An Unusual Case of Sarcoidosis with a Prolonged Fever and Progressive Arthropathy

Abstract

A 70-year-old man had developed a high fever and arthralgia in his right elbow 6 months prior. Loxoprofen improved the symptoms temporarily, but arthropathy developed in other joints. Long-term recurrent arthropathy and the fever caused activity reduction and progressive debilitation. We performed fluorine-18 fluorodeoxyglucose-positron emission tomography and detected a positive accumulation in multiple joints and lymph nodes. A lymph node biopsy revealed epithelioid cell granulomas, which, along with elevated angiotensin-converting enzyme levels, led to the diagnosis of sarcoid arthropathy. After prednisolone administration, the fever and arthralgia resolved, and his activities of daily living improved. Clinicians should be aware of this type of sarcoid arthropathy.

Introduction

Sarcoidosis is a granulomatous disorder of unknown etiology that affects many organs but rarely involves joints (1,2). In Japan, only 1.5% of sarcoidosis cases are accompanied by arthralgia (3). Articular sarcoidosis is classified into acute and chronic forms. The acute forms of sarcoid arthropathy, such as Löfgren's syndrome, often resolve spontaneously or with nonsteroidal anti-inflammatory treatment and are understood as conditions with a benign course (4).

While a fever occurs in 31% of patients with sarcoidosis in the Western literature (5) it is less common in Japan (range: 5.1-6.1%) (3). Furthermore, reports of cases with prolonged and repeated febrile reactions are extremely rarer. Nevertheless, international review articles state that sarcoidosis should be listed as a cause of a fever of unknown origin (FUO) (6,7).

We herein report a case of sarcoidosis with a recurrent fever and arthralgia that progressed to polyarthropathy and prolonged debilitation, resulting in the patient being bedridden. This case appears to be a type of sarcoid arthropathy not previously reported in Japan.

Case Report

A 70-year-old man was admitted to Oita University Hospital because of a prolonged fever and progressive polyarthralgia. The patient had experienced some degree of disability in the last few years because of progressive supranuclear palsy and been admitted to a long-term care welfare facility (nursing and welfare facility). He was able to eat and, with a cane, ambulate and excrete independently; however, self-expression was somewhat impaired. One day, he suddenly developed a fever over 38°C and swelling in his right elbow. After several days of a high fever, loxoprofen was administered, which afforded temporary relief. However, when loxoprofen was discontinued, the fever recurred and exceeded 38°C. Therefore, loxoprofen was used as needed, but arthropathy developed in other joints. The patient then complained of fatigue and a decreased appetite, resulting in a weight loss of 5 kg over 2 months. His physical activity gradually declined until he became debilitated and bedridden.

He was referred to our hospital for an examination of the unexplained fever, arthralgia, and weight loss. Blood culture results were negative, and cardiac ultrasound revealed no vegetation. In addition, no malignancy was observed in upper or lower gastrointestinal examinations. Chest roentgenogram findings were unremarkable (Fig. 1A), and computed tomography (CT) showed no abnormal findings in the lungs or abdominal organs. However, superficial and abdominal lymphadenopathy was noted; thus, a left axillary lymph node biopsy was performed to rule out lymphoproliferative diseases, such as malignant lymphoma (Fig. 1B). The results were nonspecific. Although a definitive diagnosis was not reached, the fever was relieved with regular oral loxoprofen, and his appetite improved, so he was followed up by his family physician.

Figure 1.

A) A chest roentgenogram shows no hilar lymphadenopathy or pulmonary infiltrates. B) Chest CT reveals multiple lymph nodes in the left axilla (arrows).

Three months after discharge, the patient was readmitted to our hospital because of a fever, difficulty walking with a cane secondary to whole-body joint pain, and being almost completely bedridden, resulting in general weakness. On admission, his consciousness was clouded, and urinary and fecal incontinence was noted. All joints were contracted, and the patient complained of pain with joint movement. The left hand was completely immobile. His vital signs were as follows: blood pressure, 105/40 mmHg; pulse rate, 82/min; respiratory rate, 22/min; and temperature, 37.5°C. Chest auscultation revealed coarse crackles at the base of the right lung. Lower leg edema was also observed. Bilateral axillary lymph nodes were palpable. Bilateral swelling and tenderness of the elbow, shoulder, wrist, and ankle joints were also noted. The patient's laboratory values were as follows: leukocyte count, 2,770 /μL; erythrocyte count, 263×10⁴/μL; platelet count, 13.9×10⁴/μL; hemoglobin level, 7.0 g/dL; C-reactive protein, 4.89 mg/dL; total protein, 5.80 g/dL; albumin, 2.24 g/dL; aspartate aminotransferase, 26.0 IU/L; alanine aminotransferase, 9.0 IU/L; lactate dehydrogenase, 165 IU/L; creatinine, 0.62 mg/dL; Na, 123 mEq/L; K, 4.28 mEq/L; and Cl, 90.3 mEq/L. Test results for antinuclear antibodies, rheumatoid factor, and anti-cyclic citrullinated peptide antibodies were negative. Levels of soluble interleukin-2 receptors and MMP3 were elevated (3,839 U/L and 1,384 ng/mL, respectively).

No infectious bacterial pathogens could be isolated from either blood or urinary specimens. A chest roentgenogram showed pulmonary infiltration in the right lower lung, but hilar lymphadenopathy was not noted. CT demonstrated systemic lymphadenopathy, which affected the cervical, axillary, iliac artery, inguinal, mediastinal, and hilar lymph nodes, and airspace consolidation in the right lower lung as well as bilateral pleural effusion.

We administered ampicillin/sulbactam, considering the patient to have aspiration pneumonia. In addition, diuretics, albumin infusion, and blood transfusion were administered. However, since the fever persisted, it was decided to perform fluorine-18 fluorodeoxyglucose-positron emission tomography (¹⁸FDG-PET), which detected a positive accumulation in the axillary, iliac artery, inguinal, and mediastinal lymph nodes and in the bilateral elbow, shoulder, wrist, and ankle joints (Fig. 2). We then performed a right axillary lymph node biopsy because a rheumatic disease-associated lymphoproliferative disorder was suspected. The lymph node specimens demonstrated numerous noncaseating epithelioid cell granulomas with giant cells (Fig. 3). The angiotensin-converting enzyme level was also elevated (35.4 U/mL). Sarcoidosis-related ocular and cardiac lesions were not observed. Based on the clinical features and laboratory, radiological, and pathological findings, a diagnosis of sarcoidosis-associated arthropathy was made. Magnetic resonance imaging (MRI) showed synovial effusion and high intensity in the olecranon of the right elbow joint but no synovial proliferation or destructive bone changes (Fig. 4).

Figure 2.

A) Maximum intensity projection images obtained using FDG-PET reveal an enhanced, symmetrical FDG uptake in the shoulder, elbow, wrist, finger, knee, ankle, and toe joints. The FDG uptake is also observed bilaterally in the subclavian, axillary, hilar, mediastinal, para-aortic, para-iliac artery, and inguinal lymph nodes. B) Bilateral enlarged axillary and mediastinal lymph nodes also show the accumulation of FDG. C) The soft tissue uptake in the joints is considered synovial.

Figure 3.

Histopathological findings in the specimens of enlarged right axillary lymph nodes revealing noncaseating epithelioid cell granulomas (A) and Langhans-type giant cells. (Hematoxylin and Eosin staining, A ×40, B ×400, original magnification).

Figure 4.

MRI showing synovial effusion (arrowheads) and a high intensity in the olecranon of the right elbow joint (arrows), but no synovial proliferation or destructive bone changes.

Given the impaired activities of daily living (ADL) and painful condition, we decided against performing a joint biopsy for histopathological confirmation of sarcoid arthropathy and initiated prednisolone therapy (0.5 mg/kg/day). Thereafter, the fever and arthralgia improved, and prednisolone was reduced by 5 mg every 2 weeks. Finally, his arthralgia disappeared, and his ADL recovered from being bedridden to being able to walk with a cane. The patient was discharged while receiving 10 mg of prednisone, and no relapse occurred during the 6-month follow-up period.

Discussion

This is a case of the delayed diagnosis of acute sarcoid arthropathy, which led to ADL impairment. The diagnosis of sarcoidosis is challenging because of the absence of sarcoidosis-specific symptoms and findings, such as bilateral hilar lymphadenopathy (BHL), pulmonary infiltrates, skin lesions, and uveitis. A review of 186 cases of the most common type of acute arthritis, Löfgren's syndrome, found that erythema nodosum was present from the beginning in many patients, and BHL on chest radiography was seen in 97% of patients (8). Sato et al. reviewed nine patients with acute sarcoid arthritis in Japan and reported that one and six patients did not show BHL and erythema nodosum, respectively. One of these patients did not have BHL, erythema nodosum, or pulmonary infiltrates but was diagnosed with sarcoidosis due to uveitis (9). On the second admission, lung shadows and pleural effusion were observed, both of which were judged to be due to decreased ADL and malnutrition, not sarcoidosis lung lesions. The patient's stay in the nursing home and his difficulty in self-expression of symptoms may have contributed to the arthropathy progression and delayed diagnosis of sarcoidosis.

Sarcoidosis-related musculoskeletal manifestations are uncommon, but joints, bones, and muscles may be affected. The severity varies greatly, ranging from arthralgia to extensive destructive bone lesions. The most common musculoskeletal manifestation of sarcoidosis is acute arthritis that occurs as part of Löfgren's syndrome; however, fewer cases are reported in Japan (9,10) than in the U.S. and Europe. The ankles are the most frequently involved joints in acute sarcoid arthritis, and the natural course of acute arthritis usually ends in complete resolution within a few months (11). However, a recent 5-year follow-up study of Löfgren's syndrome reported that 11 of 133 patients (8%) continued to have active disease, and 8 (6%) experienced several relapses between 18 months and 20 years after complete remission (2). It should be noted that acute-onset sarcoid arthropathy can develop into polyarthritis with multiple relapses over a long period of time, as in the present case.

In our case, the MRI findings of the patient's joint showed no synovial proliferation or destructive bone changes, despite the long-term persistence or recurrence of arthropathy, unlike rheumatoid arthritis. Extensive subcutaneous and soft tissue edema is commonly seen on MRI around the ankles without evidence of bone or cartilage lesions, synovial thickening, or synovitis in acute sarcoid arthritis of Löfgren's syndrome (12). Cantini et al. also reviewed MRI findings of acute sarcoid arthritis with ankle edema and confirmed that tendinitis is one of the symptoms (13). They observed mild synovitis without synovial proliferation. Similar findings were reported in a study on 36 patients with Löfgren's syndrome; an ultrasonographic examination showed that 92% of patients had subcutaneous edema, and 38.8% had tendonitis, indicating that periarticular lesions were most common in acute sarcoid arthropathy (14). Collectively, the lesions in acute sarcoid arthropathy are more often extra-articular than articular, and subcutaneous edema and tendinitis are almost consistently seen as periarticular abnormalities. Therefore, even if acute sarcoid arthropathy is prolonged, as seen in this case, it is unlikely to lead to joint destruction.

The present patient presented with the characteristic findings of the symmetrical accumulation of FDG in the joints and lymph nodes. FDG-PET/CT plays an important role in the diagnostic workup of patients with FUO (6,7). A recent meta-analysis reported that FDG-PET/CT successfully identified the source of the fever in 58% of patients with classic FUO in whom a series of fever workup studies failed (15). FDG-PET/CT allows imaging of large areas of the body, is an excellent method for identifying the most metabolically active lesions, and yields high biopsy positive rates. In the present case, the first trial of a lymph node biopsy did not yield significant findings; however, at the second biopsy, with FDG-PET/CT guidance, the biopsy site was again defined as a lymph node, and a diagnosis of sarcoidosis was made.

Previous studies confirmed the efficacy of non-steroidal anti-inflammatory drugs and corticosteroids for acute sarcoid arthropathy. The therapeutic effect of loxoprofen was observed in this case, but it was limited. In contrast, prednisolone was very effective, and the patient's ADL improved with the resolution of the fever and arthralgia. Finally, prednisolone helped obtain a reversible clinical course.

The clinical course of this patient was extremely unusual, with a prolonged fever, progressive arthritis, and a debilitating, bedridden condition that eventually improved dramatically with prednisolone. Clinicians should be aware of this type of sarcoid arthropathy.

The authors state that they have no Conflict of Interest (COI).