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Flashcards in Autoimmune Diseases Deck (73):

What is myasthenia gravis?

Myasthenia gravis is an autoimmune condition that affects the nerves and muscles, and causes certain muscles to become weak (mainly voluntarily controlled muscles)


What are the symptoms of myasthenia gravis?

  • Progressive weakness and fatigability of striated muscles
  • Proximal muscles are most often affected and weakness in ocular muscles results in ptosis and diplopia.
  • Associated symptoms include depressed or absent reflexes and decreasing amplitude of responses on repetitive nerve stimulation.


When is Myasthenia Gravis most commonly seen?

MG can occur at any age, but is most commonly seen in women during the third and fourth decades and in middle-aged men.


What does an injection of edrophonium cause in a patient with Myasthenia Gravis?

Injection of edrophonium causes a transient resolution of symptoms.


What is Myasthenia Gravis associated with?

It is associated with other autoimmune disorders and hyperthyroidism.


What is the differential diagnosis for Myasthenia Gravis?

Lambert-Eaton myasthenic syndrome (LEMS)


How do autoantibodies cause Myasthenia Gravis?

  • Blocking ACh receptors
  • Degrading ACh receptors


What is edrophonium?

Short acting acetylcholinesterase inhibitor


Describe the pathophysiology of Myasthenia Gravis

Antibodies block and degrade the AChRs

This causes a reduction in the number of AChRs available at the muscle endplate and flattening of the postsynaptic folds.

Consequently, even if a normal amount of ACh is released, fewer endplate potentials will be produced, and they may fall below the threshold value for generation of an action potential.

The end result of this process is inefficient neuromuscular transmission.


What causes the fatigability seen in Myasthenia Gravis?

Inefficient neuromuscular transmission together with the normally present presynaptic rundown phenomenon results in a progressive decrease in a number of nerve fibres being activated by successive nerve fibre impulses. This explains the fatigability seen in MG patients.


How much do the number of AChRs need to reduce by for a patient with Myasthenia Gravis to become symptomatic?



What are the mechanisms for Myasthenia Gravis?

  • Cross-linking 2 adjacent AChRs with anti-AChR antibody, thus accelerating internalization and degradation of AChR molecules
  • Causing complement-mediated destruction of junctional folds of the postsynaptic membrane
  • Blocking the binding of ACh to AChR
  • Decreasing the number of AChRs at the NMJ by damaging the junctional folds on the postsynaptic membrane, thereby reducing the surface area available for insertion of newly synthesized AChRs


What is seronegative Myasthenia Gravis?

Patients without anti-AChR antibodies are recognized as having seronegative MG (SNMG).


What causes seronegative Myasthenia Gravis?

Many patients with SNMG have antibodies against muscle-specific kinase (MuSK).

MuSK plays a critical role in postsynaptic differentiation and clustering of AChRs. Patients with anti-MuSK antibodies are predominantly female, and respiratory and bulbar muscles are frequently involved.

Another group has reported patients who exhibit prominent neck, shoulder, and respiratory weakness


What is the role of the thymus in the pathogenesis of Myasthenia Gravis?

The role of the thymus in the pathogenesis of MG is not entirely clear, but histopathologic studies have shown prominent germinal centers.

Epithelial myoid cells normally present in the thymus do resemble skeletal muscle cells and possess AChRs on their surface membrane.

These cells may become antigenic and unleash an autoimmune attack on the muscular endplate AChRs by molecular mimicry.


How many patients with Myasthenia Gravis have some degree of thymus abnormality?



How can Myasthenia Gravis be diagnosed?

  • A rapid diagnosis can be made with the edrophonium (Tensilon) test. This fast-acting acetylcholinesterase inhibitor will cause a transient resolution of symptoms in the myasthenic patient.
  • Repetitive nerve stimulation tests will demonstrate a characteristic decrement of evoked potential amplitude.
  • Antibody tests can confirm the diagnosis and are used to follow treatment response. Eighty percent of patients with general myasthenia have ACh receptor antibodies and 40% of patients without them have antibodies to muscle-specific kinase (anti-MuSK).


How can Myasthenia Gravis be treated?

Acetylcholinesterase inhibitors (pyridostigmine) are first-line treatment.

These medications inhibit the enzyme that degrades ACh (acetylcholinesterase) and allow ACh to build up in the neuromuscular junction. Because of associated thymic abnormalities (thymic hyperplasia or thymoma), thymectomy is a common intervention early in generalized MG.

If symptoms persist, immunosuppressive therapy is initiated, primarily with corticosteroids and immunosuppressants.


What is Myasthenic Crisis?

Myasthenic crisis is a serious complication characterized by severe weakness and respiratory and pharyngeal muscle paresis leading to respiratory failure.

It can be spontaneous or occur after an infection or surgical stress.


How is Myasthenic Crisis treated?

  • Early elective intubation
  • Withdrawal of anticholinergic medication
  • Plasmapheresis or intravenous immunoglobulin


What is Scleroderma?

Scleroderma is a long term autoimmune disease that results in hardening of the skin. In the more severe form, it also affects internal organs.


What are the types of Scleroderma?

Localised Scleroderma - only affects the skin 

  • Two types: Linear and Morphoea

Systemic Sclerosis

  • Two types: Limited and Diffuse


What are the symptoms of Localised Morphoea?

  • Discoloured oval patches on the skin
  • Can appear anywhere on the body
  • Usually itchy
  • Patches may be hairless and shiny (may improve after a few years and treatment may not be needed)


What are the symptoms of Localised Linear Scleroderma?

  • Thickened skin occurs in lines along the face, scalp, legs or arms
  • Occasionally affects underlying bone and muscle
  • May improve after a few years, although can cause permanent growth problems, such as shortened limb


What are the symptoms of Limited Systemic Sclerosis?

  • A milder form that only affects skin on the hands, lower arms, feet, lower legs and face, although it can eventually affect the lungs and digestive system too
  • Often starts as Raynaud's phenomenon (a circulation problem where fingers and toes turn white in the cold) other typical symptoms include thickening of the skin over the hands, feet and face, red spots on the skin, hard lumps under the skin, heartburn and problems swallowing (dysphagia)
  • Tends to get gradually worse over time, although it's generally less severe than diffuse systemic sclerosis and can often be controlled with treatment


What are the symptoms of Diffuse Systemic Sclerosis?

More likely to affect internal organs

Skin changes can affect the whole body

Other symptoms can include:

  • weight loss
  • fatigue
  • joint pain
  • stiffness

Symptoms come on suddenly and get worse quickly over the first few years, but then the condition normally settles and the skin may gradually improve


How is Scleroderma diagnosed?

Physical Examination

Blood Tests - ANA by indirect immunofluorescence.


What are the limited symptoms of scleroderma known as?

CREST syndrome


Who is scleroderma most common in?

This disease most commonly affects women age 30-50 years.


What is the prevalence of Scleroderma?

The prevalence of this disease is 240 cases per million people and has been increasing due to earlier detection and longer patient survival after diagnosis.


Describe the pathogenesis of scleroderma

Symptoms in scleroderma are the result of progressive tissue fibrosis and occlusion of microvasculature resulting from excessive production and deposition of type I and type III collagen from activated fibroblasts.


What causes scleroderma?

While the etiology of this pathology is unknown, studies point to a combination of environmental risk factors such as viruses or toxin exposure and genetic factors such as production of Scl-70 antibodies and expression of MHC haplotypes DQ7 and DR2.


What are the risk factors associated with Scleroderma?

  • Viruses
  • Toxin exposure
  • Genetic factors
    •  production of Scl-70 antibodies
    • expression of MHC haplotypes DQ7 and DR2.


What is seen in 90% of scleroderma patients?

Positive ANA by indirect immunofluorescence.


What antibodies are associated with scleroderma?

  • Anti-topoisomerase I (Scl 70) antibody is (about 20% of cases)
  • Anti-RNA polymerase III antibody (about 20% of cases)
  • Anti-centromere antibodies (20% to 25% of cases)

The remaining 40% have scleroderma but do not have an as-yet-identified scleroderma-specific autoantibody.


What is Scl 70 antibody associated with?

Anti-topoisomerase I (Scl 70) antibody is seen in about 20% of cases and is associated with an increased risk of interstitial lung disease and with diffuse skin involvement


What is Anti-RNA polymerase III antibody associated with?

Anti-RNA polymerase III antibody (also about 20% of cases) is associated with renal crisis


What are Anti-centromere antibodies associated with?

Anti-centromere antibodies (20% to 25% of cases) are associated with limited skin involvement and a better overall prognosis


Describe the pathophysiology of scleroderma

The precise pathophysiology is unknown, but many models have been postulated.

Early in the course of the disease, immune system activation, endothelial-cell activation and damage, and fibroblast activation all occur.

Selection and activation of a hyper-proliferative fibroblast subpopulation is also implicated. These cells, which produce high levels of collagen, are over-represented in scleroderma.


How does the activation of the immune system affect sclerosis?

The activation of the immune system is of paramount importance in the pathogenesis of systemic sclerosis.

Antigen-activated T cells promote disease activity by infiltrating the skin and producing pro-fibrotic cytokines.

A diverse variety of cytokines is capable of inducing, in vitro, the scleroderma fibroblast phenotype of enhanced proliferation and synthetic function.


What profibrotic cytokines cause fibrosis in scleroderma?

  • Transforming growth factor-beta (TGF-beta)
  • Interleukin-4 (IL-4)
  • Platelet-derived growth factor (PDGF)
  • Connective-tissue growth factor.


What causes vasculopathy in scleroderma?

Vasculopathy may be linked to TGF-beta and PDGF, and antiendothelial cell autoantibodies.


How is scleroderma managed?

Treatment of symptoms:

  • Arthralgias: paracetamol or nonsteroidal antiinflammatory drugs
  • Myositis: glucocorticoids (first choice), methotrexate, and azathioprine
  • Pruritus: moisturizers, histamine 1(H1)- and histamine2 (H2)- blockers, tricyclic antidepressants
  • Pulmonary fibrosis: cyclophosphamide 
  • Raynaud's phenomenon: calcium channel blockers, prazosin, reserpine, or topical nitrates; cervical sympathectomy is reserved for severe cases -
  • Renal hypertension: angiotensin-converting enzyme inhibitors 
  • Skin changes: D-penicillamine or methotrexate


What is pemphigus?

Pemphigus is a rare group of blistering autoimmune diseases that affect the skin and mucous membranes


What is Nikolsky's sign?

When pressure is applied to the skin with a sliding motion, the skin rubs off


What are the different types of pemphigus?

  • Pemphigus vulgaris
  • Pemphigus foliaceous
  • Paraneoplastic pemphigus.


What is the most common form of pemphigus?

Pemphigus vulgaris


How is pemphigus characterised?

Pemphigus is characterized by shallow, painful erosions and blisters that easily rupture with friction or pressure. Mucosal surfaces are also frequently involved


Describe the pathophysiology of pemphigus

Blisters in pemphigus vulgaris are associated with the binding of IgG autoantibodies to keratinocyte cell surface desmosomal proteins desmoglein 1 and desmoglein 3.

These antibodies bind to keratinocyte desmosomes and to desmosome-free areas of the keratinocyte cell membrane.

The binding of autoantibodies results in a loss of cell-to-cell adhesion, a process termed acantholysis. The antibody alone is capable of causing blistering without complement or inflammatory cells.


What are desmosomes?

Desmosomes are highly organised intercellular junctions which mediate strong adhesion between cells. In addition to these adhesive functions, desmosomal components are also involved in signal transduction pathways and epidermal organisation


What autoantibodies are seen in the mucocutaneous form of pemphigus vulgaris?

Pathogenic antidesmoglein 1 and antidesmoglein 3 autoantibodies.


What autoantibodies are seen in the mucosal form of pemphigus vulgaris?

Antidesmoglein 3 autoantibodies only


What autoantibodies to patients with active pemphigus vulgaris have?

Patients with active disease have circulating and tissue-bound autoantibodies of both the immunoglobulin G1 (IgG1) and immunoglobulin G4 (IgG4) subclasses.


How many patients with active pemphigus produce autoantibodies to desmoglein?

More than 80%


Describe the correlation between autoantibodies and disease activity in patients with pemphigus

Disease activity correlates with antibody titers in most patients.

In patients with pemphigus vulgaris, the presence of antidesmoglein 1 autoantibodies, is more closely correlated with the course of the disease compared with antidesmoglein 3 autoantibodies.

Lack of in vivo antibody binding (reversion to a negative result on direct immunofluorescence) is the best indicator of remission and can help predict a lack of flaring when therapy is tapered


How is pemphigus diagnosed?

To diagnose pemphigus, a skin biopsy must be done to demonstrate anti-desmoglein autoantibodies by direct immunofluorescence on the skin biopsy. These antibodies appear as IgG deposits along the desmosomes between epidermal cells, a pattern reminiscent of chicken wire.

Acantholysis may also be seen (individual keratinocytes are detached and free floating).

Anti-desmoglein antibodies can also be detected in a blood sample using the ELISA technique.

Increased serum levels of antibodies to desmoglein 1 and 3 correlate with disease activity


How is pemphigus treated?

Treatment of this disease requires oral steroids. Oral steroids must be continued to prevent recurrence of the disease.

Other agents such as azathioprine or cyclophosphamide may be used in conjunction with steroids to decrease the steroid dose and lessen the side effects related to high-dose steroids.

Mycophenolate mofetil is becoming more widely used as a steroid-sparing agent, but there is limited data supporting its use.

In severe cases, plasmapheresis may be required. The lesions should be treated as burns are treated.


What is pemphigoid?

Pemphigoid is a rare autoimmune disorder that can develop at any age, but that most often affects the elderly.

Pemphigoid is caused by a malfunction of the immune system and results in skin rashes and blistering on the legs, arms, and abdomen


When is pemphigoid most commonly seen?

In people aged 60 and older.


What are the symptoms of pemphigoid?

The disease is characterized by prodromal erythematous papules that develop into large, tense blisters filled with serous to bloody fluid.

The collapsed bullae leave deep erosions and crusts.

The condition is often more pruritic than painful, and the mucous membranes are rarely involved.

Nikolsky’s sign (separation of the outer layer of the epiderms when lateral pressure is applied to the skin) is negative.


How is pemphigoid diagnosed?

The diagnosis of Bullous pemphigoid is confirmed by immunostaining a skin biopsy specimen.

The immunostain in Bullous pemphigoid reveals fluorescence at the dermal-epidermal junction


What is the difference between pemphigus and pemphigoid?

Pemphigoid produces a split in the cells where the epidermis and the dermis (the layer below the epidermis) meet, causing deep, tense (taut or rigid) blisters that do not break easily. Direct immunofluorescence studies show a linear band of immunoglobulin G deposit along the dermal-epidermal junction

Pemphigus, on the other hand, causes a separation within the epidermis, and the blisters are soft, limp, and easily broken. Direct immunofluorescence using an anti-IgG antibody shows intercellular IgG deposits in the epidermis and the early intraepidermal vesicle caused by acantholysis.


Describe the pathophysiology of pemphigoid

Autoantibodies are directed against 2 hemidesmosomal proteins, designated BP180 and BP230.

Bullous pemphigoid autoantibodies (with the help of complement activation), the infiltration of inflammatory cells, and the release of proteases and various inflammatory mediators, including cytokines, are essential for lesion formation.


What are hemidesmosomes?

Hemidesmosomes are protein complexes that mediate the stable attachment of basal cells to the underlying basement membrane in epithelial tissues, such as the skin.

Hemidesmosomes contain at least 5 components which include bullous pemphigoid antigens BP230 (BPAg1) and BP180 (BPAg2)


What is immunodominance?

Immunodominance is the immunological phenomenon in which immune responses are mounted against only a few of the antigenic peptides out of the many produced.


Which part of the BP180 protein in the hemidesmosomes is most immunodominant?

The non-collagenous 16A domain that encompasses 76 amino acids and localises directly adjacent to the transmembrane region has been identified as an immunodominant region of the BP180 ectodomain.


Which autoantibody is thought to be responsible for bullous pemphigoid?



What is the function of BP180NC16A in Bullous Pemphigoid?

In most bullous pemphigoid sera, circulating antibodies to BP180NC16A are detected with serum levels correlating with disease activity.

Bullous pemphigoid autoantibodies (with the help of complement activation), the infiltration of inflammatory cells, and the release of proteases and various inflammatory mediators, including cytokines, are essential for lesion formation.

Studies revealed that antihuman BP180NC16A antibodies and neutrophils are responsible for this tissue injury.


What evidence is there to show that antibodies against BP180 cause pemphigoid?

Using an IgG passive transfer approach, there exists in vivo evidence that rabbit antibodies directed against the murine BP180NC16A homologue are pathogenic in mice.

These in vitro and in vivo data demonstrate that antibodies specific for the BP180NC16A domain are pathogenic.

It is clear that the binding of anti-BP180 antibody to its target is the critical first step in sub-epidermal blister formation in bullous pemphigoid.


Why does eosinophilia occur in bullous pemphigoid?

Bullous pemphigoid often provokes blood and tissue eosinophilia, which suggests chemoattractants may modulate the eosinophil infiltration.

Eotaxin and interleukin (IL)-5 are strongly associated with the tissue eosinophilia of bullous pemphigoid.

These findings suggest that eotaxin and IL-5 may be important for eosinophil migration in bullous pemphigoid lesions and that therapies that aim to inhibit production of eotaxin and IL-5 may improve inflammation and blister formation


How is bullous pemphigoid treated?

For mild cases, topical steroids may be used.

More severe cases may require systemic steroid therapy.

Systemic steroid-sparing agents such as azathioprine, mycophenolate mofetil, cyclophosphamide, or methotrexate may be used in combination with oral prednisone.

For patients who are unable to tolerate systemic steroids, azathioprine, dapsone, or tetracycline plus nicotinamide may be used.


Is bullous pemphigoid chronic or acute?



How does the course of bullous pemphigoid progress?

Because of the chronic nature of bullous pemphigoid, patients often require long-term use of immunosuppressant agents.

Disease recurrence is common