. SLE-ILDs
• SLE is a multisystem disorder afflicting joints, skin,
kidneys, CNS, serosa surfaces of internal organs
including heart and lungs. The disease is more
prevalent in women of reproductive age and African
Americans
• Almost all patients are ANA positive. Four or more
criteria are required to establish the diagnosis
• Although respiratory symptoms associated with SLE
are often absent, abnormal PFT- and HRCT-findings
are common, and the prognosis is significantly worse
in patients experiencing pulmonary complications

47. SLE-ILDs
• Clinically significant ILDs affects only 3% to 8% of the
lupus population. In most cases, acute lupus pneumonitis
(ALP) with a DAD-pattern heralds the development of ILD
• Bilateral alveolar infiltrates are present on cxr on
presentation
• Similar to most other CTD-ILDs, NSIP is the most commonly
observed histopathological pattern, but LIP,OP and UIP have
all been described
• Diffuse alveolar hemorrhage (DAH) and ALP are
characterized by acute onset of dyspnea with fever, cough
and hemoptysis
• Treament:IV methyl prednisolone 1 to 2 g daily in divided
doses for 3 to 4 days before tapering.

49. MCTD-ILDs
• MCTD patients are characterized by positive anti-U1
RNP antibodies and have features of more than one
CTD
• While a large number of patients with MCTD have
pulmonary involvement, most have relatively mild
disease, and many are asymptomatic
• Pleural effusions, ILD consistent with NSIP and
sometimes UIP, and PAH, either as a result of CTD-
ILD or in isolation, have all been described in MCTD

50. MCTD-ILD
Histologic pattern of NSIP and/ or UIP are noted which may progress to honey comb
lung
Predisposed to aspiraton pneumonia, reflux esophagitis with esohageal dilatation
Pleurisy is reported in 40% cases
Pleural effusion in 5 % cases

51. Who to treat in chronic CTD-ILDs
• Not every patient with CTD-ILD requires treatment i.e.
patients with low likelihood for progression
• Serial HRCT and PFTs are most helpful in objectively
determining disease severity and likelihood of progression
over time
• There is strong consensus that patients with disease extent <
10% on HRCT and/or FVC >75% and/or DLCO >65%, in the
absence of respiratory symptoms, can be carefully monitored
every 3–6 months for evidence of progression

52. Prognosis of CTD-ILDs
• CTD-ILDs cause significant morbidity & mortality. Usually,
the ILD is the cause of death in patients with CTD-ILDs
• In general, the prognosis for CTD-ILDs is worse than that of
IPF especially if the underlying histopathologic pattern is
UIP and the patient has concomitant pulmonary HTN
• However, RA-ILD (with underlying NSIP pattern) have a
better prognosis than IPF
• Generally, most forms of CTD-ILDs have better prognosis
than idiopathic ILD
• Among CTD-ILDs, PM/DM-ILDs & SSc-ILDs are associated
with higher mortalities. The 3-year survival rate is <50%

53. Indicators of poor prognosis in CTD-
ILDs
– DLCO < 50% of predicted
– FVC < 60% of predicted
– Pulmonary HTN
– Resting hypoxemia
– Acute Lupus pneumonitis
– Patients with >20% of the lungs affected
– Male sex
– RA-ILDs
– PM/DM-ILDs with normal CK levels, negative anti-
Jo antibody & pulmonary HTN

54. Thank you