CONNECTIVE TISSUE

DISEASES (1)
Dr. Nizar Abdulateef
Professor & Consultant Rheumatologist
OBJECTIVES

Describe briefly the pathophysiology, have a good idea on the clinical features,
and how to diagnose and manage patients with the following connective
tissue diseases (CTDs):
• Systemic lupus erythematosus (SLE)
• Sjogren’s syndrome (SS)
• Systemic Sclerosis (SSc)
• Mixed connective tissue disease (MCTD)
• Idiopathic inflammatory myopathies including Polymyositis (PM) &
Dermatomyositis (DM)
SYSTEMIC LUPUS ERYTHEMATOSUS
Patient

• A 24 year old woman

• Presented 2 months previously with dyspnea and chest pain.
• Initially treated as pneumonia progressed to ICU admission
• 5 seizures in ward (started on phenytoin)
• No history of medicines, allergies, family risk
• Admitted to Medical City (Baghdad Teaching Hospital) Blood tests
done, started on prednisone
On Examination

• Apyrexial, RR 18, HR 119, BP 96/70 rash on face and body

• Not anaemic, no oedema, palpable cervical LN
• CVS: tachycardia
• Resp, Abdo, neuro: normal
• Musculo-skeletal: No arthritis
Laboratory Investigations

• Hb 11 (MCV 90.6), Plt 110 000 WCC 3.6 (N61%, M4%, L35%)
• ESR 36, CRP 2.7
• Urinalysis 4+ protein, red cells and granular casts +
• ANA, Anti-Sm, Anti dsDNA, Ro, La Positive
• Low C3, C4
Other investigations

• CXR: Residual Pleural effusion, heart size normal

• ECG: normal
• Echo: pending
Introduction to SLE

• Auto-immune disorder
• Multisystem microvascular inflammation
• Formation of autoantibodies
• Chronic with relapsing and remitting course
 Skin CNS

Blood
Malar rash Neurological damage
Discoid rash Affective disorder
Lung

IFN signature
Plasma blasts
Anemia
Thrombocytopenia
Inflammation
Serum
Spleen

Anti-nuclear antibodies
Kidney
Glomerulonephr
itis
Joi fl ts Splenomegaly

Arthrlis
Pathophysiology

• Mechanism for autoantibodies:

• Defect in apoptosis, ↑cell death → disturbance in immune tolerance
• Plasma + nuclear antigens on cell surface
• Dysregulated lymphocytes target Ag (normally intracellular)
• Immune complexes formation in microvasculature → complement
activation + inflammation
• Ag-Ab complexes deposition in basement membranes of skin and
kidneys
Etiology

• Unknown
• At least 10 gene loci known to ↑ risk
• Genetic predisposition (10x monozygotic twins)
• Human leukocyte Ag: ↑ HLA-DR2, HLA-DR3 + HLA-B8
• Null complement alleles + congenital ↓complement (esp C4, C2 etc)
Epidemiology

• SLE : the most common CTD.

• Prevalence 3/10 000 in Caucasians to 20/10 000 in Afro- Caribbeans.
• 90% are women. Peak age 20-30 yrs. 5-year survival >90%.
• Mortality is usually due to organ failure or overwhelming sepsis, both
modifiable by early effective intervention. 5X increased mortality.
Premature cardiovascular disease and chronic steroids use.
History
• Constitutional - fatigue, fever, weight loss
• Skin - malar rash, photosensitive, discoid lupus, alopecia, Raynaud phenomenon, livido reticularis
• Musculoskeletal - arthralgia, myalgia, arthritis
• Renal
• Neuropsychiatric - headache, mood disorders, cognitive disorders, psychosis, seizures, TIA/ stroke,
movement disorders, mononeuritis
• Pulmonary - chest pain, dyspnoea
• Gastrointestinal - Abdominal pain, jaundice
• Cardiac - heart failure/chest pain
• Haematologic -‘cytopenias’
• Other - miscarriages
On examination
• Constitutional - lymphadenopathy, hepatosplenomegaly
• Musculoskeletal - Jaccoud arthropathy
• Dermatologic - capillaroscopy
• Renal
• Neuropsychiatric
• Cardiopulmonary - friction rubs, pulmonary embolism, Libman-Sacks
endocarditis
• GIT - peritonitis, pancreatitis, mesenteric
Rash
• Common, precipitated by UV light.
• Three types of rash: The classic butterfly facial rash (up to 20% of
patients): erythematous, raised and painful or itchy, over the cheeks
with sparing of the nasolabial folds.
• Subacute cutaneous lupus erythematosus (SCLE) rashes are migratory,
non-scarring and either annular or psoriaform.
• Discoid lupus lesions are characterised by hyperkeratosis and follicular
plugging, and may cause scarring alopecia.
• Diffuse, non-scarring alopecia may occur with active disease.
• Other skin manifestations include periungual erythema (reflecting
dilated capillary loops), vasculitis and livedo reticularis, which is also a
common feature of the antiphospholipid syndrome.
Diagnostic criteria

• American College of Rheumatology 4/11 criteria (sens 85%, specif

95%)
• Serositis - heart, lung, peritoneum Oral ulcers - painless esp palate
Arthritis - non-erosive
• Photosensitivity
Diagnostic criteria

• Blood disorders - ↓RBC (Coombs +), PLT, WCC, Lymphocytes

• Renal involvement - proteinuria /± casts ANA - titer > 1:160
• Immunologic phenomena - LE cells, anti-dsDNA Ab, anti-Sm Ab,
antiphospholipid Ab,
• Neurological disorders - seizures/ psychosis
• Malar rash - cheeks + nasal bridge
• Discoid rash - rimmed with scaling
Laboratory studies
• High clinical suspicion/ high ANA titres
• SLE Screen:
1 . FBC and diff
2. S-creatinine
3. Urinalysis with microscopy
4. Basic inflammatory markers
5. Antibodies to dsDNA
6. Complement
7. ANA subtypes (anti-Sm, Ro, La)
Autoantibody tests

• ANA - screening test (95% sensitivity) Anti-dsDNA (high specificity,

sens 30%) Anti-Sm (most specific Ab for SLE, 30% sens) Anti-Ro/anti-
La (15% in SLE, neonatal disease) Anti-ribosomal P (uncommon, assoc
lupus cerebritis) Anti-RNP (overlap)
• Anticardiolipin (antiphospholipid Ab syndrome) Lupus Anticoagulant
(antiphospholipid syndrome) Coombs test (Ab on RBC’s)
• Anti-histone (drug-induced lupus)
Radiological studies

• Joint x-rays: no erosions, periarticular osteopenia + soft tissue

swelling
• CXR/CT chest: Pleural effusion, interstitial lung disease, pneumonitis,
pulmonary emboli, alveolar hemorrhage
• CT Brain or Brain MRI ± angiography: lupus white matter changes,
vasculitis or stroke
• Echo: pericardial effusion, pulmonary hypertension or Libman-Sacks
endocarditis
Lupus nephritis
• I

• Class I - Minimal mesangial

Normal light microscopy
Abnormal electron microscopy

• Class II - Mesangial proliferative

Hypercellular on light microscopy
•Class III - Focal proliferative
<50% glomeruli involved
•Class IV - Diffuse proliferative
>50% glomeruli involved;
segmental/global
• Class V - Membranous
Predominantly nephrotic disease

• Class VI - Advanced sclerosing

Chronic lesions and sclerosis
Differential diagnosis

• Drug induced lupus erythematosis

• Vasculitis
• Leukemia
• HIV
• Multiple sclerosis
• Parvovirus or other viral infections
Treatment principles
• Depends on disease severity
• Fever, skin, musculoskeletal and serositis = milder disease
• CNS and renal involvement - aggressive Rx
• Emergencies:
- severe CNS involvement
- systemic vasculitis
- profound thrombocytopenia (TTP-like syndrome)
- rapidly progressive nephritis
- diffuse alveolar hemorrhage
Medications used

• NSAIDS
• Chloroquine
• Steroids
• Cyclophosphamide
• Azathioprine
• Mycophenolate
• Rituximab
• Plasma exchange / IVIG
Preventive care
• Medication-related (steroid) complications (Ca, vit D,
bisphosphonates)
• Aggressive BP and lipid control
• Immunization (complement deficient)
• Stress-dose steroid for patients on corticosteroids (surgery/ infection)
• Avoid UV exposure
• Avoid estrogen therapies
• Pregnancy planning
Management

• Patients with mild disease restricted to skin and joints can be

managed with analgesics and/or
• NSAIDs, + hydroxychloroquine (200-400 mg/d).
• Short courses of oral steroids for rash, synovitis, pleurisy and
pericarditis.
Management

• Life-threatening disease affecting the kidney, CNS or cardiovascular system

requires high-dose steroids and immunosuppressives.
• Pulse methylprednisolone (500 mg-1 g i.v) +cyclophosphamide (2 mg/kg i.v.), at 2-
3 weekly intervals on 6-8 occasions.
• Mycophenolate mofetil (MMF) with high dose steroids for renal involvement in
SLE have fewer adverse effects. Then switch to oral prednisolone (40-60 mg daily)
and azathioprine, methotrexate or MMF.
• Co-trimoxazole (960 mg thrice weekly) for preventing Pneumocystis pneumonia,
and mesna is given with bolus cyclophosphamide to reduce haemorrhagic
cystitis.
• Antiphospholipid syndrome who had previous thrombosis require life-long
warfarin. If repeated thromboses occur despite warfarin, the INR target should be
3.0-4.0.
Prognosis

• Benign to rapidly progressive

• Better for skin + musculoskeletal vs renal + CNS
• Death rate 3X age-general population
• Mortality
• Nephritis (most within 5 yrs of symptoms)
• Infections (active SLE + Rx - most common)
• CVS disease (50X more MI than other woman)
• Malignancy (chronic inflammation + Rx)
Summary

• Autoimmune disorder
• Multiple manifestations
• Aggressive investigation and treatment
• Continued surveillance
SJOGREN’S SYNDROME
• A 60-year-old female complains of dry mouth and a gritty sensation in
her eyes. She states it is sometimes difficult to speak for more than a
few minutes. There is no history of diabetes mellitus or neurologic
disease. The patient is on no medications.

• On exam, the buccal mucosa appears dry and the salivary glands are
enlarged bilaterally.

• What is the most likely diagnosis?

Sjögren’s syndrome

• This is an autoimmune disorder of unknown cause characterised by

lymphocytic infiltration of salivary and lachrymal glands, leading to
fibrosis and exocrine failure.
• Age of onset is between 40 and 50, 9:1 female.
• Primary or secondary to other autoimmune diseases.
Clinical features

Eye symptoms
• Keratoconjunctivitis sicca, are due to lack of lubricating tears.
• Conjunctivitis and blepharitis may lead to filamentary keratitis due to
tenacious mucous filaments binding to the cornea and conjunctiva.
Oral symptoms
• Dry mouth and typically the patient needs water to swallow food.
• Dental caries

The disease is associated with a 40-fold increased lifetime risk of lymphoma.

Investigations

• Schirmer tear test, which measures tear flow over 5 minutes using
absorbent paper strips placed on the lower eyelid; a normal result is more
than 6 mm of wetting.
• Staining with rose Bengal may show punctate epithelial abnormalities over
the area not covered by the open eyelid.
• Lip biopsy which shows focal lymphocytic infiltrate of the minor salivary
glands.
• Elevated ESR
• Hypergammaglobulinaemia
• ANA and RF
• Anti-Ro and anti-La antibodies
Management

• Treatment is symptomatic.
• Lachrymal substitutes e.g. hypromellose eye drops, viscous lubricating ointment at night.
• Soft contact lenses for corneal protection in filamentary keratitis, occlusion of the
lachrymal ducts
• Artificial saliva and oral gels
• Stimulation of saliva flow by sugar-free chewing gum or lozengesl, oral hygiene and
prompt treatment of oral candidiasis, vaginal dryness is treated with lubricants.
• Extraglandular and MSK manifestations may respond to steroids and immunosuppressive
drugs
• If lymphadenopathy or salivary gland enlargement develops, biopsy should be performed
to exclude malignancy.