Significance of connective tissue diseases features in pulmonary fibrosis

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Figure 1.
High-resolution computed tomography scan of a 59-year-old female patient with undifferentiated connective tissue disease, showing patterns of nonspecific interstitial pneumonia (with ground-glass opacification and traction bronchiectasis) and oesophageal dilation. Features of systemic sclerosis were present (Raynaud's phenomenon, megacapillaries at nailfold capillaroscopy, oesophageal hypomotility, anti-topoisomerase-1 antibodies), but no sclerodactily or telangiectasia was visible at 5 years follow-up.

Table 1. Key symptoms to detect underlying connective tissue disease

Organ	Main manifestations to be evaluated^#
Peripheral circulation	Raynaud’s phenomenon
Skin	Sclerodactily
	Digital ulcerations or scars
	Telangiectasia
	Violaceous erythematous rash over the interphalangeal joints, knuckles, elbows and knees (Gottron's sign)
	Lilaceous rash of the eyelids
	Rash of the neck and upper chest and shoulders (heliotrope rash, e.g. photosensitivity)
	Mechanics’ hand
Joints	Joint pain or swelling (arthritis, arthralgia) Morning stiffness
Muscle	Muscle pain and muscle weakness
Mouth and eyes	Dry mouth and dry eyes (sicca syndrome)

Table 2. Indicative criteria for which patients may be referred for rheumatologic evaluation

	Features suggesting CTD
Demographics	Female sex Age <50 years
Clinical manifestations	Any patient with extra-thoracic manifestations highly suggestive of CTD:
	Raynaud’s phenomenon, oesophageal hypomotility, inflammatory arthritis of the metacarpophalangeal joints or wrists, digital oedema, symptomatic keratoconjonctivitis sicca
Lung histopathology	All cases of NSIP, LIP or ILD patterns with histopathology features that might suggest CTD:
	Extensive pleuritis, dense perivascular collagen, lymphoid aggregates with germinal centre formation, prominent plasmacytic infiltration
Biology	Patients with positive high-titre antinuclear antibodies (>1:320) or rheumatoid factor (>60 IU·mL⁻¹), nucleolar staining antinuclear antibodies or specific antibodies (anti-cyclic citrullinated peptide, anti-Scl70, anti-Ro, anti-La, anti-dsDNA, anti-Smith, anti-RNP, anti-tRNA synthetase)

CTD: connective tissue disease; NSIP: nonspecific interstitial pneumonia; LIP: lymphoid interstitial pneumonia; ILD: interstitial lung disease; RNP: ribonucleoprotein. Adapted from [37].

Table 3. Diagnostic criteria for undifferentiated connective tissue disease (UCTD)

	UCTD diagnostic criteria^#	Broader definition of UCTD^#^,¶
A. Symptoms associated with CTD	At least one of: 1) Raynaud’s phenomenon; 2) arthralgias/multiple joint swelling; 3) morning stiffness; 4) dry mouth or dry eyes (Sicca features); 5) proximal muscle weakness	At least one of: 1) Raynaud’s phenomenon; 2) arthralgias/multiple joint swelling; 3) photosensitivity; 4) unintentional weight loss; 5) morning stiffness; 6) dry mouth or dry eyes (Sicca features); 7) dysphagia; 8) recurrent unexplained fever; 9) gastro-oesophageal reflux; 10) skin changes (rash); 11) oral ulceration; 12) nonandrogenic alopecia; 13) proximal muscle weakness
B. Positive autoimmune serology	Positive finding of at least one of: 1) ANA (high titre); 2) RF (high titre); 3) positive ENA; 4) anti-Scl70 antibody; 5) anti-RNP antibody; 6) anticentromere antibody; 7) SS-A or SS-B; 8) Jo-1 antibody	Positive finding of at least one of: 1) ANA; 2) RF; 3) anti-Scl70 antibody; 4) SS-A or SS-B; 5) Jo-1 antibody; 6) ESR (>2 times normal), CRP

CTD: connective tissue disease; ANA: antinuclear antibody; RF: rheumatoid factor; ENA: extractable nuclear antigen; RNP: ribonucleoprotein; SS-A: anti-Ro; SS-B: anti-La; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein. ^#: a diagnosis of UCTD requires having one or more of the symptoms outlined in A, and one or more of the laboratory findings listed in B; ^¶: criteria proposed by Kinder et al. [5]. Reproduced from [6] with permission.