**6. Characteristics of the subsets of SS**

#### **6.1 Idiopatic**

Clasically it is the most frequent subset of SS and it represents up to 70% of the cases in old series (Requena, 2007). It predominates in women, especially in patients aged under 45 years. Most recently, this subset has become less prevalent possibly due to the better study of the patients (Corazza et al, 2008).

#### **6.2 Parainflammatory**

This group encompasses the SS associated or triggered by inflammatory and infectious conditions. There is a broad number of entities related with SS, some of them only based on isolated or few case reports, which makes difficult to assess the true power of the association (reviewed by Requena, 2007; von den Driesch, 1994; Cohen, 2007). The best documented inflammatory diseases associated with SS are Beçhet disease, bowel inflammatory disease, rheumatoid arthritis, lupus erythematous, and other autoimmune collagenosis. The infectious conditions more related with SS are oropharingeal infection (especially due to streptococcus pyogenes) and intestinal infections by *Salmonella* and *Yersinia*. Less constantly SS has been linked to other bacterial infections, tuberculosis, lepra, histoplasmosis, toxoplasmosis, HIV, and viral hepatitis. Recent reports suggest that the patients with previous oropharingeal infection have a less severe form of this syndrome (Borges Da Costa et al, 2009).

#### **6.3 Paraneoplastic SS**

It is a well established subset of SS with an obvious interest. Up to 20% of SS are paraneoplastic (Cohen & Kurzrock, 1993). The SS may precede (sometime in years) or follow the malignancy. It also may arise in relation with the recurrence of previous malignancy. There are some characteristics more related to paraneoplastic than to non-paraneoplastic SS: a) lack of female predominance; b) advanced age; c) presence of anemia and/or other hematological disturbances; d) extracutaneous involvement; e) atypical, pustular, or necrotic skin lesions (Cohen & Kurzrock, 1993; Watanabe et al, 2009). The majority of paraneoplastic SS are associated with hematologic malignancies, especially with acute myelogenous leukemia and myelodysplastic syndromes (Buck et al, 2008). About 15% of paraneoplastic SS are related with solid cancers, predominating breast, gastrointestinal, and genitourinary origin.

#### **6.4 Drug-induced SS**

More than 25 drugs have been related to the flare of SS, but the most frequently implicated is the granulocyte-colony stimulating factor (G-CSF). Other drugs that are commonly associated with the development of SS are trimethoprim-sulphamethoxazole, oral contraceptive pills, retinoids, minocicline, hydralazine, carbamacepine, bortezomib, and imatinib. As it is usual in other skin eruptions induced by drugs, the disease fades with the withdrawal of the drug and flares up if it is re-administrated.

#### **6.5 SS associated with pregnancy**

It is not unanimously considered as a subgroup of SS, but its existence should be taken into account due to its relative frequency.

Clasically it is the most frequent subset of SS and it represents up to 70% of the cases in old series (Requena, 2007). It predominates in women, especially in patients aged under 45 years. Most recently, this subset has become less prevalent possibly due to the better study

This group encompasses the SS associated or triggered by inflammatory and infectious conditions. There is a broad number of entities related with SS, some of them only based on isolated or few case reports, which makes difficult to assess the true power of the association (reviewed by Requena, 2007; von den Driesch, 1994; Cohen, 2007). The best documented inflammatory diseases associated with SS are Beçhet disease, bowel inflammatory disease, rheumatoid arthritis, lupus erythematous, and other autoimmune collagenosis. The infectious conditions more related with SS are oropharingeal infection (especially due to streptococcus pyogenes) and intestinal infections by *Salmonella* and *Yersinia*. Less constantly SS has been linked to other bacterial infections, tuberculosis, lepra, histoplasmosis, toxoplasmosis, HIV, and viral hepatitis. Recent reports suggest that the patients with previous oropharingeal infection have a less severe form of this syndrome (Borges Da Costa

It is a well established subset of SS with an obvious interest. Up to 20% of SS are paraneoplastic (Cohen & Kurzrock, 1993). The SS may precede (sometime in years) or follow the malignancy. It also may arise in relation with the recurrence of previous malignancy. There are some characteristics more related to paraneoplastic than to non-paraneoplastic SS: a) lack of female predominance; b) advanced age; c) presence of anemia and/or other hematological disturbances; d) extracutaneous involvement; e) atypical, pustular, or necrotic skin lesions (Cohen & Kurzrock, 1993; Watanabe et al, 2009). The majority of paraneoplastic SS are associated with hematologic malignancies, especially with acute myelogenous leukemia and myelodysplastic syndromes (Buck et al, 2008). About 15% of paraneoplastic SS are related with solid cancers, predominating breast, gastrointestinal, and genitourinary

More than 25 drugs have been related to the flare of SS, but the most frequently implicated is the granulocyte-colony stimulating factor (G-CSF). Other drugs that are commonly associated with the development of SS are trimethoprim-sulphamethoxazole, oral contraceptive pills, retinoids, minocicline, hydralazine, carbamacepine, bortezomib, and imatinib. As it is usual in other skin eruptions induced by drugs, the disease fades with the

It is not unanimously considered as a subgroup of SS, but its existence should be taken into

withdrawal of the drug and flares up if it is re-administrated.

**6. Characteristics of the subsets of SS** 

of the patients (Corazza et al, 2008).

**6.2 Parainflammatory** 

**6.1 Idiopatic** 

et al, 2009).

origin.

**6.3 Paraneoplastic SS** 

**6.4 Drug-induced SS** 

**6.5 SS associated with pregnancy** 

account due to its relative frequency.

## **7. Clinical variations and associations with other dermatoses**

The typical cases of SS present very characteristics clinicopathological manifestations so that their diagnosis usually does not represent particular difficulty. Nevertheless, the SS may occasionally show a different clinical picture or it may be associated with other cutaneous signs making difficult to set the diagnosis and/or imply a change in the patient´s management. There is controversy about the need of describing such cases as "atypical" SS or as individualizing them as different entities.

#### **7.1 Overlap and relationship with other ND**

The group of ND represents a *continuum* of diseases that share clinical, histopathological, and causal features. The individualization of each entity is mainly based on clinical criteria. This fact explains that SS occasionally shares clinical characteristics with other ND (overlap), especially with generalized vesiculobullous forms of pyoderma gangrenosum. Other ND such as Behçet disese, bowel bypass syndrome, and neutrophilic eccrine hidradenitis may clinically resemble SS (Mizuashi et al, 2010). Sometimes patients with these features can only be diagnosed generically as suffering a ND, without a more specific denomination. In the same way, there have been reported patients suffering both SS and other ND (either simultaneously or sequentially) (Callen, 1985; Sherertz, 1987; Villanueva et al, 1989; Ginarte et al, 1997).

#### **7.2 Chronic recurrent annular neutrophilic dermatosis**

As its denomination indicates, it is a subtype of SS characterized by erythematoedematous plaques with a chronic and recurrent evolution. It has neither extracutaneous signs, nor fever or neutrophilia (Christensen et al, 1989; Romero et al, 1994; Cabanillas et al, 2008).

#### **7.3 Subcutaneous fat involvement**

Frequently, patients with SS have nodular lesions, especially on anterior aspects of the legs. These nodules are the clinical manifestation of the alteration of the subcutaneous fat, which can be originated by two different mechanisms. The first one called subcutaneous SS is characterized by a neutrophilic inflammatory infiltrate located on subcutaneous fat (either exclusively or accompanied by dermal affectation). Such infiltrate is usually located in fat lobules, but occasionally it may be septal or mixed (Cohen & Kurzrock, 2003). In a recent study, subcutaneous SS was shown by 16% of the patients (Abbas et al, 2010). The second possibility of subcutaneous fat involvement in SS is the association between this syndrome and erythema nodosum. This association is relatively frequent (up to 30% of the cases) and can be explained because both entities share several common features: essentially both are reactive dermatoses triggered by similar stimuli and pathogenically mediated by neutrophils. They are also treated with similar treatments (Ginarte et al, 1997; Ginarte & Toribio, 2000; Ginarte & Toribio, 2007). Due to the different significance of subcutaneous SS and erythema nodosum, it is necessary to make a deep biopsy from one of the nodules.

#### **7.4 Sweet syndrome in infancy**

About 16% of SS appears in children (Abbas et al, 2010). Pediatric SS is similar to that in adult population, with only three differences: a) it is associated with immunodeficiency

Sweet Syndrome 127

the erythema multiforme. Other clinical differential diagnosis are drug eruptions and Behçet disease. All of these entities can be ruled out by means of a skin biopsy. Other ND (atypical pyoderma gangrenosum, bowel bypass syndrome, neutrophilic eccrine hidradenitis), vasculitis (specially erythema elevatum diutinum), and erythema nodosum may occasionally set problems with differential diagnosis both from the histopathological and

Clinic criterium: abrupt onset of tender or painful erythematous or violaceus plaques or

Histopathological criterium: predominantly neutrophilic infiltration in the dermis

The definite diagnosis of SS demands the fulfillment of both major criteria and at least two

1. Clinical criterium: abrupt onset of tender or painful erythematous plaques or nodules

2. Histopathological criterium: predominantly neutrophilic infiltration in the dermis

1. Preceded by a nonspecific respiratory or gastrointestinal tract infection or vaccination

a. Inflammatory diseases such as chronic autoimmune disorders, infections

c. Segmented-nuclear neutrophils and stabs > 70% in peripheral blood smear

4. Excellent response to treatment with systemic corticosteroids or potassium iodide

b. Hemoproliferative disorders or solid malignant tumors

2. Accompanied by periods of general malaise and fever (>38ºC) 3. Three of four of the following laboratory values during onset:

Accompanied by fever, arthralgia, conjunctivitis, or underlying malignancy

Good response to systemic steroids and not to antibiotics

clinical points of view.

without leukocytoclastic vasculitis

Table 4. Diagnostic criteria by Su y Liu (1986)

without leukocytoclastic vasculitis

occasionally with vesicles, pustules or bullae

Preceded by fever or infections

**Major criteria** 

nodules

**Minor criteria** 

Leukocitosis

of the minor criteria

**Major criteria** 

**Minor criteria** 

or associated with:

c. Pregnancy

a. ESR > 20 mm

b. C-reactive protein positive

Table 5. Diagnostic criteria by von den Driesch (1992)

d. Leukocytosis > 8000

(HIV infection and other immune disorders), b) it is less associated with malignancy (although it is necessary to investigate this condition), and c) it is particularly susceptible to recurrences (Mohr et al, 2010).
