INFLAMMATORY CONNECTIVE TISSUE DISORDERS

 

NOTES

INFLAMMATORY CONNECTIVE

TISSUE DISORDERS

GENERALLY, WHAT ARE THEY?

▪ Chronic autoimmune disorders

characterized by infl ammation; primarily

affect connective tissue

▪ Production of autoantibodies → deposition

of immune complexes → complement

activation → tissue destruction

▪ Infl ammatory cytokines stimulate

fi broblasts → increased collagen deposition

(fi brosis)

▪ Affects multiple organ systems

▫ Skin, heart, respiratory system, urinary,

gastrointestinal (GI) tract

CAUSES

▪ Genetic, environmental factors

COMPLICATIONS

▪ Skin necrosis; renal, cardiac failure;

pulmonary insuffi ciency; GI refl ux/bleeding

PATHOLOGY & CAUSES

▪ Constitutional symptoms

▫ Low grade fever, fatigue, weight loss

▪ Specifi c to disease, organ systems affected

▫ “Butterfl y skin rash” specifi c to systemic

lupus erythematosus (SLE)

SIGNS & SYMPTOMS

DIAGNOSTIC IMAGING

Barium swallow X-ray

▪ GI involvement

LAB RESULTS

▪ Blood tests

▫ Hematologic abnormalities, increased

infl ammatory markers, complications

(e.g. increased creatinine refl ecting renal

failure)

▪ Serological tests

▫ Antibodies, confi rm diagnosis

OTHER DIAGNOSTICS

▪ Physical examination (e.g. characteristic

skin rashes)

▪ Pulmonary function tests

▫ Pulmonary involvement

DIAGNOSIS

▪ Usually symptomatic (e.g. analgesics)

MEDICATIONS

▪ Steroids/other immunosuppressive agents

▫ Reduce infl ammation

TREATMENT

640 OSMOSIS.ORG

Figure 112.1 Sclerodactyly in an individual

with CREST syndrome.

osms.it/CREST-syndrome

CREST SYNDROME

▪ Form of limited systemic sclerosis

▪ Composed of fi ve features; see mnemonic

▫ Calcinosis: deposition of calcium under

skin

▫ Raynaud’s syndrome: episodic, dramatic

constriction of arteries in hands

▫ Esophageal dysmotility: atrophied

muscle in esophagus without signifi cant

infl ammation/fi brosis

▫ Sclerodactyly: fi brosis of skin of digits

▫ Telangiectasia: dilation of small blood

vessels

▪ Caused by chronic autoimmune

infl ammation triggered mainly by

anticentromere antibodies (ACAs)

▪ More benign clinical course than other

forms of sclerosis

PATHOLOGY & CAUSES

▪ Calcifi c nodules under the skin

▪ White-blue-red transitions in skin color in

response to triggers (e.g. low temperature,

stress)

▪ Dysphagia (due to esophageal dysmotility)

▪ Sclerodactyly

▪ Telangiectasias (esp. hands, face)

SIGNS & SYMPTOMS

LAB RESULTS

▪ Serum blood tests

▫ ↑ ANAs: sensitive for systemic sclerosis

▫ ↑ ACAs: highly specifi c (limited systemic

sclerosis); confi rm diagnosis

OTHER DIAGNOSTICS

▪ Clinical history, physical examination

DIAGNOSIS

MEDICATIONS

▪ Steroids

▪ If sclerosis progresses, stronger

immunosuppressants (e.g. cyclosporine)

TREATMENT

MNEMONIC: CREST

Features of CREST syndrome

Calcinosis

Raynaud’s syndrome

Esophageal dysmotility

Sclerodactyly

Telangiectasia

COMPLICATIONS

▪ Ischemic ulcers, gangrene, predisposition

to chronic skin infections (due to sclerosis,

severe ischemia of skin)

▪ Upper GI bleeding (due to mucosal

telangiectasias)

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641

osms.it/fibromyalgia

FIBROMYALGIA

▪ Chronic condition of central sensitization;

hypersensitivity to pain, sleep disturbances

▫ ↓ serotonin (inhibits pain signals)

▫ ↑ substance P, ↑ nerve growth factor

(involved in propagating pain signals)

▫ Predominance in individuals who are

biologically female

CAUSES

▪ Genetic factors

▪ Environmental factors (child abuse)

▪ Negative emotions (depression, anxiety,

negative beliefs) can amplify pain

PATHOLOGY & CAUSES

▪ Low threshold to pain

▪ Widespread muscle pain

▪ Extreme tenderness in various parts of

body

▪ Sleep disturbances → fatigue, headache

▪ Diffi culty concentrating, remembering

things; AKA “fi bro fog”

SIGNS & SYMPTOMS

OTHER DIAGNOSTICS

Diagnostic Criteria

▪ Pain in ≥ seven areas of body with

symptom severity (SS) of ≥ 5 (of 12)/pain in

≥ fi ve areas of body with SS of ≥ 9 (of 12)

▪ Final score between 0–12

▪ Symptoms present ≥ three months

▪ Pain not due to another disorder

DIAGNOSIS

MEDICATIONS

▪ If non-pharmacologic measures fail, drug

therapy

▪ Antidepressants

▫ Inhibit pain by elevating levels of

serotonin, norepinephrine

▫ Tricyclic antidepressants (TCAs):

amitriptyline fi rst line treatment

▫ Serotonin-norepinephrine reuptake

inhibitors (SNRIs): milnacipran

▪ Anticonvulsants

▫ Slow nerve impulses, relieve sleep

disturbances

PSYCHOTHERAPY

▪ Cognitive behavioral therapy (CBT)

▫ Manage pain, change negative feelings

OTHER INTERVENTIONS

▪ Physical therapy, relaxation techniques,

sleep hygiene to reduce pain, fatigue

TREATMENT

Symptom severity (SS) measures

▪ Fatigue; waking unrefreshed; cognitive

symptoms; somatic symptoms

▫ 0: no problem

▫ 1: slight/mild/intermittent

▫ 2: moderate/considerable/often present

▫ 3: severe, continuous, life disturbing

642 OSMOSIS.ORG

osms.it/mixed-connective-tissue-disease

MIXED CONNECTIVE

TISSUE DISEASE (MCTD)

▪ Overlap autoimmune syndrome;

constellation of SLE, systemic sclerosis,

polymyositis; may not occur simultaneously

▪ Can evolve into classic SLE/systemic

sclerosis

COMPLICATIONS

▪ Pulmonary hypertension; interstitial lung

disease; renal disease

PATHOLOGY & CAUSES

▪ Arthralgias (due to polyarthritis)

▪ Myalgias (due to mild myositis)

▪ Swollen hands with puffy fi ngers (due to

synovitis)

▪ Sclerodactyly

▪ Early development of Raynaud

phenomenon

▪ Fatigue

▪ Low-grade fevers

SIGNS & SYMPTOMS

▪ Confi rmation requires characteristic clinical

presentation

LAB RESULTS

▪ High serum levels of anti-U1

ribonucleoprotein (anti-U1-RNP) antibodies

▪ High ANAs, RF, anti dsDNA, anti Sm, anti

Ro

DIAGNOSIS

▪ Depends on predominant autoimmune

disease

MEDICATIONS

▪ Corticosteroids

▫ Suppress immune system

TREATMENT

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643

osms.it/polymyalgia-rheumatica

POLYMYALGIA RHEUMATICA (PMR)

▪ Immune-mediated rheumatic condition

affecting joints, sparing muscles

▪ Most commonly affects shoulder, hip joints

▪ Usually occurs in individuals who are

biologically female > 50; mean age 70

▪ Strongly associated with giant-cell arteritis,

AKA temporal arteritis

▪ Can regress without treatment after 1–2

years/remain chronic

CAUSES

▪ Genetic defects: specifi c allele of human

leukocyte antigen (HLA)-DR4

▪ Environmental factors: exposure to

adenovirus/human parvovirus B19

PATHOLOGY & CAUSES

▪ Joint pain, stiffness (shoulder, hip joints)

▫ Often starts unilaterally, progresses to

bilateral within few weeks

▫ More severe after prolonged inactivity

(e.g. morning)

▫ Typically lasts > one hour

▫ Affects nearby nerves in muscle →

muscle pain (referred pain)

SIGNS & SYMPTOMS

LAB RESULTS

▪ Increased serum infl ammatory markers

▫ Erythrocyte sedimentation rate (ESR)

▫ C-reactive protein (CRP)

▪ Biopsy

▫ Infl ammation in joints

OTHER DIAGNOSTICS

▪ Physical examination

▫ Decreased passive range of motion of

affected joints

DIAGNOSIS

MEDICATIONS

▪ Low dose of corticosteroids

▫ Suppress immune response

TREATMENT

▪ Constitutional symptoms

▫ Low grade fever (interleukins act as

pyrogens)

▫ Fatigue

▫ Loss of appetite → weight loss

▪ If severe headache, jaw pain, vision

problems

▫ Temporal arteritis

644 OSMOSIS.ORG

osms.it/raynauds-disease

RAYNAUD'S DISEASE

▪ Vasospasm of skin arteries in response to

triggers, resulting in skin color transitions

▪ Exposure to trigger → stimulation of

sympathetic nerves in arteriole walls →

vasospasm of arterioles → decrease in

blood fl ow

▪ Usually affects hands, fi ngers, toes; can

affect nose, ears, lips

▪ Common triggers

▫ Emotional stress; low temperatures;

nicotine; caffeine; medications that

affect sympathetic nervous system (e.g.

pseudoephedrine)

TYPES

Primary: Raynaud phenomenon/disease

▪ Common in pregnant individuals, people

who work in jobs involving vibration (e.g.

jackhammer)

Secondary: Raynaud syndrome

▪ Connective tissue disorders

▫ Systemic lupus erythematosus (SLE),

scleroderma, mixed connective tissue

disease

▪ Disorders affecting blood vessels

▫ Buerger’s disease, Takayasu’s arteritis,

thromboangiitis obliterans

▪ Medications

▫ Beta blockers, nicotine

COMPLICATIONS

▪ Ulceration, infarction, tissue necrosis,

gangrene (if severe)

PATHOLOGY & CAUSES

▪ Vasospasm → changes in skin color of

hands, fi ngers, toes

▫ White: ischemia

▫ Blue: hypoxia after prolonged ischemia

▫ Red: reactive hyperemia (vasospasm

ends, oxygenated blood rushes into

tissue)

▪ Raynaud phenomenon

▫ Affects hand fi ngers, toes symmetrically;

severity remains constant

▪ Raynaud syndrome

▫ Asymmetrical; progressive severity

▪ Swelling, numbness, tingling, pain (due to

reactive hyperemia)

SIGNS & SYMPTOMS

▪ Based upon description of episodes

DIAGNOSTIC IMAGING

▪ Nailfold capillary microscopy to examine

fi nger capillaries

▫ Normal appearance: Raynaud

phenomenon

▫ Damaged appearance: Raynaud

syndrome

DIAGNOSIS

MEDICATIONS

▪ Vasodilators (e.g. calcium channel blockers)

SURGERY

▪ If severe, surgery to cut sympathetic nerve

fi bers supplying affected areas

OTHER INTERVENTIONS

▪ Avoid triggers

TREATMENT

OSMOSIS.ORG

 Chapter 112 Infl ammatory Connective Tissue Disorders

645

Figure 112.2 A hand with pale fi ngers

caused by Raynaud’s disease.

osms.it/scleroderma

SCLERODERMA

▪ AKA systemic sclerosis

▪ Chronic infl ammatory autoimmune disease,

can result in widespread damage to small

blood vessels, excessive fi brosis

▫ T helper cells activated by unknown

antigen → release cytokines →

stimulate infl ammatory cells, fi broblasts

→ chronic infl ammation, excessive

collagen deposition

▫ Mediators released by infl ammatory

cells → damage microvasculature →

ischemic injuries, scarring

▪ Primarily affects skin, can involve visceral

organs

▫ GI tract, kidneys, heart, muscles, lungs

TYPES

Limited (80%)

▪ Skin involvement limited to fi ngers,

forearms, face

▪ Late visceral involvement

PATHOLOGY & CAUSES

▪ Some individuals develop CREST syndrome

▫ Calcinosis, Raynaud’s phenomenon,

esophageal dysmotility, sclerodactyly,

telangiectasia

▪ Associated with anticentromere antibodies

▪ Relatively benign

Diffuse (20%)

▪ Widespread skin involvement

▪ Early visceral involvement

▪ Rapid progression

▪ Associated with anti-DNA topoisomerase I

antibodies

▪ Poor prognosis

RISK FACTORS

▪ More common in individuals who are

biologically female (3:1 ratio)

▪ Average age of onset: 35–50

▪ Genetic factors

▪ Environmental factors (e.g. viruses, toxins,

drugs)

646 OSMOSIS.ORG

Figure 112.3 The fi nger of an individual

with systemic sclerosis showing sclerosis,

erythema and ulcer formation.

Figure 112.4 A rash on the back of

an individual with a form of localised

scleroderma known as morphea.

COMPLICATIONS

▪ Excessive skin fi brosis → painful ulcers,

disfi gurement, disability

▪ Severe internal organ involvement → renal,

cardiac failure; pulmonary insuffi ciency;

intestinal malabsorption

▪ Raynaud phenomenon

▫ Precedes other symptoms, present in

almost all individuals

▪ Cutaneous changes of face, extremities

▫ Skin thickening, tightening, sclerosis

(most common); edema, erythema

(precede sclerosis)

▪ GI involvement

▫ Esophageal fi brosis → dysphagia, GI

refl ux

▫ Small intestine involvement →

abdominal pain, obstructions,

constipation, diarrhea, malabsorption

syndrome (weight loss, anemia)

▪ Pulmonary involvement with interstitial

fi brosis

▫ Right-sided cardiac dysfunction/

pulmonary hypertension

▪ Cardiac involvement

▫ Pericardial effusions, myocardial fi brosis

→ congestive heart failure, arrhythmias

▪ Renal involvement (diffuse disease) → fatal

hypertensive crisis (rare)

SIGNS & SYMPTOMS

DIAGNOSTIC IMAGING

▪ Upper endoscopy

▫ Esophageal fi brosis/refl ux esophagitis

LAB RESULTS

▪ Serologic tests

▫ ↑ ANAs in almost all individuals with

systemic sclerosis; low specifi city

▫ ↑ ACAs highly specifi c (limited)

▫ Anti-topoisomerase I antibodies (antiScl-70) highly specifi c (diffuse)

▪ Complete blood count (CBC)

▫ Anemia due to malabsorption,

increased serum creatinine due to renal

dysfunction

OTHER DIAGNOSTICS

▪ Clinical presentation

▫ Skin thickening, swollen fi ngers,

Raynaud’s phenomenon, GI refl ux

▪ Pulmonary function tests

▫ Restrictive ventilatory defect due to

pulmonary interstitial fi brosis

DIAGNOSIS

OSMOSIS.ORG

 Chapter 112 Infl ammatory Connective Tissue Disorders

647

▪ Depends on disease subset, severity of

internal organ involvement

MEDICATIONS

▪ Usually symptomatic

▫ Analgesics for musculoskeletal pain

TREATMENT ▫ Proton pump inhibitors for

gastroesophageal refl ux

▫ Calcium channel blockers for Raynaud’s

phenomenon

▫ Angiotensin converting enzyme (ACE)

inhibitors for renal hypertensive crisis

▪ Immunosuppressive therapy initiation:

diffuse skin/severe internal organ

involvement

osms.it/sjogrens-syndrome

SJOGREN'S SYNDROME (SS)

▪ Chronic autoimmune infl ammatory disease;

lymphocytic infi ltration, destruction of

exocrine glands of eyes, mouth

▪ Proposed mechanisms

▫ Immune reactions against antigens of

viral infection of exocrine glands

▫ Autoimmune T cell reaction against

unknown self antigen expressed in

salivary, lacrimal glands

▪ Variety of extraglandular manifestations

may occur

▪ Usually occurs in individuals who are

biologically female, 50–60 years

CAUSES

▪ Primary: sicca syndrome

▪ Secondary (to other autoimmune diseases):

rheumatoid arthritis (most common)

COMPLICATIONS

▪ Periodontal complications; oral infections;

mucosal associated lymphoid tissue (MALT)

lymphoma

PATHOLOGY & CAUSES

▪ Dry eyes

▫ Irritation, itching, foreign body sensation,

keratoconjunctivitis

▪ Oral dryness refl ecting salivary

hypofunction

▪ Salivary gland enlargement (parotid,

submandibular, etc.)

▪ Extraglandular manifestations

▫ Musculoskeletal symptoms (arthralgias,

arthritis); rashes; interstitial nephritis,

vasculitis

SIGNS & SYMPTOMS

▪ Clinical presentation: persistent dry eyes/

mouth, parotid gland enlargement

DIAGNOSTIC IMAGING

Parotid gland MRI

▪ Honeycomb pattern

Salivary gland ultrasound

▪ Multiple hypoechoic areas

LAB RESULTS

▪ CBC

▫ Leukopenia, thrombocytopenia, anemia

▪ ↑ ESR

▪ Urinalysis

DIAGNOSIS

648 OSMOSIS.ORG

Figure 112.5 A lymphocytic infi ltrate in

a minor salivary gland excised from an

individual with Sjögren’s syndrome.

MEDICATIONS

▪ Mild SS

▫ Secretagogues

▫ Local treatment for ocular, oral dryness

(e.g. artifi cial tears)

▪ Moderate to severe SS

▫ Immunosuppressive treatment

TREATMENT

▫ Proteinuria/hematuria refl ecting

glomerulonephritis

▪ Labial salivary gland biopsy (confi rm

diagnosis)

▫ Focal lymphocyte foci (collections of

tightly aggregated lymphocytes)

▪ Serologic tests (support diagnosis)

▫ ↑ antinuclear antibodies (ANAs) in 95%

of individuals

▫ ↑ rheumatoid factor (RF) in 50–75%

of individuals with/without rheumatoid

arthritis

▫ Anti-Sjögren syndrome A (SSA) (Ro),

Anti-Sjögren syndrome B (SSB) (La)

specifi c to SS, found elevated only in

55%, 40% of individuals, respectively

OTHER DIAGNOSTICS

Tear defi ciency tests

▪ Schirmer test

▫ Measures refl ex tear production; wetting

of test paper < 5mm indicative of tear

defi ciency

▫ Ocular surface staining with

Rose Bengal stain and slit-lamp

examination—assess tear break-up time

(TBUT); TBUT < 10 seconds indicative

of tear defi ciency

▪ Salivary gland tests

▫ Salivary gland scintigraphy: low uptake

of radionuclide characteristic of SS

▫ Sialometry: low volume of saliva

indicative of salivary gland hypofunction

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 Chapter 112 Infl ammatory Connective Tissue Disorders

649

Figure 112.6 A butterfl y rash on the

face of an individual with systemic lupus

erythematosus.

osms.it/systemic-lupus-erythematosus

SYSTEMIC LUPUS

ERYTHEMATOSUS (SLE)

▪ Chronic systemic autoimmune disorder;

wide range of clinical, serological features

▪ Periods of fl are-ups, remittance

▪ Environmental triggers damage DNA →

apoptosis → release of nuclear bodies

▪ Clearance of apoptotic bodies ineffective

due to genetic defects → increased amount

of nuclear antigens in bloodstream →

initiates immune response → production of

antinuclear antibodies → bind to antigens,

form immune complexes

▪ Complexes deposit in tissues (e.g.

kidneys, skin, joints, heart) → Type III

hypersensitivity reaction

▪ Individuals may develop antibodies

targeting molecules (e.g., phospholipids) of

red, white blood cells → marking them for

phagocytosis → Type II hypersensitivity

reaction

RISK FACTORS

▪ Genetic defects associated with SLE

▪ UV radiation

▪ Smoking

▪ Viral, bacterial infections

▪ Medications (e.g. procainamide,

hydralazine, isoniazid, estrogens)

▪ More common in individuals who are

biologically female, of reproductive age

COMPLICATIONS

▪ Cardiovascular disease

▫ Libman–Sacks endocarditis, myocardial

infarction (MI)

▪ Serious infections; renal failure;

hypertension

PATHOLOGY & CAUSES

▪ Fever, joint pain, rash in sun-exposed areas

▪ Typical rashes

▫ Malar rash (butterfl y rash): over cheeks

▫ Discoid rash: plaque-like/patchy

redness, can scar

▫ General photosensitivity: typically lasts

few days

SIGNS & SYMPTOMS

▪ Antiphospholipid syndrome

▫ Hypercoagulable state; individuals

prone to develop clots (e.g. deep vein

thrombosis, hepatic vein thrombosis,

stroke)

650 OSMOSIS.ORG

Figure 112.7 An MRI scan of the head of

an individual with SLE who presented with

altered mental status and seizures. There

a numerous small infarcts suggestive of

cerebral vasculitis. The individual improved

after treatment with steroids.

▪ Goal: prevent relapses, limit severity

MEDICATIONS

▪ Long term therapy

▫ Antimalarial agents

▪ Mild to moderate manifestations

▫ Non-steroidal anti-infl ammatory drugs

(NSAIDs), low doses of corticosteroids

▪ Severe/life-threatening manifestations

▫ High doses of corticosteroids, intensive

immunosuppressive drugs

OTHER INTERVENTIONS

▪ Avoid sun exposure

▪ Physical exercise

▪ Balanced diet

▪ Smoking cessation

▪ Immunizations

TREATMENT

OTHER DIAGNOSTICS

Diagnostic criteria (4 of 11)

▪ Malar rash

▪ Discoid rash

▪ General photosensitivity

▪ Oral/nasal ulcers

▪ Serositis

▪ Arthritis in ≥ two joints

▪ Renal disorders

▪ Neurologic disorders

▪ Hematologic disorders

▪ Antinuclear antibodies

▫ Very sensitive, not specifi c

▪ Other antibodies

▫ SLE specifi c: anti-Smith, anti-dsDNA

▫ Anti-phospholipid: anticardiolipin

(false-positive test for syphilis); lupus

anticoagulant (lupus antibody); anti-beta

2 glycoprotein I

DIAGNOSIS ▪ Weight loss

▪ Ulcers in oral/nasal mucosa

▪ Serositis (e.g. pleuritis/pericarditis)

▪ Libman–Sacks endocarditis: formation of

nonbacterial vegetations on ventricular,

atrial valve surfaces; mitral, aortic valves

(most common)

▪ Myocarditis

▪ Renal disorders

▫ Abnormal levels of urine protein, diffuse

proliferative glomerulonephritis

▪ Neurologic disorders

▫ Seizures, psychosis

▪ Hematologic disorders

▫ Anemia, thrombocytopenia, leukopenia

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 Chapter 112 Infl ammatory Connective Tissue Disorders

651

Figure 112.8 A histological section of a

lymph node from an individual with lupus

lymphadenopathy. There is necrosis, with an

absence of neutrophils, and large numbers of

hematoxylin bodies.

Figure 112.9 Histological appearance of the

glomerulus in a case of lupus nephritis. There

is global mesangial cell proliferation and

abundant mesangial matrix