Collagen Vascular Diseases & Structural Proteins

Secondary Collagen Diseases

Ankylosing Spondylitis (AS)

Key Feature: Chronic inflammatory arthritis affecting the spine, predominantly in young to middle-aged males (20-40). The disease begins with inflammation of the sacroiliac joints and progresses upward.

HLA-B27 genetically associated
Starts with sacroiliitis, causes persistent back pain
Inflammation + scarring with new bone deposition
Bamboo spine: fusion of vertebrae → loss of height
Positive Schober test (spinal mobility)
Serious complication: aortic dissection

Fragile X Syndrome

Large testicles (macro-orchidism)
Pill-shaped head deformity
Mitral valve prolapse (MVP)
Mental retardation
Autosomal recessive inheritance

Tertiary Syphilis

Treponema pallidum attacks the vaso vasorum (small blood vessels feeding arterial walls).

Tree-bark appearance: wrinkled intima of aorta
Obliterative endarteritis: inflammation narrowing vessel lumen
Progressive aortic damage

Takayasu's Disease (Granulomatous Aortitis)

Epidemiology: Primarily affects young Asian females.

Granulomas progressively destroy the aorta
Starts in aorta, spreads systemically
Presents with weak pulse (pulseless disease)
Risk of aortic dissection as granulomas chew through vessel wall

CREST Syndrome: The Mildest Form of Scleroderma

CREST is a patchy, limited form of scleroderma with predictable features and the most favorable prognosis. Patients are positive for anti-centromere antibodies.

CREST Mnemonic Match

C

R

E

S

T

Telangiectasias

Scleroderma of fingertips

Calcinosis cutis

Esophageal dysmotility

Raynaud's phenomenon

C - Calcinosis Cutis

Dystrophic calcium deposits appear in the skin, particularly on fingertips and elbows. These are deposits of calcium in areas of tissue damage.

R - Raynaud's Phenomenon

Vasospastic attacks triggered by cold or emotional stress. Fingers turn white → blue → red during rewarming.

E - Esophageal Dysmotility

Scarring of the smooth muscle of the esophagus impairs peristalsis. Leads to GERD, dysphagia, and reflux complications.

S - Scleroderma (Sclerodermatitis)

Progressive tightening of skin, particularly between fingers (scleroderma of fingertips). Skin becomes waxy and tight, restricting movement.

T - Telangiectasias

Dilated capillaries creating a spidery appearance on skin and mucous membranes. These are permanent vascular dilations.

Scleroderma & Progressive Systemic Sclerosis (PSS)

Scleroderma (Full-Blown Disease)

Severe scarring of smooth muscle affecting skin, blood vessels, and GI tract. More severe than CREST with systemic manifestations.

Anti-smooth muscle antibody marker
Anti-SCL-70 antibody (anti-topoisomerase)
Most onion-skinning occurs in kidney vessels
Raynaud's phenomenon as early sign
Progressive skin fibrosis

Progressive Systemic Sclerosis (PSS) - Severe Form

The most severe form with extensive internal organ involvement. Systemic manifestations include:

Interstitial lung disease (75%): Progressive dyspnea, pulmonary fibrosis
Pulmonary vascular disease: Pulmonary hypertension
Patchy myocardial fibrosis: Conduction abnormalities, arrhythmias
Sclerodermal renal crisis: Acute renal failure
Anti-topoisomerase antibody (anti-SCL-70)

Rheumatoid Arthritis (RA)

The most common arthritis in middle-aged females. Unique because it's the only arthritis attacking the joint lining (synovium) and the only arthritis to involve C1-C2 vertebrae in this demographic.

Immunology

Rheumatoid factor (RF): Antibody against Fc portion of IgG
Anti-CCP antibody: More specific than RF, better predictive value
Target: Synovium (joint lining), forming pannus (inflamed tissue)

Clinical Presentation

Most common arthritis in middle-aged females
Morning stiffness lasting >1 hour (hallmark)
Symmetrical joint involvement (bilateral hands, wrists, feet)
Affects MCP and PIP joints preferentially
Tingling in all 4 extremities (from C1-C2 subluxation)

RA Diagnostic Criteria (Need ≥3)

Morning stiffness >1 hour duration
Symmetrical arthritis
Rheumatoid nodules present
High ESR (elevated)
X-ray erosions visible
Positive anti-CCP or RF antibodies
Swelling of ≥3 joints

Treatment Protocol

Escalation Strategy:

Methotrexate as first-line DMARD
Within 90 days, add TNF inhibitor (biologics)
Follow treatment plan minimum 2 years
Monitor for infections (immunosuppression)

RA Variants

Felty's Syndrome: RA + leukopenia + splenomegaly
Behçet's Disease: RA + GI ulcers + high incidence uveitis (eye inflammation)

Sjögren's Syndrome & Related Conditions

Sjögren's Syndrome

Autoimmune destruction of lacrimal and salivary glands leading to xerophthalmia (dry eyes) and xerostomia (dry mouth). Often occurs with RA.

RA + dry mouth + dry eyes = Sjögren's
Decreased lacrimal and salivary gland function
Antibodies: Ro (SSA), La (SSB)
Increased risk of lymphoma

Sicca Syndrome

Similar presentation to Sjögren's but WITHOUT rheumatoid arthritis. Isolated dry eyes and dry mouth without systemic disease.

Anti-Ro Antibody (SSA)

Critical Association: Anti-Ro antibodies cross the placenta and can cause congenital heart block in the fetus. This is a major concern for pregnant women with Sjögren's syndrome.

The Four Bad Associations of Cardiolipin Antibodies

Cardiolipin antibodies are associated with serious systemic manifestations:

Stimulates intrinsic clotting system → Hypercoagulability, thrombosis
Blocks von Willebrand factor → von Willebrand-like disease, bleeding
Multiple spontaneous abortions → Recurrent pregnancy loss
False positive VDRL (syphilis test) → Positive RPR/VDRL without actual syphilis

Systemic Lupus Erythematosus (SLE)

Chronic, multisystem autoimmune disease of unknown cause affecting virtually every organ system. The #2 cause of arthritis in middle-aged females.

Epidemiology & Pathophysiology

Female predominance (90% female, reproductive age)
Can affect any and every organ system
Immune complex deposition causes organ damage
Photosensitivity (sun exposure worsens disease)

Clinical Features (% of patients)

Fatigue (90%): Often debilitating
Arthritis (90%): Non-erosive, symmetrical
Skin manifestations (50%): Butterfly rash, photosensitivity
Raynaud's phenomenon (50%)
Renal involvement: Glomerulonephritis, proteinuria
CNS involvement: Seizures, psychosis, cognitive impairment
Hematologic: Anemia, leukopenia, thrombocytopenia

The Butterfly Rash

Classic malar (cheek) rash appearing in approximately 50% of SLE patients. Typically appears in a butterfly distribution across the cheeks and nose, often triggered or worsened by sun exposure.

Diagnostic Antibodies

Anti-dsDNA (double-stranded DNA): Most specific for SLE, most nephrotoxic (70% positive). Predicts renal disease.
Anti-Smith (anti-Sm): 30% positive, highly specific, never in other diseases
Anti-cardiolipin: Associated with thrombosis and fetal loss
Antinuclear antibodies (ANA): Present in >95%

Renal Involvement (Lupus Nephritis)

Renal failure is the most common cause of death in SLE
Immune complex glomerulonephritis
Ranges from microscopic hematuria to acute renal failure
Proteinuria, hypertension, and declining GFR

Treatment

NSAIDs for mild disease
Corticosteroids for moderate-severe disease
Mycophenolate: Immunosuppressive agent
Cyclophosphamide: For severe lupus nephritis
Hydroxychloroquine (Plaquenil) for skin and joint manifestations

Drug-Induced Lupus (DIL)

Antibodies: Anti-histone antibodies (NOT anti-dsDNA)

Medications causing DIL:

Hydralazine
Isoniazid (INH)
Procainamide
Penicillamine
Phenytoin
Ethosuximide

Memory: HIPPE medications

Mixed Connective Tissue Disease (MCTD)

A hybrid disease with features of multiple collagen vascular diseases. Characterized by anti-ribonuclear protein (RNP) antibodies.

Overlap features from SLE, scleroderma, myositis, RA
Better prognosis than SLE
Responds well to corticosteroids

Elastin: Structure and Function

Elastin Properties

Elastin provides compliance (ability to stretch and expand) and recoil (ability to return to original shape) to tissues.

Found in: Lungs (alveolar walls), arteries (elastic laminae), skin, ligaments
Contains amino acids: Glycine, proline, lysine, hydroxypoline, desmosine
NO hydroxylysines (unlike collagen)
Has unique crosslink: Desmosine

Elastin Crosslinking

Lysines are positioned in pairs (2-by-2 arrangement). The positive charges on adjacent lysines repel each other, which creates the elastic recoil property—the fiber "wants" to return to its relaxed state.

Elastase Enzyme

A digestive enzyme that destroys elastin by cutting at specific amino acid sites.

Cuts elastin to the right of: GLY, ALA, SER
Alpha-1 antitrypsin: Protease inhibitor that blocks elastase and trypsin
Sources: Released by neutrophils and bacteria during infection
Smoking inhibits alpha-1 antitrypsin → uncontrolled elastase activity
Alpha-1 antitrypsin decreases with aging

Emphysema: Elastin Destruction

Characterized by destruction of alveolar walls and loss of elastic recoil. FOUR TYPES:

Panacinar emphysema: Alpha-1 antitrypsin deficiency. Uniform destruction throughout alveolus. Affects lower lobes.
Centroacinar emphysema: Smoking-related. Proximal alveoli destroyed, distal preserved. Affects upper lobes.
Disto-acinar emphysema: Aging-related. Distal alveoli affected, proximal preserved. Minimal symptoms.
Bullous emphysema: Caused by Staph aureus and Pseudomonas aeruginosa. Forms large air-filled bullae (blebs) that rupture → spontaneous pneumothorax.

Who Fears Staph + Pseudomonas?

High-risk groups for bullous emphysema and severe infections:

Neutropenic patients (low WBC)
Burn patients (compromised skin barrier)
Cystic fibrosis patients (mucociliary clearance defect)
Diabetics (impaired immune function)

Antibiotic Coverage:

Staph aureus: 1 antibiotic (e.g., Nafcillin or Vancomycin)
Pseudomonas: 2 antibiotics (double coverage, e.g., Ceftazidime + Tobramycin or Piperacillin-tazobactam + Fluroquinolone)

Keratin: Structure and Function

Keratin is synthesized primarily for tensile strength—the ability to withstand pulling and stretching forces. It contains abundant cysteine residues that form strong disulfide crosslinks.

Composition

High cysteine content → Disulfide bonds (S-S) provide tensile strength
Alpha-helix and beta-sheet secondary structures
Forms tight crosslinks between polypeptide chains

Tissues Requiring Tensile Strength

Bone: Collagen matrix + mineralization
Cartilage: Collagen fibrils resist compression
Ligaments: Keratin fibrils resist pulling forces
Tendons: Keratin + collagen for elasticity + strength
Nails: Multiple keratin layers for structural integrity
Fascia: Tough keratin-rich connective tissue sheet
Hair: Alpha-keratin provides structure and strength