Sex-Specific Manifestations of Löfgren's Syndrome

Abstract

Motivation: It has been debated whether patients need to have erythema nodosum to be classified as having Löfgren's syndrome. In this study, we have therefore in detail evaluated and compared a large number of patients with an acute onset of sarcoidosis and bilateral hilar lymphadenopathy (BHL), with or without erythema nodosum (EN). This study is important because it may lead to a more accurate definition of Löfgren's syndrome, and an exact phenotype of patients is crucial in modern medical research. Background: Löfgren's syndrome is commonly regarded as a distinct clinical entity. Methods: We have in detail evaluated a large group of patients (n ϭ 150) with an acute onset of sarcoidosis with BHL, in most cases with fever, EN, and/or bilateral ankle arthritis or periarticular inflammation. Within this group, 87 patients had EN (EN positive), whereas 63 were without EN (EN negative), though with distinct symmetric ankle inflammation. Results: EN-positive and EN-negative patients were identical in every aspect except that there were significantly more women in the ENpositive group: 58 women (67%) in the EN-positive group compared with only 17 (27%) women in the EN-negative group (p Ͻ 0.0001). In all other aspects, such as age, smoking habits, seasonal clustering of disease onset, rate of positive biopsies, chest radiography, pulmonary function, bronchoalveolar lavage cell distributions including the typically increased CD4/CD8 ratio, and clinical development of the disease, the EN-positive and EN-negative groups were close to identical. The two groups were also identically strongly associated with HLA-DRB1*0301/DQB1*0201, with 60 (69.0%) and 44 (69.8%) patients having this particular HLA type in the EN-positive and EN-negative groups, respectively. Such patients recovered to the same degree-that is, at almost 100%. Conclusions: We conclude that manifestations of Löfgren's syndrome differ between men and women, with EN found predominantly in women, whereas a marked periarticular inflammation of the ankles or ankle arthritis without EN is seen preferentially in men.

A Japanese Patient with Löfgren’s Syndrome with an HLA-DR12 Allele and Review of Literature on Japanese Patients

“…The onset of disease was in March in four of the eight Japanese cases with known onset date (50%). This supports the observations of previous reports that mentioned a seasonal clustering of Löfgren's syndrome in the spring months (Mana et al 1999;Grunewald and Eklund 2007). Fever had developed in eight cases (75%), which was high compared to 38% of 186 patients revisited by Mana et al (1999).…”

“…We searched the literature in English and in Japanese for Japanese patients who were diagnosed with Löfgren's syndrome with the confirmation of all three symptoms, arthritis, EN, and BHL, and reviewed the clinical characteristics of twelve patients, including our case (Table 1) (Iino et al 1991;Koseki et al 1998;Higashimoto et al 2002;Niimi et al 2003;Oshima et al 2003;Izumo et al 2005;Ohta et al 2006;Sugimoto et al 2006;Kosaka et al 2007;Takasa et al 2012;Mori et al 2013). Ten patients shown in Table 1 were women (83.3%), with a mean age of 34 years (range, 23-52 years), which was similar to the age range of patients in previous reports from Europe and the United States (Mana et al 1999;Grunewald and Eklund 2007). The onset of disease was in March in four of the eight Japanese cases with known onset date (50%).…”

“…HLA class II alleles (HLA class II can form a complex with antigenic proteins and T-cell receptors to provide the first signal for T-cell activation) have been frequently reported as being involved in the development of sarcoidosis (Moller and Chen 2002), and several infectious agents (e.g., Propionibacterium acnes, Borrelia burgdorferi and Mycobacterium tuberculosis) have been implicated as potential causes of sarcoidosis (ATS/ERS/WASOG Committee 1999; Iannuzzi and Fontana 2011). Further, especially for Löfgren's syndrome, the greater prevalence in certain geographic areas and seasonal clustering during spring, as described previously, suggest that a combination of genetic predisposition and environmental factors are important in the development of this condition (ATS/ERS/ WASOG Committee 1999; Mana et al 1999;Grunewald and Eklund 2007).…”

“…Abbreviations: AAo, ascending aorta; DAo, descending aorta; LN, lymph node; PA, pulmonary artery; SVC, superior vena cava. Löfgren's syndrome, an acute type of sarcoidosis, has been reported to be more frequent in some geographical areas and races, particularly in young white women from the Nordic countries and Ireland, and has a favorable prognosis (Mana et al 1999;Grunewald and Eklund 2007). Owing to its relatively common occurrence in Europe and the United States, a patient with Löfgren's syndrome presenting with the three characteristic symptoms can be diagnosed without biopsy in these countries (ATS/ERS/WASOG Committee 1999; Mana et al 1999;Iannuzzi and Fontana 2011).…”

“…The disease accounts for 20-30% of the cases of sarcoidosis in white individuals (ATS/ERS/WASOG Committee 1999). Löfgren's syndrome is reported to be more frequent in young white women (Grunewald and Eklund 2007), but it is very rare in Japan. Therefore, most studies on Löfgren's syndrome, including human leukocyte antigen (HLA) typing, have been reported form Western countries, while there is no review on the association between HLA typing and Japanese Löfgren's syndrome.…”