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Connective tissue disease and the lung 

Connective tissue disease and the lung
Chapter:
Connective tissue disease and the lung
Author(s):

Stephen Chapman

, Grace Robinson

, John Stradling

, Sophie West

, and John Wrightson

DOI:
10.1093/med/9780198703860.003.0022
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date: 06 December 2021

Differential diagnosis and standard tests

Patients with connective tissue diseases often develop pulmonary complications, for which they should be referred to a chest physician. Patients typically present with symptoms of dyspnoea, cough, fever, or chest pain. They may often already be on immunosuppressive drugs.

Differential diagnosis

In practice, a few tests (see Box 22.1) will help distinguish the main differential diagnoses.

Opportunistic pulmonary infection

  • May be in those on immunosuppressive drugs or functionally immunosuppressed from underlying disease

  • Any usual organism, but also TB, NTM, PCP, fungi, CMV

  • Often acute onset, with non-specific features of low-grade fever, productive cough, raised inflammatory markers

  • Can be very unwell and need full supportive treatment with ICU.

Original connective tissue disease now affecting the lung

  • Often inflammation or fibrosis

  • Usually more indolent presentation, with dry cough and dyspnoea, but can become acutely unwell on background of chronic lung disease

  • Fine inspiratory crackles on auscultation

  • Consider development of PHT in patients with systemic sclerosis.

New pathology

  • Unrelated to the original condition, including pulmonary thromboembolic disease, heart failure.

Drug side effects

  • Methotrexate—pneumonitis occurs in 5% of patients receiving methotrexate. Potentially life-threatening. Mortality 15–20%. Cough, fever, dyspnoea, widespread crackles, restrictive defect, and pulmonary infiltrates on CXR and CT. Peripheral eosinophilia in 50%. BAL lymphocytosis. Usually subacute onset but may be sudden. Usually within 4 months of starting methotrexate. Non-specific histological findings. No more common in those with pre-existing lung disease. Treatment: stop the drug; commence steroids (high-dose methylprednisolone is often used), and avoid methotrexate in the future. Can be reversible. Can get mild intractable cough with methotrexate

  • Leflunomide—pneumonitis may occur although appears to be rare; consider this diagnosis, and discontinue the drug if new or worsening respiratory symptoms. Avoid leflunomide in patients with pre-existing ILD

  • Anti-TNF-α‎ therapy—includes infliximab (a monoclonal antibody), etanercept (a receptor fusion protein), and adalimumab (a humanized IgG1 antibody). All may predispose to severe infection (viral, bacterial, and fungal), particularly when used in association with other immunosuppressants. Opportunistic infection is common, including PCP and mycobacterial disease (both tuberculous, see Connective tissue disease and the lung pp. [link][link], and non-tuberculous, see Connective tissue disease and the lung pp. [link][link]). The risk of mycobacterial disease appears to be less with etanercept than with infliximab and adalimumab. All patients should be screened for latent TB prior to starting anti-TNF-α‎ drugs (see Connective tissue disease and the lung pp. [link][link]). Concern has also been raised that these drugs may lead to increased rates of malignancy, and a recent meta-analysis has shown a dose-dependent increase in cancer diagnoses in RA patients treated with infliximab. ILD may worsen on these drugs; consider stopping anti-TNF-α‎ if pre-existing ILD worsens

  • Penicillamine—causes obliterative bronchiolitis in RA. Can also cause HP and a pulmonary-renal syndrome causing alveolar haemorrhage. May respond to stopping the drug

  • Gold—alveolar opacities seen on HRCT, with associated fever and skin rash. BAL lymphocytosis. Treatment: stop the drug, and commence steroids. Usually reversible.

For an approach to:

  • Diffuse lung disease, see Connective tissue disease and the lung p. [link]

  • Diffuse alveolar haemorrhage, see Connective tissue disease and the lung p. [link]

  • Pulmonary disease in the immunocompromised host (non-HIV), see Connective tissue disease and the lung p. [link].

Further information

British Society for Rheumatology. Rheumatoid arthritis guidelines on safety of anti-TNF therapies. Rheumatology 2010;49:2217–19.Find this resource:

Rheumatoid arthritis (RA)

  • Persistent deforming symmetrical peripheral arthropathy with non-articular manifestations, including vasculitis

  • Pulmonary/pleural disease is commoner in men and occasionally occurs before the development of joint problems

  • Pneumonia is a common terminal event, causing 15–20% of RA deaths.

Pleuritis

Frequent, occurring in >30% of patients and usually mild. Pleuritic pain, with no obvious other cause.

Pleural effusion

Usually asymptomatic. Fluid is typically exudative, with a low glucose, low pH, and usually a lymphocytosis, may be pseudochylous (see Connective tissue disease and the lung p. [link]). Often in association with other lung manifestations. Need to exclude other causes for effusion such as empyema or malignancy. If problematic, may require drainage and steroids (see Connective tissue disease and the lung p. [link]).

Pulmonary fibrosis

Similar to the IIPs (see Connective tissue disease and the lung p. [link]), minor pulmonary fibrosis found in up to 60% of patients in lung biopsy studies, but CXR changes only seen in 1–5%. Hence symptomatic disease is unusual. Tends to occur in patients who have multi-system disease, including vasculitis, and those with nodules, seropositive disease, and high ANA titres. More common in men, and smoking is a risk factor for fibrosis development.

  • Presents with progressive dyspnoea

  • Examination Clubbing and bilateral basal crepitations

  • PFTs Low kCO, restrictive pattern

  • Radiologically and histologically similar to UIP, with subpleural basal reticular pattern, but can be like NSIP

  • Treatment Steroids or immunosuppressants do little to change the course but should be tried.

Acute pneumonitis also recognized, which presents with rapidly deteriorating dyspnoea and development of respiratory failure, or acute deterioration on a background of chronic fibrosis. Acute pneumonitis tends to be more steroid-responsive.

Pulmonary nodules

Occur in <5% of patients with RA. Usually found incidentally on CXR. Only occur in seropositive disease, and patients may have other nodules elsewhere such as elbows and fingers. Single or multiple; may measure up to 7cm, mainly subpleural or along interlobular septa. May cavitate and rarely cause haemoptysis or pneumothorax. Mostly asymptomatic. Main differential diagnosis is lung cancer. Usually followed on CT to ensure they are of stable size. They typically show mild uptake on PET, consistent with other benign lesions. May need biopsy to exclude malignancy.

Organizing pneumonia

The clinical syndrome of pneumonia, with fever, dyspnoea, cough and weight loss, and multifocal consolidation, which do not respond to antibiotics. Can be disease- or drug-induced (gold) or have no obvious cause, i.e. cryptogenic (COP, see Connective tissue disease and the lung pp. [link][link]). Confirmed by transbronchial or open lung biopsy showing acini filled with loose connective tissue and a variable inflammatory infiltrate. Often a dramatic response to steroids. May need long-term immunosuppression.

Small airways disease and obliterative bronchiolitis

Evidence of mild small airways disease found in about a third when looked for on HRCT, but often asymptomatic, variable histology. Obliterative bronchiolitis is a rarer problem, with lymphocytic infiltration of terminal bronchioles progressively obliterated by inflammatory connective tissue.

  • May present with dyspnoea, dry cough, and hyperinflated chest, with basal crepitations and mid-inspiratory ‘squeak or squawk’

  • PFTs Irreversible obstructive pattern, hypoxia

  • CXR Hyperinflation, no infiltrates

  • HRCT Mosaic pattern

  • Biopsy shows destruction of terminal bronchiolar wall by granulation tissue, effacement of the lumen, and replacement of the bronchiole by fibrous tissue. Irreversible pathology, usually unresponsive to treatment

  • May be rapidly progressive

  • Can give trial of oral steroids, continuing with high-dose inhaled steroids if any response. Penicillamine was thought to be a causative factor, but the evidence for this is now weaker. Consider transplant.

Vasculitis

rarely involves the lung and very rarely causes pulmonary haemorrhage. Rare cause of PHT.

Cricoarytenoid arthritis

Seen in studies in up to 75% of patients with RA by fibre-optic laryngoscopy and HRCT, but rarely symptomatic (commoner in women). Unrelated to lung fibrosis. Can cause sore throat, hoarse voice, upper airways obstruction with stridor, or OSA. Flow–volume loop may be abnormal. This may need tracheostomy and steroids—oral and joint injection.

Bronchiectasis

is often subtle with minimal clinical features but may be found in 30%. Traction bronchial dilation may be seen in association with pulmonary fibrosis. Diagnosis made on HRCT.

Sjögren’s syndrome

causing mucosal drying, often in association with ILD, produces dry cough and increased airway infections (see Connective tissue disease and the lung p. [link])

Caplan’s syndrome

RA, single or multiple chest nodules, and coal-worker’s pneumoconiosis, see Connective tissue disease and the lung pp. [link][link] (now rare).

Further information

Amital A et al. The lung in rheumatoid arthritis. Press Med 2011;40:e31–48.Find this resource:

Systemic lupus erythematosus (SLE)

  • Multi-organ autoimmune disease, mainly affecting women

  • dsDNA antibodies present in high titres, and these may be the causative agent

  • Can also get a drug-induced lupus syndrome (see Box 22.2), improves on stopping drug

  • Pulmonary disease (lung, vasculature, pleura, diaphragm) often seen and may be a presenting feature of the disease

  • American College of Rheumatology classification—see Box 22.3.

Pleural disease

Most common manifestation of pulmonary disease. Often asymptomatic but may have pleuritic pain due to pleuritis with a pleural rub. (‘Pleuritic’ pain may also be due to musculoskeletal causes.) Pleural effusions found in 50% of patients, which may cause breathlessness. These are often bilateral and exudative, with a neutrophilia, or a lymphocytosis if the effusion is chronic. Can be haemorrhagic. Rarely develops into fibrothorax. Pleural biopsy findings are non-specific. Need to exclude other causes for effusion such as empyema or malignancy. If symptomatic, may need treatment with NSAIDs or steroids.

Atelectasis

Associated with pleurisy or effusion.

Diffuse ILD

Occurs in up to 70% of patients, but usually mild and asymptomatic. Radiologically similar to rheumatoid lung fibrosis. Only 5% develop clinical disease similar to UIP, with dyspnoea, cough, and basal crackles. May be associated with pleuritic pain. PFTs show restrictive defect with reduced kCO. Rarely, progressive and severe.

Acute lupus pneumonitis

In <2%, severe illness with mortality rate >50%. Cough, dyspnoea, fever, pleuritic pain, hypoxia. Widespread crackles. CXR shows infiltrates, which may be widespread. Histologically, non-specific acute alveolar wall injury. Need to exclude infection, pulmonary oedema. Treatment: steroids and cytotoxic drugs may be necessary, may have good response. Can progress to chronic interstitial pneumonitis.

PHT

due to pulmonary vasoconstriction, rather than pulmonary vasculitis. Commoner in those with Raynaud’s phenomenon. Associated with poorer prognosis: 50% 2y mortality. Diagnosed on echo. Need to exclude PE as a cause, especially in those with antiphospholipid antibodies. Treatment as for idiopathic PHT (see Connective tissue disease and the lung pp. [link][link]).

PE

Commoner in the 20–30% with antiphospholipid antibodies.

‘Shrinking lung syndrome’

Dyspnoea (± episodic pleurisy) caused by reduced lung volumes and poor respiratory reserve, probably due to diaphragmatic muscle weakness. Small lungs on CXR. Normal lung parenchyma on CT. Restrictive lung function tests, with normal/high kCO. May improve with steroids.

Alveolar haemorrhage

Rare. May be life-threatening. Can have associated glomerulonephritis. Acute dyspnoea, with infiltrates on CXR. Raised kCO. Treat with high-dose steroids + cyclophosphamide.

Chronic organizing pneumonia (COP or bronchiolitis obliterans)

See Connective tissue disease and the lung pp. [link][link].

Further information

Keane M, Lynch J. Pleuropulmonary manifestations of SLE. Rare diseases 7. Thorax 2000;55:159–66.Find this resource:

Polymyositis and dermatomyositis

These are two separate idiopathic inflammatory myopathies:

  • Polymyositis (PM) causes symmetrical proximal muscle weakness

  • Dermatomyositis (DM) has a characteristic rash

  • Diagnostic criteria in Box 22.4.

CK levels raised up to 50 times normal. ANA and myositis-specific antibodies positive. DM is frequently associated with underlying malignancy, including lung, oesophagus, breast, colon, and ovary, so therefore needs thorough investigation. Pulmonary complications are a common and frequent cause of death, occuring in both conditions. As with other connective tissue diseases, differentiation of the pulmonary problems from those due to drugs and infection is important.

ILD

in 20–30% (commoner when CK levels normal and/or antisynthetase +ve (see further text); less common when DM is associated with malignancy). Patients present with dyspnoea, cough, arthralgia, and fevers, with fine bibasal crackles.

  • HRCT shows patchy consolidation and peripheral reticular pattern

  • Histology Wide variation, with UIP, NSIP, COP, and diffuse alveolar haemorrhage all reported, related to steroid response

  • Lung involvement frequently associated with antisynthetase antibodies

  • May require treatment with steroids or cyclophosphamide.

Ventilatory failure

Due to intercostal and diaphragm muscle weakness. Restrictive defect on PFTs.

Chronic organizing pneumonia

Poorer prognosis if associated with features of fibrosis.

PHT

2° to lung disease.

Pulmonary vasculitis

Causing haemoptysis (rarely alveolar haemorrhage).

Aspiration pneumonia

In 20%, associated with marked increase in mortality. Caused by dysphagia and pharyngeal muscle weakness and regurgitation.

Antisynthetase syndrome

A subset with polyarthritis, fever, and Raynaud’s, in addition to myositis, that have serum antibodies to one or more of the aminoacyl-transfer RNA synthetases, a family of intracytoplasmic enzymes involved in protein synthesis. Antibodies to Jo-1, PL-7, PL-12, OJ, and EJ are the ones that have been recognized and for which specific tests are available.

Spontaneous pneumomediastinum

Occurs rarely (acute retrosternal pain, neck and face subcutaneous emphysema), usually in association with ILD, in DM more often than PM.

Further information

Tzioufas AG. Antisynthetase syndrome. Connective tissue disease and the lung https://www.orpha.net/data/patho/Pro/en/Antisynthetase-FRenPro8611.pdf.

Systemic sclerosis

This disease affects women more than men (4:1), has HLA associations, and often presents in the fifth decade. It is largely a clinical diagnosis, and there are several types:

  • Limited cutaneous (many have CREST syndrome). 60% of systemic sclerosis cases. Patients often have long-standing Raynaud’s, developing non-pitting oedema of the fingers, which become ‘sausage-shaped’. Develop thick, shiny skin after a few weeks to months. Later, they can develop skin changes on the hands, face, and neck, microstomia, digital and facial telangiectasia, intra- and subcutaneous calcification, and oesophageal dysmotility (74%). Patients can also develop pulmonary fibrosis (26%), PHT (21%), and cardiac (9%), oesophageal (90%), and renal disease (8%), but less common than in diffuse cutaneous disease

  • Diffuse cutaneous Abrupt-onset disease, with widespread symmetrical itchy, painful swelling of fingers, arms, feet, legs, and face, and associated constitutional symptoms. There is oedema, which is replaced by tight, shiny skin, bound to underlying structures extending proximal to the wrists, within a few months. There is cutaneous thickening, as well as hypo- or hyperpigmentation. Raynaud’s phenomenon is present, as well as skin sclerosis on the trunk and upper arms, arthropathy, renal disease (18%), pulmonary fibrosis (41%), PHT (17%), cardiac (12%) and GI disease (90%)

  • Overlap syndromes, or mixed connective tissue diseases, have features of systemic sclerosis, together with those of at least one other autoimmune rheumatic disease such as SLE, RA, PM. Over time, other organ involvement may develop and evolve into a more defined disease

  • Systemic sclerosis sine scleroderma Vascular or fibrotic visceral features without skin scleroderma. May or may not have Raynaud’s phenomenon. May develop ILD, oesophagitis, arrhythmias, malabsorption, pseudo-obstruction, renal failure (>2% of cases)

  • Environmentally induced Contentious but may result from exposure to vinyl chloride, pesticides, or epoxy resins.

Pulmonary complications are the most common cause of death.

Pulmonary fibrosis

is seen at post-mortem in up to 80% of patients. ANA is positive in 60% and of speckled or nucleolar type. Pulmonary involvement is seen, particularly if Scl-70 antibody is present. Anti-centromere antibodies, however, are associated with reduced risk. Micro-aspiration from oesophageal dysmotility may be contributory.

  • Present with dyspnoea and a history of Raynaud’s

  • Examination Signs of systemic sclerosis, fine bibasal crackles

  • PFTs show restrictive defect and reduced kCO. Rapidly falling kCO is a poor prognostic sign. HRCT shows mostly NSIP pattern but can be UIP pattern. May need open lung biopsy to confirm diagnosis

  • Treatment with steroids and cyclophosphamide. An RCT of oral cyclophosphamide vs placebo in patients with active alveolitis and scleroderma-related ILD showed a modest, but significant, effect on FVC, dyspnoea, and QoL (Taskin DP et al. N Engl J Med 2006;354:2655–66)

  • Prognosis Systemic sclerosis-associated ILD has a better prognosis than pure UIP. This may be related to slower disease progression, rather than any greater response to immunosuppressive treatment; 15% of patients have progressive and severe disease. Associated increased risk of lung cancer.

PHT

May be isolated or 2° to ILD. Isolated PHT is characteristic of limited cutaneous disease, especially in those with cutaneous telangiectasias and anti-centromere antibodies. Pathologically similar to PPH. Subintimal cell proliferation, endothelial hyperplasia, and the obliteration of small intrapulmonary vessels.

  • Presents with dyspnoea, RV hypertrophy, and right heart failure

  • Diagnosis by echo

  • Treatment as for PPH (see Connective tissue disease and the lung pp. [link][link]). May respond to prostacyclin infusions or may need transplant

  • Prognosis Better than for those with PPH.

Chest wall limitation

by skin scleroderma over chest (‘hide-bound chest’), very rare.

Chronic organizing pneumonia

See Connective tissue disease and the lung pp. [link][link].

Aspiration pneumonia

Uncommon and due to oesophageal dysmotility.

Bronchiectasis

Often seen on HRCT, but much less commonly of clinical significance.

Further information

McMahan ZH, Hummers LK. Systemic sclerosis—challenges for clinical practice. Nat Rev Rheumatol 2013;9:90–100.Find this resource:

Sjögren’s syndrome

  • Inflammation, lymphocytic infiltration, and destruction of primarily the salivary and lachrymal glands

  • Keratoconjunctivitis sicca or xerostomia (dry eyes and dry mouth) is usually evidence of 1° disease but, when associated with connective tissue disease, especially RA, is 2° Sjögren’s

  • Classical sicca syndrome includes dry eyes and mouth, with parotid or salivary gland enlargement

  • Pulmonary involvement occurs in about 25%, commoner in women and in their 60s.

Pleuritic

chest pain.

Airways inflammation

BHR, chronic bronchitis, and small airways disease. Mild abnormalities on PFTs, rarely significant.

Dry cough

Atrophy of mucus gland in trachea and bronchi and lymphoplasmocytic infiltrate (xerotrachea). Possibly a higher incidence of chest infections. Treatment: nebulized saline, physiotherapy, inhaled steroids.

Diffuse lung disease

Develops later, often asymptomatic, but may have cough, dyspnoea, and crackles on examination. PFTs show a restrictive defect and NSIP, LIP, or UIP pattern on CT.

Lymphoma

Unusual but is 40 times more common in Sjögren’s syndrome, especially in patients with high levels of immunoglobulins, autoantibodies, and cryoglobulins. Usually non-Hodgkin’s B-cell lymphoma. Can mimic OP.

OP

Pleural thickening/effusion

Rare.

PHT, thromboembolism

Rare.

Ankylosing spondylitis

  • Chronic inflammatory disease causing spinal ankylosis with sacroiliac joint involvement

  • 90% of Caucasian patients are HLA-B27 +ve.

Pulmonary fibrosis

occurs in 5–15%, especially those with advanced disease. Typically bilateral in the upper lobes. May develop cysts/cavities and become colonized with Aspergillus.

Pleural involvement

Pleuritis and apical pleural thickening.

Restrictive defect

Due to costovertebral rigidity causing fixed restrictive deformity of the thorax, rarely leading to respiratory failure with nocturnal hypoventilation. Nocturnal NIV may be indicated.

Behçet’s syndrome

  • Systemic vessel vasculitis involving arteries and veins of all sizes, with recurrent painful oral ± genital ulceration, skin lesions, arthritis, and chronic relapsing uveitis, which can cause blindness

  • Marked geographical distribution, with greatest prevalence in Turkey, Iran, and Japan. Mainly young adults

  • Musculoskeletal, skin, neurological, GI, and major artery and vein involvement.

Pulmonary arterial aneurysms,

arterial and venous thrombosis, and pulmonary infarcts in <5%. Recurrent haemoptysis is the main manifestation. This can be massive and fatal. Pulmonary aneurysms are seen as non-cavitating shadows on CXR and confirmed by CT. These are associated with DVT, therefore making anticoagulation difficult due to possible haemoptysis from the aneurysm.

Pleural effusion, eosinophilic pneumonia

Both rare.

Autoantibodies: disease associations

Antinuclear antibody (ANA)

+ve in

SLE

99%

RA

32%

Juvenile RA

76%

Chronic active hepatitis

75%

Sjögren’s syndrome

68%

Systemic sclerosis

64%

Polymyositis

Polyarteritis nodosa

Myasthenia gravis

Autoimmune thyroid disease

Extensive burns

Normal controls

0–2%

Extractable nuclear antigen (ENA)

(done by lab if ANA +ve)

Anti-dsDNA—SLE

Anti-Sm—SLE

Anti-topoisomerase-1—diffuse scleroderma

Anti-centromere—limited scleroderma

Anti-Scl-70—lung fibrosis in scleroderma

Anti-Jo-1 and other synthetases—myositis

Anti-Ro—Sjögren’s, SLE, foetal heart block

Anti-RNP—SLE, scleroderma, myositis, mixed connective tissue disease, and RA

PR3(c)-ANCA (proteinase 3)—GPA (Wegener’s)

MPO(p)-ANCA (myeloperoxidase)—microscopic polyangiitis

RhF

+ve in

RA

70–80%

Sjögren’s syndrome

<100%

Felty’s syndrome

<100%

Systemic sclerosis

30%

Still’s disease

Rarely +ve

Infective endocarditis

<50%

SLE

<40%

Normal controls

5–10%

Also:

  • Neoplasms, after radio- or chemotherapy

  • Hyperglobulinaemic states

  • Dermatomyositis