UIP and NSIP

Presented by Mays Najdat

3rd year board candidate of Rheumatology
 What is nonspecific interstitial pneumonia (NSIP)?
• Nonspecific interstitial pneumonia (NSIP) is one class of idiopathic interstitial
pneumonia (IIP). NSIP is chronic interstitial pneumonia with the homogeneous
appearance of interstitial fibrosis and inflammation. It is nonspecific as it lacks the
histopathological features of the other subtypes of the IIP. NSIP typically has bilateral
lung involvement and may have a predisposition for the lower lobes.
• NSIP can be found in a number of different diseases, including CTD(progressive SS,
DM, PM, Sjogren disease ,mixed CTD,RA and SLE), reactions to certain medications
like
• (MTX, amiodaron, statin, chemotherapeutic agents and nitrofurantoin), HIV, as well as
other conditions. Some patients also have idiopathic NSIP, which means that the specific
cause of the lung disease is unknown.
•NSIP is rare. It constitutes 14% to 36% of cases of idiopathic interstitial pneumonia
which is less common than usual interstitial pneumonia (UIP) (50% to 60%) .
• Idiopathic NSIP occurs mostly in middle-aged women who are non-smokers, while
NSIP due to connective tissue disease is equal in men and women.

•The histopathology of NSIP is characterized by a temporally homogeneous

inflammatory and fibrosing interstitial process. Fibroblastic foci and peripheral
accentuation are typically absent, which helps to differentiate it from usual interstitial
pneumonia (UIP). NSIP is also characterized by diffuse alveolar wall thickening by
uniform fibrosis, but with the preservation of the alveolar architecture.  
• Three separate groups within NSIP have been described:
• Group 1: Mainly interstitial inflammation 
• Group 2: Inflammation and fibrosis
• Group 3: Mainly fibrosis
UIP
•Usual interstitial pneumonia (UIP) refers to a morphologic entity defined by a
combination of:
(1) patchy interstitial fibrosis with alternating areas of normal lung.
(2) temporal heterogeneity of fibrosis characterized by scattered fibroblastic foci in the
background of dense acellular collagen.
(3) architectural alteration due to chronic scarring or honeycomb change.  
•The term UIP is often used interchangeably with idiopathic pulmonary fibrosis (IPF),
but other clinical conditions are associated with UIP, although less commonly,
including CTD like RA; Sjogren's disease ;DM ;PM ;SS . drug toxicity, chronic
hypersensitivity pneumonitis, asbestosis, familial IPF, and Hermansky-Pudlak
syndrome. [1] Thus, UIP is not entirely synonymous with IPF, and diagnosis of IPF
requires an exclusion of possible underlying clinical conditions, as mentioned above.
• Usual interstitial pneumonia (UIP) is more common in men than in women.
• The histopathologic hallmark of usual interstitial pneumonia (UIP) is a low
magnification appearance of the patchy dense fibrosis causing remodeling of lung
architecture, often resulting in honeycomb change and alternates with areas of less
affected parenchyma .
Diagnostic approach
Clinical evaluation:
History of patient symptoms its onset and severity ( dyspnea, cough….),
history of rheumatic diseases, medications, smoking and environmental exposures.
Fever
Wt.loss
Clubbing
Laboratory tests
• The routine tests include: LFTs, RFTs, Hematological tests, urinalysis.
• Serology for autoantibody: ACPA, RF, ANA, anti-Jo-1, CPK, aldolase,
anti-Scl-70…..
• BNP: if suspect heart failure or PH.
• Lab. Tests that seem unlikely to be helpful include: ESR, CRP and ACE.
IMAGING
• CXR: although it is useful, the correlation between the radiographic pattern and
the stage of the disease is poor, and it may be normal in early disease and in 10%
of patients.
• HRCT: contrast is not recommended unless pulmonary embolism is suspected.
• Pattern can be seen : reticular opacities, traction bronchiectasis and honeycombing
predominantly subpleural and basal distribution
• Are the imaging features of UIP. While GGO may be present ,they should be
superimposed on reticular opacities to be considered indicative of UIP.
NSIP: predominant GGO, mild or no HC and
predominantly LL.
Pulmonary function test
• Complete PFT (spirometry, lung volumes, DLCO) resting and exercise pulse
oximetry( 6MWT) are obtained in all patients.
• PFT is most helpful in assessing severity, pattern( restrictive or obstructive), and
monitoring.
• Most of interstitial disorders are restrictive.
• DLCO: reduction is common but nonspecific finding in ILD , its reduction due to
V/P mismatch.
• Moderate to severe reduction in DLCO with normal lung volumes in patient with
ILD suggest pulmonary vascular disease.
Cardiac evaluation
It is important in the initial evaluation of ILD because heart failure is a
differential diagnosis of ILD.
It include ECG,BNP and echocardiography to assess HF and PH.
There are no clear guidelines on when to obtain echocardiography in patient with
ILD but a reasonable approach is to perform it in:
1-Abnormal ECG.
2-Suspected HF.
3-Rapid onset of radiographic finding.
4-Moderate to severe reduction in DLCO.
5-Before obtaining lung bx (if not done before) to exclude occult heart failure.
Bronchoalveolar lavage
• It is performed during flexible bronchoscopy to obtain sample of cells and fluid
from distal airways and alveoli, the fluid is sent for cell count and differentiation,
gram stain, culture and cytology.
• All patients present with hemoptysis and +ILD should do BAL to confirm alveolar
source of bleeding or infection, it also beneficial in acute or rapid progressive ILD
Lung biopsy
It not routinely done and it is not recommended when the HRCT show the typical
pattern of ILD because the result of biopsy will no change treatment or prognosis.
Indication:
1-Atypical or rapid changing HRCT
2-To exclude neoplastic and infectious conditions that can mimic chronic progressive
ILD.
3-To identify a more treatable process than originally suspected (hypersensitivity
pneumonitis vs IPF)
4-Rarely, to diagnose ILD in a patient with hypoxemia, PFT strongly suggestive of
ILD, a negative evaluation of pulmonary vascular disease and normal HRCT
CTDs associated with NSIP & UP
Systemic sclerosis
ILD is one of the most common lung complications and one of the major causes of
death in scleroderma.
Higher risk of developing severe progressive ILD has been observed in:
1-Patients with diffuse skin involvement.
2-African-Americans, Native-Americans.
3-Positive for anti-topoisomerase 1 (Scl-70), anti-U3-RNP, or anti-Th/To antibodies.
4-Anti-topoisomerase positivity has been strongly linked to the carriage of the
HLA-DRB1*11 and HLA-DPB*1301 alleles, suggesting that a genetic predisposition
to ILD exist.
Systemic sclerosis
• The majority of patients with SSc-ILD have NSIP-pattern injury.
 Less commonly a UIP-pattern is observed
• NSIP identified in two-third of biopsied cases while UP identified in one-third of
the cases.
Radiologic Manifestations
• Evidence of interstitial fibrosis has been reported at chest radiography in 20%–65%
of patients. Serial radiographs obtained over several years may show progressive
loss of lung volume in addition to a worsening of the interstitial disease.
Treatment
*CYC( oral or I.V. monthly) or MMF are the drugs of choice for patients with
progressive SSc-ILD.
*Both MMF and CYC are associated with modest improvements in FVC, degree of
fibrosis on HRCT, health-related quality of life, and mRSS.
*In refractory cases, rituximab, azathioprine, or calcineurin antagonists
(cyclosporine or tacrolimus) may be considered.
Treatment with autologous HSCT may have beneficial effects on the ILD, but is
typically reserved for those with dcSSc who have failed to respond to conventional
therapy.
*In September of 2019 the FDA approved the use of nintedanib (either alone Or
Combination with MMF) for the treatment of SSc-associated ILD.
Rheumatoid arthritis
*The most serious form of pulmonary involvement occurs commonly in RA patients
is ILD but is symptomatic and progressive in less than 10% and additional 30%
subclinical, UIP pattern of ILD is most common, NSIP the next most common one.
*Risk factors: male sex, smoking, and positive autoantibodies.
Radiologic Manifestations

In the early stage, the radiographic appearance consists of irregular linear

hyperattenuating areas in a fine reticular pattern. The abnormality usually involves
mainly the lower lung zones. With the progression of disease, the reticular pattern
becomes more coarse and diffuse, and honeycombing may be seen
Treatment
• Treatment of RA-ILD remains entirely empirical. High-dose corticosteroids are
often used in patients with potentially reversible patterns such as OP or those with
flares of RA-ILD. In addition, cyclophosphamide, azathioprine, cyclosporine or
mycophenolate have been used as steroid sparing agents or in steroid-refractory
cases, biologic agents control the joint disease very well but have minimal effect
on ILD. Lung transplantation is offered by certain centers to RA-ILD patients
with limited joint disease and relatively preserved functional status.
PM&DM
• In patients with clinically significant disease, two main types of clinical presentations
have been observed. The first is characterized by subacute onset of dyspnea and
widespread basilar predominant ground glass opacities and consolidation against a
background of reticulation with traction bronchiectasis on CT.
• Many patients presenting this way progress significantly over a few weeks to months
and are refractory to therapy The presentation involves an insidious onset and slowly
progressive dyspnea. A combined pattern of NSIP and OP are observed on HRCT and
in histopathological specimens. Other patients with PM/DM can present with a UIP-
pattern of lung injury.
Radiologic Manifestations

• Initial high-resolution CT findings of pulmonary involvement in patients with

polymyositis or dermatomyositis are prominent interlobular septa, ground-glass
attenuation, patchy consolidation, parenchymal bands, irregular
peribronchovascular thickening, and subpleural lines 
Treatment

• High-dose oral prednisone is often used as first-line therapy in PM/DM-associated

ILD. In the US, azathioprine and mycophenolate are the most frequently used
immunomodulatory agents for PM/DM-ILD; however, there are case reports and
case series suggesting a role for the calcineurin antagonists. 
• In severe, rapidly progressive disease, intravenous cyclophosphamide in
conjunction with high-dose methyl prednisone has been used
•  In PM/DM the risk of malignancy is increased and screening for occult neoplasm
should be considered, particularly in patient without AS antibodies.
SLE
• Chronic interstitial lung disease/fibrosis: rare in nonoverlap SLE. More common
in patients with mixed connective tissue disease or prior acute lupus pneumonitis.
R/O medication effects (e.g., nitrofurantoin) or overlap with Antisynthtase
antibody syndrome.
• Treated by high-dose intravenous methyl prednisone (1 g daily for 72 hours)
followed by oral corticosteroids and possibly intravenous cyclophosphamide.
• In refractory , plasmapheresis and intravenous immunoglobulins have been
described. Success with rituximab has also been reported.
SOGREN DISEASE

• Although restriction and reduced DLco have been found in 17%–37.5% of

patients with SjS, clinically significant ILD is rare, and in most cases SjS-ILD
follows a mild and self-limited course. Respiratory symptoms mostly relate to dry
mucous membranes predisposing patients with SjS to hoarseness and dry cough
(due to xerotrachea).
• Patients with SjS are at increased risk of respiratory tract infections due to
impaired immune function of the mucosal barrier lining the airway epithelium.
Radiologic Manifestations

• Parenchymal abnormalities are evident at chest radiography in 10%–30% of

patients . The most common finding, a reticulonodular pattern that involves
mainly the lower lung zones, may reflect the presence of lymphocytic interstitial
pneumonia or interstitial fibrosis.
• A characteristic pattern of extensive areas of ground-glass attenuation with
scattered thin-walled cysts is seen in approximately 50% of patients with
lymphocytic interstitial pneumonia
• Treatment with systemic or oral steroid and immunosuppressive drugs.
References
1-Firestein & Kelley’s Textbook of Rheumatology.
2-Secretes of rheumatology.
3- Skills in rheumatology.
4-UP TO DATE
5-Radiopedia website