Category Archives: Anthony’s ILD Roundup

1. Necrobiotic rheumatoid nodules were discovered on biopsy in a patient with RA-ILD

What are the observed pulmonary manifestations of Rheumatoid arthritis?

Graingers and Allison’s Diagnostic Radiology, 9, 206-230.

What is epidemiology, clinical, radiologic, and pathologic criteria associated with necrobiotic rheumatoid nodules?

• Rare complication (1% with RA)
• More common in:
  • Men > Women
  • Long-standing disease
  • RF positivity
  • Active disease (esp cutaneous rheumatoid nodules’ also with joint disease, and elevated RA serologies)
• Morphology:
  • Single or multiple
  • mm to several cm in diameter
  • Well-circumscribed
  • May cavitate à leading to pneumothorax or bronchopleural fistula
  • May wax/wane
  • May be PET avid (although those >8 mm are not typically)
• Pulmonary nodules can paradoxically worsen with the start of RA therapy (most well observed with methotrexate)
• Nodules with upper/midzone predilection, located along interlobular septa or subpleural regions
• May cavitate (due to proteolytic enzymes) or rupture (leading to PTX or bronchopleural fistula)

European Respiratory Review 2015 24:1-16 (link)

Fishman’s Pulmonary Disease and Disorders, Chp 60, 5e.

In our case, a VATS biopsy was performed to rule out malignancy and infection as other causes of cavitating lung lesions.

2. Our second case featured a patient with history of Sjogren Syndrome (SS) with cystic lung disease. In this case, the mural thickening and nodularity of the cysts and presence of lymphadenopathy raised our concern for potential malignancy. Gabby Liu raised MALT lymphoma as a potential diagnosis.

What is the association between SS and MALT lymphoma?

• Among autoimmune disorders, SS is most strongly associated with the development of lymphoma
• In a small retrospective study describing biopsy-proven MALT lymphoma with lung involvement, 54% met criteria for SS

What are the commonly associated patterns of ILD in SS, and how are cystic lung diseases characterized and distinguished?

• Follicular bronchiolitis
• Lymphocytic interstitial pneumonia (LIP)
• Non-specific interstitial pneumonia (NSIP)
• Amyloidosis
• Lymphoproliferative disorders, including lymphoma

Clin Med Res. 2017; 15(1-2):6-12 (link)

AJRCCM 2015; 191(12) 1354-1666 (links 1 and 2 included below)

3. The third case involved a former smoker with CT findings of a probable UIP pattern with air trapping. The differential diagnosis included fibrotic hypersensitivity pneumonitis (fHP) vs IPF (i.e., CPFE). A bronchoscopy with BAL and lung biopsy were discussed as potential next steps for establishing diagnosis.

How is the diagnosis fHP arrived upon? How is fHP distinguished from other fibrotic ILDs?

AJRCCM 2020; 202(3):e36-e69. (link)

ILD Roundup (7/8/22) 

1. Interstitial pneumonia with autoimmune features (IPAF) was favored as a differential consideration in a patient who presented to NMH for a third opinion for her ILD 

ERS/ATS research statement (Eur Respiratory Journal 2015;46:976-987) 

On the spectrum between idiopathic interstitial pneumonias (IIP) and connective-tissue disease associated ILDs (CT-ILD) are patients with IPAF. Oftentimes patients with an “autoimmune flavor” of ILD do not meet criteria for CTD diagnosis. 

Why does the distinction matter?  

• Identifying underlying etiology impacts treatment and prognosis 
• Expedites linkage to rheumatology care, potentially facilitating CTD diagnosis 
• Accurate disease epidemiology depends on it 
• May aid in elucidation of pathophysiologic mechanism of disease 
• Defined criteria facilitate clinical trial design for future research 

What are the consensus criteria?  

All of the following must be fulfilled: 

1. Presence of interstitial pneumonia (HRCT/SLB) 
2. Exclusion of alternative etiologies 
3. Does not meet criteria for defined connective tissue disease 
4. At least one feature from 2/3 domains: 

• Clinical 
• Serologic 
• Morphologic 

Pearl from case discussion: If histopathology pattern does not fit expectation but another criterion in this  domain is met (histopathology predominantly UIP pattern, however, there was presence of lymphoid aggregates), the diagnostic criteria for IPAF may still be satisfied!

2. In the same patient as above, we discussed and ultimately decided against use of azathioprine, because she had some HRCT features suggestive of a UIP pattern 

We know that nintedanib (INPULSIS – 2014) and pirfenidone (ASCEND – 2014) are associated with decreased rate of FVC decline in patients with IPF, hence the rationale for their use. Before the advent of antifibrotics, immunosuppressive agents had been used in patients with IPF. Several retrospective studies and small RCTs suggested mortality benefit with combination of steroid + AZA or cyclophosphamide though they were confounded by inclusion of patients who did not meet diagnostic criteria for IPF. Guidelines thus differed: the British Thoracic Society weakly recommended N-acetylcysteine (NAC), prednisolone, and azathioprine based on results from IFIGENIA (decreased decline in FVC and DLCO); whereas, the ATS/ERS recommended lung transplantation and participation in clinical trials. The IFIGENIA trial was limited by substantial drop-out and lack of “no treatment” arm.

Why do we now avoid the use of immunosuppressive medications – and azathioprine in particular – in suspected IPF? 

PANTHER-IPF (NEJM 2012;366:1968-1977) 

• A double blind RCT wherein a commonly used cocktail of prednisone/azathioprine/NAC was used in 1:1:1 fashion with placebo and NAC alone 
• A previous study had shown that triple therapy performed superiorly with regards to VC and DLco preservation compared with prednisone/azathioprine alone, but no placebo-controlled data existed 
• Stopped at interim analysis when control group was found to have significant increase in death and hospitalization rates compared to placebo 

3. In another patient, the presenter mentioned that hypersensitivity pneumonitis had not been considered in a patient because he did not have any “clear exposure history”.  

How often is a diagnosis of HP arrived upon without a clear exposure history? Does identification of an exposure matter in patients with HP? 

CHEST 2013;144(5):1644-1651 

• In a retrospective review of a longitudinal ILD database, 134 consecutive patients with clinico-radiologic diagnosis of HP found that inciting antigen was not identified in 53% of cases.  
• Inability to identify target antigen was associated with significantly shorter survival (HR 1.76; 1.01-3.07) in this same cohort.  

1. Association of ANA pattern with CTD-ILDs 

We often talk about ANA titers & pattern in our ILD evaluations – what do they signify?  

• Cut-off for positive test suggested at 1:160 

• Variability based on lab/technician 
• 25-30% of health controls with low Ab titers 
• 56% +ANA with ILD of unclear cause, despite lower rate of CTD diagnosis (4-20%) in ILD population
• Increasing age associated with higher prevalence of ANA positivity

General associations to be aware of: 

• Homogenous –> dsDNA –> SLE 
• Speckled –> MCTD, Sjogren, SLE, DM 
• Centromeric or Nucleolar –> SSc 
• Cytoplasmic –> anti-synthetase syndrome 

2. Acute interstitial pneumonia/Hamman-Rich Syndrome

What are the clinical characteristics and prognosis of this rare illness? 

• Rapidly progressive (1-2 weeks) hypoxemic respiratory failure with high mortality (~50%), with bilateral GGOs and consolidation within dependent lung, no clear trigger (ddx ARDS) and without antecedent ILD (ddx flare ILD, esp IPF)
• Pathology shows diffuse alveolar damage, alveolar wall thickening and pneumocyte hyperplasia
• Progresses to pattern similar to fibrotic NSIP Clinical course and lung function change of idiopathic nonspecific interstitial pneumonia

Image source: European Respiratory Journal 2009 33:68-76.

3.Idiopathic NSIP

A retrospective analysis of 83 patients with radiological & pathological criteria for iNSIP conducted in the pre-antifibrotic era (between 1991-2006).

Interesting findings included:

• 10% of patients with iNSIP developed clinically manifest CTD during follow-up
• Scleroderma, PM/DM, RA, MCTD, PMR
• These patients tended to be younger and did not have increased risk for recurrence
• Deterioration of FVC at 6 months correlated most strongly with disease-specific mortality