Photomedicine

Urticaria Pigmentosa (UP)

Snapshot
Other common terms: UP
ICD-10 classification: Q82.2
Prevalence: Rare, exact prevalence is unknown but it is more common in Caucasians
Causes: Excess of inflammatory mast cells due to an unknown cause; mast cells trigger histamine in the affected area. Environmental factors may trigger symptoms.
Symptoms: Swelling, itchiness and a rash on the skin. May present as brown patches, hives, welts, rashes, blisters or facial flushing. Diarrhea, low blood pressure and an increased heart rate may present in certain cases.
Treatments/cures: Avoidance of causes. Anti-histamines, mast cell stabilizers and topical steroids. Immune therapies and photochemotherapy in extreme cases.
Differential diagnosis: Physical urticaria
Urticaria 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. 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. Hives may form if the skin lesions are rubbed or stroked. In addition to the skin, the bone marrow, liver, spleen, lymph nodes, or the gastrointestinal tract may be affected in rare cases of UP.

Incidence

The exact number of affected individuals with urticaria pigmentosa is unknown, but the disease is rare. 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. 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 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 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 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;
  • 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.

Cellular involvement in urticaria pigmentosa

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.

Symptoms

Urticaria pigmentosa can affect any part of the skin, but usually involves the trunk. Urticaria pigmentosa usually appears as lesions (macules), yellow-tan to red-brown in colour, with the trunk almost selectively affected. Limbs and face may be affected, but rarely so. The size of the lesions can range from 1 mm to several centimeters. Once UP becomes widespread, the lesions become symmetrical. On the skin, UP may appear as
  • Freckle like brown patches;
  • Nodules (lumps), papules or plaques
  • 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:
  • Diarrhea;
  • Fast heart rate;
  • Fainting due to low blood pressure; or
  • Rarely, some adults may develop telangiectasia eruptive macularis perstans (TEMP). TEMP is associated with red macules that overlie dilated capillaries (i.e. telangiectasia).

Systemic involvement

In adults UP can cause systemic involvement, severe allergic reaction and, rarely, death. 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. 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.

Darier sign

When the lesions are rubbed or scratched, welt or hives formation can occur on the skin. This is known as the Darier sign and is useful in the diagnosis of UP and other mastocytotic disorders.

Diagnosis

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 pigmentosa. If treatment is required, as in the more severe cases, the following options are available:
  • Antihistamines, with H1 angtagonists used to relieve skin symptoms, itching and flushing and H2 antagonists used to treat hyperacidity that may occur in patients with UP. 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.
  • Low-dose aspirin may help, although in some cases, exacerbations can occur. 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.
  • 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.Topical steroids;
  • 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.
Recently, immune therapies (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.

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 (beyond the skin) involvement is present, it is important to regularly review the progress of the condition.

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.
  • 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.

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Snapshot
Other common terms: VZV, chickenpox (varicella), shingles (herpes zoster)
ICD-10 classification: B01, B02
Prevalence: Very common with up to 1,500:100,000 reported.
Causes: Airborne transmission
Symptoms: Incubation period (2 weeks): fever, general malaise, abdominal pain, headache. Followed by skin lesions; a rash which eventually crust and heal.
Treatments/cures: No known cure. Treatment is generally avoided except in extreme cases. Relief of rash is mainstay of treatment.
Skin lesion (chickenpox) from VZV infection
Skin lesion (chickenpox) from VZV infection
The varicella zoster virus (VZV) is the cause of chickenpox (varicella), and shingles (herpes zoster). Varicella occurs as the primary infection, more commonly in childhood but can occur in adulthood. Herpes zoster is a result of reactivation of latent infection of nerve ganglia. The rate of infection is currently trending downwards with the introduction of a varicella zoster virus vaccine. Prognosis of the primary infection is generally good except in some instances. Patients who acquire the infection in adulthood have a higher mortality risk. Patients who are immunocompromised are also at risk. A developing foetus may acquire congenital problems if a primary infection occurs during pregnancy. Neonatal infections may also result in chronic complications.

Incidence

VZV infection was quite common prior to the introduction of the vaccine in 1995. Incidence rates of 1,500-1,600 per 100,000 have been reported in the USA. Since the introduction of the vaccine, reported incidence rates have markedly decreased. Where varicella was the principal problem, the hospitalization rate was 2.3-6.3: 100,000. The case-fatality rate was reported as 0.8 per 100,000 in children aged 1-4 years, and 21.3 per 100,000 in adults aged more than 20 years. A separate series reports a mortality rate of 9.22 per 100,000 consultations related to varicella. However, adults accounted for 81% of deaths despite representing only 19% of consultations. The majority of primary infections occur in children. While adults are less likely to acquire varicella, adults who do acquire the infection have a higher mortality rate. Current post-vaccine surveillance data is available from the Department of Health and Ageing (with the exception of the Australian Capital Territory, Victoria, and New South Wales). A total of 1,514 cases of varicella were reported in 2006. The highest incidence rates of varicella were 93.4:100,000 in the Northern Territory, and 48.9:100,000 in South Australia (Department of Health and Ageing, 2006). The highest incidence occurred in children aged 0-4 years (120:100,000). The overall Australian incidence was not available. A total of 1,052 cases of herpes zoster were reported in the same year. The overall rate was 5.2:100,000. Similarly, the highest rates were in South Australia (40.2: 100,000) and Northern Territory (38.7:100,000) (Department of Health and Ageing, 2006). Surveillance data prior to the introduction of the varicella vaccine in Australia is unavailable.

Causes

Skin lesion (chickenpox) from VZV infection
Skin lesion (chickenpox) from VZV infection
The main route of VZV infection is airborne transmission. In addition, direct contact may also transmit the virus. Unfortunately, even without the characteristic skin problems, a patient can still produce and spread the virus. The prodrome of varicella (non-specific symptoms such as fever and general malaise) gives little clue as to the proceeding illness. As such, preventing transmission can be difficult. Herpes zoster is a reactivation of latent VZV infection. The risk of reactivation increases with age. In addition, reactivation is associated with immune compromise. HIV infection, bone marrow disease, or immune-suppressing medications may all predispose to reactivation and severe complications. However, reactivation may also occur randomly with no discernible cause. VZV belongs to the family of herpesviruses and specifically the alphaherpesviruses. Their genome consists of double-stranded deoxyribonucleic acid (DNA) within an icosahedral nucleocapsid. The outermost layer is a lipid membrane. This confers a susceptibility to environmental factors such as heat, and detergents or solvents. Transmission between hosts usually occurs via inhalation of aerosols containing varicella zoster virus. Transmission via direct contact is less frequent but may also occur. VZV is hypothesized to be spread via leukocytes in the lymphatic system. People with obvious varicella are advised to remain at home to minimize spread of the virus. It is advised that patients not attend their usual occupation until a crust has formed over the initial lesions. Virus shedding is minimized once this has occurred. The virions first spread to local lymph nodes, where a primary viraemia occurs. The virus then infects other leukocytes and hepatocytes before producing a secondary viraemia to infect mucous membranes and skin epithelia. The time up to this point is considered to be the incubation period, which lasts approximately 14 days. Infection of the skin epithelia results in the characteristic lesions seen in varicella. Transmission of the virus is actually possible before the onset of these lesions. Following this, the virus forms a latent infection within nerve ganglia. Viral replication occurs within host cells. The virus binds to proteins on the surface of cells which induces its entry into host cells; the receptors used by VZV to facilitate cellular entry have not been identified. The host’s cellular mechanisms are then utilized to reproduce new viruses. Both humoral and cellular immunity is important in containing the infection. In immunocompromised patients, severe complications of VZV are more likely to occur

Symptoms

Skin lesion (shingles) from VZV infection
Skin lesion (shingles) from VZV infection
The incubation period of VZV is approximately 14 days, during which the patient may experience a number of non-specific symptoms such as:
  • Fever
  • General malaise
  • Abdominal pain
  • Headache
Following these symptoms, the characteristic skin lesions evolve, beginning with a macular rash, progressing to vesicles, which rupture and form hard crusts that eventually heal. Ulcerated lesions are often painful. These lesions typically develop around the entire body, but are concentrated centrally on the trunk. Lymphadenopathy is also seen. These lesions occur throughout the body, but are more concentrated around the trunk than the limbs. While this pattern is suggestive of varicella, abnormal distributions may occur. Complications of varicella include secondary bacterial infection, transient hepatitis, respiratory and neurological involvement, haemorrhagic complications, and nephritis. Congenital varicella syndrome may also occur. Patients with neurological complications may have cerebral signs, cerebellar signs, or a combination of both. Signs of meningitis such as photophobia, headache, and neck stiffness may also occur. Congenital varicella syndrome is characterized by microcephaly, limb hypoplasia, cutaneous defects, hypopigmented skin, and autonomic neuropathy. Herpes zoster: The skin lesions that occur in herpes zoster are similar to those in varicella. However, because reactivation of the virus typically occurs from one particular ganglion, the lesions occur in the distribution of a specific dermatome. The typical prodromal symptoms of fever and general tiredness may or may not be evident. However, pain in the same distribution as the skin lesions is likely, and may last even after the lesions have healed. Complications of herpes zoster include postherpetic neuralgia, and neurological involvement. Approximately 9% of patient with herpes zoster develop postherpetic neuralgia, which is characterised by pain persisting for long periods of time despite resolution of skin lesions. Only 0.2-0.5% of patients have neurological involvement; the majority recover without permanent impairment.

Treatments

Treatment for VZV infection is generally not required. However, guanosine analogues (such as acyclovir) are available. These are generally used in certain cases such as in immunocompromised patients, or in patients in whom severe infection or complications have developed. Passive immunization is also available. Immunoglobulin (antibodies) against VZV is administered to patients who are at risk of developing serious complications. This immunoglobulin is pre-formed and thus works even for immunocompromised patients. Treatment of immunocompromised adults with varicella with acyclovir does not improve skin healing rates, but can significantly reduced visceral complications. Acyclovir 10mg/kg for 7-10 days has been recommended. Administration via intravenous route over eight hours is preferred. The mainstay of treatment for VZV infection is prevention. A live attenuated vaccine was introduced in 1995. This vaccine has markedly reduced the rate of varicella. In addition, complication and mortality rates have also decreased. A similar vaccine is also available to prevent herpes zoster. Treatment is required for all patients with herpes zoster. The following regimens are recommended by Therapeutic Guidelines Ltd. (2004):
Drug Dose (oral) Frequency (Duration of 7 days)
Acyclovir 20mg/kg for children Five times daily
Acyclovir 800mg for adults Five times daily
Famiciclovir 250mg 8 hourly
Valacylovir 1000mg 8 hourly

Prevention

Individuals at high risk (e.g. pregnant women, immunocompromised individuals) should avoid patients with active disease. Children who acquired varicella should stay at home until the skin lesions have healed or crusted.

Vaccination

Active immunization:

Skin lesion (chickenpox) from VZV infection
Skin lesion (chickenpox) from VZV infection
A live-attenuated vaccine for the prevention of varicella is currently available. This vaccine works by mimicking a viral infection; the strain used is not as virulent, and does do not cause disease readily. The body is still able to recognize the foreign components of the virus, and develop an immune response and long term immunity against it. In Australia, it is recommended that newborns receive the vaccine between the ages of 12-15 months, followed by a second immunization at 4-6 years. Older children and adults who have not received the vaccine and have not previously been infected are advised to obtain the vaccine, unless there is a specific contraindication. The vaccine is available for free in Australia for those who fit the eligibility criteria (Department of Health and Ageing, 2008):
  • All children born on or after 1 May 2004 at 18 months of age
  • A one year cohort of children aged between 10 and 13 years who have not received varicella vaccine and who have not had the disease – commencement date and specific age group varies between States and Territories
The vaccine has been reported by Seward et al. (2002) to reduce mortality rates in America from 2.7-4.2:100,000 to 0.6-1.5:100,000. Other authors also support the cost-effectives of providing vaccination during infancy (Scuffham et al., 1999). Contraindications to the varicella vaccine include (Zimmerman, 1996):
  • Immuno-compromised individuals – Patients with HIV infection – Patients undergoing immunosuppressive therapy (such as high dose corticosteroid) – Patients with congenital immune deficiencies
  • Individuals with a history of anaphylaxis
  • Pregnancy
  • Untreated tuberculosis
A similar vaccine is also available for prevention of herpes zoster (reactivation of latent VZV). This vaccine is similar to the varicella vaccine, but has a higher dose of live virus. It has been shown to reduce reactivation of latent VZV (Holcomb & Weinberg, 2006). Where reactivation occurs, the rate of post-herpetic neuralgia was reduced. In addition to the contraindications listed above for the varicella vaccine, the herpes zoster vaccine should not be given to children as it has a higher viral load.

Passive immunization:

Administration of intravenous immunoglobulin against VZV is sometimes used for immunocompromised patients who have been exposed to VZV. Active immunization (i.e. live attenuated vaccine) is contraindicated in these cases as the patient would be unable to mount an adequate immune response, and may in fact develop an infection instead.

Prognosis

The mortality and morbidity rates of VZV infection have been significantly reduced since the introduction of the live attenuated vaccine in 1995. However, significant complications may still occur. Primary infection in adulthood holds a poorer prognosis than childhood infection. Higher mortality rates have been reported (Rawson, 2001). Data on the rate of severe complications is limited. A German study estimated severe complications to occur at 8.5 per 100,000 cases (Ziebold et al., 2001). Of 119 cases in the study, neurologic complications occurred in 73 children (61.3%), infectious complications occurred in 46 children (38.6%). Only eight patients reported long term complications; six due to infectious causes, and two due to neurologic complications (Ziebold et al., 2001). Immunocompromised patients have much poorer prognosis. The rate of developing congenital varicella syndrome is low. In a cohort of 362 women (15 with herpes zoster, and 347 with primary VZV infection), only one case of definite congenital varicella and two foetal deaths were documented (Harger et al., 2002). The incidence of herpes zoster increases with age. Incidence ranges from 4.2 per 1,000 person-years (age group 50-59) to 10.7 per 1,000 person-years (age group ?80) (Yawn et al., 2007). The most common complication of herpes zoster is associated pain and post-herpetic neuralgia. On average, 18% of patients may experience pain for more than 30 days. Again, this proportion increases with age Yawn et al., 2007). Other complications include ocular complications (4%), and neurological complications (3%). Less than 1% develop disseminated infection (Yawn et al., 2007).

References

  • Arvin, A M (1996). ‘Varicella-zoster virus’. Clinical microbiology reviews, 9(3), 361-381. Available online.[Accessed on 9/12/2008].
  • Balfour, H H Jr, McMonigal, K A & Bean, B (1983). ‘Acyclovir therapy of varicella-zoster virus infections in immunocompromised patients’. Journal of Antimicrobial Chemotherapy, 12(B), 169-179. Abstract available online [Accessed on 9/12/2008].
  • Department of Health and Ageing (2006). Australia’s notifiable diseases status, 2006: Annual report of the National Notifiable Diseases Surveillance System – Results: Vaccine preventable diseases. Communicable Diseases Intelligence, 3(2). Available online. [Accessed on 9/12/2008].
  • Department of Health and Ageing (2008). Varicella (chickenpox) vaccination program – common questions & answers for providers [Online]. [Accessed on 9/12/2008, no longer online].
  • Harger, J H, et al. (2002). ‘Frequency of congenital varicella syndrome in a prospective cohort of 347 pregnant women.’ Obstetrics & Gynecology, 100, 260-265. Available online. [Accessed on 9/12/2008. Link no longer active.].
  • Holcomb, K & Weinberg, J M (2006). ‘A novel vaccine (Zostavax) to prevent herpes zoster and postherpetic neuralgia’. Journal of Drugs in Dermatology, 5(9), 863-866. Abstract available online. [Accessed on 10/12/2008].
  • Marin, M, Meissner, H C & Seward, J F (2008). ‘Varicella prevention in the United States: A review of successes and challenges’. Pediatrics, 122(3), 744-751. Available online. [Accessed on 9/12/2008].
  • Rawson, H, Crampin, A & Noah, N (2001). ‘Deaths from chickenpox in England and Wales 1995-7: Analysis of routine mortality data.’ British Medical Journal, 323, 1091-1093. Abstract available online. [Accessed on 9/11/2008].
  • Scuffham, P A, Lowin, A V & Burgess, M A (1999). ‘The cost-effectiveness of varicella vaccine programs for Australia’. Vaccine, 18(5-6), 407-415. Abstract available online [Accessed on 9/12/2008].
  • Seward, J F, Watson, B M, Peterson, C L, Mascola, L, Pelosi, J W & Zhang, J X (2002). ‘Varicella disease after introduction of varicella vaccine in the United States, 1995-2000’. Journal of the American Medical Association, 287(5), 606-611. Abstract available online. [Accessed on 9/11/2008].
  • Spear, P G & Straus, S E (2007). ‘Alphaherpesviruses: Herpex simple virus and varicella-zoster virus’. Schaecter’s Mechanisms of Microbial Disease. 406-414. Lippincott Williams & Wilkins.
  • Therapeutic Guidelines Ltd. (2004). Infectious diseases. Therapeutic Guidelines: Dermatology 2nd Edition. 201-220. Therapeutic Guidelines Limited.
  • Yawn, B P, Saddier, P, Wollan, P C, StSauver, J L, Kurland, M J & Sy, L S (2007). ‘A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction’. Mayo Clinic Proceedings, 82, 1341-1349. [Accessed on 10/12/2008]
  • Ziebold, C, von Kries, R, Lang, R, Weigl, J & Schmitt, H J (2001). ‘Severe complications of varicella in previously healthy children in Germany: A 1-year survey’. Pediatrics, 108(5), e79. Available online. [Accessed on 10/12/2008]
  • Zimmerman, R K (1996). ‘Varicella vaccine: Rationale and indications for use’. American Family Physician [Online]. [Accessed on 10/12/2008, no longer online].

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Snapshot

Other common terms:UP
ICD-10 classification:  Q82.2
Prevalence: Rare, exact prevalence is unknown but it is more common in Caucasians
Causes: Excess of inflammatory mast cells due to an unknown cause; mast cells trigger histamine in the affected area. Environmental factors may trigger symptoms.
Symptoms:Swelling, itchiness and a rash on the skin. May present as brown patches, hives, welts, rashes, blisters or facial flushing. Diarrhea, low blood pressure and an increased heart rate may present in certain cases.
Treatments/cures:  Avoidance of causes. Anti-histamines, mast cell stabilizers and topical steroids. Immune therapies and photochemotherapy in extreme cases.
Differential diagnosis:  Physical urticaria

Urticaria 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. 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.

Hives may form if the skin lesions are rubbed or stroked. In addition to the skin, the bone marrow, liver, spleen, lymph nodes, or the gastrointestinal tract may be affected in rare cases of UP.

Incidence

The exact number of affected individuals with urticaria pigmentosa is unknown, but the disease is rare. 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. 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 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 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 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;
  • 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.
 

Cellular involvement in urticaria pigmentosa

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.

Symptoms

Urticaria pigmentosa can affect any part of the skin, but usually involves the trunk. Urticaria pigmentosa usually appears as lesions (macules), yellow-tan to red-brown in colour, with the trunk almost selectively affected. Limbs and face may be affected, but rarely so. The size of the lesions can range from 1 mm to several centimeters. Once UP becomes widespread, the lesions become symmetrical.

On the skin, UP may appear as

  • Freckle like brown patches;
  • Nodules (lumps), papules or plaques
  • 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:

  • Diarrhea;
  • Fast heart rate;
  • Fainting due to low blood pressure; or
  • Rarely, some adults may develop telangiectasia eruptive macularis perstans (TEMP). TEMP is associated with red macules that overlie dilated capillaries (i.e. telangiectasia).

Systemic involvement

In adults UP can cause systemic involvement, severe allergic reaction and, rarely, death. 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.

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.

 

Darier sign

When the lesions are rubbed or scratched, welt or hives formation can occur on the skin. This is known as the Darier sign and is useful in the diagnosis of UP and other mastocytotic disorders.

Diagnosis

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 pigmentosa. If treatment is required, as in the more severe cases, the following options are available:

  • Antihistamines, with H1 angtagonists used to relieve skin symptoms, itching and flushing and H2 antagonists used to treat hyperacidity that may occur in patients with UP. 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.
  • Low-dose aspirin may help, although in some cases, exacerbations can occur. 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.
  • 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.Topical steroids;
  • 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.

Recently, immune therapies (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.

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 (beyond the skin) involvement is present, it is important to regularly review the progress of the condition.

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.
  • 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.
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