What causes Sweet’s syndrome?
Autoinflammatory conditions such as Sweet’s syndrome are caused by errors in the innate immune system or this part of the immune system not working in the way that it should. The innate immune system is the body’s most primitive ‘hard-wired’ immune system and a part of the immune system that doesn’t produce antibodies. Even though we know that the immune system doesn’t work properly in Sweet’s syndrome, it’s still a poorly understood condition, and specific causes, i.e. what happens in the body that leads to the symptoms of Sweet’s syndrome, includes hypersensitivity reaction, cytokine dysregulation, and genetic susceptibility.
1. Hypersensitivity reaction.
Because the innate immune system doesn’t work in the right way, in some people with Sweet’s syndrome their immune system responds to antigens in a way that it shouldn’t, i.e. is hypersensitive and goes into overdrive, overreacting to the presence of infectious, inflammatory, drug, or tumour cell antigens (Bhat et al, 2015:257; Kasirye et al, 2011:135).
Antigens are mainly proteins or sugars on the surface of a cell or a non-living substance, that a part of your immune system called the adaptive immune system sees as a foreign invader and produces antibodies in response to. The presence of antigens associated with certain health conditions, medications and vaccinations, can potentially trigger Sweet’s syndrome by stimulating the innate immune system to activate white blood cells called neutrophils and the release of cytokines (see ‘Cytokine dysregulation’) (Gosheger et al, 2002: 70). The neutrophils migrate to skin tissues and sometimes other tissues, causing skin lesions or other symptoms of Sweet’s syndrome.
Potential triggers for Sweet’s syndrome include:
- Cancer, particularly blood cancer (malignancy-associated or paraneoplastic) in 15-20% of cases (Chen et al, 2016. Read more here.
- Infection, particularly upper respiratory tract and gastrointestinal infection, but others infections too (Cohen, 2007).
- Inflammatory bowel disease – Crohn’s disease and ulcerative colitis.
- Autoimmune conditions, e.g. rheumatoid arthritis and systemic lupus erythematosus (Ibid).
- Medications (drug-induced) in 12% of cases.
- Vaccination. This is very rare – only 11 cases reported in medical literature in the past 44 years, globally.
Other potential yet poorly understood triggers for Sweet’s syndrome include:
- Pregnancy (pregnancy-associated) in 2% of cases. This may be linked to hormonal changes, and changes within the immune system that make it more likely that an inflammatory response will occur. On rare occasions, Sweet’s syndrome has also been triggered by the contraceptives, levonorgestrel/ethinyl estradiol (Triphasil) and levonorgestrel-releasing intrauterine system (Mirena) (Cohen, 2007).
- Skin damage. In at least 8% of people with Sweet’s syndrome, when their skin is damaged, including by irritants, this can trigger the development of skin lesions. This is referred to as pathergy and is similar to another reaction called Koebner phenomenon. Potential irritants may even include natural products such as arnica cream (Shenefelt, 2011).
- Overexposure to sunlight or ultraviolet light. This can sometimes trigger Sweet’s syndrome, but we aren’t entirely sure why this happens.
In up to 50% of cases, there is no known trigger or underlying condition in Sweet’s syndrome (Resende et al, 2016). Rarely, in children, Sweet’s syndrome is a symptom of the autoinflammatory conditions, CANDLE syndrome, Majeed syndrome, and HIDS.
Cytokines are proteins and molecular messengers and part of the body’s immune system. The overproduction or inappropriate production of cytokines, known as cytokine dysregulation, can result in disease. Cytokines involved in Sweet’s syndrome include:
Endogenous granulocyte colony-stimulating factor (G-CSF).
- Endogenous G-CSF is a cytokine that’s produced by the body and associated with an increased neutrophil 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 is a factor in malignancy-associated Sweet’s syndrome (Foster et al, 2005:145, 148). Research shows that blood cancers such as leukaemia cause an increase in interleukin 1/IL-1 (see ‘Other cytokines’) which affects G-CSF levels. G-CSF then recruits neutrophils to the skin via interleukin 6/IL-6 (Yang et al, 2017).
- Granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon gamma, and interleukins (IL-) 1, 2, 3, 6, 8, and others may play a role in Sweet’s syndrome, but further research is required (Bhat et al, 2015: 527; Ginarte and Toribio, 2011; Kumar et al, 2004; Paydas, 2013: 87; Takano et al, 2017; Tartey et al, 2018).
- Anakinra (Kineret) is a biological therapy that inhibits the effects of IL-1. Refractory or persistent Sweet’s syndrome can respond well to this treatment, implying that IL-1 plays a significant role in some cases (Satoh et al, 2016).
- IL-6 has been linked to fever and pain in Sweet’s syndrome (Ozlem et al, 2011: 1975).
- IL-6 plays a role in Sweet’s syndrome that has developed secondary to the autoimmune condition, systemic lupus erythematosus, IL-6 and other cytokines possibly being a factor in both conditions (Barton et al, 2011:5).
- Tumour necrosis factor alpha (TNF-α) has been shown to affect neutrophil function in Sweet’s syndrome (Gunarneri et al, 2018). Elevated levels of TNF-α have been found within skin lesions (Smolovic et al, 2018).
- In 2017, a serum cytokine profile of a 2-year-old Japanese girl with Sweet’s syndrome where there was no underlying cause, showed that IL-6 levels were elevated prior to initial treatment with the steroid, prednisone (Takano et al, 2017). IL-1β, IL-18, neopterin (not a cytokine. Synthesised by macrophages, white blood cells that ‘eat’ debris and foreign substances, upon stimulation with interferon-gamma), and tumour necrosis factor were normal. After starting treatment, IL-6 returned to almost normal levels, IL-1β and IL-18 stayed within normal ranges, neopterin became slightly elevated and tumour necrosis factor increased after the onset of a urinary tract infection. Takano et al conclude that in children with Sweet’s syndrome, IL-6 not IL-1β may play a major role, but further research is required (Takano et al, 2017). IL-1β is considered to be the key cytokine in autoinflammatory diseases, but this doesn’t exclude Sweet’s syndrome as some of these diseases don’t have an apparent relationship with IL-1. In adults, Sweet’s syndrome is more likely to be associated with cancer and this may affect the cytokine profile.
3. Genetic susceptibility.
Sweet’s syndrome is not a genetic condition, but in some people may be associated with certain genes, gene mutations and abnormalities. These include:
The genetic marker HLA-B54.
HLA-B54 is more likely to be found in people 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, suggesting a genetic predisposition among the Japanese for Sweet’s syndrome (Bellus and Stumpf, 2003).
Abnormalities in chromosome 3q.
Structural abnormalities in chromosome 3q in bone marrow cells of two patients with Sweet’s syndrome and the blood cancers, myelodysplastic syndrome and 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; Tartey et al, 2018).
Isocitrate dehydrogenase 1 (IDH1) gene.
Mutation in the isocitrate dehydrogenase 1 (IDH1) gene in two patients with Sweet’s syndrome and IDH1-mutated myelodysplastic syndrome (Snyder et al, 2018).
Possibly mediterranean fever (MEFV) gene.
Mediterranean fever (MEFV) gene mutation, the cause of the autoinflammatory condition, familial Mediterranean fever (FMF), potentially linked to malignancy-associated Sweet’s syndrome in two Japanese patients with myelodysplastic syndrome (Jo et al, 2015). However, there’s some debate concerning whether or not this is accurate, and Koné-Paut et al have argued that this theory is ‘premature or even misleading’ for the following reasons: Sweet’s syndrome not confirmed by biopsy in the first patient; sequence analyses of MEFV showed a single, probably benign sequence variant; mutations not sufficient to cause inflammatory symptoms; symptoms not alleviated by colchicine, a treatment that’s effective in 95% of patients with FMF; FMF is typically diagnosed in childhood, and both patients were 63-years-old (Koné-Paut et al, 2015).
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 include hypersensitivity reaction, cytokine dysregulation, and genetic susceptibility.
Hypersensitivity reaction is when the presence of antigens associated with certain health conditions, medications and vaccinations, trigger Sweet’s syndrome by stimulating the innate immune system to produce molecular messengers called cytokines. This eventually leads to the activation of white blood cells called neutrophils.
Over-production or inappropriate production of cytokines, otherwise known as cytokine dysregulation, has been proven to lead to the symptoms of Sweet’s syndrome.
Sweet’s syndrome has been linked to the genetic marker HLA-B54.
Barton, J., Pincus, L., Yazdany, J., Richman, N., McCalmont, T., Gensler, L., Dall’Era, M. and Fye, K. (2011) Association of Sweet’s Syndrome and Systemic Lupus Erythematosus. Case Reports in Rheumatology; Article ID 242681, 6 pages (Hindawi).
Billström, R., Heim, S., Kristoffersson, U., Mandahl, N. and Mitelman, F. (1990) Structural chromosomal abnormalities of 3q in myelodysplastic syndrome/acute myeloid leukaemia with Sweet’s syndrome. European Journal of Haematology, Sep;45(3):150-2 (PubMed).
Chen, S., Kuo, Y., Liu, Y., Chen, B., Lu, Y. and Miser, J. (2016) Acute Myeloid Leukemia Presenting with Sweet Syndrome: A Case Report and Review of the Literature. Pediatrics and Neonatology (online).
Foster, E., Nguyen, K., Sheikh, R. and Prindiville, T. (2005) Crohn’s disease associated with Sweet’s syndrome and Sjogren’s syndrome treated with Infliximab. Clinical and Developmental Immunology, Jun; 12(2): 145–149 (PDF).
Ginarte, M. and Toribio, J. (2011) Sweet Syndrome. In Dr. Fang-Ping (Ed.) Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights. Croatia or China: Intech, pp. 119-132 (PDF).
Guarneri, C., Wollina, U., Lotti, T., Maximov, G., Lozev, I., Gianfaldoni, S., Pidakev, I., Lotti, J. and Tchernev, G. (2018) Sweet’s Syndrome (SS) in the Course of Acute Myeloid Leukaemia (AML). Open Access Macedonian Journal of Medical Sciences, Jan 13;6(1):105-107 (PMC).
Hisanaga, K., Hosokawa, M., Sato, N., Mochizuki, H., Itoyama, Y. and Iwasaki, Y. (1999) “Neuro-Sweet Disease”: Benign Recurrent Encephalitis With Neutrophilic Dermatosis. Archives of Neurology;56(8):1010-1013 (JAMA).
Kawakami, T., Ohashi, S., Kawa, Y., Takahama, H., Ito, M., Soma, Y. and Mizoguchi, M. (2004) Elevated serum granulocyte colony-stimulating factor levels in patients with active phase of sweet syndrome and patients with active behcet disease: implication in neutrophil apoptosis dysfunction. Archives of Dermatology, May:140(5):570-4 (JAMA).
Koné-Paut, I., Hentgen, V. and Touitou, I. for CeRéMAI, the French Reference Center for Autoinflammatory Diseases (2015) Correspondence in Sweet’s syndrome in patients with MDS and MEFV mutations. The New England Journal of Medicine;372(7):686-8 (online).
Kumar, G., Bernstein, J., Waibel, J. and Baumann, M. (2004) Sweet’s syndrome associated with sargramostim (granulocyte-macrophage colony stimulating factor) treatment. American Journal of Hematology, Jul;76(3):283-5 (PubMed).
Li, B., Ma, Z., Xu, X., Yin, J., Wang, X., Ren, J., Wang, S., Yang, J., Ma, T., Zhang, Q., Yu, J. and Yan, B. (2015) Multi–organ involvement of Sweet’s syndrome: a case report and literature review. Internal Medicine (Tokyo, Japan);54(3):339-43 (PDF).
Ozlem, C., Deram. B., Mustafa. S., Koray, T. Cuyan, D. and Ertugrul, T. (2011) Propylthiouracil-induced Anti-neutrophil Cytoplasmic Antibodies and Agranulocytosis together with Granulocyte Colony-stimulating Factor Induced Sweet’s Syndrome in a Patient with Graves’ Disease. Internal Medicine; 50 (18): 1973-1976 (PDF).
Shenefelt, P. (2011) Chapter 18: Herbal Treatment for Dermatologic Disorders. In Benzie, I. and Wachtel-Gator, S. (eds) Herbal Medicine: Biomolecular and Clinical Aspects. 2nd ed. Boca Raton: CRC Press.
Smolovic, B., Gajic-Veljic, M., Nikolic, M. and Muhovic, D. (2018) Pregnancy-Induced Sweet’s Syndrome Treated with Infliximab. Medical Principles and Practice: International Journal of the Kuwait University, Health Science Centre, Oct 30 (Karger).
Snyder, R., Libby, T., Raciti, P., Amin, B., Jacobson, M., Rakheja, D., Fleming, K., Bartenstein, M., Zhu, C., Goel, S., Verma, A. and Shastri, A. (2018) Myelodysplastic Syndrome and Sweet’s Syndrome Are Associated with a Mutation in Isocitrate Dehydrogenase 1. Anticancer Research, Apr;38(4):2201-2205 (IIAR Journals).
Tartey, S., Gurung, P., Dasari, T., Burton, A. and Kanneganti, T. (2018) ASK1/2 signaling promotes inflammation in a mouse model of neutrophilic dermatosis. The Journal of Clinical Investigation, Apr 9 (online).
Xenophontos, E., Ioannou, A., Constantinides, T. and Papanicolaou. E. (2016) Sweet syndrome on a patient with autoimmune hepatitis on azathioprine and CMV infection. Oxford Medical Case Reports, Feb; (2): 24–27 (PMC).
Yang, M., Kim, J., Kim, G., Song, M., Kim, H., Ko, H., Kim, M. and Kim, B (2017) Neutrophilic Dermatosis of the Palms in Association with Myelodysplastic Syndrome. Annals of Dermatology, Aug; 29(4): 495–497 (PMC).
2012-2018 Sweet’s Syndrome UK