What causes Sweet’s syndrome?

What causes Sweet’s syndrome?

Autoinflammatory conditions such as Sweet’s syndrome are caused by errors in the innate immune system, the body’s most primitive, ‘hard-wired’ immune system, and a part of the immune system that doesn’t produce antibodies. 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, includes hypersensitivity reaction, cytokine dysregulation, and genetic susceptibility.

1. Hypersensitivity reaction.

Because of errors in the innate immune system, 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 produce cytokines (see ‘Cytokine dysregulation’), which eventually leads to the activation of white blood cells called neutrophils (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 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, but others infections too (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 12% of cases.
  • Immunodeficiency.
  • Vaccination. This is very rare – only 11 cases reported in medical literature in the past 42 years, globally – and a definite connection has not been established between the Sweet’s syndrome and vaccination in some of those cases.

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 rare occasions, Sweet’s syndrome can also be triggered by the contraceptives, 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.

In up to 50% of cases, there is no known trigger or underlying condition in Sweet’s syndrome (Resende et al, 2016).


2. Cytokine dysregulation.

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.

  • 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 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).

Other cytokines.

  • 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; Takano et al, 2017).
  • 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 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 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.


Key points.

  • 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.


References.

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).

Bellus, G. and Stumpf, A. (2003) Neutrophilic Dermatosis, Acute Febrile. OMIM (online).

Bhat, Y., Hassan, I., Sajad, P., Akhtar, S. and Sheikh, S. (2015) Sweet’s Syndrome: An Evidence-Based Report. Journal of the College of Physicians and Surgeons – Pakistan, Jul;25(7):525-7 (PubMed).

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).

Cohen, P. (2007) Sweet’s syndrome – a comprehensive review of an acute febrile neutrophilic dermatosis (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 (online).

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 (online). 

Gosheger, G., Hillman, A., Ozaki, T., Buerger, H. and Winklemann, W. (2002) Sweet’s Syndrome Associated With Pigmented Villonodular Synovitis. Acta Orthopædica Belgica, Feb;68(1):68-71.

Gurung, P. and Kanneganti, T. (2016) Autoinflammatory Skin Disorders: The Inflammasome in Focus. Trends in Molecular Medicine, Jul;22(7):545–564 (0nline).

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 (online).

Jo, T., Horio, K. and Migita, K. (2015) Sweet’s syndrome in patients with MDS and MEFV mutations. The New England Journal of Medicine;372(7):686-8 (online).

Kasirye, Y., Danhof, R., Epperla, N. and Garcia-Montilla, R. (2011) Sweet’s Syndrome: One Disease, Multiple Faces. Clinical Medicine & Research, Nov;9(3-4):134-136 (online).

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 (online).

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).

Paydas, S. (2013) Sweet’s syndrome: a revisit for hematologists and oncologists. Critical Reviews in Oncology/Hematology, Apr;86(1):85-95 (online).

Resende, C., Santos, R., Pereira, T. and Brito, C. (2016) Sweet’s syndrome associated with cellulitis – a challenging diagnosis. Anais Brasileiros de Dermatologia, Jan-Feb; 91(1): 94–96 (online).

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.

Takano, Y., Fujino, H., Yachie, A. and Sumimoto, S. (2017) Serum cytokine profile in pediatric Sweet’s syndrome: a case report. Journal of Medical Case Reports, Jul 2;11(1):178 (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 (online).

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 (online).

© 2012-2017 Sweet’s Syndrome UK

Advertisements

2 thoughts on “What causes Sweet’s syndrome?

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s