Introduction

Although approximately 30% of patients with long-term unexplained fever (fever of unknown origin (FUO), see Table 1 for definition) are eventually diagnosed with rheumatologic diseases such as autoimmune disease, vasculitis, or granulomatous disease , these kinds of diseases are often not the first considered in the differential diagnosis by physicians.

Other patients present with long-term unexplained inflammation (inflammation of unknown origin (IUO), see Table 2 for definition) in the absence of fever. Underlying causes, workup, and prognosis are the same for FUO and IUO .

It should be kept in mind that most patients with FUO suffer from an uncommon presentation of a common disease instead of an uncommon disease. This makes FUO a diagnostic challenge. We present a case series of four patients with FUO because of a rheumatologic disease who were treated at our university expertise FUO center in the past years.

Case 1. Polymyalgia rheumatica

A 70-year-old woman was referred to our outpatient department after three previous admissions in a Dutch community hospital because of episodes of fever that had been present for 5 months and were accompanied by rigors, night sweats, 17 kg weight loss, fatigue, chest and abdominal pain, myalgia, arthralgia, muscle weakness, and arthritis. Laboratory evaluation showed microcytic anemia, elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), and elevated liver enzymes. Antinuclear antibodies (ANAs) were positive at multiple occasions, with repeatedly negative extractable nuclear antibodies (ENAs) and anti-double stranded DNA (anti-dsDNA) antibodies. Antineutrophil cytoplasmic antibodies (ANCAs) were negative. Extensive microbiological investigation, including 19 blood cultures and serology for different pathogens, was negative. PET/CT scan had shown high FDG-uptake in the right hip compatible with large-joint arthritis. A culture of the synovial fluid of the hip had remained sterile. Bone marrow biopsy had shown anemia of chronic disease. She had been treated with multiple courses of broad-spectrum antibiotics, which had resulted in normalization of body temperature. However, fever and inflammation reappeared quickly after each course.

At physical examination, we found a maximum body temperature of 39.2 °C, oral aphthous ulcers; limb-girdle pattern muscle weakness; and frank arthritis of the knees, shoulders, hip, and elbow. Microbiological evaluation also did not show any signs of infection. A second PET/CT was performed, showing arthritis of both shoulders and hips with bursitis and enthesopathy, and symmetrically elevated FDG uptake in the muscles around both knees. Electromyography (EMG) showed myopathy without myositis or polyneuropathy. Because of these findings, a muscle biopsy was taken from the femoral muscle. This showed abundant presence of target fibers, which is compatible with polymyalgia rheumatica. The patient was started on prednisone 30 mg/day. After 3 days, there was a remarkable improvement in her clinical condition. CRP decreased from 117 to 19 mg/L in 1 week.

Case 1. Polymyalgia rheumatica

A 70-year-old woman was referred to our outpatient department after three previous admissions in a Dutch community hospital because of episodes of fever that had been present for 5 months and were accompanied by rigors, night sweats, 17 kg weight loss, fatigue, chest and abdominal pain, myalgia, arthralgia, muscle weakness, and arthritis. Laboratory evaluation showed microcytic anemia, elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), and elevated liver enzymes. Antinuclear antibodies (ANAs) were positive at multiple occasions, with repeatedly negative extractable nuclear antibodies (ENAs) and anti-double stranded DNA (anti-dsDNA) antibodies. Antineutrophil cytoplasmic antibodies (ANCAs) were negative. Extensive microbiological investigation, including 19 blood cultures and serology for different pathogens, was negative. PET/CT scan had shown high FDG-uptake in the right hip compatible with large-joint arthritis. A culture of the synovial fluid of the hip had remained sterile. Bone marrow biopsy had shown anemia of chronic disease. She had been treated with multiple courses of broad-spectrum antibiotics, which had resulted in normalization of body temperature. However, fever and inflammation reappeared quickly after each course.

At physical examination, we found a maximum body temperature of 39.2 °C, oral aphthous ulcers; limb-girdle pattern muscle weakness; and frank arthritis of the knees, shoulders, hip, and elbow. Microbiological evaluation also did not show any signs of infection. A second PET/CT was performed, showing arthritis of both shoulders and hips with bursitis and enthesopathy, and symmetrically elevated FDG uptake in the muscles around both knees. Electromyography (EMG) showed myopathy without myositis or polyneuropathy. Because of these findings, a muscle biopsy was taken from the femoral muscle. This showed abundant presence of target fibers, which is compatible with polymyalgia rheumatica. The patient was started on prednisone 30 mg/day. After 3 days, there was a remarkable improvement in her clinical condition. CRP decreased from 117 to 19 mg/L in 1 week.

Case 2. Behcet’s disease

A 28-year-old man of Bosnian origin was referred because of a 13-year history of episodes of fever. He had previously been evaluated by 10 different medical specialists (internists, rheumatologists, and ophthalmologists) in seven different community and university hospitals in both Serbia and The Netherlands. Long febrile episodes of 2 weeks to 3 months duration had occurred in 1997, 1998, 1999, 2007, and 2009. In between these protracted attacks, he had suffered from less severe and shorter attacks several times a year. Fever could be accompanied by loss of appetite, weight loss, night sweats, abdominal pain, headache, arthralgia, aphthous ulcers, and pancytopenia, but all these were not present during all the attacks. From 2005 onwards, he had multiple episodes of anterior uveitis, which was unrelated to the fever. He also described Raynaud’s phenomena of both hands and feet. During the extensive previous evaluations, infections, autoimmune diseases, porphyria, thalassemia, familial Mediterranean fever (FMF), hyperimmunoglobulin D and periodic fever syndrome (HIDS), and TNF-receptor-associated periodic syndrome (TRAPS) had all been ruled out. Trials with multiple drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, prednisone, and anti-TNF (etanercept) had been ineffective.

Short-term treatment with the interleukin-1 receptor antagonist anakinra during an episode of fever had been given twice and had resulted in rapid reduction of inflammation both times.

At the time of our evaluation, his anti-inflammatory medication consisted of naproxen 500 mg once daily. He had no fever, but oral aphthous ulcers and hepatomegaly were present on physical examination. A month later, he developed a recognizable fever attack accompanied by malaise, arthralgia, arthritis of the fingers, pyrosis, abdominal pain, and anterior uveitis. PET/CT during the fever attack showed increased FDG-uptake in a single axillary lymph node, several small mediastinal lymph nodes, and a single para-aortic lymph node. Furthermore, there was increased uptake in the ligaments around the right knee. HLA-B51 was positive. We diagnosed this patient with Behcet’s disease. Criteria for diagnosis were the presence of oral aphthous ulcers, anterior uveitis, and HLA-B51 positivity. He was started on continuous treatment with anakinra 100 mg daily. Despite this treatment, he developed a new fever attack with arthralgia, myalgia, and erythema nodosum, and we started colchicine 0.5 mg twice daily. Anakinra and NSAIDs were continued because previous trials with colchicine monotherapy had been unsuccessful. This combination effectively eliminated fever and inflammation, but arthralgia remained.

Case 3. Systemic lupus erythematosus (SLE)

A 75-year-old man was referred after he had been admitted in two other hospitals because of fever; night sweats; diarrhea; hypoalbuminemia (serum albumin 19 g/L); and edema, which had been present for 4 months. His medical history consisted of a basal cell carcinoma located at the shoulder, deep venous thrombosis, and cataract. In the past, he had visited Africa and South America multiple times. He had been evaluated because of these problems by multiple internists, a dermatologist, otolaryngologist, dental surgeon, cardiologist, and a neurologist. Besides other imaging, two PET/CT scans had been performed, which showed high FDG-uptake in the left maxillary sinus. Laboratory investigation showed polyclonal light chain production, low complement levels, and type 3 cryoglobulinemia. ANAs, ENAs, and anti-dsDNA had all tested negative. Infections, including multiple types of tropical infections, malignancy, nephrotic syndrome, protein losing enteropathy, and amyloidosis had been excluded. He had been treated for Strongyloides infection in the absence of microbiological proof, but this had not led to resolution of the fever. Under suspicion of a dental infection, all upper teeth had been extracted, again without any effect on the inflammation.

At the time of our first evaluation, the fever and night sweats had subsided, but fatigue, weight loss, and diarrhea remained. He suffered from dryness of the mouth and decreased sensation of the feet. On physical examination, we only found small erythematous lesions on his back, which had previously been biopsied. CRP was normal, but ESR was 126 mm/h. There was a mild leukopenia with neutro- and lymphopenia.

ANA was repeated and was positive with a homogeneous pattern this time, while ENA remained negative. Complement C3 and C4 were low. We consulted a neurologist, who diagnosed symmetric sensorimotor axonal polyneuropathy of the lower legs. PET/CT again showed high FDG-uptake in the left maxillary sinus with increased thickness of the mucosa, several slightly active hilar lymph nodes, elevated uptake in the sigmoid, and hardly increased uptake in a subpleural lesion in the left upper lobe. Because of the persistently increased uptake in the sinus, an otolaryngologist was consulted, who diagnosed minimal sinusitis, which was considered not to be the cause of the fever.

We diagnosed this patient as having SLE based on four positive Systemic Lupus International Collaborating Clinics (SLICC) criteria: polyneuropathy, leukopenia, positive ANA, and low complement levels. He was referred back to the referring hospital for further treatment, where he was given hydroxychloroquine.

Case 4. Eosinophilic granulomatosis with polyangiitis

A 45-year-old male roadworker was referred because of fever, accompanied by weight loss, arthralgia, arthritis, headache, dyspnea, and cough. His symptoms had started after surgical drainage of an abscess of the infrapatellar bursa, a complication of bursitis attributed to his job. Because of these conditions, he had been evaluated for 5 months in two different hospitals by multiple specialists: rheumatologists, a dermatologist, and a pulmonologist. Laboratory evaluation showed elevated levels of ESR and CRP, and eosinophilia (eosinophils maximal 5.3 × 10 ⁹ /L). At the start of the complaints, a chest X-ray had been made, showing bilateral hilar lymphadenopathy. Over the following months, multiple chest CTs had been performed, all showing mediastinal, hilar, and axillar lymphadenopathy. These lymph nodes were proven to be FDG–PET positive. Bronchoalveolar lavage had shown many leukocytes with elevated eosinophils (8%). A lymph node had been biopsied by endobronchial ultrasound, but pathological examination revealed only reactive changes. Other lymph nodes had been removed by mediastinoscopy, which again showed only reactive changes. Because of suspected sarcoidosis, a cardiac magnetic resonance imaging (MRI) had been performed, which did not show any signs of cardiac sarcoidosis. Extensive microbiological evaluation including cultures of blood, lymph nodes, bronchoalveolar lavage fluid and synovial fluid, many serological tests and PCR tests for tuberculosis on lymph nodes and bronchoalveolar fluid had all remained negative. Bone marrow biopsy had shown remarkable eosinophilia of 18%. A kidney biopsy revealed no abnormalities.

In the absence of a diagnosis, the patient had been treated with a 3-month course of high-dose steroids under suspicion of sarcoidosis. This treatment was very effective: besides remission of fever and other symptoms, the lymphadenopathy also decreased on repeated chest CT scans. After cessation of treatment, symptoms, biochemical inflammation, and lymphadenopathy reappeared.

Two months after cessation of the steroids, we examined this patient for the first time. At that time, there were no complaints, and physical examination was normal, as were ESR, CRP, and eosinophil count. A month later, his arthralgia increased and according to the patient’s request, we treated him with 20 mg prednisone again. This again effectively reduced fever and arthralgia. Prednisone was quickly tapered and 2 months later, while on prednisone 2.5 mg daily, he again developed fever; arthralgia; and arthritis of ankles, wrist, and elbows, accompanied by eosinophilia (eosinophils 1.37 × 10 ⁹ per liter). Because of this, we stopped the steroids and admitted the patient to our internal medicine ward. A new bone marrow biopsy was performed, which showed hypercellular bone marrow with marked eosinophilia and activated T cells. A new FDG–PET/CT showed multiple FDG-positive mediastinal, hilar, and axillary lymph nodes; increased uptake in both upper pulmonary lobes and around the elbows, wrists, hips, and ankles; and in the left foot. Chest CT showed new miliary abnormalities in both lungs. His symptoms spontaneously remitted and the patient was discharged after 7 days. However, his condition deteriorated after discharge and he developed severe dyspnea. Because of this and the findings on the latest chest CT, a video-assisted thoracoscopy (VATS) with wedge excision of the left lung was performed. Pathologic evaluation showed granulomatous inflammation with central collagenous necrosis. On the basis of this finding, in combination with the marked eosinophilia, we diagnosed this patient with eosinophilic granulomatosis with polyangiitis. He was started on prednisone 60 mg again, which again was immediately effective and could be tapered slowly.