Lofgren’s Syndrome: A Unique Presentation of Sarcoidosis Masquerading as Lower Extremity Cellulitis

Abstract

Löfgren’s syndrome is an acute, self-limiting variant of sarcoidosis, typically presenting with erythema nodosum, bilateral hilar lymphadenopathy, and acute arthritis or periarthritis—most commonly involving the ankles. Its clinical overlap with other inflammatory conditions can pose a diagnostic challenge. We describe a 34-year-old male with no prior medical history who presented with bilateral ankle and foot pain, erythema, and swelling, initially diagnosed as cellulitis based on imaging findings. He has no response to broad-spectrum antibiotics. During his further hospital stay, he developed polyarthritis. Laboratory evaluation revealed neutrophilic leukocytosis, elevated inflammatory markers, and a normal serum angiotensin-converting enzyme level. Imaging showed bilateral hilar lymphadenopathy and intra-abdominal adenopathy. Bronchoscopy with bronchoalveolar lavage revealed an elevated CD4:CD8 ratio (5.0), and endobronchial ultrasound-guided transbronchial needle aspiration confirmed noncaseating granulomas. Infectious, autoimmune, and malignant causes were excluded. Based on clinical features and histology, a diagnosis of Löfgren’s syndrome was established. Nonsteroidal anti-inflammatory drug therapy led to rapid clinical improvement, and antibiotics were discontinued. Löfgren’s syndrome should be considered in patients presenting with bilateral lower extremity erythema and swelling unresponsive to antibiotics, especially when accompanied by systemic symptoms. Early thoracic imaging and consideration of sarcoidosis in the differential diagnosis can prevent misdiagnosis and unnecessary treatment.

Introduction

Sarcoidosis is a chronic, multisystem granulomatous disease of unknown etiology, most commonly affecting the lungs (approximately 95%) and skin (15.9%). ¹ While the majority of patients exhibit an insidious onset with a slowly progressive course, up to 40% may present acutely with systemic features. ² Löfgren syndrome represents an acute and self-limiting variant of sarcoidosis, classically characterized by a triad of erythema nodosum (EN), bilateral hilar lymphadenopathy, and acute polyarthritis, most commonly involving the ankles, often accompanied by fever. ³ The constellation of these clinical findings has a reported diagnostic specificity of up to 95% for sarcoidosis, permitting a diagnosis without the need for histopathological confirmation in typical cases. ⁴ EN and fever have been more frequently reported in women, whereas arthritis was more common in men.^4,5 Due to the predominant involvement of the lower extremities, Löfgren syndrome may clinically mimic other conditions such as cellulitis, deep vein thrombosis (DVT), or septic arthritis. Such overlap can result in misdiagnosis, delayed recognition of the underlying etiology, and unnecessary or inappropriate treatment. We report a case of a 34-year-old male presenting with acute lower extremity swelling and erythema initially presumed to be cellulitis, ultimately diagnosed as Löfgren syndrome in the context of newly identified sarcoidosis.

Case Presentation

A 34-year-old white male with no significant past medical history presented with a 5-day history of bilateral foot and ankle pain, swelling, and erythema. Two days prior to admission, he developed low-grade fever, chills, and polyarthralgia involving the hands and knees. He had been self-medicating with over-the-counter ibuprofen for pain relief. His social history was notable for a 20-pack-year smoking history and moderate alcohol consumption, approximately 6 drinks per week. He denied any recent travel, trauma, tick bites, or illicit drug use.

On presentation, his heart rate of 100 beats per minute and blood pressure of 151/84 mmHg, temperature was 36.9°C, respiratory rate 18 breaths per minute, and oxygen saturation was 98% on room air. Physical examination revealed bilateral ankle joint tenderness, erythema, and swelling with restricted range of motion, particularly with both active and passive movements. No other joints showed evidence of inflammation. Systemic examination was otherwise unremarkable.

Initial laboratory testing demonstrated leukocytosis with neutrophilic predominance (total leucocyte count 14,190, normal 4000-11,000) and elevated inflammatory markers, including C-reactive protein (20 mg/dL, normal 0-1 mg/dL) and erythrocyte sedimentation rate (78 mm/h, normal 0-4 mm/h). Uric acid levels were found to be low. The laboratory parameters at admission are summarized in Table 1. A contrast-enhanced computed tomography (CT) scan of the lower extremities suggested findings consistent with dorsal foot and ankle cellulitis (Figure 1). Given the concern for possible systemic infection, the patient was empirically started on intravenous vancomycin and piperacillin/tazobactam.

Table 1.

Laboratory Parameters at Admission.

Parameter	Result	Normal range
WBC (×103/µL)	14.19	4.0-11.0
RBC (×106/µL)	4.55	4.5-5.9 (male)/4.1-5.1 (female)
HGB (g/dL)	13.5	13.5-17.5 (male)/12.0-15.5 (female)
PLT (×103/µL)	268	150-450
ESR (mm/h)	78	0-14
Serum sodium (mmol/L)	138	135-145
Serum potassium (mmol/L)	4.1	3.5-5.1
Bicarbonate (mmol/L)	26	22-30
Glucose serum (mg/dL)	125	74-106
BUN serum (mg/dL)	11	9-20
Creatinine (mg/dL)	0.7	0.66-1.25
Serum calcium (mg/dL)	9.5	8.4-10.2
Serum albumin (g/dL)	4.3	3.5-5.0
Serum protein (g/dL)	7.6	6.3-8.2
Total bilirubin (mg/dL)	0.9	0.2-1.3
AST (IU/L)	18	17-59
ALT (IU/L)	13	0-50
Alkaline phosphatase (IU/L)	77	38-126
Serum uric acid (mg/dL)	2.6	3.5-8.5
CRP (mg/dL)	20.38	0-1.0
Lactic acid (mmol/L)	1.3	0.7-2.1
TSH	1.080	0.465-4.680
HbA1c	5.4%	<5.7%
Urine analysis and microscopy
Color	Yellow	Yellow
Appearance	Clear	Clear
Glucose	Negative	Negative
Bilirubin	Negative	Negative
Ketone	Trace	Negative
Specific gravity	>1.030	1.002-1.029
Blood	Negative	Negative
Ph	5.5	5.0-8.5
Protein	1+	Negative
Urobilin	1.0	0-1.0
Nitrite	Negative	Negative
Leuk esterase	Negative	Negative
WBC (#/hpf)	0-5	0-5
RBC (#/hpf)	0-2	0-2
Bacteria	Negative	Negative
Total casts	None	None
Squamous epithelial cells	Negative	Negative

Abbreviations: AG, anion gap; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; HbA1c, glycated hemoglobin; HGB, hemoglobin; PLT, platelet count; RBC, red blood cell count; TSH, thyroid-stimulating hormone; UA, uric acid; WBC, white blood cell count.

Figure 1.

Computed tomography of the lower extremities showed soft tissue swelling consistent with dorsal foot and ankle cellulitis.

Further imaging with contrast-enhanced CT of the thorax and abdomen revealed bulky bilateral mediastinal lymphadenopathy, a tree-in-bud pattern in the right lung (Figure 2), and intra-abdominal lymphadenopathy. During hospitalization, the patient developed additional signs, including erythema and swelling of the bilateral metacarpophalangeal, proximal interphalangeal, and wrist joints, as well as new-onset oral ulcers and submandibular lymphadenopathy.

Figure 2.

Computed tomography of the thorax revealed bilateral mediastinal lymphadenopathy (red arrow), tree-in-bud opacities in the right lung.

Given the progression of symptoms, an extensive diagnostic workup was initiated to rule out infectious, autoimmune, and malignant etiologies. Serologic testing, including viral panels, rheumatoid factor, antinuclear antibodies, and other autoimmune markers, were negative. Serum angiotensin-converting enzyme (ACE) levels were within normal limits (46 U/L; normal range: 9-67 U/L).

A punch biopsy of the skin over the right ankle demonstrated spongiotic and interface dermatitis with nonspecific perivascular chronic inflammation (Figure 3), which are epidermal histologic changes that may be seen with underlying inflammatory disorders, including cellulitis or periarticular inflammation. Bronchoscopy with bronchoalveolar lavage (BAL) revealed a lymphocyte count of 14% and an elevated CD4:CD8 ratio of 5. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) of mediastinal lymph nodes revealed noncaseating granulomas (Figure 4). Microbiological cultures from the BAL fluid, including tests for Mycobacterium tuberculosis, Pneumocystis jirovecii, fungal organisms, and bacterial pathogens, were negative. Bone marrow aspiration and biopsy showed granulocytic hyperplasia, supportive of an acute inflammatory process.

Figure 3.

A punch biopsy of the skin over the right ankle demonstrated spongiotic and interface dermatitis with nonspecific perivascular chronic inflammation. Spongiotic dermatitis are histologic changes that may be seen with underlying inflammatory processes, such as cellulitis or periarticular inflammation.

Figure 4.

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) of mediastinal lymph nodes revealed noncaseating granulomas without acid fast organisms, fungal organisms, or foreign bodies.

Based on the constellation of symptoms—fever, acute symmetric polyarthritis predominantly involving the ankles and small joints of the hands, bilateral hilar lymphadenopathy, and histologic evidence of noncaseating granulomatous inflammation—a clinical diagnosis of Löfgren syndrome was established. Antibiotic therapy was discontinued following the exclusion of infectious etiologies. The patient was initiated on ibuprofen 400 mg 3 times daily with significant improvement in joint pain and swelling by the time of discharge.

At outpatient follow-up 2 weeks later, the patient reported continued improvement in symptoms. Inflammatory markers had normalized, and no recurrence of joint symptoms or fever was noted. He remained off antibiotics and was managed conservatively with nonsteroidal anti-inflammatory drugs (NSAIDs), with plans for ongoing clinical monitoring.

Discussion

Sarcoidosis is a chronic multisystem granulomatous disorder of unknown etiology, usually affecting people before 50 years of age with a peak occurrence between 20 and 39 years of age. ⁶ The prevalence of sarcoidosis in the United States is estimated to be 60 per 100,000 population, with a higher occurrence in women and African Americans. ⁷ It most commonly involves the lungs (95%), skin (15.9%), lymph nodes (15.2%), eye (11.8%), and the liver (11.2%), though it can practically involve any organ system in the body. ¹ Histologic evidence of epithelioid-cell granulomas in the absence of organisms or foreign body reactions in the involved organs is the hallmark of the disease. ⁶ Sarcoidosis is usually a chronic indolent disease. However, in 5%-10% of cases, it may present acutely with a triad of fever, bilateral hilar lymphadenopathy and ankle swelling or EN called Lofgren’s syndrome. ⁴ Löfgren’s syndrome has an estimated prevalence of 10 to 12 per 100,000, predominantly affecting females in their third and fourth decades. ⁸ While EN is more common in females, males often exhibit bilateral ankle swelling due to synovitis or periarticular inflammation. ⁸

Crucially, the acute lower extremity findings in Löfgren’s syndrome—pain, erythema, warmth, and swelling—can mimic other common conditions such as cellulitis, DVT, or septic arthritis. In our case, the patient’s initial CT imaging suggested dorsal foot and ankle cellulitis, and he was empirically treated with broad-spectrum antibiotics. However, the lack of clinical improvement prompted further investigation. This case illustrates how easily Löfgren’s syndrome can be misdiagnosed as cellulitis, particularly when cutaneous manifestations like EN are absent, or when systemic symptoms are initially subtle or evolving. Such diagnostic pitfalls may lead to inappropriate treatment delays and unnecessary antibiotic exposure.

Imaging findings in Löfgren’s syndrome often reflect periarticular soft tissue inflammation. Magnetic resonance imaging and ultrasonography typically reveal subcutaneous edema and periarticular inflammation without prominent synovitis, consistent with our case. ⁹

The diagnosis of sarcoidosis is made based on a combination of clinical features, radiologic evidence (most notably bilateral hilar lymphadenopathy), and histologic confirmation of non-caseating granulomas. In typical presentations of Löfgren’s syndrome, the presence of 3 of the following 4 criteria—symmetrical ankle arthritis or periarthritis, symptom onset of less than 2 months, age less than 40 years, and EN—has shown a sensitivity of 93% and specificity of 99% for sarcoid arthritis. ¹⁰ While tissue biopsy is not always necessary in classic cases of Löfgren’s syndrome, histopathologic confirmation is often pursued when diagnosis is challenging and to exclude mimickers such as mycobacterial or fungal infections, lymphoma, drug-induced hypersensitivity reactions, and autoimmune vasculitides. Diagnostic workup typically includes acid-fast bacilli and fungal stains, cultures, interferon-gamma release assays, and autoimmune serologies.^6,8 If a biopsy is needed for diagnosis, a sample is obtained from the most easily accessible and commonly involved organs, such as the skin, lymph nodes, eye, and lungs. Bronchoscopy and transbronchial lung biopsy have a diagnostic yield of 85%, while EBUS-TBNA of intrathoracic lymph nodes has a diagnostic yield of 82%. ⁶ While the cytology of the BAL fluid in our patient was unremarkable, up to 74% of patients with Löfgren’s syndrome may show lymphocytosis with an elevated CD4/CD8 ratio (>3.5). ⁹ The serum ACE level, produced from the sarcoid granulomas, may be elevated in 15% of patients with Löfgren’s syndrome. ⁴ However, it has poor sensitivity and insufficient specificity and is not helpful for diagnosing sarcoidosis. ¹¹

Löfgren’s syndrome is usually a self-limiting illness and remits spontaneously with symptomatic treatment with NSAIDs, like in our case. Rarely, 5%-19% of patients present with parenchymal lung involvement, parotitis, facial nerve palsy, uveitis, or significant liver disease. Patients that are unable to tolerate NSAIDs may require a course of corticosteroids. ⁹ Older age at diagnosis, stage II pulmonary sarcoid on chest X-ray and need for treatment are risk factors for chronic disease. ¹⁰ One-third of cases may run an indolent course, and severe organ involvement may require treatment with immunosuppressive agents like methotrexate, ciclosporin, or azathioprine besides corticosteroids. ⁸ In refractory cases, antitumor necrosis factors such as infliximab, adalimumab, or cyclophosphamide have been used as third-line agents. ¹² This case highlights that Löfgren’s syndrome should be considered in the differential diagnosis of bilateral lower extremity erythema and swelling, particularly in young adults with systemic symptoms such as fever and polyarthralgia. Failure to recognize this acute sarcoid presentation may lead to misdiagnosis as cellulitis, resulting in unnecessary antibiotic use, and delayed diagnosis.

Conclusion

Löfgren’s syndrome represents a pathognomonic form of acute sarcoidosis marked by its self-limiting natural course. Treatment with NSAIDs is usually sufficient, with corticosteroids rarely required for more severe cases of the disease. Often, it may masquerade as other diseases like cellulitis of the leg in our patient. Hence, it is important to keep this entity as a differential while caring for younger patients with cellulitis, especially if they do not respond adequately to antibiotics. It is also important to screen for hilar lymphadenopathy with thoracic imaging in such cases to clinch the diagnosis.