What causes Sweet’s syndrome?
Autoinflammatory conditions such as Sweet’s syndrome are caused by errors in the innate immune system. However, Sweet’s syndrome itself is still a poorly understood condition, but specific causes, i.e. what happens in the body that leads to the symptoms of Sweet’s syndrome, may include hypersensitivity reaction, cytokine dysregulation and genetic susceptibility.
1. Hypersensitivity reaction.
In some people with Sweet’s syndrome, the innate immune system (a part of the immune system that doesn’t produce antibodies) can be hypersensitive and over-react to the presence of infectious, inflammatory, drug, or tumour cell antigens – antigens are proteins or substances that a part of your immune system called the adaptive immune system sees as a foreign invader and produces antibodies in response to (Bhat et al, 2015: 257; Kasirye et al, 2011: 135). This means that the presence of antigens associated with certain health conditions and medications could potentially trigger Sweet’s syndrome by causing the innate immune system to activate inflammatory cells, particularly white blood cells called neutrophils (Gosheger et al, 2002: 70). This then leads to the symptoms of Sweet’s syndrome.
Potential triggers for Sweet’s syndrome include:
- Cancer and blood disorders (malignancy-associated or paraneoplastic) in 15-20% of cases, e.g. solid tumours, and myelodysplastic syndrome which may progress to acute myeloid leukaemia (Chen et al, 2016).
- Infection, particularly upper respiratory tract and gastrointestinal infection (Cohen, 2007).
- Inflammatory bowel disease, e.g. Crohn’s disease and ulcerative colitis.
- Autoimmune conditions, e.g. rheumatoid arthritis and systemic lupus erythematosus (Ibid).
- Medications (drug-induced) in up to 5% of cases.
- Vaccination. This is so rare (only 10 cases have been reported in medical literature in the past 42 years) that a definite connection has not been established in all cases. Also, as infection is a much more common trigger for Sweet’s syndrome than vaccination, you may be more likely to develop Sweet’s syndrome as a result of not having your vaccinations than having them.
Other potential yet very poorly understood triggers for Sweet’s syndrome include:
- Pregnancy (pregnancy-associated) in up to 2% of cases. This is probably associated with hormonal changes, but further research is required. On very rare occasions, Sweet’s syndrome can also be triggered by contraception – levonorgestrel/ethinyl estradiol (Triphasil) and levonorgestrel-releasing intrauterine system (Mirena) (Cohen, 2007).
- Skin damage. When the skin is damaged or irritated, this can sometimes trigger the development of skin lesions, and this is known as pathergy. Potential irritants can even include natural products such as arnica cream (Shenefelt, 2011).
- Overexposure to sunlight or ultraviolet (UV) light. This can sometimes trigger Sweet’s syndrome, but we are not entirely sure why this happens.
Overall, in up to 71% of cases, there is no known trigger or underlying condition in Sweet’s syndrome (Tam and Ingraffea, 2015). This is referred to as idiopathic or Classical (idiopathic) Sweet’s syndrome. However, Resende et al (2016) state that it is only in up to 50% that there is no known trigger, but one of the reasons that these figures may vary is because in some countries, Sweet’s syndrome is more likely to develop secondary to infection (Ginarte and Toribio, 2011:120).
Cytokines are proteins and molecular messengers and part of the body’s immune system. The overproduction or inappropriate production of cytokines (cytokine dysregulation) can result in disease. Cytokines involved in Sweet’s syndrome include:
Endogenous granulocyte colony-stimulating factor.
- Endogenous G-CSF is a cytokine that is produced by the body, and is associated with an increased white blood cell count and skin lesions in Sweet’s syndrome patients (Ozlem et al, 2011: 1975).
- Research shows that patients with active Sweet’s syndrome have higher G-CSF levels than those whose disease is inactive, and G-CSF therapy (a treatment that helps you make more white blood cells) can trigger Sweet’s syndrome (Ginarte and Toribio, 2011; Kawakami et al, 2004; Paydas, 2013: 87).
- An increased production of G-CSF caused by cancer cells has been suggested as a potential factor in malignancy-associated Sweet’s syndrome (Foster et al, 2005: 145, 148).
- Granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon gamma, and interleukins (IL-) 1, 2, 3, 6, and 8 can play a role in Sweet’s syndrome (Bhat et al, 2015: 527; Ginarte and Toribio, 2011; Kumar et al, 2004; Paydas, 2013: 87).
- Increased levels of IL-6 have been linked to fever and pain in patients (Ozlem et al, 2011: 1975).
- IL-6 may play a role in Sweet’s syndrome that has developed secondary to the autoimmune disease systemic lupus erythematosus. This is due to IL-6 and other cytokines being a factor in both conditions (Barton et al, 2011: 5).
3. Genetic susceptibility.
Sweet’s syndrome is not a genetic condition, but may be associated with certain genes and abnormalities. These include:
The genetic marker HLA-B54.
HLA-B54 is sometimes found in those with Sweet’s syndrome, but is rare in the similar condition Behcet’s disease (Hisanaga et al, 1999). The frequency of HLA-B54 is higher in Japanese (17.9%) compared with white (0.6%) or black (0%) populations and suggests a genetic predisposition among the Japanese for Sweet’s syndrome (Bellus and Stumpf, 2003).
Please note that not everyone with the HLA-B54 genetic marker will develop Sweet’s syndrome, and it is possible to develop Sweet’s syndrome even if you don’t have this marker.
Abnormalities in chromosome 3q.
Structural abnormalities in chromosome 3q in bone marrow cells of two patients with Sweet’s syndrome and myelodysplastic syndrome or acute myeloid leukaemia (Billstrom et al, 1990).
Protein tyrosine phosphatase non-receptor type 6 (PTPN6) gene.
A mutation in the protein tyrosine phosphatase non-receptor type 6 (PTPN6) gene has been linked to some types of neutrophilic dermatoses, including Sweet’s syndrome (Gurung and Kanneganti, 2016; Li et al, 2015: 341).
Possible MEFV gene mutation.
Possibly MEFV gene mutation causing Sweet’s syndrome in patients who have developed their condition secondary to myelodysplastic syndromes (Jo et al, 2015 ). However, there is some debate concerning whether or not this is accurate, and Koné-Paut et al have argued that this theory as ‘premature or even misleading’ (Koné-Paut et al, 2015). MEFV mutations are also the cause for the autoinflammatory condition familial Mediterranean fever.
Autoinflammatory conditions such as Sweet’s syndrome are caused by errors in the innate immune system.
Sweet’s syndrome is still a poorly understood condition, but specific causes could include hypersensitivity reaction, cytokine dysregulation, or genetic susceptibility.
The presence of antigens (a protein or substance that your immune system sees as a foreign invader, and the adaptive immune system produces antibodies in response to) associated with certain health conditions and medications could potentially trigger Sweet’s syndrome by causing the innate immune system to activate inflammatory cells, particularly white blood cells called neutrophils.
Over-production or inappropriate production of proteins and molecular messengers called cytokines have been proven to cause the symptoms of Sweet’s syndrome.
Sweet’s syndrome has been linked to the genetic marker HLA-B54.
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