Rare diseases are serious, often chronic and progressive, diseases. There are thousands of rare diseases. To date, six to seven thousand rare diseases have been discovered and new diseases are regularly described in medical literature. The number of rare diseases also depends on the degree of specificity used when classifying the different entities/disorders. Until now, in the field of medicine, a disease is defined as an alteration of the state of health, presenting as a unique pattern of symptoms with a single treatment. Whether a pattern is considered unique depends entirely on the level of definition of our analysis.
For many rare diseases, symptoms and signs may be observed at birth or in childhood, as is the case of Hemophilia and Primary Immunodeficiencies.
HEMOPHILIA / HEMATOLOGY
Hemophilia is a congenital bleeding disorder that results in the blood failing to clot normally. It is caused by a deficiency of a protein in the blood called a clotting factor. People with hemophilia bleed easily and often excessively. Untreated, hemophilia can be life-threatening. There are two main types of hemophilia: “Hemophilia A” is the most common type and is caused by the deficiency of what is known as Clotting Factor VIII; “hemophilia B” is caused by deficiency of Clotting Factor IX.
Hemophilia occurs in about 1 in 10,000 births and it is much more common in males because it is an “X-linked” disorder. The number of affected persons worldwide is estimated to be about 400,000. Hemophilia A is more common than hemophilia B, representing 80-85% of all cases.
Hemophilia should be suspected in patients presenting with a history of:
- Easy bruising in early childhood.
- Spontaneous bleeding (bleeding for no apparent/known reason), especially into the joints, muscles, and soft tissues.
- Excessive bleeding following trauma or surgery.
A definitive diagnosis depends on a blood analysis to determine deficiency of Clotting Factor VIII or IX.
Because each type of Hemophilia requires a different therapy, accurate diagnosis is essential.
Hemophilia can be very successfully managed by simply replacing the deficient clotting factor. Therapy can be either “on demand” – the treatment of active bleeding, or “prophylactic” – regular maintenance of clotting factor levels to prevent bleeding. In developed countries where these factors are readily available, the life expectancy of males suffering from Hemophilia is essentially the same as for males in the general population.
Both clotting factors can be isolated from donated human plasma and they can also be engineered by means of recombinant DNA technology. There are many commercial brands from which to choose and that choice is generally made based on availability, access, price and on the risk of developing antibodies that render the factor ineffective.
Srivastava A. et al. Guidelines for the management of Hemophilia. Haemophilia (2012), 1–47
Mannucci PM et al. How we choose factor VIII to treat Hemophilia. Blood (2012) volume 119, number 18, 4108-4114
Von Willebrand Disease
The most common bleeding disorder is von Willebrand disease (VWD). It is congenital and caused by deficiency or abnormality in a plasma protein central to blood clotting known as the von Willebrand Factor (named after the Finnish physician who first identified the disorder).
Von Willebrand Factor (VWF) is the “glue” that helps platelets in the blood stick together with the vessel wall, to form a clot where a blood vessel has been ruptured. It also binds and stabilizes the clotting factor Factor VIII, so in patients with VWD, the lack of VWF activity results in premature elimination of Factor VIII in the circulation, thereby resulting in a dual defect in the body’s ability to stop bleeding. People with VWD produce normal amounts of Factor VIII, but with deficient VWF the clotting factor does not stay in the system long enough to adequately carry out its function, as in patients with type 1 and III VWD.
There are three generally recognized forms of the disease:
- Type I: The most common and mildest form of Von Willebrand Disease. Levels of von Willebrand Factor are lower than normal, and levels of Factor VIII may also be reduced.
- Type II: In this form of Von Willebrand Disease, there is normal and sufficient Von Willebrand Factor but it is abnormal and does not work properly. The abnormality in the factor can vary and accordingly there are several subtypes of Type II Von Willebrand Disease – important to determine because treatment varies with the subtype.
- Type III: The most severe form of Von Willebrand Disease in which VWF is nearly or completely absent along with very low levels of Factor VIII.
People with Von Willebrand Disease can bruise easily; suffer frequent nosebleeds that can be difficult to stop; have heavy menstrual bleeding; and experience heavier and longer than normal bleeding after injury, surgery, childbirth, or dental work. In its most severe form, it can lead to spontaneous joint and organ bleeding and can be life-threatening.
Some patients respond favorably to injection of desmopressin acetate (DDAVP) but the most effective treatment and prophylaxis for VWD – especially in its more severe forms – is therapy with plasma-derived Von Willebrand Factor products.
Federici AB. Classification and clinical aspects of von Willebrand disease. In: Textbook of Haemophilia 2nd Edition, Lee CA, Berntorp E, Hoots K (eds). Oxford: Wiley-Blackwell 2010. 302–308
IMMUNOLOGY / NEUROLOGY
Immune System Disorders
Disorders of the Immune System fall generally in three categories:
- Overactive or inappropriate immune response.
- Deficient immune response.
- Autoimmune (self-attacking) response.
Asthma and allergies are examples of an overactive immune system reacting to a non-threatening foreign substance.
Immune deficiencies (Immunodeficiencies) and autoimmune disorders are generally more serious and can be life-altering.
When one of the parts of the immune system is missing or does not work well, we say that the immune system is deficient. Most often this involves missing or defective T- or B-lymphoctyes or inadequate production of antibodies. The result is that the body is vulnerable to infections that might otherwise be easily defeated.
Immunodeficiencies can be “Primary”, i.e., present at birth and usually genetic, or “Secondary”. Secondary Immunodeficiencies have many causes, including disease, malnutrition, aging, certain medications, chemo- and radiation therapy, and stress. Probably the most well-known cause of immunodeficiency, though not the most common, is the Human Immunodeficiency Virus (HIV), which can cause AIDS (Acquired Immune Deficiency Syndrome).
There are some 185 Primary Immunodeficiencies recognized by the World Health Organization. Most common are those involving the production of antibodies and are called Primary Antibody Deficiencies (PAD’s). These disorders vary greatly in their underlying defects, but many of them can be managed and their symptoms mitigated by regular infusions of Immunoglobulin.
Kedrion’s ongoing research and development has resulted in several Immunoglobulin therapies for these conditions. Replacement therapy with Immunoglobulin in Primary Antibody Deficiencies increases life expectancy and reduces infection frequency and severity.
Abbas K. et al. “Le basi dell’Immunologia. Fisiopatologia del sistema immunitario”. Ed. Masson Elsevier 2006.
The human body can sometimes become its own worst enemy. For reasons still not fully understood the human immune system can lose some of its ability for distinguishing between self and non-self and begin attacking normal healthy cells in the body. This is a condition known as Autoimmune Disease.
There are many Autoimmune Diseases that affect millions of people and their incidence seems to be growing worldwide.
The following Autoimmune Diseases are ones for which intravenous Immunoglobulin (IVIg) therapy is indicated and approved:
- Idiopathic Thrombocytopenic Purpura (ITP). Also known as Immune Thrombocytopenic Purpura or Autoimmune Thrombocytopenic Purpura, ITP is an autoimmune bleeding disorder resulting when the immune system attacks its own blood platelets, which are important to the clotting process. For reasons not well understood, lymphocytes produce antibodies that attach to the platelets, which then do not clot effectively and are subsequently recognized as “foreign” and destroyed in the spleen. Frequent and abnormal bleeding is typical and often results in many small bruises that can look like a rash (purpura).
Children are generally affected with an acute form of the disorder that resolves spontaneously in a few months while in adults it is usually a chronic condition requiring long term treatment. The disease is rare, with an incidence of 3 cases per 100,000 inhabitants per year in those aged under 16 years and 1.6 to 2.68 cases per 100,000 inhabitants per year in adults, with a slight female preponderance.
Navarro RP et al.; Considerations for the Optimal Use of Immunoglobulin. Am J Manag Care. 2012;18:S67-S78
Abrahamson PE. The incidence of idiopathic thrombocytopenic purpura among adults: a population-based study and literature review. Eur J Haematol..2009 Aug;83(2):83-9
- Kawasaki Disease. Also known as Mucocutaneous Lymph Node Syndrome, is a form of vasculitis characterized by inflammation of blood vessels throughout the body. It primarily affects children under the age of five (and rarely over the age of eight). With proper treatment the prognosis for these children is good, but without treatment about a quarter of them will develop cardiac problems, including coronary artery aneurysms. Kawasaki Disease has become the leading cause of acquired heart disease in children in the developed world. The cause of Kawasaki Disease is still unknown with researchers divided on whether it is an infection or an autoimmune response, but effective treatment includes Primarily Intravenous Immunoglobulin.
Uehara R, Belay ED. “Epidemiology of Kawasaki disease in Asia, Europe, and the United States” J Epidemiol 2012; 22 (2): 79-85
Takahashi K et al.; Pathogenesis of Kawasaki disease. Clinical and Experimental Immunology, 2011; 164 (Suppl. 1): 20–22
Newburger JW. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics. 2004;114:1708–1733
This is a rare (affecting just 1-2 people in 100,000) Autoimmune Disease in which the immune system attacks the myelin or outer covering of nerves (and sometimes the nerves themselves) of the Peripheral Nervous System. The damage leads to tingling and weakness in the legs and can proceed to even life-threatening paralysis.
Symptoms generally reach their most severe within days or weeks when they stabilize for a period of days, weeks or even months. Most people recover from even the most severe cases, but recovery can take as little as a few weeks or as much as a few years. The cause of the autoimmune response is unknown but it is sometimes triggered by infection, surgery or vaccination.
One treatment for Guillain-Barré syndrome that can reduce symptoms and hasten recovery is high dose Immunoglobulin therapy.
Chronic Inflammatory Demyelinating Polyneuropathy
CIDP can be thought of us a chronic form of the Autoimmune Disorder Guillain-Barré syndrome caused by demyelination of peripheral nerves, resulting in loss of sensation, motor weakness, and sensory symptoms.
Its estimated prevalence ranges from 0.8 to 8.4 per 100,000 people. CIDP is often disabling with over 50% of patients having temporary disability and about 10% eventually becoming persistently disabled or dying because of the disease.
The cause of CIDP remains unknown, but there are data supporting an immune pathogenesis. Plasmapheresis (plasma exchange), oral corticosteroids and Intravenous Immunoglobulin (IVIg) therapy are effective treatments, but should be started early to avoid permanent nerve damage.
Pithadia AB et al.; Guillain-Barre syndrome (GBS). Pharmacological Report 2010; 62: 220 – 232
Köller H et al.; Chronic inflammatory demyelinating polyneuropathy. N Engl J Med.2005 Mar 31;352(13):1343-56
Mahdi-Rogers M et al.; Overview of the pathogenesis and treatment of chronic inflammatory demyelinating polyneuropathy with intravenous immunoglobulins. Biologics. 2010 Mar 24;4:45-9
E. Nobile Orazio. Intravenous immunoglobulin versus intravenous methylprednisolone for chronic inflammatory demyelinating polyradiculoneuropathy: a randomised controlled trial. Lancet Neurol 2012; 11 (6): 493-502