Löfgren Syndrome: Clinical Presentation, Clinical Course, and Literature Review

Löfgren syndrome is an acute presentation of sarcoidosis that comprises fever, bilateral and symmetric hilar lymphadenopathies, polyarthritis, and erythema. We present the case of a 34-year-old male patient who presented with ankle monoarthritis without a history of a traumatic event. Contralateral ankle arthritis associated with erythema nodosum and fever developed one week later. Laboratory tests showed anemia, thrombocytosis, and elevated inflammatory parameters. A chest CT revealed symmetrical mediastinal and hilar adenopathies. A transbronchial biopsy was compatible with granulomatous lymphadenitis, and the diagnosis of Löfgren syndrome was confirmed. Our case report and literature review emphasize the wide web of mimicry of acute sarcoidosis. Secondary forms of acute sarcoidosis are likely to benefit from additional and more complex immunomodulatory therapies. Close monitoring and follow-up should be conducted because it is possible that these patients experience higher rates of recurrence or relapse.


Introduction
Löfgren syndrome (LöS), an acute variant of sarcoidosis, was initially described by Sven Löfgren in 1953 after the compilation of more than 100 cases of febrile young adults showing a combination of erythema nodosum, ankle periarthritis, and bilateral hilar lymphadenopathies [1,2]. The overwhelming majority of patients with LöS recover spontaneously and completely, although some cases require the use of steroids and immunosuppressors to achieve remission [3]. Despite being described for more than 60 years, there is still a lack of predictors that can allow us to infer the need for therapy in these patients.
Here, we report the case of an idiopathic LöS with hepatic and hematologic involvement and perform a review of case reports and case series published in the literature. Our aim is to revise the potential predictors of prognosis and features that can indicate the need for early immunotherapy. We conducted a search on (LDH) of 268 IU/L (NR = 87-124 IU/L). All main laboratory findings are presented in Table 1.  A thoracic radiography showed symmetric perihilar adenomegalies. The lungs were clear. A CT scan of the chest showed multiple symmetrical mediastinal and hilar adenopathies, alongside a few micronodules in the lung parenchyma ( Figure 1).

FIGURE 1: CT thoracic scan.
An abdominal ultrasound showed moderate hepatomegaly (longitudinal diameter of 17.7 cm in the midclavicular line), but bile ducts were normal. Ultimately, the patient was admitted to the Internal Medicine Department for an investigation of fever, skin lesions, mediastinal lymphadenopathies, and migratory ankle arthritis.
During hospitalization, further laboratory tests showed a striking increase in the erythrocyte sedimentation rate (ESR) (98 mm/hour, NR = 0-22 mm/hour). The autoimmunity panel, including DNA double-stranded antibodies (dsDNAab), complement level, antineutrophil cytoplasm antibodies (ANCA), anticardiolipin antibodies, lupus anticoagulant, anti-β2-glycoprotein antibodies, rheumatoid factor, and angiotensinconverting enzyme (ACE) levels, was unremarkable. The first antinuclear antibodies (ANA) titers were 1/160, but extractable nuclear antigen (ENA) antibodies were negative. Normal ANA titers were posteriorly found. Infectious serologies for syphilis, Epstein-Barr virus, hepatitis B and C, and human immunodeficiency virus were negative. The intradermal tuberculin (Mantoux) test was anergic, and the interferon-gamma release assay (IGRA) was negative. Antistreptococcal O (ASO) titers and nasopharynx swab tests were also unremarkable. Serum and urinary calcium were normal. Iron kinetics, folate, and vitamin B12 levels were also normal, as were the serum protein electrophoresis, protein immunoelectrophoresis, and level and ratio of serum and urinary light chains. A skin biopsy of the lower limbs revealed signs of panniculitis compatible with erythema nodosum.
An echoendoscopy-guided bronchoscopy was conducted to perform an aspiration transbronchial biopsy. Histologic examination confirmed granulomatous lymphadenitis, which was compatible with the diagnosis of acute sarcoidosis. Bronchoalveolar lavage (BAL) was normal, except for a high CD4+/CD8+ ratio and lymphocyte count.
The diagnosis of LöS was formulated. The patient had a favorable clinical and analytical evolution during a 10-day hospitalization. Glucocorticoids were not started, and discharge was given after symptoms became mild.
The follow-up visit was arranged for three months after discharge. The patient had complete resolution of skin lesions, respiratory symptoms, and arthritis. Laboratory tests were inapparent, and chest CT showed resolution of mediastinal lymphadenopathies.

Discussion
Sarcoidosis is an immune-mediated and complex multiorgan disorder [3,4]. Despite its worldwide distribution, certain ethnicities and age groups are more affected, reflecting genetic susceptibility and common environmental factors [4,5]. Most studies support the role of several external agents in triggering an inflammatory and granulomatous response of the host [3]. Despite many years of research, its mechanisms remain poorly understood [4].
The clinical course of sarcoidosis is variable and sometimes unpredictable, ranging from acute and selflimited to chronic, progressive, and debilitating [5]. The most commonly affected organs are the lungs, although a significant proportion of patients show extrapulmonary involvement, including skin, lymph nodes, and eyes [3,4,6].
LöS is an acute presentation of sarcoidosis that comprises a pentalogy of clinical manifestations, including bilateral and symmetric hilar lymphadenopathies, fever, polyarthritis, erythema nodosum, and uveitis, and is often associated with good prognosis [3,6,7]. The combination of all five clinical features has a high specificity for the diagnosis of LöS, obviating the need for a biopsy for a definitive diagnosis [7]. Furthermore, non-classical or atypical presentations require histological confirmation of granulomatous disease and the inherent differential diagnosis, such as infections or autoimmune diseases [7,8]. Despite its resemblance to neoplastic or paraneoplastic syndromes, most cases are self-limited and do not require specific therapy [3]. Treatment with NSAIDs is the first line for symptomatic patients, but some patients have refractory or persistent manifestations that require glucocorticoids or other immunomodulators [9]. About 10% of cases progress to chronic disease extending longer than two years despite immunosuppressive therapy [10][11][12].
We report a case of acute sarcoidosis with atypical involvement, along with the classical symptoms and signs of LöS. Although rarely described, liver and hematological involvement seem natural in a pro-inflammatory and immune systemic condition. Nevertheless, the patient recovered completely in a few months, which led us to conclude that features such as anemia, thrombocytosis, and hypoalbuminemia do not seem to modify the good prognosis of LöS.
A review of case reports is presented in Table 2    Although missing in several reports, a significant proportion of patients had normal or slightly elevated ACE levels, which corroborates current literature focusing on the controversial role of ACE in the diagnosis of sarcoidosis [33,34]. This can be due to a hypothetical correlation between ACE levels and the severity of the disease as LöS constitutes a supposedly benign variant of acute sarcoidosis. However, ACE levels are independent of the pulmonary prognosis of systemic sarcoidosis and seem unable to predict the overall prognosis of LöS. High ACE levels are compatible with a full recovery, and normal ACE levels may occur in patients in need of treatment, such as steroids or other immunosuppressive drugs. Additionally, high ACE levels lack specificity as they can be associated with systemic storage diseases, liver diseases, diabetes mellitus, other granulomatous or autoimmune diseases, and infections [33,35].
Bilateral hilar lymphadenopathies, erythema nodosum, and arthralgias are the most frequently described features of LöS in the literature. Uveal disorders are also labeled as one of the cornerstones for diagnosis [3,4,6]. Nevertheless, uveitis is rarely described. It is unknown whether this represents an underdiagnosis of subclinical disease or a less common association. Lung nodules or infiltrates, as well as cardiac, peritoneal, or liver involvement, are rarely described.
Full recovery was a common denominator in all but two cases, in which both patients died of conditions unrelated to the progression of acute sarcoidosis. One case of pulmonary aspergillosis secondary to steroidal use was described by Hillerdal et al. in 1984 [15], and another case of LöS associated with the use of biologic immunomodulators for a metastatic urothelial carcinoma was described by Kim et al. in 2016 [27]. In the latter, the patient eventually succumbed to the primary tumor. Still, 17 out of the 22 patients required at least one course of steroids or other immunosuppressive drugs to achieve remission. The majority of patients were on a first trial of NSAIDs. Secondary forms of LöS related to systemic diseases or immune checkpoint blockers, as opposed to idiopathic forms or secondary forms of any other cause, seem to have more aggressive behavior, a hypothesis also formulated by Kim et al. [27]. It is possible that this behavior is related to the severity of the underlying disease per se. However, it is to be considered that the primary condition, especially in the case of systemic diseases, may create some immunomodulation in acute sarcoidosis and influence its progression. The mechanisms underlying this possible interaction are unknown.
A review of case series is presented in Table 3 with the description of 1,276 patients who presented with LöS.  As previously discussed, a higher proportion of young females was found. Bilateral hilar lymphadenopathies were more frequently described than erythema nodosum, ankle arthralgias, or periarthritis. The majority of patients underwent spontaneous remission or fully recovered after a course of NSAIDs. More than 90% of patients were in remission in less than one year. The description of recurrence, relapse, or chronic sarcoidosis was inconsistent in the series. We found a recurrence rate of 0-25%, a relapse in about 3.9% of cases, and an overall progression to chronic sarcoidosis in 0-27.4% of cases.

Conclusions
This case report and literature review emphasize the wide web of mimicry of acute sarcoidosis. Despite being associated with an overall good prognosis, the physiopathology of LöS is still widely debated, and the intricacies of its treatment lack further discussion and investigation. From our perspective, secondary forms of acute sarcoidosis are likely to benefit from additional and more complex immunomodulatory therapies. Attention should be paid to systemic diseases that may predispose to LöS, such as autoimmune or neoplastic diseases. Close monitoring and follow-up should also be performed because it is possible that these patients experience higher rates of recurrence or relapse.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.