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Löfgren syndrome is an acute, clinically distinct form of sarcoidosis characterized by the classic triad of erythema nodosum, bilateral hilar lymphadenopathy, and periarticular ankle inflammation. Occurring in approximately 5% to 10% of sarcoidosis cases, it typically affects younger adults and has high diagnostic specificity, often allowing diagnosis without tissue biopsy. The condition reflects an antigen-driven immune response in genetically susceptible individuals, with strong associations to HLA-DRB1*03 and a favorable prognosis, as most cases resolve spontaneously. This activity reviews the clinical and radiographic features, immunopathogenesis, and genetic influences of Löfgren syndrome, as well as differentiation from other granulomatous diseases. It emphasizes evidence-based evaluation and management, including appropriate use of imaging, laboratory testing, and selective pharmacologic therapy, while highlighting the importance of an interprofessional approach to optimize patient outcomes. Objectives: Identify the characteristic clinical triad of Löfgren syndrome. Differentiate Löfgren syndrome from alternative causes of granulomatous disease to avoid inappropriate management. Select appropriate management strategies for Löfgren syndrome. Collaborate with interprofessional team members to improve coordination of care and outcomes in patients with Löfgren syndrome. Access free multiple choice questions on this topic.

Löfgren syndrome represents a clinically distinct phenotype of sarcoidosis, first described in 1946 by Swedish pulmonologist Sven Löfgren. Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that most commonly involves the lungs but can affect nearly any organ system, including the skin.[1][2] Cutaneous manifestations occur in up to 33% of patients and may serve as the initial clinical sign.[3] In contrast to the more insidious and potentially chronic or relapsing course of sarcoidosis, Löfgren syndrome presents acutely and develops in approximately 5% to 10% of affected individuals. The condition most frequently involves younger adults and features the classic triad of erythema nodosum, bilateral hilar lymphadenopathy, and ankle arthritis or periarticular inflammation. Fever, malaise, and fatigue commonly accompany the presentation but are not essential for diagnosis. The presence of Löfgren syndrome demonstrates high specificity for sarcoidosis.[4] Overall, the syndrome follows a self-limited course and confers a favorable prognosis.[5][6]  Recognition of this clinical syndrome is of significant clinical value, as its characteristic presentation enables clinicians to establish a diagnosis of sarcoidosis without relying on invasive tissue biopsy.

The etiology of Löfgren syndrome, similar to sarcoidosis more broadly, remains incompletely understood and is thought to reflect a multifactorial interaction between genetic susceptibility and environmental antigen exposure. Although acute sarcoidosis is not considered an infectious disease, immune profiling studies have demonstrated humoral and cellular immune responses to selected microbial antigens, including mycobacterial proteins, in patients with sarcoidosis and Löfgren syndrome, supporting an antigen-driven host immune response rather than active infection.[4] Environmental and Occupational Exposures Environmental and occupational exposures have also been associated with the risk of sarcoidosis, reinforcing the role of host–environment interactions in disease development.[6] Cutibacterium acnes (formerly Propionibacterium acnes) has been associated with sarcoidosis through its detection in granulomatous tissue and immune recognition studies; however, Cutibacterium acnes has also been identified in individuals without sarcoidosis, indicating that microbial presence alone is insufficient to establish causation and underscoring the importance of host immune dysregulation rather than a single infectious trigger.[5] Genetic Etiologies Genetic susceptibility plays a central role in Löfgren syndrome. Among genetic factors, HLA-DRB1*03:01 has the strongest and most consistent association with the Löfgren phenotype and is linked to an acute disease onset and a favorable clinical course with high rates of spontaneous remission.[7] In contrast, other HLA alleles, including HLA-DRB1*14 and HLA-DRB1*15, have been associated with more chronic and progressive forms of sarcoidosis rather than Löfgren syndrome.[7] These findings support the concept that distinct immunogenetic profiles underlie different sarcoidosis phenotypes, with Löfgren syndrome representing a genetically and clinically favorable subset.

Löfgren syndrome occurs more commonly in women and is most frequently observed among individuals of European ancestry, particularly those of Scandinavian descent.[8] In the United States, Löfgren syndrome is less commonly reported than chronic sarcoidosis and appears to occur more often in individuals of European ancestry, in contrast to the broader United States sarcoidosis population, which disproportionately affects individuals of African ancestry.[2][8] Löfgren syndrome typically presents in young to middle-aged adults, most commonly in the third to fifth decades of life.[8] Sex-specific differences in clinical manifestations have been consistently reported, with erythema nodosum occurring more frequently in women and acute arthritis or periarticular inflammation, often involving the ankles, more commonly observed in men.[8][9] A seasonal predominance in the spring months has also been described.[8]

Sarcoidosis is thought to arise from an antigen-driven immune response in a genetically susceptible host, triggered by an as-yet unidentified antigen. Granuloma formation reflects dysregulated crosstalk between innate and adaptive immunity, with macrophage differentiation at the granuloma core and sustained antigen presentation driving T-cell activation to contain persistent antigenic stimuli that the host cannot effectively clear.[10][11] Despite extensive investigation, the underlying cause and precise pathophysiologic mechanisms remain incompletely understood. Authors have hypothesized that genetically predisposed individuals still require exposure to a specific antigen, whether exogenous or endogenous. This trigger then activates macrophages and ultimately elicits an exaggerated cellular immune response, leading to granuloma formation. The pathogenesis is very complex and not yet well understood. At the core of the process, antigen-driven activation of T lymphocytes and macrophages plays a dominant role. Granulomas and bronchoalveolar lavage samples from patients with pulmonary sarcoidosis demonstrate a mixed inflammatory infiltrate with prominent lymphocytosis.[12] The majority of lymphocytes within sarcoidal granulomas are CD4+ T helper 1 (Th1) cells, contributing to an elevated CD4/CD8 ratio in many patients. These cells secrete cytokines, eg, interleukin (IL)-2, IL-12, and interferon-gamma, promoting macrophage activation and granuloma formation. More recent studies have highlighted the role of Th17 cells, regulatory T-cell dysfunction, and antigen-specific immune responses, suggesting that an imbalance between proinflammatory and regulatory pathways contributes to persistent granulomatous inflammation and phenotypic heterogeneity in sarcoidosis.[13] Genetic factors, particularly HLA-DRB1*03–associated immune responses, are thought to promote more effective antigen clearance, which may explain the acute onset and high rates of spontaneous resolution observed in Löfgren syndrome.[10][14]

Löfgren syndrome typically does not require a histologic diagnosis. On pathology, Löfgren syndrome is similar to other forms of sarcoidosis in that it characteristically presents with noncaseating epithelioid granulomas, usually with a sparse or absent surrounding lymphocytic inflammation, also known as “naked” granulomas, seen on biopsy.[15] Necrosis is typically absent, and alternative granulomatous disorders should be considered when significant necrosis or atypical features are identified.

Löfgren syndrome is typically characterized by erythema nodosum, bilateral hilar lymphadenopathy, fever, and migratory polyarthritis.[5] Löfgren syndrome occasionally also presents with uveitis.[5] The arthritis associated with Löfgren syndrome is more prevalent in males and is distinguished by periarticular inflammation involving soft tissue and tenosynovitis, rather than true arthritis. Löfgren syndrome predominantly affects a few joints (2 to 5 joints), most commonly in the lower extremities, particularly the ankles, in a symmetric distribution. However, this condition can also involve the knees, wrists, and elbows.[16][17] Erythema nodosum manifests as painful, bright red, subcutaneous nodules that are generally symmetric on the anterior shins, in contrast to macular/papular sarcoidosis, which tends to occur at sites of repetitive trauma. These lesions, along with fever, typically resolve spontaneously within 6 weeks and may result in postinflammatory hyperpigmentation, but do not lead to scarring or atrophy. Though the resolution of lymphadenopathy may be protracted, taking up to a year, this finding completely resolves in 90% of cases. Other clinical conditions that may precipitate Löfgren syndrome include acute tuberculosis and acute presentations of endemic fungal infections, such as histoplasmosis, blastomycosis, and coccidioidosis.[18][19]

The diagnosis of sarcoidosis is primarily clinical, but also requires compatible clinical and radiographic findings, exclusion of alternative causes of granulomatous disease, and, when tissue is obtained, histologic demonstration of noncaseating granulomas. According to contemporary clinical practice guidelines, the diagnosis generally requires 3 elements: a compatible clinical and radiographic presentation, exclusion of alternative causes of granulomatous disease, and, when tissue is obtained, histologic demonstration of noncaseating granulomas.[20][21] Initial Diagnostic Evaluation In selected classic clinical presentations, a presumptive diagnosis may be made without tissue confirmation. These include Löfgren syndrome, lupus pernio, and Heerfordt syndrome, in which the combination of characteristic clinical and radiographic findings is considered sufficiently specific to establish the diagnosis without biopsy.[21] (see Image. Löfgren Syndrome) When the classic triad of erythema nodosum, bilateral hilar lymphadenopathy, and acute ankle arthritis is present, the clinical specificity for sarcoidosis approaches 99%, making tissue confirmation unnecessary in most cases.[7] Chest radiography is necessary to document mediastinal lymphadenopathy, which may present in patterns other than classic bilateral hilar adenopathy, including unilateral hilar adenopathy or right paratracheal lymphadenopathy with or without pulmonary involvement. Histologic Diagnosis Should the disease deviate from the classic course or fail to resolve within the expected time, a definitive histologic diagnosis may be necessary. The first step in diagnosis should be to determine the most appropriate site for biopsy. Of note, lesions of erythema nodosum do not show sarcoidal granulomas and are therefore not useful biopsy sites for establishing a tissue diagnosis. A comprehensive physical examination should be performed with extra caution when examining periorificial sites, including the parotid and lacrimal glands and the conjunctiva, the extremities, sites of previous trauma or tattoos, and a full lymph node assessment. Without an easily accessible superficial biopsy site, patients may require a more invasive biopsy method.

Should the disease deviate from the classic course or fail to resolve within the expected time, a definitive histologic diagnosis may be necessary. The first step in diagnosis should be to determine the most appropriate site for biopsy. Of note, lesions of erythema nodosum do not show sarcoidal granulomas and are therefore not useful biopsy sites for establishing a tissue diagnosis. A comprehensive physical examination should be performed with extra caution when examining periorificial sites, including the parotid and lacrimal glands and the conjunctiva, the extremities, sites of previous trauma or tattoos, and a full lymph node assessment. Without an easily accessible superficial biopsy site, patients may require a more invasive biopsy method. Alternatively, minimally invasive methods have emerged, including flexible bronchoscopy with bronchoalveolar lavage (BAL), endobronchial biopsy, and transbronchial biopsy to assist in the diagnosis of sarcoidosis. Several studies have noted an increase in activated CD4+ Th1 cells, a decrease in CD8+ T cells, and an increase in IgG-secreting plasma cells. Consequently, a CD4/CD8 ratio greater than 3.5 has been shown to have a 94% specificity for the diagnosis of sarcoidosis. Laboratory Studies Other laboratory tests are typically not required and remain nonspecific. Findings may include systemic lymphopenia, elevated levels of calcium, alkaline phosphatase, C-reactive protein (CRP), angiotensin-converting enzyme (ACE), or gamma globulin (polyclonal). Tuberculin skin testing or interferon-gamma release assay should be performed to help exclude tuberculosis, which can mimic both erythema nodosum and sarcoidosis.[22] Reports of thyroid dysfunction in association with cutaneous disease have been documented; clinicians should consider the evaluation of thyroid function following definitive diagnosis.[23]

Other laboratory tests are typically not required and remain nonspecific. Findings may include systemic lymphopenia, elevated levels of calcium, alkaline phosphatase, C-reactive protein (CRP), angiotensin-converting enzyme (ACE), or gamma globulin (polyclonal). Tuberculin skin testing or interferon-gamma release assay should be performed to help exclude tuberculosis, which can mimic both erythema nodosum and sarcoidosis.[22] Reports of thyroid dysfunction in association with cutaneous disease have been documented; clinicians should consider the evaluation of thyroid function following definitive diagnosis.[23] Serum ACE levels have historically shown inconsistent elevation in sarcoidosis and have correlated poorly with overall disease activity. More recent phenotype-based analyses suggest that ACE levels may instead reflect underlying immunogenetic subtypes. In a cohort of 1204 patients, 40% had ACE levels above the reference range. Patients with elevated ACE levels were more frequently classified as having non-Löfgren sarcoidosis and Scadding stage II disease, and they had a higher prevalence of extrapulmonary manifestations compared with those with normal ACE levels. HLA Testing and Biomarkers Distinct HLA associations were also observed. Patients carrying the HLA-DRB1*04 allele were more likely to have elevated ACE levels, whereas those with HLA-DRB1*03 more commonly had normal ACE levels. Notably, HLA-DRB1*03 is strongly associated with the acute Löfgren phenotype and a favorable clinical course, whereas non-DRB1*03 genotypes are more often linked to higher ACE levels, extrapulmonary involvement, and more chronic disease courses. These findings suggest that ACE elevation may reflect underlying immunogenetic phenotypes rather than overall disease burden alone.[24]

Distinct HLA associations were also observed. Patients carrying the HLA-DRB1*04 allele were more likely to have elevated ACE levels, whereas those with HLA-DRB1*03 more commonly had normal ACE levels. Notably, HLA-DRB1*03 is strongly associated with the acute Löfgren phenotype and a favorable clinical course, whereas non-DRB1*03 genotypes are more often linked to higher ACE levels, extrapulmonary involvement, and more chronic disease courses. These findings suggest that ACE elevation may reflect underlying immunogenetic phenotypes rather than overall disease burden alone.[24] Emerging biomarkers, including serum chitotriosidase, soluble interleukin-2 receptor, neopterin, serum amyloid A, KL-6, and chitinase-related proteins such as YKL-40, are currently under investigation as potential adjuncts to assess disease activity or support the diagnosis of sarcoidosis. However, according to the most recent American Thoracic Society diagnostic guideline, no serum biomarker—including ACE, chitotriosidase, or these newer investigational markers—is recommended for establishing the diagnosis, which remains based on compatible clinical–radiographic findings, exclusion of alternative causes, and histologic confirmation when necessary.[21]

For most patients with classic Löfgren syndrome, management is supportive because spontaneous remission is common. Initial therapy is directed at symptom control, typically with nonsteroidal anti-inflammatory drugs (NSAIDs) for ankle periarthritis and arthritis and constitutional symptoms. If symptoms are severe or refractory (eg, disabling ankle pain/tenosynovitis, significant functional limitation, or persistent systemic symptoms), a short course of oral glucocorticoids may be considered. A commonly used “low-dose” glucocorticoid regimen is prednisone (or prednisolone) 20 mg daily for 2 to 4 weeks, followed by a taper (eg, decrease by 5 mg every 1 to 2 weeks) with the goal of discontinuation by approximately 6 to 8 weeks, individualized to clinical response. Higher starting doses (eg, 40 mg) have been studied in pulmonary sarcoidosis, but randomized data suggest no clear advantage over 20 mg for short-term outcomes, supporting the use of the lowest effective dose when glucocorticoids are needed.[25][21][26]

The combination of fever, arthralgia, and erythema nodosum, although suggestive, is not specific for sarcoidosis. Reactions may be idiopathic or caused by several other triggers, including: Medication-induced causes, including penicillin, sulfa drugs, oral contraceptives, and immunizations Infections, eg, Streptococcus, enteric bacteria, Mycobacterium tuberculosis, coccidioidomycosis, histoplasmosis, and blastomycosis [18][19] Other systemic inflammatory diseases, eg, inflammatory bowel disease, lupus, Behcet disease Pregnancy Approximately 10% to 22% of cases of erythema nodosum are attributable to sarcoidosis. A thorough medical history can help distinguish among the above causes of erythema nodosum. Tuberculosis should be ruled out with either the Tuberculin skin test or QuantiFERON gold. A combination of classic radiographic pulmonary findings of bilateral hilar adenopathy can assist in confirming the diagnosis of Löfgren syndrome. As discussed above, if the syndrome does not follow the classic timeline, an alternative diagnosis should be considered, and histologic confirmation of the disease is necessary.

In contrast to systemic sarcoidosis, which is commonly staged radiographically to characterize pulmonary involvement, Löfgren syndrome lacks a formal staging system and is defined by a characteristic clinical phenotype. Although most patients with Löfgren syndrome demonstrate bilateral hilar lymphadenopathy without parenchymal disease, limited pulmonary involvement may be present in a minority of cases and does not negate the diagnosis or favorable prognosis.[8]

Löfgren syndrome is associated with an excellent prognosis, with spontaneous remission occurring in more than 90% of patients, typically within 1 to 2 years.[27][28] Progression to chronic sarcoidosis is uncommon, affecting fewer than 10% of patients.[27][28][29] In those who do progress, the clinical course generally evolves away from the acute Löfgren phenotype and more closely resembles nonacute sarcoidosis, most commonly manifesting as persistent pulmonary involvement or chronic inflammatory arthritis rather than recurrent erythema nodosum.[28][29] Relapse after initial remission is uncommon but has been reported, with recent longitudinal data suggesting recurrence rates of approximately 3% to 8% over extended follow-up periods.[30] Overall, long-term organ dysfunction remains rare, and outcomes are more favorable compared with other forms of sarcoidosis.[27][29] Current areas of research include investigating the correlation between HLA phenotyping and either serum ACE levels, CD3, CD4, or CD8 populations, or disease progression. A recent study by Grunewald and Eklund found that almost every Löfgren syndrome patient who was DRB1*03-positive had resolving disease within 2 years, whereas 49% of DRB1*03-negative patients developed nonresolving disease. Mucosal granulomas were identified significantly more often in DRB1*03-negative patients. Among DRB1*03-negative patients who were treated with oral steroids at disease onset, 80% developed a nonresolving disease.[31] This represents exciting research avenues that are being pursued but are not ready for bedside decision-making.

Although Löfgren syndrome typically follows a self-limited course, a small proportion of patients may progress to chronic or relapsing sarcoidosis. Persistent pulmonary disease, chronic inflammatory arthritis, or extrapulmonary organ involvement may develop in these cases. Ocular, cardiac, neurologic, renal, or hepatic manifestations may occur in patients who evolve away from the acute Löfgren phenotype. Ongoing follow-up is therefore appropriate in patients with atypical features, incomplete resolution, or new systemic symptoms.

Routine specialty consultation is not required in patients with classic Löfgren syndrome who have a typical presentation and expected clinical course. Specific symptoms, atypical features, or concern for extrapulmonary involvement should guide targeted consultation. For instance, ophthalmology consultation is indicated in patients with ocular symptoms, including eye pain, redness, photophobia, blurred vision, or suspected uveitis or episcleritis, given the risk of ocular involvement in sarcoidosis. Dermatology consultation is appropriate when cutaneous findings are atypical for erythema nodosum, ulcerative, persistent, or when diagnostic uncertainty exists regarding the skin manifestations. Rheumatology consultation may be warranted in patients with severe, persistent, or progressive inflammatory arthritis that does not respond to supportive therapy or when alternative inflammatory arthritides are being considered. Pulmonology consultation should be considered when thoracic imaging is atypical, pulmonary symptoms are progressive, or there is concern for chronic or nonself-limited sarcoidosis. Neurology or cardiology consultation is indicated when neurologic deficits, seizures, syncope, arrhythmias, or other features raise concern for neurosarcoidosis or cardiac involvement. In patients with atypical disease manifestations or failure to improve as expected, an interprofessional approach may be required to guide further evaluation and management.

Löfgren syndrome is a specific form of sarcoidosis that usually begins suddenly and is often associated with painful red nodules on the legs (erythema nodosum), joint pain or swelling, especially in the ankles, and enlarged lymph nodes in the chest. Although the symptoms can be uncomfortable, this condition is typically self-limited, and most patients spontaneously improve over time. Many patients recover within several months to a year with supportive treatment, eg, rest, nonsteroidal anti-inflammatory medications, and symptom control. Long-term complications are uncommon, and the overall prognosis is favorable. Because Löfgren syndrome has a characteristic clinical pattern, extensive testing or invasive procedures are often unnecessary when the diagnosis is clear. Patients should be encouraged to maintain regular follow-up with their healthcare team and to report new or worsening symptoms, eg, persistent shortness of breath, vision changes, neurologic symptoms, or chest pain. Education should emphasize reassurance, expected recovery, and the importance of monitoring rather than aggressive intervention in most cases.

Löfgren syndrome is a distinct acute clinical presentation of systemic sarcoidosis typically seen in patients younger than 40 years, presenting with erythema nodosum, mediastinal adenopathy, and symmetric ankle arthritis. Fever and other constitutional symptoms are frequently present but are not required for diagnosis. Chest radiography is essential to confirm bilateral hilar lymphadenopathy and, in the appropriate clinical context, may obviate the need for tissue biopsy. Mediastinal lymphadenopathy and erythema nodosum each have a broad differential diagnosis when present in isolation. When the classic triad is present, given its high sensitivity (93%) and specificity (99%) for diagnosing sarcoidosis, further invasive diagnostic evaluation is often unnecessary.[7] A key diagnostic pitfall is failure to recognize this characteristic presentation, which may lead to unnecessary laboratory testing or imaging. Conversely, if the presentation deviates from the classic features, eg, absence of bilateral hilar lymphadenopathy, progressive pulmonary disease, or clinically significant extrapulmonary organ involvement, additional evaluation, including histopathologic confirmation, is warranted. When the classic presentation is present, Löfgren syndrome is typically self-limited and associated with a favorable prognosis.

Löfgren syndrome is an acute, clinically distinct phenotype of sarcoidosis characterized by erythema nodosum, bilateral hilar lymphadenopathy, and periarticular inflammation of the ankles, often accompanied by fever and malaise. Occurring in 5% to 10% of sarcoidosis cases, it carries high diagnostic specificity and a favorable prognosis, with most cases resolving spontaneously. Pathophysiology reflects an antigen-driven immune response in genetically susceptible individuals, particularly those with HLA-DRB1*03, leading to noncaseating granuloma formation mediated by CD4+ T-helper 1–predominant inflammation. Recognition is clinically significant because the classic presentation permits diagnosis without tissue biopsy, provided alternative granulomatous diseases are excluded. Evaluation relies on clinical and radiographic findings, while laboratory markers lack specificity. Management is primarily supportive with nonsteroidal anti-inflammatory drugs, with short courses of glucocorticoids reserved for severe or persistent symptoms, alongside monitoring for atypical progression or extrapulmonary involvement. Interprofessional collaboration enhances diagnostic accuracy, minimizes unnecessary invasive procedures, and supports comprehensive care. Physicians and advanced practitioners lead diagnostic evaluation, confirm clinical criteria, and guide management decisions, while primary care clinicians facilitate early recognition, longitudinal monitoring, and coordination of care. Nurses assess symptoms, reinforce education, and monitor treatment response, while pharmacists optimize medication selection, ensure safe glucocorticoid use, and counsel on adverse effects. Radiologists and pulmonologists contribute to imaging interpretation and advanced diagnostic evaluation when needed. Coordinated communication, shared decision-making, and timely referral ensure appropriate follow-up, reduce complications, and promote high-quality, patient-centered outcomes.