COLLAGEN DISEASES I

Professor DR. Shahenaz M.

Hussien

OBJECTIVES
By the end of this lecture the student will
be able to understand the followings:
Etiology, pathogenesis, clinical
manifestation, investigations and
treatment of rheumatoid arthritis.
Etiology, clinical manifestation,
investigations, diagnosis and treatment
of systemic lupus erymatosis.

Juvenile rheumatoid Arthritis ( JRA )

- Most common of rheumatic diseases and leads to chronic
disability.
- Idiopathic synovitis of the peripheral joints with soft tissue
swelling and effusion.

Age at onset < 16yr:

-Arthritis (swelling or effusion) or presence of two or
more of the following signs :
limitation of range of motion,
tenderness or pain on motion,
and increased heat in one or more joints.
-

Duration of the disease ; 6wk or longer.

Polyarthritis 5 or more inflamed joints.

Oligoarthritis < 5 inflamed joints.
Systemic: arthritis with fever, and exclusion of other forms of
juvenile arthritis.

Etiology
Unknown immunologic susceptibility
-Environmental trigger: as viruses parvovirus B19, rubella,
Ebstein-Barr.
- Host hypersensitivity to specific self-antigens (type II
collagen) and enhanced T-cell reactivity to bacterial or
mycobacterial heat shock proteins.

Pathogenesis:
Synovitis: Villous hypertrophy and hyperplasia with
hyperemia and edema
of subsynovial tissues.
Vascular endothelial hyperplasia.
Pannus formation results in progressive erosion of
particular cartilage and contiguous bone.
- Preceding infection or trauma.
- HLA: DR8, DR5 in pauciarticular type, and DR4 in
polyarticular JRA.
- Leads to greater amounts of cytokines resulting in more
severe disease.

Clinical manifestations:
- Morning stiffness and gelling, easy
fatigability, joint pain later in the day
and joint swelling.
Oligoarticular disease (pauciarticular
50%)
- Arthritis of big joints less than 5.
- Asymmetrical or spotty.
- Knees, ankles, hips never involved
early, later indicates sign of a
deteriorating functional course.
- Two types.

Type I
25%
Girls onset

Type 2
15%
Boys onset

Chronic iridocyclitis (50%)

Acute iridocyclitis (10 20%)

Rheumatoid factor -ve

ANA +ve (60%)
No specific HLA type
Uncommon serious disability

Rheumatoid factor +ve

ANA ve
HLA B27
Achillis tendonitis, hip girdle
Sacroileitis
+Ve family history
spondyloarthropathy, acute
iridocyclitis

Polyarticular disease (35%):

- More among girls.
- No systemic
manifestations.
- Large and small joints five or more.
- Rheumatoid nodules over extensor surfaces of
elbows and over Achilles tendon associated
with a more severe course.
- Micrognathia due to temporomandibular
joint involvement.
- Cervical spine with risk of atlantoaxial
sublaxation.
-Hoarse voice due to cricoarytenoid joint
involvement.
-Two types.

Type I

Any age < 1y

Mild
Rheumatoid factor ve
Rare rheumatoid nodules

Type II
Late childhood > 8y
More severe arthritis
Rheumatoid factor +ve
Frequent nodules
Occasional vasculitis

Systemic-onset disease (15%):

- Arthritis, prominent visceral involvement:
-Hepatosplenomegaly, lymphadenopathy, and serositis
-Fever for a minimum 2wk with daily temperature spikes to at least
39.5c often associated with salmon- colored lesions over the trunk
and proximal extremities.
-koebner phenomenon: cutaneous hypersensitivity to superficial
trauma.

Diagnosis:
-No pathognomonic finding.
- Clinical
subtypes.
- Exclusion of other articular diseases.
-Elevated ESR, CRP, leukocytosis, thrombocytosis,
anemia.
Differential diagnosis:
- Other rheumatic diseases : SLE, juvenile
dermatomyositis, scleroderma
-Autoimmune hepatitis,
- chronic Mycobacterial or other infections.
- Single joint: bacterial infection, psoriatic arthritis.
- Hip joint can be due suppurative arthritis,
osteomyelitis, slipped capital femoral epiphysis,
chondrolysis of the hip.
- Persistent arthralgia: juvenile episodic arthritis,
inflammatory bowel disease.
- Less commonly: leukemia.

Causes of mono arthritis:

1. Trauma.
2. Septic arthritis
3. Mycobacterial infection
4. Chronic active hepatitis
5. Toxic synovitis of the hip.
6. Osteomyelitis with sympathetic effusion.
7. Leukemia (in 5% of causes).
8. Familial Mediterranean fever.
9. Slipped capital femoral epiphysis.
10. Sarcoidosis.

Causes of pauci articular arthritis

1. Reactive arthritis.
2. Viral
3. Pauciarticular juvenile rheumatoid arthritis. 4. Acute leukemia.

Causes poly articualr arthritis

1. Poly articular rheumatoid arthritis.
2. SLE. 3. TB.
4. Malignancies.
5. Dermatomyositis.
6. Inflammatory bowel disease: Crohn's disease, ulcerative colitis.

Laboratory findings:
- Elevated white blood cell, and platelet counts, decreased
hemoglobin and mean corpuscular volume.
- ESR, CRP.
- Elevated serum immunoglobulins, elevated ANA, positive
rheumatoid factor in older children with rheumatoid
nodules.
- Abnormal mineral metabolism with active synovitis.
- Increased IL-6.

Radiologic changes:
- Soft tissue swelling, osteoporosis, periostitis about
affected joints.
- Regional epiphyseal closure may be accelerated and
local bone growth increased or decreased, subchondral
erosions, narrowing of cartilage space,
- varying degrees of bony destruction and fusion most
frequently in the neural arch joints at C2-C3,
- MRI evaluates both joint and soft tissues

Treatment:
-Oligoarticular JRA responds to NSAIDs alone.
-Polyarticular patients and some aggressive disease with
oligoarticular JRA . Combination therapy should begin with
NSAIDs, sulfalsalazine, methotrexate and possibly other
immunosuppressive drugs.
-Azathioprine and cyclophosphamide are reserved for the very
few patients who do not respond to less aggressive therapy.
-Glucocorticoid for overwhelming inflammatory or systemic
illness.
Therapy in lower doses in addition to another drug as
methotrexate are most efficacious for ocular and
intraarticular use. Routine slit lamp for asymptomatic uveitis.
-Appropriate calcium intake, physical and occupational therapy.
-Social workers support to alleviate family stresses

Prognosis:
- Unpredictable, variable physical function limitations
- Chronic uveitis may result in posterior synechiae and
blindness.
- Functional limitation risk has been associated with:
- Older age at onset, rheumatoid factor positivity,
rheumatoid nodules, early cervical spine or hip arthritis.
- Anemia non responsive to iron therapy, exaggerated
by gastrointestinal bleeding. Due to NSAID.
- Rare digital endarteritis threatening auto amputation
which may respond to I.V prostaglandin E1.
- Development of manifestations of other rheumatic
diseases overlapping syndrome.
- Orthopedic complications: leg length discrepancy,
secondary scoliosis, popliteal cysts, flexion contractures.
- Psychological adaptation, continuing chronic pain
syndromes.

SYSTEMIC LUPUS ERYTHEMATOSIS

- Unknown etiology.
- Multi organ disease.
- Auto antibodies against self-antigens which
result into damage of target organs such as
the kidneys, blood-forming cell and CNS.
- Unpredictable history and course.
- Acute life-threatening disease, spontaneous
remission smoldering over years, or rapid
death.
- Initial presentation may be atypical as
parotitis, abdominal pain, transverse myelitis.

Etiology:
- Many factors: genetics, hormones and the
environment contribute to immune dysregulation.
- Auto antibodies against DNA and other antigens:
ribosome's, platelets, coagulation factors,
immunoglobulins, erythrocytes, leukocytes.
- Anti-double stranded DNA antibodies with
circulating and tissue- bound immune complexes
lead to complement fixation and recruitment of
inflammatory cells and then tissue injury.
- Polyclonal activation of B lymphocytes results
in elevated immunoglobulin levels and elevated
autoantibody levels.
- Dysregulation of apoptosis leads to the
presence of self- reactive lymphocytes.

Etiology:
- Defects in macrophage phagocytosis and handling of
immune complexes.
- Complement abnormalities.
- Exposure to ultraviolet rays in sun light can exacerbate
SLE manifestations through damage to nuclear
material.
- Drug-induced lupus: anticonvulsants, sulfonamides,
antiarrhythmic drugs, these patients have antihistone
antibodies

Pathogenesis:
- Fibrinoid deposits in blood vessel walls of
affected organs.
- Parenchyma may contain hematoxylin bodies
representing degenerated cell nuclei.
Rheumatoid nodules, and granulomas in
affected tissues.

Clinical manifestations:
- Fever, fatigue, arthralgia, arthritis, rash.
- Intermittent or persistent symptoms.
Cutaneous:
- Malar, butterfly rash: nasal bridge and cheeks,
photosevsitive.
- Discoid lesions more in adults.
- Mucous membranes: vasculitic erythema to ulcers
on palate and nasal mucosa.
-Vasculitic-appearing erythematous macular
eruptions on fingers, palms, soles.
-Purpura and livedo reticularis which is lace like
bluish, purplish or erythematous discoloration of
the skin due to vascular instability.
-Raynaud phenomenon, -subacute psoriasiform or
annular skin lesions, bullous lesions, and alopecia.

CLINICAL
MANIFESTATIONS

Musculoskeletal: - Arthralgia, arthritis, tendinitis,

myositis, osteonecrosis of bones secondary to
vasculopathy or corticosteroid therapy.
Serositis: pleural, pericardial, peritoneal.
- Hepatosplenomegaly,
lymphadenopathy.
Gastrointestinal: due to vasculitis: pain,
diarrhea, infarction, melena, inflammatory
bowel disease and hepatitis.
Cardiac: valvular thickening, verrucous
endocarditis (Libman Sacks disease),
cardiomegaly, myocarditis, conduction
abnonmalies, heart failure, coronary artery
vasculitis or thrombosis.

Clinical manifestations:
Pulmonary: Acute pulmonary hemorrhage, pulmonary infiltrates
(superimposed infection), chronic fibrosis.
Neurologic:
CNS, peripheral nervous tissue, memory loss,
cognitive dysfunction.
- Neuro psychiatric manifestations, severe psychosis.
Arterial and venous thrombosis:
- Antiphospholipid antibody syndrome, in any
organ leads to thrombocytopenia and Raynaud
phenomenon.
Renal disease:
Leads to hypertension, peripheral edema, renal
vascular changes, electrolyte abnormalities,
nephrosis, acute renal failure.

Diagnosis:

- Clinical, laboratory manifestations revealing

multisystem disease.
- Presence of 4 of 11 criteria serially or simultaneously

1- Malar rash: fixed erythema, flat, raised over malar

eminences.
2- Discoid rash: erythematous raised patches with
adherent keratotic scaling and follicular plugging.
3- Photosensitivity: rash as a result of unusual reaction
to sunlight.
4- Oral ulcers: oral or nasopharyngeal painless
ulceration.
5- Arthritis: nonerosive arthritis of two or more
peripheral joints, tender, swollen, effusion.
6- Serositis: pleurisy or pericarditis or peritonitis or all.
7- Renal disorder: persistent proteinuria, cellular casts,
(RBC, Hb, granular, tubular, or mixed).

8- Neurologic disorder: seizures, psychosis.

9- Hemolytic disorder:
- With reticulocytosis or
- Leukopenia on two or more occasions or
- Lymphopenia on two or more occasions or
-Thrombocytopenia.
10- Immunologic disorder: - Positive LE cell. or
- Anti-DNA antibody or
- Anti-smooth muscle nuclear antibodies.
-Presence of antiphospholipid antibodies.
-Antinuclear antibody: abnormal titer in absence of
drugs inducing lupus syndrome.
11- Renal biopsy.

Laboratory findings:
- Elevated ANA titers: screening tool.
- Anti-double-stranded DNA are more specific and
measures degree of disease activity.
- Total hemolytic complement (CH50), C3, C4, are
decreased in active disease.
- Anti- Smith antibody.
- Hypergammaglobulinemia.

Antibodies found in SLE:

- Coombs antibodies cause hemolytic anemia.
- Antiphospholipid antibodies cause antiphospholipid
syndrome.
- Lupus anticoagulant causes coagulopathy.
- Antithyroid antibodies cause hypothyroidism.
- Antiribosomal antibodies cause lupus cerebritis.

Treatment:
- Regimen depends on affected target organs and disease
activity and severity.
- Frequent reevaluation of patients and monitoring
indefinitely.
NSADs: for arthralgia and arthritis. Watch for
hepatotoxicity.
Hydroxychloroquine: for mild manifestations, skin
lesions, fatigue, arthritis, arthralgia.
Corticosteroids: control symptoms and autoantibodies
production, improves kidney disease, but exclude
tuberculosis before treatment.
1- 1-2 mg/kg/day Prednisone oral in divided doses until
complement level increases to within normal range,dose
is tapered over 2-3 years to lowest effective dose.

Treatment:
2- Alternate-day dose of csorticosteroid.
3- Pulse intravenous corticosteroid 30mg/kg/day,
maximum1gm over 30min daily for 3days in severe
cases.
4- Intermittent steroid pulse therapy in
combination with oral low-dose daily.
5- Cytotoxic therapy in severe disease:
intravenous.
- Cyclophosphamide: maintains renal function
and prevents progression particularly with diffuse
proliferative glomerulonephritis.
- Treatment of vasculitis, pulmonary hemorrhage,
CNS disease refractory to corticosteroids.

Treatment
- Azathioprine: Can prevent renal disease progression,
causes secondary infections, gonadel dysfunction, risk of
malignancies.
- Methotrexate, cyclosporine and mycophenolate mofetil.
- Bone marrow stem cell transplantation.

Staging by renal biopsy:

- Class 1: no abnormalities on light and electron
microscopy and immunofluorescence studies.
- Class 2a: minimal immunoglobulin and complement
deposition in mesangium, good prognosis for renal
function.
- Class 2b: mesangial glomerulonephritis: increased
lymphocyte infiltration of the mesangium with variable
prognosis.

Staging by renal biopsy:

- Class 3: focal and segmental proliferative
glomerulonephritis near capillaries, necrosis and
lymphocyte infiltration, chronic renal disease.
- Class 4: diffuse proliferative glomerulonephritis:
majority of glomeruli with cellular infiltration,
mesangeal cellular proliferation, crescent
formation and scarring leads to end-stage renal
disease.
- Class 5: membranous glomerulonephritis:
thickened capillary walls, subepithelial deposits
along basement membrane associated with
proteinuria, chronic renal disease, poor response
to treatment.

* Neonatal lupus:
Lupus in newborns results from maternal transfer of IgG
autoantobodies in the 12-16 weeks gestation.
- Manifests as congenital heart block, cutaneous lesions, hepatitis,
thromocytopenia, neutropenia, pulmonary and neurologic
disease.
- At 6w of age skin lesion develops on the face and scalp lasts for 34 months. 25% develops scar.

Treatment: supportive
- Congenital heart block is permanent requires cardiac pacing even
antenatally.
- Slightly prolonged P-R intervals, cardiomyopathy is rare.

Differential diagnosis:
Infantile multisystem inflammatory disease:
-Rare, fever rash, arthropathy, chronic meningitis, seizures,
uveitis, and lymphadenopathy
-Requires long-term
immunosuppression.