CONTENTS
- Overview of connective tissue disease-related ILD (CTD-ILD)
- Interstitial pneumonia with autoimmune features (IPAF)
- Rheumatoid arthritis (RA)
- Scleroderma
- Lupus
- Sjogren syndrome
- Myositis
- Mixed connective tissue disease (MCTD)
- Questions & discussion
abbreviations used in the pulmonary section:
- ABPA: Allergic bronchopulmonary aspergillosis 📖
- AE-ILD: Acute exacerbation of ILD 📖
- AEP: Acute eosinophilic pneumonia 📖
- AIP: Acute interstitial pneumonia (Hamman-Rich syndrome) 📖
- ANA: Antinuclear antibody 📖
- ANCA: Antineutrophil cytoplasmic antibodies 📖
- ARDS: Acute respiratory distress syndrome 📖
- ASS: Antisynthetase Syndrome 📖
- BAL: Bronchoalveolar lavage 📖
- BiPAP: Bilevel positive airway pressure 📖
- CEP: Chronic eosinophilic pneumonia 📖
- COP: Cryptogenic organizing pneumonia 📖
- CPAP: Continuous positive airway pressure 📖
- CPFE: Combined pulmonary fibrosis and emphysema 📖
- CTD-ILD: Connective tissue disease associated interstitial lung disease 📖
- CTEPH: Chronic thromboembolic pulmonary hypertension 📖
- DAD: Diffuse alveolar damage 📖
- DAH: Diffuse alveolar hemorrhage 📖
- DIP: Desquamative interstitial pneumonia 📖
- DLCO: Diffusing capacity for carbon monoxide 📖
- DRESS: Drug reaction with eosinophilia and systemic symptoms 📖
- EGPA: Eosinophilic granulomatosis with polyangiitis 📖
- FEV1: Forced expiratory volume in 1 second 📖
- FVC: Forced vital capacity 📖
- GGO: Ground glass opacity 📖
- GLILD: Granulomatous and lymphocytic interstitial lung disease 📖
- HFNC: High flow nasal cannula 📖
- HP: Hypersensitivity pneumonitis 📖
- IPAF: Interstitial pneumonia with autoimmune features 📖
- IPF: Idiopathic pulmonary fibrosis 📖
- IVIG: Intravenous immunoglobulin 📖
- LAM: Lymphangioleiomyomatosis 📖
- LIP: Lymphocytic interstitial pneumonia 📖
- MCTD: Mixed connective tissue disease 📖
- NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
- NSIP: Nonspecific interstitial pneumonia 📖
- NTM: Non-tuberculous mycobacteria 📖
- OP: Organizing pneumonia 📖
- PAP: Pulmonary alveolar proteinosis 📖
- PE: Pulmonary embolism 📖
- PFT: Pulmonary function test 📖
- PLCH: Pulmonary Langerhans Cell Histiocytosis 📖
- PPFE: Pleuroparenchymal fibroelastosis 📖
- PPF: Progressive pulmonary fibrosis 📖
- PVOD/PCH Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis 📖
- RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease 📖
- RP-ILD: Rapidly progressive interstitial lung disease 📖
- TNF: tumor necrosis factor
- UIP: Usual Interstitial Pneumonia 📖
prevalence of clinically significant ILD in different connective tissue diseases
- Scleroderma: 40%.
- Idiopathic inflammatory myopathy: 20-30%.
- Mixed connective tissue disease: 20%.
- Rheumatoid arthritis: 5-10%.
- Sjogren syndrome: 5-10%.
- Lupus: Rare.
histologic association of different patterns with various connective tissue disorders
- For patients with a known underlying connective tissue disorder, the histologic pattern often doesn't affect prognosis or treatment. (For such patients, surgical biopsy to determine the histologic pattern is clinically unhelpful.)
- For patients without a known underlying connective tissue disorder, associations may be helpful in predicting which connective tissue disorder patients may have, or be at risk of developing. (Shah 2019)
- UIP/IPF pattern:
- Most closely associated with rheumatoid arthritis.
- Also associated with scleroderma, idiopathic inflammatory myositis.
- NSIP: Suggests scleroderma, idiopathic inflammatory myositis, rheumatoid arthritis, mixed connective tissue disease.
- Organizing pneumonia: especially associated with myositis, rheumatoid arthritis, lupus.
- DAD (diffuse alveolar damage): associated with lupus, myositis, MCTD (mixed connective tissue disease). (34602377)
- LIP (lymphocytic interstitial pneumonia): Suggests Sjogren syndrome.
- UIP/IPF pattern:
review of systems
- Joint pain and/or swelling? Morning stiffness?
- Skin changes (including rash/thickening/tightening/fissuring)?
- Raynaud phenomenon? (Associated with scleroderma, lupus, Sjogren syndrome, mixed connective tissue disease).
- Dry eyes and/or dry mouth?
- Muscle pain and/or weakness?
- Oral ulcers?
- Unexplained rash?
- Hematuria?
examination
- Swelling/tenderness of small joints.
- Skin, nails, and hair changes are of particular importance, e.g.:
- Nailfold capillary abnormalities: Suggest scleroderma, myositis, or MCTD (mixed connective tissue disease).
- Periungual erythema: suggests lupus or dermatomyositis.
autoantibody panel
testing for patient with ILD and suspected connective tissue disease:
- Extractable Nuclear Antigens (ENA panel) – RNP, Sm, SSa, SSb.
- MyoMarker panel – evaluation for idiopathic inflammatory myositis. (34488971) This is a send-out test to the Mayo Clinic (test ID FMYO3).
- Antinuclear antibody (ANA) – screening test for lupus, scleroderma-related ILD, and MCTD (mixed connective tissue disease).
- RF (rheumatoid factor)
- Anti-citrullinated protein antibodies (CCP).
- Anti Scl-70.
- Anti-double stranded DNA.
- Creatinine kinase (CK).
- Aldolase.
- CRP (C-reactive protein).
- Ferritin (for ICU patients, or when MDA5 disease is a consideration).
- Antineutrophil cytoplasmic antibodies (ANCA).
- (💡 Consider additionally screening for hepatitis B and hepatitis C, if aggressive immunosuppression is likely imminent).
autoantibodies in specific diseases
rheumatoid arthritis
- Rheumatoid factor:
- Positive in ~75% of patients with RA.
- Rheumatoid factor is not specific for RA (for example, it is seen in ~25% of patients with lupus).
- Higher titers are correlated with RA-ILD.
- Anti-CCP antibody (anti-citrullinated protein antibodies):
- Similar sensitivity as compared to rheumatoid factor.
- Specificity is higher for rheumatoid arthritis (~95-98%).
scleroderma
- Scleroderma-associated interstitial lung disease:
- Associated with anti-Topoisomerase I (anti-SCL-70).
- >90% of patients are ANA positive.
- Scleroderma-related pulmonary hypertension:
- Associated with anticentromere antibody (ACA). This has limited sensitivity, but is very specific for scleroderma.
- Other tests which may be positive:
- Anti-polymyositis-systemic sclerosis antibody (Anti-PM-Scl) – found in half of patients who have an overlap between scleroderma and dermatomyositis. This phenotype is discussed further below: 📖
- Anti-ribonucleic acid polymerase III (anti-RNA pol III).
- Anti-U3-ribonucleoprotein antibody (anti-U3-RNP).
- Anti-Th/To antibody.
lupus
- ANA: Present in nearly all patients with lupus, but nonspecific.
- Anti-double-stranded DNA (dsDNA):
- Sensitivity of ~60%, but highly specific to lupus.
- Anti-dsDNA titers may correlate with disease activity.
- Anti-Smith antibody (Sm): Sensitivity of ~25%, but specific for lupus.
- p-ANCA may be present in ~20% of patients with lupus.
Sjogren syndrome
- ANA is positive in ~75% of patients.
- Anti-SSA (Ro) antibody positive in ~60% of patients. (34602377)
- Anti-SSB (La) antibody positive in ~25% of patients. (34602377)
myositis
- Increased creatine kinase (CK) and aldolase.
- ANA is often negative, but cytoplasmic fluorescence may be seen.
- Anti-SSa (Ro) antibody may be present.
- Different phenotypes may have various antibodies, including:
- Anti-tRNA synthetase antibodies (Jo-1, PL-7, PL-12, et. al.)
- Anti-MDA5 antibody.
- Anti-Mi-2 antibody.
- Anti-polymyositis-systemic sclerosis antibody (anti-PM-Scl antibody).
MCTD (mixed connective tissue disease)
- ANA is positive in nearly all patients.
- Anti-U1 RNP antibody is more specific (but this may also occur in lupus or scleroderma).
interpreting ANA (antinuclear antibody) results
causes of positive ANA include:
- Infection:
- HCV.
- Mononucleosis (EBV).
- Endocarditis.
- Rheumatologic:
- MCTD (mixed connective tissue disease (>95%).
- Lupus, including drug-induced lupus (>95%).
- Scleroderma (~75%).
- Sjogren syndrome (~75%).
- Myositis (~50%).
- Rheumatoid arthritis (~30%).
- Autoimmune hepatitis, primary autoimmune cholangitis, primary biliary cholangitis.
- Myasthenia gravis.
- Diabetes.
- Autoimmune thyroid disease.
- May be seen in otherwise healthy people (usually in low titer, with a homogeneous or speckled pattern).
associations with various ANA staining patterns:
- Homogeneous: (>1:320 meets criteria for IP-AF)
- May suggest antibody against DNA-histone complex (e.g., dsDNA, histones, or deoxyribonucleoprotein). (24645948)
- May be seen in lupus, drug-induced lupus.
- Speckled pattern: (>1:320 meets criteria for IP-AF)
- May suggest antibody to Smith, small nuclear RNPs (snRNPs) including anti-U1RNP, SSA/Ro, SSB/La, Scl-70, centromere (“discrete speckled pattern”), RNA polymerase II or III, helicase, topoisomerase, or anti-Ku.
- May be seen in lupus, mixed connective tissue disease (anti-RNP antibody), Sjogren syndrome, scleroderma, myositis.
- Peripheral/rim pattern:
- May suggest antibody to dsDNA or nuclear envelope antigens.
- May be seen in lupus or autoimmune hepatitis.
- Nucleolar pattern: (any positive titer meets criteria for IP-AF)
- May suggest antibody to nucleolar RNA, RNA polymerase I, anti-PM-SCL antibody.
- May be seen in diffuse scleroderma, hepatocellular carcinoma.
- Centromeric pattern: (any positive titer meets criteria for IP-AF)
- May suggest antibody to centromeres.
- May be seen in limited cutaneous scleroderma.
- Anticytoplasmic antibodies:
- These are not anti-nuclear antibodies (ANA), but they may be detected when evaluating for ANA.
- These may include the following autoantibodies:(23190225)
- anti-Ro antibody.
- anti-mitochondrial antibodies.
- anti-signal recognition particle (srp) antibody, which may be seen in myositis.
- anti-tRNA synthetase antibodies, which correlate with antisynthetase syndrome.
- Anti-MDA5 antibody.
- In the context of pulmonary disorders, anticytoplasmic antibodies may raise the possibility of myositis (and specifically, antisynthetase syndrome or anti-MDA5 syndrome). (34602377)
interstitial pneumonia with autoimmune features (IPAF)
- IPAF describes patients with ILD that have a combination of clinical, serologic, and morphologic autoimmune features that don't fulfill existing rheumatologic criteria for a diagnosable connective tissue disease. However, some features are present that suggest an underlying rheumatologic disorder.
diagnostic criteria for IPAF
- (1) Presence of an interstitial pneumonia (based on CT scan or surgical lung biopsy).
- (2) Exclusion of alternative causes of the ILD.
- (3) Doesn't meet criteria for a defined connective tissue disease.
- (4) At least one feature from at least two of the following domains:
- (4a) Clinical domain:
- Distal digital fissuring (mechanic's hands).
- Distal digital tip ulceration.
- Inflammatory arthritis or polyarticular morning joint stiffness >1 hour.
- Palmar telangiectasia.
- Raynaud phenomenon.
- Unexplained digital edema.
- Unexplained fixed rash on the digital extensor surfaces (Gottron's sign).
- (4b) Serologic:
- ANA with a speckled or homogeneous pattern at >1:320 titer.
- ANA with a nucleolar or centromere pattern at any titer.
- Rheumatoid factor above twice the upper limit of normal.
- Antibodies to cyclic citrullinated peptides (anti-CCP).
- Anti-double stranded DNA antibody.
- Anti-SSA (Ro) antibody.
- Anti-SSB (La) antibody.
- Anti-U1-ribonucleoprotein antibody (anti-RNP).
- Anti-Smith antibody (Anti-Sm).
- Anti-topoisomerase (Scl-70) antibody.
- Anti-transfer ribonucleic acid-synthetase antibodies (e.g., Jo-1, PL7, PL12).
- anti-polymyositis-systemic sclerosis antibody (anti-PM-Scl).
- Anti-MDA-5.
- (4c) Morphologic:
- Radiologic pattern of ILD based on CT scan:
- NSIP.
- OP.
- NSIP/OP overlap.
- LIP.
- (Note that UIP isn't included.)
- Histologic pattern based on surgical lung biopsy:
- NSIP.
- OP.
- NSIP/OP overlap.
- LIP.
- Interstitial lymphoid aggregates with germinal centers.
- Diffuse lymphoplasmacytic infiltration +/- lymphoid follicles.
- (Note that UIP isn't included.)
- Multi-compartment involvement (in the addition of interstitial pneumonia):
- Unexplained pleural effusion or thickening.
- Unexplained pericardial effusion or thickening.
- Unexplained intrinsic airway disease (airflow obstruction, bronchiolitis, or non-traction bronchiectasis).
- Unexplained pulmonary vasculopathy.
- Radiologic pattern of ILD based on CT scan:
radiological patterns most often seen:
- UIP (50%), especially in association with these signs which may suggest a rheumatologic origin:
- Anterior upper lobe sign: anterior upper lobe-predominant fibrosis, with relative sparing of the remainder of the upper lobes and fibrosis of the lower lobes.
- Exuberant honeycombing sign: extensive honeycombing comprising >70% of the fibrotic portions of the lung.
- Straight-edge sign: isolation of fibrosis in the lung bases, with a sharp demarcation in the craniocaudal plane.
- NSIP (25%).
- Hypersensitivity pneumonitis (8%).
- NSIP with overlapping organizing pneumonia (7%).
- Organizing pneumonia (4%). (28350485)
management
- IPAF is a research designation. Similar to ARDS, IPAF doesn't reflect the presence of any specific disease. Therefore, IPAF doesn't necessarily correlate with any specific treatment.
- In practice, patients who require therapy are often treated using the treatment pathway of a disorder that most closely resembles their clinical presentation.
- Patients with rapidly progressive disease could be treated with the management strategy for rapidly progressive ILD: 📖
summary of rheumatoid arthritis
- Clinical manifestations:
- Inflammatory arthritis (usually symmetric, small and large joints).
- Joint deformities.
- Severe (“malignant”) rheumatoid arthritis may cause rheumatoid nodules, mononeuritis multiplex, cutaneous ulcers, skin infarction, digital necrosis, episcleritis, and iritis. (34602377)
- Labs: 📖
overview of pulmonary involvement in RA
- Parenchymal lung disease:
- Interstitial lung disease (RA-ILD).
- Pneumonia (potentially related to immunosuppression).
- Rheumatoid nodules.
- Drug-induced lung disease (e.g., methotrexate toxicity ).
- Airway disease:
- Bronchiolitis obliterans.
- Bronchiectasis (15% of patients; this may increase risk of infection during therapy for RA). (28552544; Tenebeck 2022)
- Follicular bronchiolitis.
- Cricoarytenoid arthritis (may cause extrathoracic obstruction).
- Pleural disease:
- RA pleuritis.
- Pulmonary hypertension is often seen (may relate to ILD, or cardiac disease).
basics
- RA-ILD is the most serious pulmonary problem associated with RA.
- Pattern: (32780179)
- ~40% is UIP (usual interstitial pneumonia).
- ~30% is NSIP (nonspecific interstitial pneumonia).
- ~10% is OP (organizing pneumonia).
epidemiology
- RA-ILD tends to occur in patients with late-onset RA, often in their 50s-60s.
- RA-ILD usually occurs within the first five years of RA diagnosis. Usually ILD follows arthritis, but in ~15% of patients ILD may precede arthritis.
- RA-ILD is associated with: (Murray 2022; Fishman 2023)
- Subclinical radiologic abnormalities are common. However, clinically overt fibrosis on chest radiograph occurs in only ~5% of patients with RA. (Murray 2022; Fishman 2023) Despite this low frequency of RA-ILD (~5%), since RA itself is very common, RA-ILD is a prominent cause of connective tissue disease-related ILD. (37055086)
clinical presentation
- Symptoms are similar to IPF (most commonly dyspnea, sometimes dry cough).
- Clubbing occurs in up to 75% (more often than in other connective tissue diseases). (Murray 2022)
- Acute exacerbation of ILD may occur with high mortality.
radiology
- CT scan usually resembles UIP (e.g., reticulation and honeycombing in a basal and subpleural distribution, without substantial ground glass opacification). However, scans may also resemble NSIP (e.g., with greater degrees of ground glass opacification). (Murray 2022)
- In comparison to IPF, some radiographic features may suggest rheumatoid arthritis:(Shepard 2019)
- Substantial fibrosis in the anterior upper lobes (in addition to basilar fibrosis).
- Exuberant honeycombing that affects the vast majority of the lung (“honeycomb lung”).
- Isolation of fibrosis to the lung bases, without extension along the lateral margins of the lungs on coronal images (straight-edge sign).
- ~20% of patients may have superimposed pleural disease.
diagnosis
- Surgical lung biopsy is generally unnecessary, since treatment is similar regardless of the histopathological pattern. (Murray 2022)
treatment
- Optimal treatment is unclear. Management varies depending on whether the ILD clinically and radiologically resembles UIP, NSIP, OP, or DAD.
- RA-UIP (i.e., patients whose disease resembles IPF):
- Immunosuppression is ineffective for IPF, but this probably doesn't hold true for RA-UIP.
- Some case reports have found benefit from immunosuppression. It may be reasonable to trial prednisone at a dose of 10-40 mg/day with careful assessment of efficacy. If effective, transition to a steroid-sparing agent may be considered. (34602377)
- Antifibrotic therapy is a rational treatment (e.g., nintedanib), especially if there is deterioration of pulmonary function tests over time.
- RA-NSIP (i.e., patients with significant ground glass opacities)
- NSIP is usually more steroid-responsive than UIP.
- Immunosuppressive therapy, including steroid and mycophenolate mofetil, might be reasonable (based on extrapolation of data from scleroderma).
- RA-OP
- RA-DAD (i.e., acute ILD exacerbation resembling ARDS).
- Pulse dose steroid should be started as soon as possible. The prognosis is poor. (34602377)
- Patients with rapidly progressive disease may be treated with the management strategy for rapidly progressive ILD: 📖
- Additional aspects of the management of AE-ILD (acute exacerbation of ILD) are discussed further here: 📖
basics
- Nodules may occur in the lung parenchyma, endobronchial mucosa, pleura, and/or subcutaneous tissue.
- Caplan syndrome refers to a superimposition of rheumatoid nodules upon a background of parenchymal pneumoconiosis (e.g., silicosis or coal workers pneumoconiosis).
epidemiology
- Nodules occur in <1% of patients with rheumatoid arthritis. They are usually preceded by signs and symptoms of extrapulmonary RA.
- Nodules are associated with:
- Subcutaneous rheumatoid nodules.
- Active joint disease.
- Rheumatoid factor is positive, with high titer.
- Male sex.
- Smoking.
symptoms
- Nodules are generally asymptomatic.
- Cavitation may rarely cause a pneumothorax, or severe hemoptysis.
- Laryngeal nodules may rarely cause upper airway obstruction.
radiology
nodule attributes
- Size ranges from a few mm to 7 cm.
- Size may wax and wane, in relationship to subcutaneous nodules (if serial scans are available).
- Border is usually smooth.
- About half may cavitate, yielding a thick-walled cavity with a smooth inner lining (over time this may become thin-walled).
distribution & configuration
- Multiple nodules are usually present.
- Distribution is mainly subpleural, often in contact with the pleura.
- Nodules are usually predominant in the middle and upper lung.
- Satellite nodules may occur. A row of adjacent nodules may occur, leading to a subpleural rind of tissue. (32386648)
diagnosis
differential diagnosis includes:
- Malignancy.
- Infectious granulomatous disease.
- (More complete differential diagnosis of macronodular disease: 📖)
rheumatoid lung nodule score:
- One point for each of the following features:
- Four or more nodules.
- Peripheral location.
- Cavitation.
- Satellite nodules.
- Smooth border.
- Sub-pleural rind of tissue.
- Subcutaneous rheumatoid nodule.
- Seropositive rheumatoid arthritis.
- A score of 4 or more suggests rheumatoid nodules with reasonable sensitivity (95%) and specificity (85%). However, this is intended only as a rough guide that may not apply well to patients with unique circumstances (e.g., immunocompromise, or high exposure to tuberculosis). (32386648)
diagnostic approach
- For symptomatic patients with concern for possible infection, an appropriate infectious workup should be undertaken. Tissue diagnosis isn't required after infection has been excluded. (32386648)
treatment
- Nodules are generally asymptomatic, so treatment is rarely needed.
- The main issue is exclusion of malignancy (which in some cases may require biopsy).
- If nodules are symptomatic, then treatment may involve immunosuppression.
summary of scleroderma
clinical manifestations:
- Raynaud phenomenon.
- Digital ischemia/ulceration.
- Digital edema.
- Skin thickening.
- Telangiectasia on face/hands/oral mucosa.
- Calcinosis cutis (subcutaneous calcium deposits).
diffuse versus limited cutaneous involvement
- Limited cutaneous systemic sclerosis:
- This was previously known as CREST syndrome (calcinosis, Raynaud disease, esophageal dysmotility, sclerodactyly, and telangiectasia). Skin involvement is usually distal to the elbows and knees, without facial involvement.
- Correlates with anticentromere antibody (ACA).
- Pulmonary involvement often centers on pulmonary hypertension.
- Diffuse cutaneous systemic sclerosis:
- This involves proximal as well as distal skin.
- Correlates with anti-topoisomerase I (Anti-Scl-70).
- Pulmonary involvement often centers on interstitial lung disease.
- Anti-Scl-70 antibodies and anticentromere antibodies are almost always mutually exclusive, with both being present in <0.5% of patients with systemic sclerosis. (Walker 2019)
overview of pulmonary involvement in scleroderma
- Interstitial lung disease.
- Pulmonary vascular disease:
- Pulmonary embolism.
- Pulmonary hypertension (which may include components of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis).
- Aspiration pneumonitis (scleroderma may cause esophageal reflux).
- Pneumonia (may relate to immunosuppression).
- Drug-related toxicity.
- Chest wall restriction.
- (Pleural effusion rarely occurs due to scleroderma.)
basics
- Clinically, this behaves similarly to IPF (idiopathic pulmonary fibrosis).
- Pathology:
- NSIP in >75% of patients (especially fibrotic NSIP).
- UIP is found in <10%.
- DAD is rare (described in some case reports).
epidemiology
- ILD predominantly affects patients with diffuse cutaneous systemic sclerosis. It is rare in patients with limited cutaneous scleroderma (the types of scleroderma are discussed above).
- Among patients with diffuse cutaneous systemic sclerosis:
- ~60% of patients have clinically significant ILD.
- ILD is a leading cause of death.
- Risk factors for ILD:
- Male sex.
- Severe skin involvement.
- anti-SCL-70 positivity.
- High serum CK (creatine kinase) levels. (34602377)
clinical presentation
- Dyspnea on exertion, dry cough.
radiology
- Fibrotic NSIP is the most common pattern seen:
- Ground glass opacities may initially predominate in cellular NSIP, but not in the fibrotic phase of NSIP.
- Subpleural and basal fibrosis develop (e.g., traction bronchiectasis, limited honeycombing).
- Pulmonary hypertension may be seen.
- Esophageal dilation may be seen.
- Lymphadenopathy is frequently seen. (Walker 2019)
laboratory studies
- >90% of patients are ANA positive.
- Interstitial lung disease and diffuse cutaneous systemic sclerosis correlate with anti-Scl-70 antibody.
diagnosis
- Diagnostic evaluation will vary, depending on each patient's specific clinical and imaging findings.
- Surgical lung biopsy is generally unnecessary, since treatment is similar regardless of the histopathological pattern. (Murray 2022) Indeed, the prognosis appears to be the same regardless of whether surgical biopsy shows UIP (usual interstitial pneumonia) or NSIP (nonspecific interstitial pneumonia). (12070056)
management
- Any GERD (gastroesophageal reflux disease) should be treated aggressively, as this may exacerbate pneumonitis.
- Not all patients require treatment, since limited interstitial lung disease can stabilize. Factors which may support treatment include:
- Deterioration in serial imaging or PFTs.
- Severe respiratory disease (e.g., extensive radiologic involvement, PFTs showing restriction or moderate-severe reduction in DLCO).
- Duration of systemic disease <2-5 years.
- Positive anti-Scl70 serology.
- Prominent ground glass opacities on CT scan, without traction bronchiectasis or reticulation.
- Treatment may involve various immunosuppressive medications.
- Cyclophosphamide reduces deterioration of pulmonary function, but after stopping cyclophosphamide the benefit may be lost. (17717203)
- Mycophenolate mofetil is as effective as cyclophosphamide, yet with a superior safety profile. (SLS II trial, 27469583)
- Tocilizumab has been demonstrated to prevent progression of ILD, at a dose of 162 mg subcutaneous injection weekly. (focuSSed trial; 32866440)
- Rituximab was demonstrated to improve the FVC from 1.51 liters to 1.65 liters (in comparison to cyclophosphamide, which didn't improve the FVC). (30053212)
- Antifibrotic therapy:
- The SENCIS study demonstrated that nintedanib diminished the decline in FVC (forced vital capacity). (31112379) Nintedanib is often reserved for patients with deteriorating PFTs despite therapy with mycophenolate mofetil. However, there isn't high-level evidence regarding how these medications should be combined.
- Pirfenidone hasn't been investigated yet for scleroderma, but is probably effective.
- Patients with rapidly progressive disease may be treated with the management strategy for rapidly progressive ILD: 📖
- ⚠️ Steroid is controversial, since this may provoke a scleroderma renal crisis at doses >15 mg prednisone/day. Steroid has been used for management of treatment initiation or for exacerbation management, with some series suggesting safety. (32780179; 23790734) However, ACR 2023 guidelines strongly recommend against steroid therapy.
prognosis
- Median survival is ~5-8 years.
- PFTs may provide some prognostication:
- Normal PFTs may suggest ~90% 5-yr survival.
- Restriction suggests ~60% 5-yr survival.
- DLCO <40% suggests ~10% 5-yr survival.
basics
- Scleroderma patients may have two pathologies which lead to pulmonary hypertension:
- (i) Pulmonary arterial obstructive lesions, which are similar to idiopathic pulmonary arterial hypertension. This seems to be the predominant pathology in most patients.
- (ii) Pulmonary venous remodeling can occur, which reflects a component of PVOD/PCH (pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis). Further discussion of PCH/PVD is here: 📖
epidemiology
- Pulmonary arterial hypertension occurs in ~10% of patients with scleroderma. (Murray 2022)
- Pulmonary hypertension frequently occurs in the absence of interstitial lung disease.
- Pulmonary hypertension is six times more common in limited cutaneous systemic sclerosis. Isolated pulmonary hypertension (without interstitial lung disease) arises mostly in the context of limited scleroderma. Such patients are often positive for anticentromere antibody (rather than anti-Scl-70).
symptoms
- Rapidly progressive dyspnea.
- Eventual deterioration leads to right heart failure.
radiology
- Patients with PCH/PVOD (pulmonary capillary hemangiomatosis/pulmonary veno-occlusive disease) may have evidence of this on CT scan:
- Interlobular septal thickening, pleural effusions.
- Ground glass opacification with mosaic attenuation.
- Centrilobular ground glass micronodules.
management
- (1) Most patients seem to have predominantly pulmonary arterial disease (similar to idiopathic pulmonary arterial hypertension). Management of this is discussed further here: 📖
- (2) Some patients may have a significant component of pulmonary capillary hemangiomatosis/pulmonary veno-occlusive disease. This is harder to treat, since it may cause patients to respond poorly to pulmonary arterial vasodilators. Further discussion of this entity is here: 📖
thumbnail of lupus
clinical manifestations
- Malar rash, photosensitivity, nasal/oral ulcers, hair loss.
- Acute cutaneous lupus reflects systemic disease activity, but chronic cutaneous lupus doesn't. (34602377)
- Arthralgia/arthritis.
- Pleuritis and/or pericarditis.
- Neurologic involvement.
- Hematologic manifestations (normocytic anemia, thrombocytopenia, leukopenia).
tests
- Discussed above: 📖
overview of pulmonary involvement in lupus
- Parenchymal disease:
- Pneumonia:
- Bacterial pneumonia (#1 cause of infiltrates).
- Unusual organisms related to immunocompromise.
- Acute lupus pneumonitis.
- Diffuse alveolar hemorrhage.
- Cardiogenic pulmonary edema / volume overload (may relate to myocarditis, coronary artery disease, or renal dysfunction).
- Organizing pneumonia.
- Catastrophic antiphospholipid antibody syndrome (CAPS).
- Chronic interstitial lung disease related to lupus.
- Pneumonia:
- Pulmonary vascular:
- PE (may relate to antiphospholipid syndrome).
- Chronic pulmonary hypertension related to lupus and/or CTEPH (chronic thromboembolic pulmonary hypertension).
- Pleural disease:
- Lupus pleuritis.
- Uremic effusion due to renal failure.
- Diaphragm:
- Shrinking lung syndrome.
- Airway disease:
- Bronchiolitis obliterans.
- Bronchiectasis can occur, but is often asymptomatic. (Fishman 2023)
basics
- Diffuse alveolar hemorrhage (DAH) may be caused via two mechanisms:
- (1) Immune complex deposition with capillaritis.
- (2) Bland hemorrhage, due to associated antiphospholipid antibody syndrome. (Fishman 2023)
epidemiology
- Only ~1.5-4% of all lupus patients may develop DAH. However, DAH is more common in lupus than in other connective tissue diseases. (Murray 2022)
- DAH usually occurs early in the disease course (on average within ~2-5 years of the initial diagnosis).
- DAH may rarely be the initial presentation of lupus. However, unlike acute lupus pneumonitis, most cases occur in the context of known lupus. (Fishman 2023)
- The mean age of onset of DAH is 30 years.
- There is a 6:1 female predominance. (22934226)
symptoms
- DAH may vary from subclinical to massive. The onset is usually relatively abrupt.
- Hemoptysis is absent in up to half of patients.
- Many patients are febrile (potentially mimicking pneumonia).
radiology
- Bilateral, diffuse airspace opacification. There is usually sparing of the apices and periphery. (22934226)
- Unlike acute lupus pneumonitis, pleuritis and pericarditis are usually absent. (Fishman 2023)
- Further discussion of the radiology of DAH: 📖
laboratory studies
- Falling hemoglobin may be a sign of diffuse alveolar hemorrhage.
- ~75% of cases are with lupus nephritis (pulmonary-renal syndrome). (Fishman 2023)
- Complement levels are frequently low. (22934226)
- (Laboratory studies investigating for antiphospholipid antibody should be sent early, as this may affect therapy.)
differential diagnosis
- Common causes of lung disease in lupus are listed at the top of this section.
diagnosis
- Bronchoscopy is generally necessary to confirm the diagnosis of DAH and exclude infection.
- Lung biopsy is generally inadvisable, as with other etiologies of diffuse alveolar hemorrhage (lung biopsy is high risk, and the pulmonary pathology is often nonspecific). If a tissue diagnosis is desired, renal biopsy may be more helpful for patients with active urinary sediment.
treatment
- (1) Steroid is the mainstay of acute therapy (e.g., pulse-dose methylprednisolone). Additional immunosuppressive therapies may be utilized as well (e.g., mycophenolate or azathioprine, possibly rituximab). Some reports anecdotally describe the successful use of plasmapheresis or intravenous immunoglobulin (IVIG), but there is no conclusive evidence regarding this.
- More aggressive immunosuppression may be reasonable in patients with evidence of systemic lupus activity.
- (2) For most patients with DAH, any coagulopathy should be aggressively treated (with a goal of preventing any further hemorrhage into the lungs).
- However, if DAH is caused by antiphospholipid syndrome, this is complicated. Anticoagulation for patients with antiphospholipid antibody syndrome might theoretically be beneficial (with the concept that microthrombi are causing venous congestion that leads to hemorrhage – especially in the context of catastrophic antiphospholipid syndrome). (27842704) Anticoagulation may need to be held temporarily for acute hemorrhage, but should often be restarted soon thereafter. Multidisciplinary discussions may help elucidate the optimal management. (31493005)
prognosis
- Mortality has historically been very high (~50%). However, this may be decreasing over time. (22934226)
- Recurrent DAH is common, especially in the absence of immunosuppression. (Fishman 2023)
basics
- Pathologically, this is DAD (diffuse alveolar damage) caused by lupus.
- Clinically, this behaves similarly to AIP (acute interstitial pneumonitis) and other causes of ARDS.
epidemiology
- Acute lupus pneumonitis occurs in ~1-4% of patients with lupus. (Murray 2022)
- It mostly affects younger patients with a recent lupus diagnosis.
- Among half of patients with acute lupus pneumonitis, this is the initial manifestation of lupus.
symptoms
- Acute lupus pneumonitis usually occurs during a lupus flare (e.g., with simultaneous pleuritis, pericarditis, arthritis, and/or nephritis).
- Pulmonary symptomatology resembles pneumonia:
- Fever
- Dyspnea, tachypnea.
- Cough (usually nonproductive, but hemoptysis may occur).
- Intubation is often required. Lupus pneumonitis may be difficult to distinguish from other etiologies of ARDS.
radiology may include
- (1) Bilateral alveolar infiltrates (may be patchy or densely consolidated).
- (2) Pleural effusion in half of patients.
- (3) Cardiac involvement (including pericardial effusion, or myocardial dilation due to myocarditis).
laboratory studies
- Patients generally have positive ANA (antinuclear antibodies).
- Lupus pneumonitis may be associated with anti-Ro/SSA autoantibody.
- Active lupus nephritis may be present (making this a rare form of pulmonary-renal syndrome).
differential diagnosis
- Infection outnumbers lupus pneumonitis by a factor of ~30, so the possibility of infection should be very strongly considered.
- DAH (diffuse alveolar hemorrhage).
diagnosis
- Acute lupus pneumonitis is largely a diagnosis of exclusion (although evidence of active systemic lupus does support the diagnosis indirectly).
- Diagnosis may often require bronchoscopy to exclude infection or DAH (diffuse alveolar hemorrhage).
treatment
- Antibiotics are often started initially, prior to excluding infection.
- Steroid therapy:
- For patients with severe respiratory failure, steroid may be started with pulse-dose methylprednisolone.
- In the absence of respiratory failure, 1-1.5 mg/kg/day prednisone may be started.
- Mycophenolate may be added.
- Patients may be treated with the management strategy for rapidly progressive ILD: 📖. This may involve combination therapy that could involve a calcineurin inhibitor, immunosuppression (e.g., azathioprine or mycophenolate), rituximab, and intravenous immunoglobulin or plasma exchange. (34602377)
prognosis
- Mortality is high (historically ~50%, but hopefully lower currently).
- Recurrence is frequent.
- Diffuse alveolar damage may progress to chronic parenchymal scarring. Clinically, survivors may develop chronic interstitial lung disease (section below).
basics
- Histology may reflect numerous patterns:
- Most often fibrosing NSIP (nonspecific interstitial pneumonitis).
- UIP (usual interstitial pneumonia).
- OP (organizing pneumonia).
- LIP (lymphocytic interstitial pneumonia)
- Follicular bronchiolitis.
epidemiology
- Affects <5% of patients with lupus. (Murray 2022)
- Risk factors may include:
- Older age.
- History of acute lupus pneumonitis (UIP is known to occur following acute lupus pneumonitis).
- anti-RNP antibodies (or clinical features suggestive of mixed connective tissue disease). (Murray 2022)
clinical presentation & disease course
- (1) Patients may initially present with acute lupus pneumonitis (discussed above).
- (2) ILD may have a more insidious onset:
- The insidious form of ILD usually occurs several years after the diagnosis of lupus. (Fishman 2023)
- Symptoms may include dyspnea, dry cough, and pleuritic chest pain.
radiology
- Radiographic appearance often resembles UIP (usual interstitial pneumonia).
diagnosis
- Surgical lung biopsy is generally unnecessary, since treatment is similar regardless of the histopathological pattern. (Murray 2022)
treatment
- Little data is available.
- Response to immunosuppression may depend on the radiological pattern (nonspecific organizing pneumonia or organizing pneumonia are more likely to respond to therapy than usual interstitial pneumonia).
epidemiology
- Severe pulmonary hypertension in lupus is rare (~1% of patients).
- Group I (pulmonary arterial hypertension):
- May occur in ~5% of patients, usually later in the disease course.
- Associated with Raynaud phenomenon, digital vasculitis, serositis, anti-RNP antibodies, and rheumatoid factor. (Fishman 2023)
- Group IV (CTEPH; chronic thromboembolic pulmonary hypertension)
- May occur in patients with antiphospholipid antibody syndrome.
presentation
- Pulmonary hypertension should be suspected in patients with dyspnea on exertion and an unremarkable chest radiograph.
evaluation
- Thorough evaluation is needed to look for contributing factors to pulmonary hypertension. The diagnosis and evaluation of pulmonary hypertension are discussed in the pulmonary hypertension chapter: 📖
treatment
- Some reports describe improvement with immunosuppressive therapy.
- Group I pulmonary hypertension therapy is discussed further here: 📖
- Group IV pulmonary hypertension therapy is discussed further here: 📖
basics
- This is a rare phenomenon that occurs in <1% of lupus patients. (Murray 2022)
- Lung volumes gradually shrink, due to extrapulmonary restriction. However, the precise pathogenesis remains debated. It might involve some combination of:
- Pleural inflammation interfering with normal phrenic nerve stimulation.
- Diaphragmatic atrophy.
- Pleuritic chest pain.
- Pleural inflammation/adhesions. (Murray 2022)
epidemiology
- Shrinking lung syndrome often develops in the later stages of lupus, and among patients without evidence of other major organ involvement. (36494129)
- ~10-fold female predominance.
clinical presentation
- Unexplained dyspnea that is progressive over weeks or months.
- Pleuritic chest pain occurs in most patients. (36494129)
- Orthopnea may be notable (one clinical feature of diaphragmatic weakness).
radiology
- Lung volumes are usually small.
- Parenchyma is generally unremarkable, although basilar atelectasis may occur.
- Pleural thickening, nodules, and/or adhesions may occur. (36494129)
pulmonary function testing
- Spirometry shows extra-parenchymal restriction. However, DLCO may be reduced.
- Most patients have diaphragmatic weakness (e.g., impaired negative inspiratory force).
- Sniff testing may show minimal excursion of the diaphragm.
laboratory studies
- There is no correlation with ANA titers or complement levels.
differential diagnosis
- It may be difficult to sort out shrinking lung syndrome from steroid-induced myopathy.
- The full list of lupus-related pulmonary disorders is shown above.
treatment
- Appropriate treatment is unknown. No treatment with definitive efficacy exists. (Murray 2022) Fortunately most patients stabilize over time.
- Case reports describe the use of various immunosuppressives (e.g., steroid, azathioprine, methotrexate). (36494129) However, steroid is not often effective – and it carries a potential risk of exacerbating myopathy. (Fishman 2023)
- Nocturnal noninvasive ventilation might be reasonable to promote lung recruitment.
thumbnail of Sjogren syndrome
- Clinical manifestations:
- Sicca syndrome (ocular and oral dryness).
- Arthralgias.
- Parotid gland enlargement.
- Raynaud phenomenon (~1/3 of patients).
- Tests: 📖
- Epidemiology:
- Second most common connective tissue disease, after rheumatoid arthritis. (Teneback 2022)
- 9-fold female predominance. (Walker 2019)
- May be associated with other connective tissue diseases (e.g., rheumatoid arthritis, lupus, scleroderma, and primary biliary cholangitis).
pulmonary complications of Sjogren syndrome
- Interstitial lung disease: (32892887)
- Most commonly NSIP (nonspecific interstitial pneumonitis).
- UIP (usual interstitial pneumonia).
- OP (organizing pneumonia).
- Chronic bronchitis (due to desiccation of the tracheobronchial tree):
- Recurrent pneumonia, bronchitis.
- Bronchiectasis (may involve the lower lobes, suggestive of aspiration). (Teneback 2022)
- Bronchial hyperresponsiveness.
- Lymphoproliferative disorders:
- Follicular bronchiolitis.
- LIP (lymphocytic interstitial pneumonitis).
- Light chain deposition disease.
- MALT lymphoma.
- Lymphomatoid granulomatosis.
- Pulmonary amyloidosis.
- Uncommon findings:
- Pulmonary hypertension.
- Rheumatoid-like pulmonary nodules may occur.
investigation and management
- For patients with known Sjogren syndrome, lung biopsy is often unnecessary (since the treatment is similar regardless of the exact histopathology). However, biopsy may be needed in some cases to exclude alternative diagnoses (especially lymphoma).
- Below is a consensus guideline for the evaluation and management of pulmonary disease in Sjogren syndrome. (33075377)
- Patients with rapidly progressive disease may be treated with the management strategy for rapidly progressive ILD: 📖
thumbnail on inflammatory myositis
clinical manifestations
- Proximal muscle weakness.
- Rash and photosensitivity:
- Heliotrope rash (around eyes).
- Shawl sign (erythema around neck) and V-sign (erythema over the neck).
- Gottron's sign (erythema over knuckles).
- Inverse Gottron's sign (lesions over the palmar side of the fingers).
- Periungual erythema (around fingernails).
- Mid-facial erythema involving the nasolabial folds (unlike lupus, which spares the nasolabial folds).
- Holster sign (involvement of lateral hips).
- Mechanic's hands (distal digital fissuring) – discussed further in the section below on ASS (antisynthetase syndrome).
- Raynaud phenomenon.
- Calcinosis cutis (subcutaneous calcium deposits).
- Nailfold changes (capillary loop dilation; cuticles that are hypertrophic and ragged). (31774962)
- Arthritis (polyarthritis may correlate with the risk of interstitial lung disease). (Walker 2019)
- Sicca syndrome (ocular and oral dryness).
tests: discussed above 📖
pulmonary associations with myositis
- Parenchymal involvement:
- (1) Inflammation:
- NSIP (nonspecific interstitial pneumonia) is most common.
- Organizing pneumonia.
- Diffuse alveolar damage (DAD) causing fulminant respiratory failure.
- Usual interstitial pneumonia (UIP).
- Patients may progress through a sequence of DAD, then OP, and finally fibrotic NSIP. This sequence can explain why biopsies may frequently reveal both DAD and OP together. (Walker 2019)
- (2) Infection:
- Aspiration pneumonia (due to pharyngeal muscle weakness).
- Opportunistic infection (due to immunosuppressive medications).
- (3) Diffuse alveolar hemorrhage due to capillaritis (rare, but can occur.)
- (4) Cardiogenic pulmonary edema:
- Cardiac involvement is the 3rd leading cause of death.
- Abnormalities include conduction abnormalities, myocarditis, coronary artery atherosclerosis, pericardial abnormalities, and valvular disease. (Walker 2019)
- (1) Inflammation:
- Respiratory muscle weakness.
- Pulmonary hypertension (usually secondary to interstitial lung disease; isolated pulmonary arterial hypertension is rare). (ERS handbook 3rd ed.)
- Lung cancer is associated with some forms of dermatomyositis – so there should be a heightened index of suspicion for malignancy within <3-5 years of diagnosis. (31774962)
- (Pleural disease is rarely due to myositis itself, but it may result from heart failure, infection, or associated malignancy.)
Myositis-associated ILD has a few distinctive phenotypes: ASS (antisynthetase syndrome), anti-PM-Scl phenotype, and anti-MDA5 phenotype. Understanding these phenotypes may assist with diagnosis and prognostication.
phenotype #1/3: antisynthetase syndrome (ASS)
basics
- Antisynthetase syndrome (ASS) is a subtype of inflammatory myopathy associated with a group of antibodies that bind to tRNA synthetase enzymes. (33678283)
epidemiology
- Antisynthetase syndrome is seen in ~25% of patients with either polymyositis or dermatomyositis. (36764512)
- Patients have a broad age range, with a mean age of 50 years old.
- There is a 2:1 female predominance.
clinical features often include
- Arthritis.
- Fevers.
- Raynaud phenomenon.
- Mechanic's hands (horizontal fissures along the lateral and palmar aspects of the fingers).
- Sensitivity of ~70% for patients with ASS.
- Specificity is very high for the diagnosis of myositis associated with interstitial lung disease. Mechanic's hands are most often seen in ASS, but they can also be seen in anti-MDA-5 dermatomyositis (section below), or in myositis-related interstitial lung disease associated with other autoantibodies (e.g., anti-PM-Scl, anti-R052, anti-Ku). (36088095)
- Hyperkeratosis may also affect the feet (“hikers feet”). If there is doubt about whether the hand manifestations could be due to occupational exposures (e.g., the patient actually works as a mechanic), examine the feet for hyperkeratosis.
- Inflammatory myositis, often with relatively acute onset.
- Interstitial lung disease:
- The clinical presentation is usually dyspnea on exertion and a nonproductive cough.
- Respiratory failure may be the predominant clinical feature. (33678283)
laboratory findings
- Creatinine kinase and aldolase are often elevated.
- Results of immunofluorescence to detect ANA (antinuclear antibodies):
- ANA may be positive with a speckled pattern in up to 80% of patients. (Fishman 2023) This seems to reflect the presence of anti-SSa (anti-Ro) antibodies. (32386650)
- ANA may occasionally reveal cytoplasmic antibodies (rather than nuclear antibodies).
- A normal ANA test doesn't exclude myositis-related interstitial lung disease. (33563457)
- Antibodies against aminoacyl-tRNA synthetases are generally present, but there are many of them (including anti-Jo1, anti-PL-7. anti-PL-12, anti-EJ, anti-OJ, anti-KS, anti-Zo, anti-Ha/YRS. (33563457) Antibody levels correlate and fluctuate with disease activity. (33678283)
- Anti-Jo-1 is the most commonly found antisynthetase antibody (~40% of cases). 69% of patients have lung involvement (often chronic and slowly progressive), whereas 84% have myopathy (which often presents first). (37435671) Clinical associations include arthralgias and mechanic's hands. (36764512)
- Anti-PL-7 is found in ~15% of cases. 75% of patients have lung involvement, whereas 66% have myopathy. Associations include heliotrope rash, severe ILD, and pericardial effusions. (36764512)
- Anti-PL-12 is found in ~10% of cases. 91% of patients have lung involvement, whereas 33% have myopathy. Associations include Raynaud phenomenon and isolated ILD that may be severe. (33563457, 33678283, 36764512)
- Anti-EJ is found in ~10% of cases. 98% of patients have lung involvement, whereas 56% have myopathy. (36764512)
- Anti-OJ is found in ~4% of cases. 100% of patients have lung involvement, whereas 44% have myopathy. Associations include severe myopathy, myocardial involvement, and a lower incidence of Raynaud phenomenon. (36764512, 37435671)
- Anti-KS is found in ~4% of cases. 100% of patients have lung involvement, whereas 5% have myopathy. (36764512)
radiology
- Radiological forms: (34488971; 34602377)
- Most common:
- NSIP (nonspecific interstitial pneumonia) may be seen most often.
- NSIP-OP overlap (nonspecific interstitial pneumonia – organizing pneumonia) may be especially suggestive of myositis-associated ILD.
- Other forms that may be seen:
- UIP (usual interstitial pneumonia).
- Most common:
- Radiological findings most often include GGO (ground-glass opacities), reticulation, and traction bronchiectasis. (32386650) Honeycomb formation is less common.
phenotype #2/3: anti-PM-Scl phenotype
basics
- Relatively uncommon phenotype.
- May manifest a clinical overlap between scleroderma and antisynthetase syndrome. (35840503)
clinical features
- Scleroderma.
- Myositis.
- Raynaud syndrome.
- Mechanic's hands.
- Arthritis.
laboratory findings
- Anti-PM-Scl antibody.
- ANA assay may reveal a nucleolar staining pattern.
radiology
- May tend to cause an OP-NSIP overlap (organizing pneumonia – nonspecific interstitial pneumonia). This may progress to fibrosis (“fibrotic organizing pneumonia”).
phenotype #3/3: melanoma differentiation-associated protein 5 disease (MDA5)
basics
- Anti-MDA5 disease accounts for ~6% of patients with autoimmune myositis. (33036118)
- MDA5 is part of the innate immune response, able to induce IL-1 and other inflammatory cytokines. It appears that anti-MDA5 antibodies are directly pathogenic via stimulating inflammation. (36088099) Anti-MDA5 antibody levels correlate with the severity of lung disease, treatment response, and disease relapse. (33036118)
laboratory findings
- Anti-MDA5 antibody.
- Anti-SSa (aka, anti-Ro) is present in ~60% of patients and correlates with a worse prognosis (this may also correlate with ANA in a speckled pattern). (36088095)
- Ferritin elevation correlates with disease severity. (33036118) Ferritin >1500 ng/ml correlates with worse outcomes. (33792516) Patients with myositis may develop hemophagocytic lymphohistiocytosis, so markedly elevated ferritin should raise concern for this possibility. (31575703)
clinical presentation
- Pulmonary manifestations: Interstitial lung disease tends to be rapidly progressive. However, some patients may deteriorate over months, whereas others deteriorate over weeks. (33036118)
- Amyopathic dermatomyositis: MDA5 is primarily associated with cutaneous findings of dermatomyositis without muscle weakness.(31171118; 33036118) Patients often have dermatologic features associated with dermatomyositis, for example: (37164587)
- Gottron's papules (pink or violaceous lesions affecting the interphalangeal and/or metacarpophalangeal joints). (36088099)
- Heliotrope rash.
- Mechanic's hands can occur. (36088095)
- Raynaud syndrome.
- Cutaneous features that are highly specific for anti-MDA-antibody: (36764512; 36088095)
- Palmar papules.
- Deep ulcerations with punched-out borders
- Skin necrosis.
radiology
- More common patterns: (37164587; 33792516)
- DAD (diffuse alveolar damage).
- NSIP (nonspecific interstitial pneumonitis).
- OP (organizing pneumonia), OP-NSIP overlap.
prognosis
- Prognosis is poor, with 6-month mortality on the order of 50%. (37435671)
diagnosis of myositis-associated ILD
diagnostic information:
- Myositis-associated ILD is generally diagnosed based on a combination of the following pieces of information:
- (1) CT scan.
- (2) History and physical examination, with attention to:
- Dermatological manifestations (especially mechanic's hands).
- Raynaud phenomenon.
- Proximal muscle weakness.
- Arthritis.
- (3) Laboratory studies, including:
- MyoMarker panel.
- ANA (antinuclear antibody).
- Creatinine kinase.
- Aldolase.
- Anti-SSa (Ro) antibody.
- CRP (C-reactive protein).
- Ferritin (note that patients with myositis may develop HLH (hemophagocytic lymphohistiocytosis). (31575703)
- 💡 Consider additionally screening for hepatitis B and hepatitis C, if aggressive immunosuppression is likely imminent.
- Lung biopsy is usually unhelpful. As with other connective tissue disease-associated lung diseases, myositis-associated ILD may be associated with a variety of different histologic patterns, which are nonspecific in nature and don't affect management (e.g., nonspecific interstitial pneumonia, usual interstitial pneumonia, organizing pneumonia, and lymphocytic interstitial pneumonia). (33678283, 34488971)
differential diagnosis of a disease flare
- Increased activity of interstitial lung disease.
- Respiratory muscle weakness (myopathy).
- Related to myositis.
- Related to steroid-induced myopathy.
- Drug-induced lung disease.
- Opportunistic infection.
- Pulmonary embolism.
- (More on the differential diagnosis of an ILD flare here: 📖)
management of myositis-associated ILD
general principles of treatment:
- Myositis-associated ILD is somewhat unique among most CTD-ILDs in a few regards:
- It often causes a rapidly progressive ILD that causes respiratory failure and death within a period of days to weeks.
- It is frequently refractory to steroid (even pulse-dose methylprednisolone). (33678283; 33036118, 36088099, 37164587) Among patients with rapidly progressive ILD, steroid therapy alone leads to a 50% mortality after three months. (37435671)
- Combination therapy is generally required for effective treatment (figure below).
- For patients with acute respiratory failure in the ICU, most immunosuppressive agents work too slowly to be effective (e.g., mycophenolate or azathioprine take effect over weeks to months). These agents should be initiated, but they cannot be relied upon for prompt efficacy. More rapid-acting therapies are necessary for prompt remission induction:
- Rapid-acting anti-inflammatory agents:
- Steroid.
- JAK inhibitors.
- Other more rapidly acting immunomodulators:
- Calcineurin-inhibitors might act somewhat faster than anti-metabolites (azathioprine/mycophenolate).
- Rituximab.
- Rapid-acting therapies to suppress autoantibodies:
- IVIG (intravenous immunoglobulin).
- Plasma exchange.
- Rapid-acting anti-inflammatory agents:
- There is no high-quality RCT data for this disease, so the following discussion is based on retrospective studies and published expert opinion.
steroid
- Steroid is generally a component of remission induction. Prolonged therapy is generally necessary, so simultaneous initiation of a steroid-sparing agent is rational.
- Dose:
- Severe disease: may start with a pulse dose of 500-1,000 mg/day methylprednisolone for three days followed by 1 mg/kg/day prednisone.
- Otherwise, the starting dose is often ~1 mg/kg/day prednisone.
- Following remission induction and the initiation of a steroid-sparing agent, steroid may be weaned down over several months. (36764512)
azathioprine 💉 or mycophenolate 💉
- Retrospective studies suggest that these agents may stabilize lung function, exerting a steroid-sparing effect. (36764512)
- Relatively slow onset of efficacy makes these suboptimal choices for patients in need of acute remission induction. However, once disease has been controlled, these may be excellent agents to sustain remission.
calcineurin inhibitors (esp. tacrolimus)
- Calcineurin inhibitors appear to be more rapid-acting and more effective than antimetabolites (mycophenolate or azathioprine). This may reflect a more direct activity on interleukin-2 signaling. (36764512)
- One series of 23 patients with disease refractory to steroid plus methotrexate, mycophenolate, or azathioprine found that the addition of tacrolimus caused improvement among 94% of patients. (28864644)
- Tacrolimus may be the preferred immunosuppressive agent for the sickest patients, especially those with known antisynthetase syndrome or MDA-5-associated ILD.
- However, this speed and efficacy comes at the cost of an increased toxicity profile. Renal dysfunction or acute kidney injury may be a relevant contraindication in the context of acute illness. (36764512)
- A recent prospective multicenter open-label RCT compared tacrolimus+prednisone versus cyclosporine+prednisone. Tacrolimus was associated with a nonsignificant trend towards reduced disease progression, suggesting that it may be the favored calcineurin inhibitor. (33179395)
- Further discussion of tacrolimus pharmacology here: 📖
rituximab
- Autoantibodies in myositis-associated ILD appear to cause pneumonitis, so rituximab is a rational component of therapy (especially for patients with antisynthetase syndrome or anti-MDA5-associated ILD).
- Numerous small, retrospective studies support the efficacy of rituximab. (36764512)
- The dose is 1,000 mg on day 0 and day #14. Treatment may subsequently be repeated every six months. (36764512)
- Risks:
- Viral hepatitis reactivation.
- Severe COVID infection.
- Progressive multifocal leukoencephalopathy (rare).
- IgG has a 3-week half-life, so rituximab alone will have a delayed onset. (33036118) For more rapid efficacy, rituximab may be combined with plasmapheresis or intravenous immunoglobulin. (28552544)
JAK inhibitors (esp. tofacitinib)
- JAK inhibitors are oral agents that rapidly suppress the signaling of several cytokines. The ability of JAK inhibitors to promptly decrease inflammation is an advantage for achievement of rapid remission induction in the context of uncontrolled disease. JAK inhibitors may be especially effective in patients with MDA5 associated ILD (who suffer from elevated IL-1 and downstream inflammation, including hyperferritinemia).
- Two retrospective studies suggest mortality benefit from tofacitinib use in MDA-5-associated ILD. (36764512) The studied dose is 5 mg PO BID. (37126103)
- Baricitinib may be considered if tofacitinib isn't available, although it is supported by little evidence. (36970295)
IVIG (intravenous immunoglobulin)
- The usual dose is 2 grams/kg in divided doses over 3-5 days (e.g., 400 mg/kg daily for five days).
- IVIG has the advantage that it doesn't cause immunosuppression. The primary drawback is cost.
- Several retrospective studies support benefit from IVIG. (36764512)
- Further discussion of IVIG: 💉
PLEX (plasma exchange)
- PLEX is the most aggressive therapy to achieve rapid clearance of pathological autoantibodies. It may be considered as adjunctive therapy for patients in fulminant respiratory failure despite aggressive immunosuppression. (36764512)
- Further discussion of PLEX: 💉
antifibrotic therapy
- Immunosuppressive therapy is indubitably the front-line therapy for patients with myositis-associated ILD. However, patients with progression despite immunosuppressive treatment may benefit from antifibrotic treatment (especially nintedanib).
(cyclophosphamide)
- One small, retrospective study found equivalent efficacy across either cyclophosphamide, azathioprine, or mycophenolate. (23517887) This is consistent with a large RCT in patients with scleroderma which found that mycophenolate and cyclophosphamide had equivalent efficacy.
- No evidence exists that cyclophosphamide is more effective or faster acting than any other steroid-sparing agent for treatment of myositis-associated ILD. (36764512)
- Given that cyclophosphamide is more toxic yet equivalently efficacious when compared to other agents, there is little rationale to support its use.
treatment of anti-MDA5-associated ILD
- Anti-MDA5-associated ILD may be particularly fulminant and difficult to treat.
- JAK inhibition may be especially useful in anti-MDA5-associated ILD.
- Up-front aggressive combination therapy may afford patients the greatest likelihood of remission induction. (31314977)
general approach to CTD-ILD with rapidly progressive ILD (RP-ILD)
overall concept: a general approach to RP-ILD
- RP-ILD (rapidly progressive ILD) may be roughly defined as progressively deteriorating hypoxemia and pulmonary infiltrates within a time frame of <3 months.
- Below are the provisional ACR 2023 guidelines for the management of RP-ILD associated with connective tissue disease.
- This approach is similar to therapy for myositis-associated ILD (section above). In practice, myositis is the most common cause of RP-ILD associated with connective tissue diseases.
- A general approach to RP-ILD has the advantage of being guideline-recommended and more broadly applicable to non-myositis ILD (e.g., acute lupus pneumonitis).
2023 ACR guidelines for the management of RP-ILD (conditional pending publication of the final manuscript)
- Pulse dose IV methylprednisolone is recommended as a front-line therapy.
- Guidelines recommend that the following therapies shouldn't be utilized as first-line therapies: methotrexate, leflunomide, azathioprine, TNF inhibitors, abatacept, tocilizumab, nintedanib, pirfenidone, and plasma exchange.
- Up-front triple therapy is recommended for patients with confirmed/suspected MDA-5 or severe disease.
thumbnail of mixed connective tissue disease (MCTD)
- Patients have clinical manifestations that include features of lupus, polymyositis, and scleroderma:
- Raynaud phenomenon.
- Sclerodactyly, digital ischemia, telangiectasias.
- Dermatomyositis rashes.
- Myositis.
- Arthritis.
- Sicca syndrome.
- Aseptic meningitis. (34602377)
- Tests: discussed above 📖
pulmonary manifestations
- Infection:
- Infectious complications of immunosuppression.
- Aspiration pneumonia can occur (especially in patients with features of scleroderma or polymyositis-dermatomyositis).
- Pulmonary vascular disease:
- Pulmonary arterial hypertension may occur.
- MCTD is the second most common cause of connective tissue disease related to pulmonary hypertension (after scleroderma). (Walker 2019)
- Pulmonary emboli may occur due to antiphospholipid antibody syndrome.
- Pulmonary arterial hypertension may occur.
- Interstitial lung disease may occur (usually NSIP; less often, UIP or OP patterns).
- Patients are treated similarly to scleroderma-associated ILD or myositis-associated ILD, depending on which disorder the patient most closely mimics. (34602377)
- Respiratory muscle dysfunction can occur (among patients with features of polymyositis/dermatomyositis).
- Pleural effusions are uncommon (~5%) and usually small.
- Diffuse alveolar hemorrhage has been reported in a few cases. (Fishman 2023)
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- 2023 ACR guidelines: Preliminary summary has been published here.
Books:
- Shah, P. L., Herth, F. J., Lee, G., & Criner, G. J. (2018). Essentials of Clinical pulmonology. In CRC Press eBooks. https://doi.org/10.1201/9781315113807
- Shepard, JO. (2019). Thoracic Imaging The Requisites (Requisites in Radiology) (3rd ed.). Elsevier.
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- Palange, P., & Rohde, G. (2019). ERS Handbook of Respiratory Medicine. European Respiratory Society.
- Rosado-De-Christenson, M. L., Facr, M. L. R. M., & Martínez-Jiménez, S. (2021). Diagnostic imaging: chest. Elsevier.
- Murray & Nadel: Broaddus, V. C., Ernst, J. D., MD, King, T. E., Jr, Lazarus, S. C., Sarmiento, K. F., Schnapp, L. M., Stapleton, R. D., & Gotway, M. B. (2021). Murray & Nadel’s Textbook of Respiratory Medicine, 2-Volume set. Elsevier.
- Fishman's: Grippi, M., Antin-Ozerkis, D. E., Cruz, C. D. S., Kotloff, R., Kotton, C. N., & Pack, A. (2023). Fishman’s Pulmonary Diseases and Disorders, Sixth Edition (6th ed.). McGraw Hill / Medical.