Lofgren Syndrome


Article Author:
Falon Brown


Article Editor:
Laura Tanner


Editors In Chief:
Jon Parham
Abigail Frank
Jon Sivoravong


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
5/5/2019 10:39:19 PM

Introduction

Lofgren syndrome is a clinically distinct phenotype of sarcoidosis, first described in 1946 by Swedish pulmonologist Sven Lofgren. Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that commonly involves the lungs with the second most commonly affected organ being the skin.[1] Cutaneous manifestations of sarcoidosis are seen in up to 33% of patients and may be the first clinical sign of the disease.[2] In contrast to the often-insidious onset, slow disease progression and chronic disease course typical of sarcoidosis, Lofgren’s syndrome presents acutely. It typically presents in younger patients with acute onset erythema nodosum (EN), bilateral hilar lymphadenopathy, fever, and migratory polyarthritis, and without granulomatous skin involvement. Lofgren’s syndrome portends a favorable prognosis.[3][4]

Etiology

Etiology and pathophysiology of cutaneous sarcoidosis are poorly understood and attributable to both genetic and environmental factors. Though acute sarcoidosis is not infectious, there is some thought that selected cases may be due to abnormal host reaction to exposure to one or more infective agents, such as Mycobacterium tuberculosis or Propionibacterium or environmental exposures, such as beryllium, dust, or other occupational agents.[5][6][7]

Epidemiology

Sarcoidosis affects patients of all ages and races. The incidence and clinical presentation of sarcoidosis differ depending on gender, ethnicity, geographic location, and genetic background. In the United States, women are affected more often than men with an overall African American predominance.[8] Worldwide, the incidence of sarcoidosis is highest in Scandinavians (Sweden and the United Kingdon) and lowest in Spain and Japan.[8]

Lofgren syndrome consistently appears to be more common in females. It occurs most commonly in European Caucasians, especially patients with Scandinavian descent. Young to middle age adults are more likely to present with this disease with a median age of 37 years old. Specific manifestations of the components of Lofgren syndrome differ based on gender, whereas erythema nodosum is found predominantly in women and arthropathy/arthritis is seen more commonly in men. It classically occurs in the spring months.

Pathophysiology

In general, sarcoidosis is thought to be a polygenic disorder. The impact of HLA alleles on the pathogenesis of sarcoidosis varies significantly, depending upon disease subtype and racial group. In the case of Lofgren syndrome, HLA-B8/DR3 has a strong association with the disease and also with overall disease resolution.[9]

Despite a rigorous investigation, research has not unveiled a cause or proven pathophysiologic mechanism. The hypothesis is that hosts may have a genetic predisposition but still require exposure to a specific antigen whether it be exogenous or endogenous. This trigger then activates macrophages and ultimately leads to 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, T cells play a dominant role in this immune reaction. Studies have shown that granulomas and bronchioloalveolar lavage samples from patients with pulmonary sarcoidosis shown mixed infiltrate with prominent lymphocytosis.[10]

The majority of lymphocytes within sarcoidal granulomas are CD4+T helper 1 (Th1) lymphocytes, contributing to an overall elevated CD4/CD8 ratio. CD4+T cells secrete interleukin (IL)-2, IL-12, IL-18, and interferon (IFN)-gamma, which in combination with the release of tumor necrosis factor (TNF)-alpha by macrophages and some CD8+T cells, leads to persistent Th1 activity, persistent IFN-gamma elevation and macrophage accumulation within the tissue. Compartmentalization of granuloma-forming CD4+ T lymphocytes and monocytes/macrophages within peripheral tissues leads to systemic lymphopenia and decreased systemic CD4/CD8 ratio.

Despite this understanding, the evidence is emerging noting bronchioloalveolar lavage samples may have CD4 to CD8 ratio is of less importance because it can increase, be normal, and even decrease.[10] Studies have also noted patients with active sarcoidosis with elevated Th17 to Treg ratio in the peripheral blood and bronchoalveolar lavage fluid.[11]

Histopathology

Lofgren syndrome typically does not require a histologic diagnosis. On pathology, it similar to other forms of sarcoidosis in that it characteristically presents with non-caseating epithelioid granulomas, usually with a sparse or absent surrounding lymphocytic inflammation, also known as “naked” granulomas, seen on biopsy.[12]

History and Physical

Lofgren syndrome is a constellation of the following findings: erythema nodosum, bilateral hilar lymphadenopathy, fever, and migratory polyarthritis.[3] It occasionally also presents with uveitis.[3]

 The arthritis of Lofgren syndrome occurs more often in men, and with periarticular inflammation involving soft tissue and tenosynovitis rather than true arthritis. It typically involves ankles symmetrically but can also involve knees, wrists, and elbow.

Erythema nodosum presents as painful, bright red, subcutaneous nodules that are typically symmetric on the anterior shins, in contrast to macular/papular sarcoidosis which has a predilection for sites of repetitive trauma. These lesions along with the fever typically remit spontaneously within 6 weeks and may resolve with post-inflammatory hyperpigmentation but without scarring or atrophy. Resolution of lymphadenopathy may delay, taking up to one year, but does resolve completely in 90% of cases.

Evaluation

The diagnosis of sarcoidosis is complex with no definitive test exists. It requires clinical-radiographic correlation, exclusion of alternative disease that can induce granuloma formation, such as tuberculosis, and histologic detection of noncaseating granulomas. There are several specific clinical situations where a presumptive diagnosis can be made based on clinic radiographic findings alone, and biopsy is not considered necessary.[13][14] Bilateral hilar lymphadenopathy, migratory polyarthralgia, erythema nodosum, and fevers of Lofgren syndrome is one such example.[15]

Chest radiography is still necessary to make this diagnosis though may see a variety of alternative pathology other than classic bilateral hilar adenopathy, including unilateral hilar adenopathy or right paratracheal lymphadenopathy with or without pulmonary involvement.

Should disease deviate from the classic course or fail to resolve within expected time 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 will not show sarcoidal granulomas and are therefore not useful biopsy sites to establishing the diagnosis. A comprehensive physical examination should be performed with extra caution taken to throughout examine periorificial sites, including parotid glands, lacrimal glands, and conjunctiva, extremities, sites of previous trauma or tattoos, and 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 the increased amount of activated CD4+ Th1 cells, decreased 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.

Other lab tests are not typically required and remain quite non-specific. Findings may include systemic lymphopenia, elevated levels of calcium, alkaline phosphatase, C-reactive protein (CRP), acetylcholinesterase (ACE), or gamma globulin (polyclonal). Tuberculin skin test or measurement of IFN-gamma in undiluted plasma should be performed in all patient to exclude the diagnosis of tuberculosis which can mimic both erythema nodosum and sarcoidosis.[16] There are reports of thyroid dysfunction in association with cutaneous disease, consider the evaluation of thyroid function following definitive diagnosis.[17]

Treatment / Management

Treatment of Lofgren syndrome is typically supportive with spontaneous resolution occurring over 1 to 2 years. Constitutional symptoms and arthralgias are treatable with non-steroidal anti-inflammatory drug or colchicine. In rare, severe cases may warrant corticosteroids use which can usually be tapered quickly over a few weeks to months.[18]

Differential Diagnosis

The reaction pattern of fever, arthralgia, and lesions of erythema nodosum, though suggestive are not specific for sarcoidosis. Reactions may be idiopathic or caused by several other triggers including:

  • Medication-induced causes of penicillin, sulfa drugs, oral contraceptives, immunizations
  • Infections such as Streptococcus, enteric bacteria, Mycobacterium tuberculosis, coccidioidomycosis, histoplasmosis, blastomycosis
  • Other systemic inflammatory diseases like 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 between many of the above causes of erythema nodosum. Tuberculosis should be ruled out with either Tuberculin skin test or QuantiFERON gold. Combination of classic radiographic pulmonary findings of bilateral hilar adenopathy can assist in confirming the diagnosis of Lofgren syndrome. As discussed above, if syndrome does not follow the classic timeline alternative diagnosis should be considered, and histologic confirmation of disease is necessary.

Prognosis

Lofgren syndrome portends an excellent prognosis is associated with a greater than 90% chance of spontaneous remission within 2 years.

Pearls and Other Issues

Lofgren syndrome is a specific acute clinical presentation of systemic sarcoidosis, consisting of a classic triad of fever, erythema nodosum, and bilateral hilar adenopathy; however, this characteristic triad is not always present and has also been associated with migratory polyarthritis, especially involving ankles in men. Must have a chest radiograph to confirm hilar adenopathy. Otherwise, no specific confirmatory tests are necessary. There is significant overlap among other known etiologies of erythema nodosum which can also contribute to systemic granuloma formation. Should presentation deviate from classic findings listed above further workup and, histopathologic correlation is required. Ultimately, sarcoidosis remains a diagnosis of exclusion.

Enhancing Healthcare Team Outcomes

Sarcoidosis is a multisystem disorder with no known etiology. The diagnosis and management of sarcoidosis, especially Lofgren syndrome, requires a multi-specialty and multidisciplinary approach that including dermatology, pulmonology, radiology, and ophthalmology, with assistance from specialty-trained nursing staff and pharmacists who can assist in patient education and coordinating symptomatic management. This healthcare team approach can lead to better patient outcomes resulting from the delivery of optimal care. [Level V]


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Attributed To: Image courtesy S Bhimji MD

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Lofgren Syndrome - Questions

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A 44-year-old Scandinavian woman presents complaining of arthralgia in both knees, elbows, and ankles unrelieved by over the counter acetaminophen. X-ray of joints all normal. She is treated with over the counter ibuprofen 800 mg q8h as needed for pain; however, after one week of therapy, she returns to the clinic with persistent pain and a new rash on her lower extremities, consistent with erythema nodosum. She denies recent illness or cough but endorses intermittent mild low-grade fever and general fatigue. What is the next best step in the diagnosis of this patient?



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What finding would be atypical for a patient with Lofgren syndrome?



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A 35-year-old white woman from evaluated for a 2-week history of painful erythematous nodules scattered across her anterior shins and ankle pain. Her temperature is 101.3 F, blood pressure 120/80 mmHg, pulse 79 beats/minute, and respiratory rate 20 breaths/minute. On exam, there are several well-demarcated erythematous tender nodules on bilateral anterior lower extremities, swelling of bilateral ankles with tenderness to palpation and restricted active range of motion. Chest radiograph shows bilateral hilar lymphadenopathy. What is the diagnosis?



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A 35-year-old white woman from evaluated for a 2-week history of painful erythematous nodules scattered across her anterior shins and ankle pain. Her temperature is 101.3 F, blood pressure 120/80 mmHg, pulse 79 beats/minute, and respiratory rate 20 breaths/minute. On exam, there are several well-demarcated erythematous tender nodules on bilateral anterior lower extremities, swelling of bilateral ankles with tenderness to palpation and restricted active range of motion. Chest radiograph shows bilateral hilar lymphadenopathy. What is the next best step in management?



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A 35-year-old white woman from evaluated for a 2-week history of painful erythematous nodules scattered across her anterior shins and ankle pain. Her temperature is 101.3 F, blood pressure 120/80 mmHg, pulse 79 beats/minute, and respiratory rate 20 breaths/minute. On exam, there are several well-demarcated erythematous tender nodules on bilateral anterior lower extremities, swelling of bilateral ankles with tenderness to palpation and restricted active range of motion. Chest radiograph shows bilateral hilar lymphadenopathy. Which of the following is the best option for management of this patient?



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Lofgren Syndrome - References

References

Wanat KA,Rosenbach M, Cutaneous Sarcoidosis. Clinics in chest medicine. 2015 Dec     [PubMed]
Ponhold W, [The Löfgren syndrome: acute sarcoidosis (author's transl)]. Rontgen-Blatter; Zeitschrift fur Rontgen-Technik und medizinisch-wissenschaftliche Photographie. 1977 Jun     [PubMed]
JAMES DG,THOMSON AD,WILLCOX A, Erythema nodosum as a manifestation of sarcoidosis. Lancet (London, England). 1956 Aug 4     [PubMed]
Ferrara G,Valentini D,Rao M,Wahlström J,Grunewald J,Larsson LO,Brighenti S,Dodoo E,Zumla A,Maeurer M, Humoral immune profiling of mycobacterial antigen recognition in sarcoidosis and Löfgren's syndrome using high-content peptide microarrays. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases. 2017 Mar     [PubMed]
Ishige I,Eishi Y,Takemura T,Kobayashi I,Nakata K,Tanaka I,Nagaoka S,Iwai K,Watanabe K,Takizawa T,Koike M, Propionibacterium acnes is the most common bacterium commensal in peripheral lung tissue and mediastinal lymph nodes from subjects without sarcoidosis. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG. 2005 Mar     [PubMed]
Newman LS,Rose CS,Bresnitz EA,Rossman MD,Barnard J,Frederick M,Terrin ML,Weinberger SE,Moller DR,McLennan G,Hunninghake G,DePalo L,Baughman RP,Iannuzzi MC,Judson MA,Knatterud GL,Thompson BW,Teirstein AS,Yeager H Jr,Johns CJ,Rabin DL,Rybicki BA,Cherniack R, A case control etiologic study of sarcoidosis: environmental and occupational risk factors. American journal of respiratory and critical care medicine. 2004 Dec 15     [PubMed]
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