Urticaria Pigmentosa (UP)

Last updated: 9 July 2009.

Introduction

Urticaria PigmentosaUrticaria Pigmentosa (UP) is a rare disease that affects the skin and occasionally other parts of the body. UP is a type of mastocytosis (also known as mastocytoma), which affects a sub-type of immune cells known as mast cells. UP is characterised by skin lesions and itching. Click here for more information. (UP) is a rare disease that affects the skin and occasionally other parts of the body. UP is a type of mastocytosis (also known as mastocytoma), which affects a sub-type of immune cells known as mast cells. UP is characterised by skin lesions and itching. Hives may form if the skin lesions are rubbed or stroked.

Incidence

The exact number of affected individuals with Urticaria PigmentosaUrticaria Pigmentosa (UP) is a rare disease that affects the skin and occasionally other parts of the body. UP is a type of mastocytosis (also known as mastocytoma), which affects a sub-type of immune cells known as mast cells. UP is characterised by skin lesions and itching. Click here for more information. is unknown. It has been estimated that mastocytosis, of which UP is the most common sub-type, is present in 1 in 1000 to 1 in 8000 individuals who attend a dermatologyDermatology is the branch of medicine encompassing the study of skin, diseases of the skin and the relationship of cutaneous lesions to systemic disease. clinic. The disease is more common in children than in adults. Childhood UP usually resolves or becomes less severe before adulthood. Conversely, adults with UP may develop a more aggressive form of the disease with a prolonged clinical course and systemic involvement. Men are slightly more frequently affected by UP than women. Also, UP is more common in Caucasians compared with other races.

Causes

Urticaria PigmentosaUrticaria Pigmentosa (UP) is a rare disease that affects the skin and occasionally other parts of the body. UP is a type of mastocytosis (also known as mastocytoma), which affects a sub-type of immune cells known as mast cells. UP is characterised by skin lesions and itching. Click here for more information. is caused by an excess of inflammatory mast cells, which are made in the bone marrow and help fight infections. Mast cells, when activated, release a compound called histamine, which causes swelling, itchiness and redness in the affected area. It is not known what causes the excess of mast cells that characterises UP, but environmental triggers have been identified that activate mast cells and cause symptoms associated with UP. These include:

• Stress;
• Heat or cold;
• Venoms, such as bee stings;
• Certain foods, such as lobster, crayfish, cheese, hot beverages and spicy foods;
• Alcohol; and
• Certain drugs, such as narcotics and quinine.

Symptoms

Urticaria PigmentosaUrticaria Pigmentosa (UP) is a rare disease that affects the skin and occasionally other parts of the body. UP is a type of mastocytosis (also known as mastocytoma), which affects a sub-type of immune cells known as mast cells. UP is characterised by skin lesions and itching. Click here for more information. can affect any part of the skin, but usually involves the trunk. Limbs and face may be affected, but rarely so. The size of the lesions can range from 1 mm to several centimeters.

On the skin, UP may appear as

• Brown patches;
• Itchy rashes;
• Hives or welts may arise if the lesions are rubbed or scratched. This phenomenon is known as the Darier sign and the presence of Darier sign may aid in the diagnosis of mastocytosis;
• Blister formation; and/or
• Flushing of the face.

Rarely, if other parts of the body are involved, UP can cause:

• Diarrhoea;
• Fast heart rate;
• Fainting due to low blood pressure; or
• Very rarely, with systemic involvement, severe allergic reaction and death.

It should be noted that the systemic symptoms mentioned above are very rare in individuals diagnosed with UP, but may occur with other forms of mastocytosis, such as aggressive systemic mastocytosis.

Diagnosis of UP is based on the appearance of the skin, the presence of the Darier sign, elevated levels of urine histamine and skin biopsy that confirms the presence of increased numbers of mast cells.

Treatments

Identifying and avoiding the environmental triggers may be sufficient in preventing the symptoms of mild forms of Urticaria PigmentosaUrticaria Pigmentosa (UP) is a rare disease that affects the skin and occasionally other parts of the body. UP is a type of mastocytosis (also known as mastocytoma), which affects a sub-type of immune cells known as mast cells. UP is characterised by skin lesions and itching. Click here for more information.. If treatment is required, as in the more severe cases, the following options are available:

• Antihistamines;
• Mast cell stabilizers, such as Disodium cromoglicate;
• Low-dose aspirin may help, although in some cases, exacerbations can occur;
• Photochemotherapy;
• Topical steroids;
• Interferon therapy; and/or
• Imatinib.

The immune therapies (interferon and Imatinib) are reserved for individuals with severe forms of UP with systemic involvement.

Introduction

Urticaria Pigmentosa (UP) is a rare disease that affects the skin and rarely other organ systems. UP is a form of cutaneous mastocytosis, a condition characterised by mast cell hyperplasia. Mast cells are formed in the bone marrow from pluripotent stem cells, under the influence of stem cell factor (SCF). SCF aids mast cell proliferation and survival. Mast cells are the primary effector cells in immunoglobulin E (IgE) mediated inflammatory reactions. They have been implicated both in innate and acquired immune responses. Mastocytosis is characterised by a pathological accumulation of mast cells and associated symptoms. In addition to the skin, the bone marrow, liver, spleen, lymph nodes, or the gastrointestinal tract may be affected in rare cases of UP.

Epidemiology and prevalence

The exact number of affected individuals with Urticaria Pigmentosa is unknown. UP is, however, rare in the general population. It has been estimated that mastocytosis, of which UP is the most common sub-type, is present in 1 in 1000 to 1 in 8000 individuals who attend a dermatology clinic. Although UP can occur at any age, the disease is more common in children than in adults. About 75% of cases occur during infancy or early childhood. Incidence peaks again in mid-adulthood (30 to 49 years).

Childhood-onset UP usually resolves or becomes less severe before adulthood. Conversely, adult-onset UP may develop a more aggressive form of the disease with a prolonged clinical course and systemic involvement. Men are slightly more frequently affected by UP than women. Also, UP is more common in Caucasians compared with other races.

Clinical features

Urticaria Pigmentosa usually appears as macules in infancy, in the first few months after birth. The macules are yellow-tan to red-brown in colour, with the trunk almost selectively affected. The limbs, face and scalp are usually spared. The macules, after the onset of UP, become widespread in a symmetrical fashion. The skin lesions may remain small and freckle-like, or may evolve into nodules, papules or plaques. Blisters and bullae can occur in children. When the lesions are rubbed or scratched, welt or hives formation can occur locally. This is known as the Darier sign and is useful in the diagnosis of UP and other mastocytotic disorders. In terms of size, the skin lesions can range from 1 mm to several centimeters. Flushing can occur spontaneously following mild skin trauma. Itching is another common symptom associated with UP. About 50% of childhood-onset UP resolves before childhood, whilst the remainder of individuals usually experiences a decrease in symptoms as they reach adulthood. In adults, UP may develop for the first time or may recur after episodes in childhood. Adult-onset UP is characterised by a varying number of lesions, which are itchy and can be unsightly. In adults, UP is usually a chronic condition and other organ systems may be involved. Rarely, some adults may develop telangiectasia eruptive macularis perstans (TEMP). TEMP is associated with red macules that overlie dilated capillaries (i.e. telangiectasia).

Adult-onset UP may lead to systemic involvement and about 85% of individuals with all forms of systemic mastocytosis have UP as a characteristic feature. About 15 – 30% of adults with skin lesions have extra-cutaneous symptoms. Headache and itching are common symptoms. Involvement of the vasculature can lead to palpitations, lightheadedness (due to hypotension) and syncope. If the gastrointestinal system is affected, nausea, vomiting, abdominal pain, diarrhoea, gastritis and peptic ulcers can occur. Hepatomegaly and splenomegaly with mast cell infiltration is often present. Lymphadenopathy is present in some cases. Involvement of the bone marrow can lead to fractures, anaemia and osteoporosis.

UP is diagnosed based on findings from history and physical examination. The presence of the Darier sign may aid in the diagnosis but a skin biopsy is often required to confirm the diagnosis. Dermal mast cell infiltrates are seen histologically, especially in the papillary dermis. The presence of mast cell granules using the Giemsa stain or toluidine blue stain confirms the diagnosis of UP. In nodular UP, mast cells are present in dense aggregates and may extend into the subcutaneous tissue. Biochemical testing, including urinary histamine levels can be used as a diagnostic modality. Also, total tryptase level, a marker of mast cell degranulation, is elevated in UP lesions in patients with systemic involvement. Complete blood count may be helpful in revealing anaemia and other blood disorders. A bone marrow biopsy may be indicated in patients with hepatomegaly, splenomegaly, or lymphadenopathy, to rule out associated haematological disorders. A bone scan or gastrointestinal imaging may be helpful if relevant symptoms are present in patients with UP.

Aetiology and pathogenesis

Urticaria Pigmentosa is caused by an excess of inflammatory mast cells, which are made in the bone marrow and help fight infections. Mast cells, when activated, release histamine, which causes swelling, pruritis and redness in the affected area. It is not known what causes the excess of mast cells that characterises UP, but environmental triggers have been identified that activate mast cells and cause symptoms associated with UP. These include:

• Stress;
• Physical stimuli, such as heat or cold, exercise and sunlight;
• Venoms, such as bee stings;
• Certain foods, such as lobster, crayfish, cheese, hot beverages and spicy foods;
• Alcohol; and
• Certain drugs, such as narcotics and quinine.

The mechanisms involved in the pathogenesis of UP is not known. Increased mast cell growth factors in skin lesions of UP are thought to stimulate mast cell proliferation, melanocyte proliferation and the production of melanin pigment. The hyperpigmentation associated with UP can be attributed to melanocyte proliferation and melanin production. It has been hypothesized that BCL-2, a protein that prevents apoptosis, is upregulated in patients with UP and other forms of mastocytosis, leading to a reduction in mast cell apoptosis. Mutations in the proto-oncogene, KIT, which encodes a cytokine receptor that binds to stem cell factor and allows mast cell proliferation and survival, have been identified in patients with UP. The precise role of these mutations in the disease process is not clear. Interleukin-6 is elevated in patients with UP and is correlated with the severity of the condition. The systemic involvement of UP is thought to be mediated by mast cell-derived modulators, such as histamine and prostaglandins. Mast cell infiltration can also explain the development of extra-cutaneous symptoms.

Prevention

The precise causes of Urticaria Pigmentosa are unknown and, therefore, the disease cannot be prevented or cured. It is, however, possible to identify factors that may trigger UP and to circumvent them. Certain foods, physical exertion and stress are potential triggers in exacerbating UP and these should be avoided. Lesions should not be rubbed or scratched, as this may cause hives. In rare cases, where anaphylactic reactions can occur, patients need to be educated about symptoms and treatments, including the use of injectable adrenaline (also known as epinephrine), or EpiPen, where necessary. If extra-cutaneous involvement is present, it is important to regularly review the progress of the condition.

Treatment

Histamine H1 antagonists can be used to relieve urticaria, pruritis and flushing associated with Urticaria Pigmentosa. Histamine H2 antagonists are used to treat hyperacidity that may occur in patients with UP. As not all mast cells have H1 receptors, H2 antagonists can also relieve cutaneous symptoms. For anaphylaxis, both H1 and H2 antagonists need to be used. In the rare, but severe, possibility of anaphylaxis, a medical alert bracelet must be worn and an injectable adrenaline (epinephrine) solution should be carried at all times. A similar course of action is needed if circulatory collapse and shock occurs.

Mast cell stabilizers, such as Disodium cromoglicate, inhibit mast cell degranulation following exposure to specific antigens. These agents improve diarrhoea, abdominal pain, headaches and bone pain associated with UP. Several weeks of treatment may be needed before improvement in symptoms is noticed.

Paradoxically, low-dose aspirin has been shown to be of benefit in some patients with UP. Treatment with low-dose aspirin is usually restricted to patients with vascular collapse who are unresponsive to H1 and H2 antagonists, as aspirin has the potential to cause degranulation of mast cells and worsen the symptoms.

High potency topical steroids may offer transient relief from symptoms, especially with pruritis. The lesions, however, invariably tend to recur. For severe UP with systemic involvement, systemic steroids may be necessary.

Photochemotherapy, or PUVA, utilizes long wave UVA radiation (340 - 400 nm) for the treatment of UP. Irradiated skin shows a reduction in mast cells. Two to three treatments are required each week for several months. PUVA reduces the severity of pruritis and improves the appearance of skin lesions. Recurrence is likely to occur within 12 months and further PUVA therapy may be necessary.

More recently, interferon therapy and Imatinib have been used in the treatment of severe UP with systemic manifestations. The long-term efficacy of these treatments is not known.

Prognosis

The prognosis of Urticaria Pigmentosa depends on the age of onset. UP generally begins during infancy or early childhood. The prognosis of childhood-onset UP is good, with resolution of the disease, or marked improvement in symptoms before adulthood. If UP begins in late-childhood or during adulthood, the prognosis is poor, as the disease tends to be persistent with systemic involvement. Haematological malignancies are a severe, but remote, possibility.

References

• Alto, W A & Clarcq, L (1999). ‘Cutaneous and systemic manifestations of mastocytosis’. American Family Physician, Vol 59(11), pp. 3059-3060.
• Ben-Amitai, D, Metzker, A, Cohen, H A (2005). ‘Paediatric Cutaneous Mastocytosis: A Review of 180 Patients’. The Israel Medical Association Journal, Vol 7, pp. 320-322.
• Carter, M C & Metcalfe, D D "Chapter 150. Biology of Mast Cells and the Mastocytosis Syndromes" (Chapter). In Wolff, K, Goldsmith, L A, Katz, S I, Gilchrest, B, Paller, A S & Leffell, D J: Fitzpatrick's Dermatology in General Medicine, 7th Edition: online.
• Dermnetnz.org (2006). Urticaria Pigmentosa. [Online]. Available online. [Accessed 08/12/2008].
• emedicine.com (2008) Mastocytosis. [Online]. Available online. [Accessed 08/12/2008].
• nlm.nih.gov (2008) Urticaria Pigmentosa. [Online]. Available online. [Accessed 08/12/2008].
• Ritambhra, H M & Tahlan, A (2001). ‘Urticaria Pigmentosa’. Indian Journal of Dermatology, Venereology and Leprology, Vol 67(1), pp. 33-34.
• Simon, J C, Pfieger, D & Schopf, E (2000). ‘Recent advances in phototherapy’. European Journal of Dermatology, Vol 10(8), pp. 642-645.
• Slavkovic-Jovanovic, M, Jovanovic, D, Petrovic, A & Mihailovic, D (2008). ‘Utricaria Pigmentosa: a case report’. ACTA Dermatovenereologica APA, Vol 17(2), pp. 79-82.

Online Resources:

• Urticaria Pigmentosa – an article from DermNet New Zealand
• Patient Information handout on Mastocytosis from the American Academy of Family Physicians
• Information on Urticaria Pigmentosa from the Royal Children’s Hospital, Melbourne, Australia
• MastoKids.Org contains links to various resources and support groups
• Information for Caregivers from the Mastocytosis Society

Online Associations:

• MastoKids.Org – A support group for parents and caregivers of children with UP and mastocytosis
• The UK Mastocytosis Support Group
• Mastocytosis Support Forum, Canada