Diagnostic and therapeutic challenges in a patient with coexisting ankylosing spondylitis and Löfgren’s syndrome: A case report

Abstract

Löfgren’s syndrome is an acute variant of sarcoidosis, characterized by the classic triad of erythema nodosum, bilateral hilar lymphadenopathy, and arthralgia or arthritis. Its low incidence in the Chinese population contributes to limited clinical awareness and diagnostic challenges. We report the case of a Chinese man with long-standing ankylosing spondylitis who had been experiencing recurrent joint swelling, pain, and fever over the past year. At the most recent presentation, he had developed tender, erythematous subcutaneous nodules on the limbs, clinically consistent with erythema nodosum, and was diagnosed with ankylosing spondylitis and Löfgren’s syndrome. A comprehensive review of his treatment course revealed a favorable response to glucocorticoid therapy. Notably, he had received adalimumab for ankylosing spondylitis over the past year, and the temporal relationship suggested that adalimumab precipitated Löfgren’s syndrome relapse. We further reviewed the literature comparing Löfgren’s syndrome between Western and Asian populations. Our findings indicate that Asian Löfgren’s syndrome patients are more likely to receive a delayed diagnosis and often require lengthier glucocorticoid therapy. These differences may stem from genetic predispositions influencing disease expression and immune response. Therefore, we recommend that glucocorticoid regimens for Löfgren’s syndrome in Chinese patients be carefully titrated and monitored. In a similar manner, when Löfgren’s syndrome coexists with other rheumatic immune diseases, tumor necrosis factor-α inhibitors such as adalimumab should be used with heightened vigilance to minimize disease relapse.

Introduction

Sarcoidosis is a multisystem granulomatous disease of unknown etiology, defined histopathologically by the presence of noncaseating epithelioid granulomas. Although it primarily affects the lungs and intrathoracic lymph nodes, the disease can also involve the skin, liver, eyes, and nervous system. Clinical manifestations vary widely, ranging from asymptomatic to severe progressive disease. ¹ Löfgren’s syndrome (LS), a distinct acute form of sarcoidosis, typically presents with the triad of erythema nodosum (EN), bilateral hilar lymphadenopathy (BHL), and arthritis. ² The epidemiology of LS shows marked geographic and racial variations. It is prevalent among Caucasians, particularly those residing in Europe; however, it is exceedingly rare in Asian populations. This difference is believed to reflect underlying genetic susceptibility. ² Due to overlapping symptoms with primary rheumatic diseases—such as reactive arthritis and ankylosing spondylitis (AS)—and its rarity in Asia, LS is frequently underrecognized or misdiagnosed. When sarcoidosis coexists with autoimmune diseases, diagnostic confusion increases. We report the case of a male patient with AS complicated by LS who presented with recurrent arthritis, fever, and EN over the past year. His clinical trajectory was further complicated by prior adalimumab use. Through clinical review and literature comparison, we aimed to improve awareness regarding atypical LS presentations in patients with AS and inform safer biologic selection in rheumatologic practice, especially within East Asian populations.

Case presentation

In August 2024, a man in his late 30s was admitted to the rheumatology outpatient clinic of the Third People’s Hospital of Yuhang District, Hangzhou City, China, presenting with a 13-month history of recurrent bilateral ankle swelling, pain, and fever, followed by the appearance of painful subcutaneous nodules over both lower limbs 2 weeks prior. His medical history included AS diagnosed before 10 years and intermittent analgesics use. In June 2023, he sought treatment at another hospital for lower extremity swelling, pain, and fever. The physical examination at that time showed erythema, warmth, edema, and tenderness in both lower limbs as well as pain and limited range of motion in both ankle joints. He denied pain in the neck, lower back, or hip. The bilateral Patrick’s test, Schober test, and occiput to wall test were negative. Laboratory testing revealed an erythrocyte sedimentation rate (ESR) of 91 mm/h (normal: 0–15 mm/h), C-reactive protein (CRP) level of 146 mg/L (normal: 0–6 mg/L), procalcitonin level of 0.07 ng/mL (normal: 0–0.50 ng/mL), and blood uric acid level of 265 μmol/L (normal: 155–357 μmol/L). No bacterial growth was found in the blood cultures from both sides. Complete blood count; urinalysis; stool examination; tumor markers test; thyroid function test; and serologic screens for hepatitis B, hepatitis C, human immunodeficiency virus (HIV), and syphilis were normal. Antinuclear antibody test was negative, human leukocyte antigen B27 (HLA–B27) test was positive, and T-SPOT.TB assay was negative. Ultrasound examination of the bilateral ankle joints showed effusion in the posterior tendon sheaths on both sides, with subcutaneous soft tissue swelling around the right ankle and the dorsum of the foot (Figure 1). Chest computed tomography (CT) demonstrated enlarged mediastinal lymph nodes and nodular soft‑tissue density lesions at the pulmonary hila, with relatively clear margins and a course distinct from that of adjacent pulmonary vessels (Figure 2).

Figure 1.

Bilateral foot ultrasound (June 2023). (a) Left posterior tibial tendon sheath effusion (red arrow); (b) right posterior tibial tendon sheath effusion (red arrow); (c) subcutaneous soft-tissue edema on the dorsal right foot (red arrow).

Figure 2.

Chest CT (June 2023). Mediastinal lymph nodes are enlarged (green arrow). Nodular soft‑tissue density lesions at the pulmonary hila, with relatively clear margins and a course distinct from adjacent pulmonary vessels (red arrow). CT: computed tomography.

He was initially prescribed 15 mg oral prednisone daily, resulting in rapid symptom improvement within 3 days. Subsequently, the medication was switched to 90 mg oral etoricoxib once daily. However, 1 week after discontinuing prednisone, symptoms recurred, accompanied with fever (Temperature up to 38.7°C). Following re-evaluation, he was administered 40 mg subcutaneous adalimumab every 2 weeks with 15 mg oral prednisone daily. Symptoms resolved within 1 week. The prednisone dosage was then gradually tapered over the next 3 months. After 4 months of stable disease with adalimumab, treatment was switched to methotrexate (10 mg qw) combined with oral hydroxychloroquine (0.2 g qd), which was continued until the current presentation. Two weeks before this visit, he developed recurrent bilateral ankle swelling and pain with fever (Temperature up to 38.5°C). Concurrently, erythematous, tender nodules appeared on his lower limbs, prompting referral to the rheumatology department of our hospital.

Physical examination at this time revealed multiple tender, erythematous nodules scattered on the limbs, predominantly on both lower extremities. Both ankles exhibited swelling, warmth, tenderness, and restricted range of motion. Laboratory tests showed a CRP level of 65 mg/L (normal: 0–6 mg/L), ESR of 75 mm/h (normal: 0–15 mm/h); and increased angiotensin-converting enzyme level of 143 U/L (normal: 10–55 U/L). Skin biopsy of a nodule from the left upper arm revealed dermal and subcutaneous noncaseating granulomatous inflammation without evidence of infection or malignancy (Figure 3). Chest CT scan revealed diffuse nodular shadows in both lungs, swelling of the mediastinal lymph node, and multiple nodules in the subcutaneous soft tissue (Figure 4(a) and (c)). Magnetic resonance imaging (MRI) of the right foot showed a small accumulation of fluid in the right ankle joint, with slight swelling of the subcutaneous soft tissue on the dorsum of the foot and ankle (Figure 5).

Figure 3.

Pathology of nodules from the left upper arm. Subcutaneous granulomatous nodules composed of epithelioid histiocytes, multinucleated giant cells, and lymphocytes were observed, without caseous necrosis. The arrows indicate Langhans giant cells (100×).

Figure 4.

Comparison of chest CT scans (August 2024 and November 2024). (a and c) Diffuse nodular opacities in both lungs, enlarged hilar lymph nodes (red arrow), enlarged mediastinal lymph nodes (green arrow), and multiple nodules in the subcutaneous soft tissues (yellow arrow). (b and d) Compared with the August 2024 scan, the pulmonary nodules in both lungs showed marked improvement. The hilar and mediastinal lymph nodes were markedly reduced in size, and the nodules within the subcutaneous soft tissues were essentially absorbed. CT: computed tomography.

Figure 5.

Right foot MRI. A small effusion is present in the right ankle joint, and the subcutaneous soft tissue over the dorsal foot and ankle is mildly swollen (red arrow). MRI: magnetic resonance imaging.

Based on his medical history and auxiliary examinations, diagnoses of LS and AS were confirmed. The patient was prescribed 15 mg prednisone daily, and methotrexate (10 mg qw) was continued. Within 3 days, his temperature normalized, the swelling and pain in both ankle joints disappeared, and he recovered the ability to walk independently before hospital discharge. After 20 days, a follow-up examination at the outpatient department revealed a normal CRP level and an ESR of 29 mm/h. Subsequently, the patient was regularly monitored on an outpatient basis. By November 2024, both ESR and CRP levels were within normal limits, and a chest CT scan showed significant improvement over previous results (Figure 4(b) and (d)). Over the next 3 months, the glucocorticoid dosage was gradually reduced, and subsequently, the medicine was discontinued; the patient was constantly monitored, and no relapse was observed. To date, he remains in satisfactory health with the regimen.

We have deidentified the patient’s details and obtained approval from the Ethics Committee of The Third People’s Hospital of YuHang District, Hangzhou city (202512261449000159439) for publication of this case report. The reporting of this study conforms to the Case Report (CARE) guidelines. ³ We obtained written informed consent from the patients for treatment and publication of this report.

Discussion

During the period of illness, the patient mainly exhibited symptoms of fever (body temperature >38°C) and bilateral ankle swelling and pain—clinical features atypical for AS.^4,5 Notably, chest CT performed in June 2023 revealed enlarged mediastinal lymph nodes and nodular soft-tissue density at the bilateral hila, whereas the bilateral ankle ultrasound demonstrated subcutaneous and soft-tissue edema accompanied with tendon sheath effusion, without synovial thickening or synovitis. Neither finding is readily explained by AS. Therefore, we believe that the patient should have been considered for both AS and LS 1 year previously. In a study involving 186 patients with LS, approximately 19% presented with ankle periarthritis as the initial and sole clinical manifestation. ⁶ Two weeks prior to his current presentation, our patient developed recurrent bilateral ankle swelling, pain, fever, and tender EN of the extremities; chest CT showed BHL, and the clinical picture aligned with the typical triad of LS.

However, establishing a diagnosis in this case was challenging because the patient received adalimumab treatment for 4 months. Such agents can induce a rare nodular reaction whose clinical, imaging, and pathological features closely mimic those of idiopathic sarcoidosis. ⁷ Patients may develop skin nodules or hilar or mediastinal lymphadenopathy and exhibit noncaseating granulomas on histology, which complicates differentiation. ⁸ This gives rise to the question: does this presentation reflect the natural course of LS or a drug-induced nodular reaction to adalimumab? A retrospective cohort study conducted in Spain has reported LS recurrence and relapse rates of 8% and 4%, respectively, indicating that symptom relapse may represent the natural course of the disease. ⁹

However, the potential contribution of adalimumab merits careful consideration. During histopathologic evaluation, we deliberately avoided the typical EN in both lower extremities and collected samples from the skin of the upper arm. The biopsy showed noncaseating granulomatous inflammation, a pattern that differs from typical EN. Thus, we concluded that the cutaneous lesion represented a sarcoidosis-related manifestation rather than simple, isolated EN. The patient developed a full LS triad after 4 months of adalimumab therapy, reflecting a strong temporal association. Thus, we believe that adalimumab was the main cause of this LS relapse.

Sarcoidosis is a global condition with significant regional and ethnic differences in incidence and clinical presentation. Epidemiological studies have indicated that the disease is most common in the United States and Scandinavian countries and significantly less common among Asian populations. In South Korea and Japan, the prevalence is only 1 to 5 per 100,000 population.^10,11 LS is an acute form of sarcoidosis, particularly rare in Asian populations, with only 26 cases reported in Japan. ¹² A search of domestic medical databases has revealed only two case reports of LS and one study that recorded 22 sarcoidosis patients with LS.^13–15 In Sweden, LS accounts for 30% of sarcoidosis cases, which may be related to genetic factors and ethnic genetic history. ² Consequently, most LS research originates from Western countries where establishing a diagnosis is not difficult. Clinical diagnosis is possible without biopsy in patients with the classic triad of bilateral pulmonary lymph node enlargement (BHL, EN, and arthritis). ² However, in China, the rarity of LS often complicates diagnosis. When a patient also has a rheumatic immune disease, LS is easily overlooked. In Japan, at least 19% of LS cases were diagnosed with an average delay of >5 months, highlighting the degree of difficulty in diagnosing LS in Asian populations. ¹² Clinically, the proportion of patients who get fever appears to be higher in the Asian population. In a study involving 26 patients with LS in Japan, 18 had fever (approximately 69.2%). ¹² The patients in the two case reports from China and the patient in this case all had fever. In contrast, in the two observations made in Western countries, fever prevalence rates were 34.3% and 37.6%.^13,14 Among the 26 patients with LS in Japan, the prevalence of EN, BHL, and arthritis was 73.1% (19 cases), 100% (26 cases), and 65.4% (17 cases), respectively. ¹² Both cases reported previously in China exhibited the above triad.^13,14 The patient in this case only presented with fever, joint swelling and pain at the first visit, which further increased the difficulty in establishing an early diagnosis.

The genetic basis of LS varies considerably between Asian and Western populations. In Western patients, LS is typically considered a self-limiting disease, especially for human leukocyte antigen–DR3 (HLA-DR3)–positive individuals, who usually recover within 1–2 years. For patients experiencing systemic symptoms or severe joint pain, treatment options include nonsteroidal anti-inflammatory drugs and colchicine. ² A few patients who are unable to tolerate nonsteroidal anti-inflammatory drugs or have severe symptoms may be administered low doses of oral glucocorticoids for a short period, with gradual reductions over weeks to months. However, studies on Asian populations have shown more frequent use of oral glucocorticoid therapy. For instance, a Japanese study has reported that 58.3% of patients were treated orally with glucocorticoids. Two cases in China, documented in 2016 and 2019, also involved oral glucocorticoid therapy.^13,14,16 The patient in our case responded well to glucocorticoid therapy over the past year; however, he relapsed after treatment discontinuation. These findings suggest that a higher proportion of LS patients of Asian ethnicity is treated with glucocorticoid therapy, indicating a need for more conservative clinical management.

In the literature, remission refers to the absence of symptoms with normalization of radiological and laboratory findings; relapse is defined as disease reappearance during tapering or after treatment discontinuation and recurrence as reappearance after at least 1 year of spontaneous remission. ⁹ Patients with LS are usually not followed up after remission of clinical signs. However, 3%–6% of LS patients experience disease recurrence several years after complete recovery. ¹⁷ In a study involving 26 LS patients in Japan, 3 cases of recurrence were reported, whereas follow-up data for other patients in China were not available. ¹² This case involved two distinct relapses; the first occurred shortly after glucocorticoid tapering, suggesting insufficient duration or intensity of anti-inflammatory therapy, and the second might be associated with adalimumab treatment. In addition, the patient did not undergo HLA-DR3 typing, which limited our ability to characterize the condition from an immunogenetic perspective. Given the higher frequency of glucocorticoid use among LS patients in Asia, we recommend regular monitoring and structured follow-up. Additionally, cautious tapering of glucocorticoid dosage is advised to minimize relapse risk. For LS patients with concurrent rheumatic immune diseases such as AS, it is advisable to use tumor necrosis factor-α (TNF-α) inhibitors such as adalimumab with caution. If the use of such agents is deemed necessary, patients should be closely monitored and followed up for drug-induced sarcoid-like reactions (DISRs). We believe that our research contributes valuable insights into the clinical management of LS in Asian populations.

Conclusions

The genetic basis of LS influences its epidemiology and treatment across populations. In Western cohorts, LS is typically self-limiting with a favorable prognosis, and glucocorticoids are required only in very few cases. In contrast, clinical observations from Asia suggest that a higher proportion of patients receive glucocorticoid therapy; however, the relationship between genetic background and treatment remains unclear due to a lack of large-scale prospective studies. Consistent with previous Asian cases, the clinical course of this patient suggests that individualized treatment strategies—often involving long-term anti-inflammatory therapy and careful hormone tapering—are necessary in Asian populations. Additionally, caution is warranted when using TNF-α inhibitors in LS patients with concurrent rheumatic immune diseases. Finally, systematic monitoring and long-term follow-up are essential to detect early signs of recurrence and optimize outcomes in Asian LS patients.