What is a connective tissue disorder?

What is a Connective Tissue Disorder?

Connective tissue disorders are a group of autoimmune-mediated systemic diseases that affect the body's connective tissue—the structural framework supporting organs, blood vessels, muscles, tendons, ligaments, fascia, bone, joints, and skin—and include conditions such as systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis (scleroderma), Sjögren syndrome, mixed connective tissue disease, idiopathic inflammatory myopathies, relapsing polychondritis, and ankylosing spondylitis. 1

Core Pathophysiology

Connective tissue comprises approximately 50% of all body protein and provides vascular and structural support throughout the body. 2 In connective tissue disorders, the underlying pathogenesis involves autoimmune mechanisms that target these ubiquitous structural components, leading to multisystem involvement. 3, 4

The disorders are characterized by:

• Autoimmune-mediated inflammation affecting collagen, elastin, and other connective tissue components 1, 3
• Altered connective tissue structure, with disorganization of collagen and elastin fibers resulting in softer, less rigid tissue than normal 5, 6
• Systemic manifestations due to the widespread distribution of connective tissue throughout the body 2, 4

Major Disease Categories

The primary connective tissue disorders include:

Well-Defined Entities

• Systemic lupus erythematosus (SLE): Multisystem autoimmune disease with variable organ involvement 1, 3
• Rheumatoid arthritis (RA): Primarily affects joints but can involve lungs and other organs; RA-related interstitial lung disease accounts for approximately 39% of CTD-associated ILD 1
• Systemic sclerosis (scleroderma): Characterized by tissue fibrosis and vascular abnormalities; SSc-related ILD accounts for approximately 31% of CTD-associated ILD 1
• Sjögren syndrome: Affects exocrine glands and can involve multiple organ systems 1, 4
• Idiopathic inflammatory myopathies: Including dermatomyositis, polymyositis, and antisynthetase syndrome 1, 3
• Mixed connective tissue disease (MCTD): Features overlapping characteristics of multiple CTDs 1, 7
• Relapsing polychondritis: Recurrent inflammation and destruction of cartilage and connective tissues 1

Hypermobile Ehlers-Danlos Syndrome (hEDS)

• Most common type of Ehlers-Danlos syndrome, affecting connective tissue structure 5
• Diagnosed using the Beighton scale: ≥6/9 points for prepubertal children, ≥5/9 for adults under 50, ≥4/9 for adults over 50 5
• Clinical triad includes joint hypermobility, pain, and systemic manifestations 5
• Up to 98% of hEDS patients meet criteria for disorders of gut-brain interaction 1, 5

Undifferentiated Connective Tissue Disease (UCTD)

• Patients present with signs and symptoms suggestive of systemic autoimmune disease but do not meet full classificative criteria for defined CTDs 8
• Approximately 75% maintain an undifferentiated clinical course rather than evolving to a defined CTD 8
• Most characteristic features include arthritis/arthralgias, Raynaud's phenomenon, and leukopenia, with neurological and kidney involvement virtually absent 8

Clinical Manifestations

Musculoskeletal

• Joint hypermobility, arthritis, and arthralgias are common across multiple CTDs 1, 5, 8
• Asthenic syndrome and kyphotic spinal deformity occur in 75% of hEDS cases 5, 6

Pulmonary Involvement

• Interstitial lung disease (ILD) represents a major complication, accounting for nearly 20% of all ILDs in Europe and the USA 1
• Chronic cough is a frequent respiratory manifestation in autoimmune and collagen disorders 1
• Progressive pulmonary fibrosis causes irreversible lung damage and represents a primary cause of death along with cardiovascular comorbidities 1
• Early lung function loss can occur asymptomatically or present with nonspecific symptoms like fatigue, cough, or dyspnea on exertion 1

Gastrointestinal

• Up to 60% of hEDS patients experience gastrointestinal symptoms 5
• Nearly 98% of hEDS patients meet diagnostic criteria for disorders of gut-brain interaction 1, 5

Other Systems

• Cardiovascular, dermatologic, hematologic, and neurologic manifestations vary by specific disorder 3, 2, 4
• Any anatomic location of the respiratory system can be affected 1

Important Clinical Pitfalls

Early detection is critical because irreversible organ damage (particularly lung function loss) can occur asymptomatically in early stages, and symptoms may be masked by other organ involvement or comorbidities. 1 Maintaining high clinical suspicion for pulmonary involvement is essential, as early recognition allows intervention to stabilize or slow irreversible damage. 1

Multidisciplinary collaboration between rheumatology, pulmonology, and other specialties is essential for optimal management, as these disorders require both rheumatologic and organ-specific expertise. 1