What is Sweet syndrome

Sweet syndrome also called acute febrile neutrophilic dermatosis or Gomm-Button disease, is a rare recurrent and rare skin disease caused by the release of cytokines, with diverse possible etiologic causes ¹. Sweet syndrome is characterized by the onset of painful erythematous-violaceous skin lesions that appear mainly on the face, neck, back and arms ². Sweet’s syndrome is named after the English dermatologist, Dr Robert Sweet, who first described it in 1964. Sweet syndrome presents clinically with polymorphic skin lesions, fever, inflammation of the joints (arthritis) and peripheral leukocytosis (white blood cells). Sweet syndrome is a type of neutrophilic dermatoses, a group of conditions characterized by intense neutrophilic dermal infiltration without infection or vasculitis. In general, Sweet syndrome occurs idiopathically but may occur in association with pregnancy, drugs, infections and hematological malignant disease ³. Sweet syndrome usually regresses spontaneously and treatment is primarily to control the basic disease ¹. Remission of cutaneous symptoms is variable; without treatment the lesions may persist for several months or even experience spontaneous remission ¹. In case of relapse, there is strong association with malignant diseases such as cancer recurrence ².

Sweet syndrome disease is universally distributed among the races. In adults, women are more commonly affected, mainly with the idiopathic and drug-induced forms ¹. The first episode generally occurs between the ages of 30 and 50 years ⁴. Sweet syndrome cases associated with cancers, on the other hand, are equally distributed between the genders ⁴. Sweet syndrome cases described in children are rare (8% of the total), equally distributed between the genders and are preceded by three to one week by infectious diseases of the upper respiratory tract ². Only approximately 80 children have been reported in the medical literature.

Individuals with Sweet syndrome should receive a thorough clinical examination to detect any possible underlying malignancy or disorder that may be associated with Sweet syndrome, including a complete hematologic evaluation. Usually, treatment of the underlying cancer results in the resolution of symptoms in malignancy-associated Sweet syndrome. However, treatment with corticosteroids as with the classic form is often recommended.

The most common treatment for Sweet’s syndrome is corticosteroid pills, such as prednisone. Signs and symptoms often disappear just a few days after treatment begins, but recurrence is common.

Drug-induced Sweet syndrome usually goes away after the affected individual stops taking the offending medication. Treatment with corticosteroids may also be used to treat this form of Sweet syndrome.

Figure 1. Sweet syndrome rash

Footnote: A 29-year-old woman in the 20th week of her second pregnancy presented with a fever and a 2-week history of painful, itchy skin lesions that had appeared suddenly on her neck and face and had spread to her trunk and limbs. The patient had infiltrated and well circumscribed, purple-red plaques with a pustular component on her face (left) and right hand (right). She began a 2-week course of prednisone taken orally (1 mg/kg each day). The cutaneous lesions and systemic symptoms resolved, and the pregnancy continued without further problems.

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Sweet syndrome causes

In most cases, the cause of Sweet’s syndrome isn’t known. In some people, it’s triggered by an infection, illness or certain medications. Sweet’s syndrome can also occur with some types of cancer, most often leukemia and lymphoma. Occasionally, Sweet’s syndrome may be associated with a solid tumor, such as breast or colon cancer.

Sweet’s syndrome may also occur as a reaction to a medication — most commonly a type of drug that boosts production of white blood cells.

The underlying conditions that can cause Sweet syndrome:

• Classical Sweet’s syndrome occurs in over 50% of cases, especially in middle-aged women. In these cases, the symptoms of Sweet’s syndrome start after a non-specific chest or gastrointestinal infection.
• Immunologic disease is seen in around 15% of Sweet’s syndrome cases. This includes inflammatory bowel disease and connective tissue disorders such as rheumatoid arthritis.
• Cancer is seen in about 10 to 20% of Sweet’s syndrome cases. Blood-related disorders such as leukaemia and solid organ tumours (bowel, breast, or kidney cancer) are the most common cancers seen in association with Sweet’s syndrome.
• Drug-induced Sweet’s syndrome may be caused by bone-marrow cell growth factors, certain antibiotics, anti-epileptic or anti-inflammatory medications. There are many other medications known to have caused Sweet’s syndrome.
• Pregnancy is known to cause Sweet’s syndrome.
• Other reactive neutrophilic disorders are associated with Sweet’s syndrome. These conditions are characterised by lesions occurring in areas of minor skin injury (known as “pathergy”) and include conditions such as pyoderma gangrenosum.

Some researchers speculate that Sweet syndrome occurs as an allergic reaction (reactive process) to an unknown agent. In such instances, there is an oversensitive, or hypersensitivity, reaction by the immune system to a specific agent such as a bacterial or viral infection, cancer or certain type of drug.

Cytokine dysregulation may also play a role in the development of the disorder. Cytokines are specialized proteins secreted from certain immune system cells that either stimulate or inhibit the function of other immune system cells. If these cytokines malfunction, it can result in overstimulation of the immune system in response to a specific agent.

Many people with classic Sweet syndrome experience an upper respiratory infection, gastrointestinal infection, or influenza-like illness that precedes their skin lesions by one to three weeks. In women, classic Sweet syndrome may occur during pregnancy. Pregnancy-associated Sweet syndrome typically presents in the first or second trimester. There does not appear to be any fetal risk, and the syndrome may recur with subsequent pregnancies.

In some cases, classic Sweet syndrome may also be associated with autoimmune and inflammatory disorders such as inflammatory bowel disease: ulcerative colitis or Crohn’s disease.

Drug-induced Sweet syndrome develops after using certain medications, the most commonly associated drug is known as granulocyte-colony stimulating factor. This drug is used to stimulate the production of neutrophils. A wide variety of additional drugs have been associated with Sweet syndrome, although less often.

More research is necessary to determine the exact underlying mechanisms that contribute to and ultimately cause the development of Sweet syndrome.

Risk factors for Sweet syndrome

Sweet syndrome is uncommon, but certain factors increase your risk, including:

• Sex. In general, women are more likely to have Sweet’s syndrome than are men.
• Age. Though older adults and even infants can develop Sweet’s syndrome, the condition mainly affects people between the ages of 30 and 60.
• Cancer. Sweet’s syndrome is sometimes associated with cancer, most often leukemia. Sometimes, Sweet’s syndrome may be associated with a solid tumor, such as breast or colon cancer.
• Other health problems. Sweet’s syndrome may follow an upper respiratory infection, and many people report having flu-like symptoms before the rash appears. Sweet’s syndrome can also be associated with inflammatory bowel disease.
• Pregnancy. Some women develop Sweet’s syndrome during pregnancy.
• Drug sensitivity. Sweet’s syndrome may result from a sensitivity to medication. Drugs linked to Sweet’s syndrome include azathioprine (Azasan, Imuran), granulocyte colony stimulating factor, certain antibiotics and some nonsteroidal anti-inflammatory drugs.

Sweet syndrome symptoms

The main sign and symptom of Sweet’s syndrome is small red tender or painful bumps (nodules or papules) on your arms, legs, face or neck. They may also occur on the thighs and trunk. They often appear abruptly after a fever or upper respiratory infection. Papules are solid, raised lesions; nodules are slightly larger and may extend deeper into the skin. These initial lesions are usually several millimeters to centimeters in diameter, but sometimes up to an inch in diameter, flat or slightly elevated, irregularly-shaped, and inflamed. They tend to grow slowly, eventually joining together (coalescing) to form larger, irregular plaques or painful clusters. Small pus-filled blisters (pustules) may develop.

In some individuals, neutrophils may accumulated in the fatty layer of tissue just below the skin (subcutaneous fat) rather than in the dermis. Affected individuals often develop reddish (erythematous) discoloration of the skin and small bumps (nodules) on the skin. The arms and legs are most often affected.

Individuals with Sweet syndrome also experience fever, fatigue, headaches, a general feeling of ill health (malaise), muscle pain (myalgia), and inflammation and pain of the joints (arthritis and arthralgia). Fever can precede the development of skin symptoms by days or weeks.

Sweet syndrome can potentially affect most organ systems of the body. The most common organ system involved outside of the skin is the eyes. Affected individuals can develop inflammation of the conjunctiva, the delicate membrane that lines the eyes (conjunctivitis) or inflammation of the thin layer of tissue (episclera) covering the whites of the eyes (episcleritis). Less often, additional symptoms can occur including the formation of bumps on the limbus, which is the border of the cornea and the whites of the eyes (limbal nodules), glaucoma, inflammation of the iris, which is the colored portion of the eye (iritis), and inflammation and ulceration of the cornea (peripheral ulcerative keratitis).

In most individuals, Sweet syndrome occurs without any underlying disorder. In these individuals with classic Sweet syndrome, onset of the disorder usually follows an infection of the upper respiratory tract or gastrointestinal system.

Less often, Sweet syndrome is associated with a malignancy, most often a malignancy that affects the blood (hematologic malignancies), such as certain types of leukemia and, rarely, cancers of the genitourinary and gastrointestinal tracts. In some cases, individuals with malignancy-associated Sweet syndrome may have lesions affecting the mucous membranes of the mouth (oral mucosa).

Drug-induced Sweet syndrome has skin (cutaneous) symptoms are similar to those seen in the classical form.

Sweet syndrome complications

There is a risk of the skin lesions becoming infected. Follow your doctor’s recommendations for caring for the affected skin.

In cases where Sweet’s syndrome is associated with cancer, the eruptions of the lesions may be the first sign of cancer either appearing or recurring.

Sweet syndrome prognosis

The outcome of Sweet’s syndrome may be related to that of the underlying disorder if present, eg malignancy, rheumatoid arthritis etc.

With treatment, the fever and blood count usually improve within a couple of days and the rash clears within a few weeks. Some cases will clear without treatment over a number of weeks.

Recurrent episodes of Sweet’s syndrome affect about one-third of all Sweet’s syndrome cases and some will require long-term therapy.

Most areas of Sweet’s syndrome fade without permanent marks but the appearance of pigmentation (brown marks) may take several months to fade.

Sweet syndrome diagnosis

Your dermatologist might be able to diagnose Sweet’s syndrome simply by looking at the lesions. But you’re likely to have certain tests to rule out conditions that have similar symptoms and to search for the underlying cause. These tests include:

• Blood tests. A sample of your blood may be sent to a laboratory where it’s checked for an unusually large number of white blood cells and neutrophil count. Blood tests also show inflammatory markers, such as ESR (erythrocyte sedimentation rate) as being raised.
• Skin biopsy. Your doctor may remove a small piece of affected tissue for examination under a microscope. The tissue is analyzed to determine whether it has the characteristic abnormalities of Sweet’s syndrome.
• Other tests such as urine tests, bone marrow testing, cancer screening and imaging studies (x-rays, CT scans) and tests to rule out infection are sometimes needed to look for associated conditions of Sweet’s syndrome.

Sweet syndrome treatment

The treatment of Sweet syndrome is directed toward the specific symptoms that are apparent in each individual. In some cases, Sweet syndrome may resolve itself with no treatment, although this can take weeks to months. But medications can speed the process dramatically.

The most common medications used for Sweet’s syndrome are corticosteroids, which come in a variety of forms, including:

• Pills. Oral corticosteroids, such as prednisone, work very well but will affect your entire body. Unless you only have a few lesions, you’ll likely need to take oral corticosteroids. Long-term use can cause side effects, such as weight gain, insomnia and weakened bones.
• Creams or ointments. These preparations usually affect just the portion of skin where they’re applied, but can cause thinning skin.
• Injections. Another option is to inject a small amount of corticosteroid right into each lesion. This may be less feasible for people who have a great number of lesions.

In most cases, treatment with low doses of corticosteroids such as methylprednisolone or prednisone has proven effective in eliminating symptoms, sometimes rapidly resolving symptoms. However, Sweet syndrome often recurs periodically despite therapy. For isolated lesions, local therapy may consist of topical corticosteroids (creams of gels) or directly injecting corticosteroids into the lesion (intralesional corticosteroid).

Although corticosteroids are the mainstay of treatment and often effective in treating Sweet syndrome, there are no standardized treatment protocols for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with Sweet syndrome.

Sometimes other medications are prescribed for Sweet’s syndrome, usually for people who don’t tolerate long-term corticosteroid use well. Some of the more commonly prescribed medication alternatives to corticosteroids are:

• Dapsone
• Potassium iodide
• Colchicine (Colcrys, Mitigare)

A variety of additional drugs have been used to treat individuals with Sweet syndrome including cyclosporine, indomethacin and clofazimine.

The skin lesions associated with Sweet syndrome usually heal without scars, unless open sores were present (ulceration). The affected area may remain discolored for months after the lesion has resolved.

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