What Is Sweet Syndrome?

Introduction¹

When you hear the word ‘sweet’ you immediately think about nice and lovely things, in addition to thinking about sweet foods and desserts. However, not everything “sweet” in life is good, because sometimes it could refer to something really bad and painful, like the sweet syndrome.

Acute febrile neutrophilic dermatosis (AFND), or sweet syndrome, is a rare skin disorder that is typically characterised by acute-onset tender plaques or nodules on the neck, face, trunk, arms, or legs, as well as fever and headaches. Sometimes it can be associated with arthralgia, ophthalmologic manifestations (eye diseases), and rarely oral or genital lesions.

Sweet syndrome was first described by the English doctor Robert Douglas Sweet in 1964, and the disorder was named after him.

Sweet syndrome causes²

The main cause of the sweet syndrome is not known, yet etiologically, there are three main triggers of it:

Classical or idiopathic

In this situation, the sweet syndrome occurs with other medical conditions like streptococcal upper respiratory infections, gastrointestinal infections, mycobacterial infections, collagen vascular disorders, immune thrombocytopenic purpura, pemphigus vulgaris, autoimmune thyroiditis, inflammatory bowel disease, Still's disease (a rare systemic inflammatory disorder), SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis), and pregnancy-associated. 

Malignancy-associated

Some cancers can be associated with sweet syndrome, especially acute myelogenous leukaemia and myelodysplastic syndrome, as well as solid organ malignancy.

Drug-induced

The most commonly associated drugs with sweet syndrome are granulocyte colony-stimulating factors (GCSFs), trans-retinoic acid, imatinib, bortezomib, oral contraceptives, and propylthiouracil. There are also some reports that suggest that there is an association between sweet syndrome and antibiotics, antiepileptics, NSAIDS (anti-inflammatory drugs), retinoids (anti-inflammatory drugs for the skin), and diuretics (increased water excretion).

Pathophysiology of sweet syndrome²

The exact pathophysiology of AFND is still unknown. However, there are some hypotheses about it:

• The dysregulation of the secretion of cytokines (proteins that help in controlling inflammation in the body) might lead to dysfunction of the apoptosis of neutrophils (a type of white blood cells that helps the immune system fight infections) after doing their job.
• A defect in the transcriptional regulation of a certain protein called PTPN6 has been found to play a role in the pathophysiology of sweet syndrome.
• Some people have certain mutations in their genes that could contribute to this condition.

Sweet syndrome symptoms³

• The sudden onset of tender or painful bumps, like papules (which are solid and raise lesions) or nodules (which are slightly larger than papules and may extend deeper into the skin), on the arms, legs, face, or neck, may also occur on the thighs and trunk. The initial lesions are inflamed, irregularly-shaped, flat, and sometimes slightly elevated, and are usually several millimetres to centimetres in diameter (sometimes up to an inch). They grow slowly, finally joining together (coalescing) to form larger, irregular plaques.
• Sometimes, neutrophils may accumulate in the fatty layer of the skin tissue (subcutaneous fat) rather than in the dermis (middle layer of skin), and that leads to a reddish discoloration of the skin.
• Fever, headaches, and fatigue.
• General feeling of tiredness and illness.
• Muscle and joint pain.
• It is common that other organs can be affected by this condition, like the eyes. It could cause inflammation in the conjunctiva or episclera, and less commonly, it could cause inflammation in the iris, glaucoma, and nodule formation on the limbus (the border of the whites and the cornea of the eyes).
• Other organs that can also be affected by sweet syndrome are: bones, brain, ears, eyes, kidneys, intestines, liver, heart, lung, mouth, muscles, and spleen, particularly when associated with a malignancy that includes a site outwith the skin, which occurs in up to 50% of reported cases or is present in patients with multiorganic affection. The most common site of these is the lungs, and the symptoms can vary between upper respiratory tract infection with flu-like symptoms in its early stages and acute respiratory distress syndrome.⁴

Sweet syndrome complications

Usually, sweet syndrome resolves without any marks or outcomes, with or without treatment. However, subcutaneous neutrophilic panniculitis can sometimes leave scars on the skin because of the demolition of the fatty tissue below the skin. In general, the patient gets affected by AFND only once, but about a third of patients may suffer from recurrent episodes, mostly in patients who have malignancy-associated sweet syndrome, and severe ulcerative cases of it may persist despite the treatment.⁵

In some cases of panniculitis, it has been noticed that there might be various localised complications, such as scarring in the case of ulcerative lesions and tissue degeneration.²

Sweet syndrome diagnosis⁴

There is no specific test or procedure to diagnose sweet syndrome; therefore, there is a diagnostic criteria that has been followed.

The criteria for classical and malignancy-associated AFND:

Major criteria

• Abrupt commencement of painful, red nodules or plaques.
• Histopathological findings of thick neutrophilic infiltrate without evidence of leukocytoclastic vasculitis.

Minor criteria

• Fever higher than 38 °C.
• Association with inflammatory disease, bloodborne internal organ malignancy, or pregnancy, or in case it is preceded by upper respiratory tract infection, gastro-intestinal infection, or vaccination.
• Great response to treatment with systemic corticosteroids or potassium iodide.
• Abnormalities in at least three of these four laboratory tests: erythrocyte sedimentation rate> 20mm/h; high C-reactive protein, leukocytes >8000, with >70% neutrophils.

In classical AFND

There must be both major criteria and at least two minor criteria in order to be diagnosed.

In malignancy-associated AFND

The patient must precede, follow, or appear concurrent with the diagnosis of the patient's neoplasm (new, abnormal growth) and classical AFND diagnostic criteria.

In drug-induced AFND

There must be all these five criteria:

• Abrupt commencement of painful erythematous nodules or plaques.
• Histopathological findings of thick neutrophilic infiltrate without evidence of leukocytoclastic vasculitis.
• Fever higher than 38 °C.
• Temporal relation between the use of the medication and clinical presentation or relapse with readministration.
• Disappearance of lesions after stopping the drug or treating the patient with corticosteroids.

Differential diagnosis of sweet syndrome¹,²

Several conditions have similar symptoms and signs to sweet syndrome, like:

• Allergic contact dermatitis
• Cellulitis
• Hypersensitivity drug reaction
• Erythema nodosum or multiforme
• Leukocytoclastic vasculitis
• Leukaemia cutis (blood cancer)
• Herpes simplex
• Behcet’s disease (rare, chronic inflammation in the body vessels)
• Cutaneous vasculitis, which includes erythema elevatum diutinum, cutaneous polyarteritis nodosa, granuloma faciale, and cockade purpura
• Wells syndrome (eosinophilic cellulitis)
• Reactive erythemas, like erythema multiforme and annular urticaria
• Granulomatous disorders like inflammatory granuloma annulare, sarcoidosis, and palisaded neutrophilic granulomatous dermatitis

Sweet syndrome treatment⁶

First-line treatment

Usually, in mild, localised cases, topical or intralesional corticosteroids may be effective. The recommended course for this situation is a dose of 0.5mg to 1mg per kg of prednisolone for 4-6 weeks. When needed, treatment with low-dose steroids may have to be continued for a longer time to prevent exacerbations, and if remission doesn’t occur after 3 months, then there must be the addition of a second-line steroid-sparing agent.

Second-line treatment

It includes dapsone, colchicine 500 mcg tds, indomethacin (an NSAID) 150 mg per day in the first week, and then 100 mg per day for two weeks, and ciclosporin.

Other drugs

These drugs have been reported to be efficacious in various studies, which are: cyclophosphamide, cyclosporine, thalidomide, clofazimine, IVIG (antibodies given by IV), and TNF-alpha antagonists (anti-inflammatory antibodies).²

FAQs

Is sweet syndrome fatal?⁷

There have been studies about different cases of sweet syndrome associated and not associated with hematologic malignancy, and the results showed that the mortality rate in the patients who have hematologic malignancy is significantly higher than the patients who don’t have it, which indicates that the cause of death is probably the hematologic malignancy, not the sweet syndrome.

How rare is sweet syndrome?⁸

This condition is very rare, and only several hundred cases have been reported. It can affect anyone, even infants and children, but it affects women more than men, usually between the ages of 30 and 50.

Is sweet syndrome leukaemia?³

Sweet syndrome is not leukaemia, but it can be associated with some malignancies, which are usually hematologic cancers like certain types of leukaemia.

Is sweet syndrome an autoimmune disease?³

Sweet syndrome is not an autoimmune disease, but it can be associated with certain autoimmune diseases like inflammatory bowel disease, for example.

Summary

Sweet syndrome is not dangerous or life-threatening; it is a dermatologic disorder that mostly happens because of an underlying condition and normally resolves with or without treatment, or when this condition is treated. So, the bottom line is that we can’t protect ourselves from getting affected by AFND because there is not a specific, known cause for it, but we can protect ourselves in general by following a healthy lifestyle, which can for sure make us more resistant to disease.