Löfgren’s syndrome: genetic associations, clinical course and outcome

Abstract

Sarcoidosis is a systemic inflammatory disease of unknown origin, characterized by non-caseating granulomas and a variable clinical course. Löfgren’s syndrome is a well-defined, acute phenotype with a distinct presentation and generally favorable prognosis. This thesis focuses on genetic factors influencing disease susceptibility, clinical manifestations, and long-term outcomes in Löfgren’s syndrome. Löfgren’s syndrome presents acutely with fever, bilateral hilar lymphadenopathy (BHL), erythema nodosum (EN), and/or bilateral ankle arthritis. In contrast to non-Löfgren sarcoidosis, which develops gradually and shows heterogeneous features, Löfgren’s syndrome has a uniform and acute presentation. Prognosis is excellent, especially in patients carrying the HLA-DRB1*03 allele, with approximately 95% recovering within two years. Diagnosis is based on clinical and radiological findings. The combination of acute onset, BHL, EN, and ankle arthritis has high diagnostic accuracy, making histological confirmation unnecessary in typical cases. The syndrome is more common in Scandinavian countries, the Netherlands, and Spain, and rare in the UK, US, and Asia. Sarcoidosis likely results from an interaction between genetic predisposition and environmental triggers. Seasonal clustering in spring supports the role of environmental factors. The human leukocyte antigen (HLA) region on chromosome 6 plays a central role in antigen presentation and disease outcomes. HLA-DRB1*03 is associated with disease susceptibility and favorable prognosis, while HLA-DRB1*15 is linked to chronic disease. SNP-based tagging methods allow efficient identification of these alleles. Immunologically, sarcoidosis is characterized by increased lymphocytes and an elevated CD4+/CD8+ ratio in bronchoalveolar lavage fluid. HLA-DRB1*03 positive patients show distinct immune profiles, including higher CD4+/CD8+ ratios and lower CD103+CD4+/CD4+ ratios, suggesting genotype-driven immune responses. Long-term follow-up showed that 94% of patients recovered, though relapse occurred in a minority. Patients without HLA-DRB1*03, especially those with HLA-DRB1*15, had a higher risk of chronic or recurrent disease. Beyond the HLA region, other genes contribute to sarcoidosis. The ANXA11 gene (SNP rs1049550) is consistently associated with sarcoidosis across phenotypes, with the T allele having a protective effect, possibly through effects on apoptosis and intracellular transport. The MIF gene is linked to clinical manifestations rather than disease susceptibility. The MIF -173C allele is associated with erythema nodosum, indicating a role in symptom expression. The CCR5 gene (SNP rs1799987) is associated with Löfgren’s syndrome. The G allele increases receptor expression but reduces activity, potentially explaining strong initial inflammation followed by a milder course. CCR5 may be a therapeutic target. Treatment depends on disease severity. Corticosteroids are first-line therapy, but many Löfgren’s syndrome patients do not require treatment due to spontaneous remission. Fatigue may persist, particularly in patients without HLA-DRB1*03. In conclusion, Löfgren’s syndrome is a genetically influenced phenotype strongly associated with HLA-DRB1*03 and favorable outcomes. The disease arises from interactions between genetic, environmental, and immune factors. Genetic markers such as HLA, ANXA11, MIF, and CCR5 provide insights into disease mechanisms and support personalized treatment strategies.