Jdms Case Study Guidelines


Initial Management
Patient was initially treated with polygam 2g/kg twice a week and oral steroids (meticorten) 2mg/kg daily. Physiotherapy and Occupational therapy were prescribed daily and she was assessed by a dietician for nutritional support.

Week 1-3
For the first three weeks of treatment the patient reported feeling better, with joint swelling and pain resolving. She still complained of proximal muscle weakness but this had also improved since admission.

Week 3-4
After three weeks the patient started feeling unwell again with proximal weakness worsening and unable to move from a lying to sitting position without assistance. She also started drooling excessively and was reluctant to eat.

A Barium swallow was ordered but was normal. Treatment with polygam and oral steroids was continued. Muscle biopsy was ordered with showed an inflammatory myopathy.

Week 5
Patient continues to deteriorate. Developing bulbar speech and inability to swallow.

Patient was intubated and admitted to medical ICU for intermittent positive pressure ventilation (IPPV). She was continued on treatment with polygam, also given methyl prednisone IV and 15 mg of Methotrexate sub cutaneously.

Week 6
Patient continued to deteriorate. ESR, CRP and CK levels remained elevated. She also developed pseudomembranous colitis (treated with metronidazole) and MRSA sepsis (treated with meropenem and Vancomycin). Child had a cardiac arrest and was successfully resuscitated.

Tracheostomy was placed and Rituximab therapy, a monoclonal antibody was started.

Week 8
Patient started to respond to treatment showing steady improvement, able to sit up unassisted and move arms, head and feet.

Patient was released from ICU to high care. Nerve conduction studies were done which showed a secondary axonopathy. Treatment and therapy were continued

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Evaluation – Questions & answers

What is the diagnosis?

Juvenile dermatomyositis (JDMS), which is a systemic vasculopathy affecting primarily the skin and muscles. Females are affected twice as often as males and there are typically two peak ages of onset; adults at 50 years and children at 5-10 years. This is typically a small vessel vasculitis which can also affect the GIT (especially the oesophagus), myocardium and lungs. Calcinosis is a complication that is observed most often in children or adolescents. The weakness experienced is variable. It can have a gradual onset with slowly progressive weakness or it can be catastrophic with severe weakness (or paralysis) with swallowing abnormalities and myocarditis. The prognosis depends on the severity of the myopathy, the presence of a malignancy, and/or the presence of a cardiopulmonary involvement.
Diagnosis is also based on a set of the following criteria proposed by Bohan and Peter; where the presence of three of the findings listed indicates probable myositis; four indicates myositis and diagnosis of juvenile dermatomyositis requires the skin changes mentioned in point 5 (see below).
  • Proximal muscle weakness (upper or lower extremity and trunk); typically symmetrical
  • Elevated serum creatine kinase (CK) or aldolase levels
  • Muscle biopsy showing inflammation, damage or other characteristic changes in muscle tissue
  • Myopathic changes on electromyogram (EMG)
  • Skin rash

– Heliotrope rash (reddish-purple erythema on the upper eyelids, often with oedema)
– Gottron’s sign (reddish-purple nodules on the extensor surface of finger, elbow or other joints)

What is believed to trigger the autoimmune response in dermatomyositis?

In dermatomyositis an autoimmune reaction is thought to be triggered by an initial infection with a pathogen expressing protein antigens similar in structure to a membrane protein found on capillary endothelial cells in muscle and skin. Initially a normal immune response occurs which is initiated by phagocytes such as dendritic cells that engulf the pathogen and later present the pathogen-derived peptide antigens to naive CD4+ helper T lymphocytes in the lymph node for activation.

Where is the autoimmune reaction in dermatomyositis first triggered?

A normal antibody response to a pathogen that triggers an autoimmune reaction in dermatomyositis is first initiated by follicular dendritic cells in the B cell zone of the regional lymph node. These cells trap pathogen-derived antigens on there surface and present them to naive B cells for priming.

What is a normal antigen specific B lymphocyte activation?

Primed B lymphocytes are activated in the T cell zone by previously activated CD4+ helper T lymphocytes that recognise a peptide antigen derived from the same pathogen protein as recognised by the B cell. These CD4+ helper T cells have previously been activated by dendritic cells. Activated B lymphocytes then differentiate into plasma cells that secrete antibodies that will bind to the protein on the pathogen surface. The first antibody produced in a primary immune response is always IgM but later CD4+ helper T lymphocytes can also induce isotype switching to IgG antibodies of higher affinity.

What is the normal antibody mediated destruction process of a pathogen?

Class IgM and IgG antibodies are secreted and bind to the surface of the pathogen tagging them for destruction by the innate immune system. The components of this system include classical complement activation, antibody-dependant cell cytotoxicity mediated by natural killer cells and enhanced phagocytosis.

What antibody process occurs in dermatomyositis?

In dermatomyositis these antibodies trigger similar immune attacks on capillary endothelial muscle and skin due to the recognition of the these membrane proteins by the antibodies. This is because of structural similarities between a protein on capillary endothelial cells in muscle and skin and a protein antigen derived from a pathogen. These cells provide activation signals to autoreactive B cells that orchestrate autoimmune reactions that become self-perpetuating and do not require the presence of the initial triggering pathogen.

What are the processes which are involved in destroying the capillary endothelial cells in dermatomyositis?

Bound antibodies on the surface of capillary endothelial cells in muscle and skin initiate an innate immune response which ultimately leads to destruction of these cells which include activation of the classical complement cascadeantibody-dependant cell cytotoxicity and receptor-mediated phagocytosis. In skin this immune response is characterised by a rash.

In dermatomyositis what are the effects of destruction of the muscle cell capillaries

The destruction of the capillaries in muscle leads to necrosis of the muscle fibre cells and inflammation due to lack of oxygen and nutrient supply. The necrotic muscle fibre cells then attract dendritic cells and macrophages which engulf the muscle derived intracellular antigens resulting in secondary autoimmune antibody responses to muscle-specific antigens via activation of autoimmune B cells by autoimmune CD4+ helper T lymphocytes. There is an infiltration of CD4+ helper T lymphocytes and B lymphocytes into inflamed muscle that promotes phagocytosis and antibody production.

How is autoreactive B lymphocyte activation altered in dermatomyositis?

In normal immune responses, CD4+ helper T lymphocytes would not recognise self-peptides on HLA class II receptors because they would have been deleted in the thymus. However in dermatomyositis, a breakdown in this mechanism causes autoreactive CD4+ helper T lymphocytes that are able to recognise self-peptides on HLA class II receptors to escape from the thymus. These cells are then activated by dendritic cells and later by macrophages allowing them to provide T cell help to autoreactive B cells. Activation of the B cells thus leads to the generation of autoimmune antibody secreting plasma cells and new memory cells.The autoreactive antibodies continue to bind self-antigen on capillary endothelial cells leading to ongoing muscle destruction and skin inflammation as a consequence.

What are the aims of therapy and what therapy can be initiated?

Because the autoreactive antibodies continue to bind self-antigen on capillary endothelial cells with resulting muscle destruction and skin inflammation therapy must be targeted at this process. What has appeared to be successful is Rituximab an antiCD20 monoclonal antibody which removes B lymphocytes due to aiming therapy against CD-20 receptors.

Rituximab a monoclonal antibody therapy has been shown to have five possible mechanisms of action against dermatomyositis

CD20-induced apoptosis
Classical complement activation
C3b opsonisation and phagocytosis
IgG opsonisation and phagocytosis
Antibody-dependent cell cytotoxicity by natural killer cells

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Ничего более абсурдного Сьюзан слышать еще не доводилось. Цифровая крепость - не поддающийся взлому код, он погубит агентство. - Если бы я сумел слегка модифицировать этот код, - продолжал Стратмор, - до его выхода в свет… - Он посмотрел на нее с хитрой улыбкой.

Сьюзан потребовалось всего мгновение. Стратмор сразу заметил изумление, мелькнувшее в ее глазах, и взволнованно изложил свой план: - Если бы я получил ключ, то смог бы взломать наш экземпляр Цифровой крепости и внести нужные изменения… - Черный ход, - сказала Сьюзан, мгновенно забыв о том, что Стратмор ей лгал.


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