Coexisting Sacroiliac Arthritis and Chronic Nonbacterial Osteomyelitis in an Adolescent with Ehlers-Danlos Syndrome: A Case Report and Treatment Success

Introduction

Chronic nonbacterial osteomyelitis (CNO) is a very rare autoimmune disease occurring mainly in children and young adults [1], with a female predominance [2]. It manifests as osteoarticular pain, often at night, joint swelling, and pressure soreness [3]. Additionally, general inflammatory symptoms such as fever, weakness, and weight loss may be present [4]. Laboratory tests can reveal slight elevations in inflammatory parameters such as C-reactive protein (CRP) and leukocytes [5]. Imaging studies such as X-rays, magnetic resonance imaging (MRI), and scintigraphy are mainly used in the diagnosis [6]. Whole-body MRI is a key test in the CNO diagnosis and evaluation of the effectiveness of treatment [7]. The disease should be differentiated from bacterial osteoarthritis, juvenile idiopathic arthritis, and malignant bone tumors [8]. Therefore, in many patients, tissue biopsy should be considered as a method of definite distinction between malignant bone tumor and bone lesions associated with CNO [9]. Sacroiliac arthritis is also a rare condition that occurs in children. The typical symptoms of sacroiliac joint involvement in adults, or back pain, are rarely reported in children and adolescents. MRI of the musculoskeletal system is the most sensitive test used to detect arthritis [10]. Inflammatory lesions detected on MRI allow confident diagnosis in oligosymptomatic or asymptomatic cases [11]. Ehlers-Danlos syndromes (EDS) is a heterogeneous group of hereditary connective tissue disorders, with the prevalence estimated to be between 1 in 5000 and 1 in 100 000. The syndrome manifests as excessive joint mobility, soft and hyperextensible skin, abnormal wound healing, and easy bruising [12]. The international classification of EDS was published in 2017 proposing 13 different variants of EDS because of mutations in 19 genes [13]. The main types are classical, vascular, hypermobile, arthrochalasis, kyphoscoliotic and classical, vascular, hypermobile, arthrochalasis, kyphoscoliotic, and dermatosparaxis, with the causative collagen pathology being different for each type. It is crucial to identify the specific type of EDS, particularly the vascular type, which may lead to potentially life-threatening consequences such as arterial rupture and organ perforation [14]. EDS can be caused both by autosomal dominant or autosomal recessive inheritance patterns, depending on type. Most mutations are inherited, but there are several reports of spontaneous mutations resulting from identical genotypes and phenotypes [15–18]. As there is no specific treatment for patients with EDS, they must be consulted by a multidisciplinary healthcare team including cardiologists, orthopedists, rheumatologists, and geneticists, with the primary role of the family medicine provider, whose job is to coordinate management [15]. Although the most common comorbidities in patients with EDS are gastrointestinal functional disorders, hernias, asthma, pneumonia, and osteoporosis [19], there are indications that EDS could also increase the risks of multiple rheumatological conditions such as psoriasis, ankylosing spondylitis, rheumatoid arthritis, and fibromyalgia [20].

Case Report

In November 2022, a 17.5-year-old female patient was admitted to the Clinical Department of Pediatrics and Rheumatology at the St. Louis Regional Specialized Children’s Hospital in Cracow due to pain in the scapula, thoracic spine, shoulders, and iliac region. She was originally from in central Europe and was middle-class. Her symptoms had been present for 5 months, and were particularly severe in the morning. In addition, there was morning stiffness lasting up to about 1 hour. The was on long-term risedronate sodium acid 35 mg, methotrexate 20 mg, and folic acid 15 mg once a week and vitamin D3 2000 units a day.

The patient’s past medical history was as follows. In June 2014, the 8-year-old patient was admitted to the Regional Children’s Hospital in Bydgoszcz due to post-traumatic right metatarsal bone fracture with presence of edema and pain. She was treated conservatively for 1 month, without clinical improvement. Therefore, it was decided to perform a computed tomography (CT) scan, which revealed an irregular osteolytic focus measuring 6×9 mm, with thinning of the cortical layer and contrast enhancement within the epiphysis of the meta-tarsal bone of the right hallux. In July 2014, she was referred to the Department of Orthopedics at the University Hospital in Bydgoszcz, where a planned partial excision of the tumor of the 1st and 2nd metatarsal bones of the right foot was performed. The histopathological result identified a metacarpal intraosseous lipoma. In October 2014, she developed left thigh pain of variable intensity, up to 7/10 on the Visual Analogue Scale (VAS), appeared mainly at night, waking her from sleep, and it subsided spontaneously. She underwent physical therapy (massage, laser therapy, cryotherapy), which brought short-term relief. On an outpatient basis, an X-ray of the left hip joint was performed, which did not reveal any abnormalities, while an ultrasound showed probable overload changes in the lateral aspect of the left thigh. In January 2015, she was admitted to the Department of Pediatrics, Hematology, and Oncology at the University Hospital in Bydgoszcz for further diagnostics. The laboratory tests revealed elevated CRP to 13.66 mg/L (reference value <10 mg/L). Physical examination found pain in the left thigh, restriction of internal rotation, and external rotation, as well as abduction and protrusion in the left hip joint, and positive Gaenslen’s test and Patrick’s test on the left side. MRI of the pelvis and hip joints was performed, revealing an ambiguous area within the left femur in the lower-lateral part of the neck, including the trochanter, and in the proximal part of the shaft at a length of about 115 mm, extending to the soft tissues around the altered bone. Re-hospitalization was recommended to differentiate the reported lesion, with consideration of a disseminated proliferative process, including lymphoma or inflammatory lesions in the course of systemic diseases. During hospitalization, palpable, non-painful, cohesive submandibular lymph nodes up to 15 mm in size were found. In laboratory tests, elevated CRP to 11.72 mg/L (reference value <10 mg/L), slight elevation of plasma immunoglobulin G (IgG) and immunoglobulin A (IgA) levels were noted. In the myelogram, single atypical cells, suggestive of cancer cells, were detected. An abdominal ultrasound showed enlargement of the spleen to 131 mm in length. The patient was discharged home with the recommendation to continue taking paracetamol on an interim basis.

A week later, in mid-February 2015, a scintigraphy was performed, which described increased linear accumulation of radiopharmaceutical in the greater trochanter, in the medial margin of the subtrochanteric region of the left femur, focally in the projection of the sternoclavicular joints, the cranial segments of ribs IV–V, and in the projection of the shafts of the first and fifth metatarsal bones of the right foot. The image was described as ambiguous, and the examination did not differentiate the nature of the lesions between active proliferative and inflammatory processes.

A week later, she was admitted to the Department of General and Oncologic Surgery for Children and Adolescents at the University Hospital in Bydgoszcz for a surgical biopsy of soft tissue and bone in the left thigh. The histopathological result identified dysplasia fibrosa ossis, with a component of chronic inflammatory exudate. In mid-April 2015, she was again admitted to the Department of Pediatrics, Hematology and Oncology at the University Hospital in Bydgoszcz and reported worsening pain involving the entire left lower limb and right knee. Physical examination revealed an abnormal gait, with limping on the left lower limb. The laboratory tests showed an elevation of CRP to 12.5 9 mg/L (reference value <10 mg/L) and in the proteinogram a slight elevation of total protein to 8.6 g/dL (reference value 6–8 g/dL). An X-ray of the left thigh was taken, which showed a greater thickening of the cortical layer than before, as well as a periosteal reaction in the lesser trochanter.

The MRI of the lower limbs was also performed and compared with the MRI from January 2015. The examination showed partial regression of the extent and enhancement of hyperintense areas in the right hip joint acetabulum bone, sacrum of the S1 segment, in the L5 shaft, and a small focus in the left pubic bone shaft. Images of the remaining hyperintense lesions in the left femur and pelvic bones revealed no significant differences from the previous examination. Considering the clinical presentation and the results of laboratory and imaging findings, a suspicion of chronic nonbacterial osteomyelitis was raised. The patient was released home with the recommendation to take diclofenac 25 mg twice a day and cloxacin 500 mg once a day and was referred to the Orthopedic Outpatient Clinic of the University Children’s Hospital in Cracow for further diagnostics.

The patient was readmitted to the Department of Pediatrics, Hematology and Oncology at the University Hospital in Bydgoszcz due to severe chest and epigastric pain, which occurred after 7 days of oral administration of diclofenac and cloxacin. The above medications were discontinued and treatment with a proton pump inhibitor was initiated, achieving complete resolution of the problems. Because of the suspicion of gastritis and family history (Leśniowski-Crohn’s disease in the father), gastroscopy and colonoscopy were performed. The histopathological result was inconclusive, and a diagnosis of non-infectious gastroenteritis and colitis was made. In June 2015, the diagnosis of CNO was confirmed at the Orthopedic Outpatient Clinic of the University Children’s Hospital in Cracow, and disodium pamidronate was started intravenously at a dose of 120 mg every 2 months. After 2 years, remission of the disease was achieved and pharmacotherapy was discontinued. In November 2018, a follow-up whole-body MRI was performed, which showed no inflammatory changes. In February 2019, the patient was referred to the Department of Pediatrics, Hematology, Oncology, and Rheumatology with spinal pain of severity 6/10 on the VAS scale, with no improvement after 2 weeks of diclofenac administration. Physical examination revealed significant painful limitation of spinal mobility in all planes, and she was unable to move her spine while prone. Treatment with naproxen was initiated and an urgent consultation at the Orthopedic Outpatient Clinic of the University Children’s Hospital in Cracow was recommended. In May 2019 at the Orthopedic Outpatient Clinic of the University Children’s Hospital in Cracow it was decided to reintroduce administration of disodium pamidronate intravenously at a dose of 180 mg. After 2 weeks, the pain subsided. A readmission to the department was scheduled 1 month later, during which a bone scintigraphy was performed, revealing no focal lesions. Another dose of 180 mg disodium pamidronate intravenously was administered in November 2019, achieving remission. In May 2020, the patient again reported to the Orthopedic Outpatient Clinic in Cracow due to recurrence of spinal pain in spite of treatment with analgesics. The performed skeletal scintigraphy revealed the accumulation of tracer in the posterior region of the left sixth rib, the corpus of the sternum, and the thoracic 5 to thoracic 8 (Th5-Th8) vertebrae.

Due to an active inflammatory process in these locations, it was decided to introduce methotrexate therapy at a dose of 20 mg once a week and folic acid at a dose of 15 mg every 2 days after methotrexate. Treatment continued until January 2021, when the pain recurred again. The patient was referred to the Orthopedic Outpatient Clinic in Cracow with thoracic and lumbar spine pain of significant intensity, causing problems with standing up. Treatment was modified by adding sodium risedronate at a dose of 35 mg orally once a week, to the already-administered methotrexate with folic acid. At a follow-up visit in December 2021, the patient reported improvement in her general condition and was pain free.

In May 2022, another bone scintigraphy was performed, in which tracer was concentrated in the corpus and manubrium of the sternum, Th5-Th8 vertebrae, and the right sacroiliac joint. Due to the suspicion of coexisting arthritis, the patient was referred to the Clinical Department of Pediatrics and Rheumatology at the St. Louis Regional Specialized Children’s Hospital in Cracow.

Physical examination at the Clinical Department of Pediatrics and Rheumatology at the St. Louis Regional Specialized Children’s Hospital in Cracow revealed knee and elbow joint hyperextension, hypermobility of the phalanges, increased range of motion at the hip joints, with normal strength and muscle tone. Of note was the patient’s height of 182 cm, which was above the 100th percentile for age and the presence of reticular rash on the skin of the right side of the mandible. Her family history included a father under biological treatment for ankylosing spondylitis and coexisting Leśniowski-Crohn’s disease and a mother with a diagnosis of sarcoidosis.

Blood laboratory tests performed during hospitalization revealed minor leukocytosis up to 10 550/μL (reference value 4190–9430/μL), normal CRP value <5 mg/L (reference value <10 mg/L), decrease in erythrocytes to 3 550 000/μL (reference value 4 100 000–5 100 000/μL), hemoglobin to 9.6 g/dL (reference value 10.8–13.3 g/dL), hematocrit to 28.7% (reference value 33.4–40.4%), and an increase in platelets to 366 000/μL (reference value 194 000–345 000/μL), with no other significant abnormalities. Her liver and kidney parameters were both normal: blood urea nitrogen 4.29 mmol/L (reference value 2.7–7 mmol/L), creatinine 63.55 μmol/L (reference value 40–69 μmol/L), aspartate aminotransferase 19 Units/L (reference value 15–45 U/L), and alanine aminotransferase 15 International Units/mL (reference value 10–40 IU/mL). In addition, she was negative for human leukocyte antigen B27 (HLA-B27) and human leukocyte antigen-Cw6 (HLA-Cw6). The flexibility of the joints, the presence of mandibular skin lesions, and difficult-to-heal scars from diagnostic biopsies (Figure 1) suggested Ehlers-Danlos Syndrome (EDS) classical type. The patient met 2 of the major criteria of classical EDS presented by Malfait et al in The 2017 international classification of the Ehlers-Danlos syndromes [16], which were skin hyperextensibility and general joint hypermobility, and 3 minor criteria, which were soft, doughy skin, skin fragility, and the complications of joint hypermobility. Based on these clinical criteria, a diagnosis of EDS of the classical type was made. Accordingly, the patient was consulted by a cardiologist, who performed an electrocardiogram and a transthoracic echocardiogram, which did not reveal any pathologic findings.

MRI of the thoracic spine showed a deepened kyphosis with right-sided thoracic curvature, as well as reduced height of the anterior parts of the Th5-Th7 vertebral bodies with irregularity of the end plates, fracture of the superior end plate of the Th3 vertebral body, intervertebral discs from Th2/Th3 to Th7/Th8 with reduced height, and features of dehydration. In addition, regions of bone marrow edema within the Th3, Th4, and Th7 vertebral bodies and the head of seventh rib on the left side confirmed inflammation of bones (Figure 2).

A musculoskeletal system MRI was also performed, showing bilateral bone marrow edema in the sacrum and in the right iliac bone within the area adjacent to the sacroiliac joint (Figure 3), and areas corresponding to foci of adipose tissue metaplasia were visible in the same bones.

The patient was diagnosed with active sacroiliac arthritis overlapping CNO, with the coexistence of EDS. She was released from the hospital with modified treatment: risedronate sodium 35 mg, methotrexate 20 mg, and folic acid 15 mg once a week, and vitamin D3 2000 units a day, with additional treatment of meloxicam 15 mg once a day and sulfasalazine 500 mg twice a day.

At the follow-up visit at the Clinical Department of Pediatrics and Rheumatology at the St. Louis Regional Specialized Children’s Hospital in Cracow in December 2022, she reported no new concerns, and her medical condition had improved. Physical examination revealed a reticular rash on the skin of the right side of the mandible, on the skin of the thigh in the left ileal region, and on the dorsal surface of the right foot at the metatarsophalangeal border with healed per prima excisional scars. The joint contours were not enlarged, the knee and elbow joints were hyperextended, there was hypermobility of the phalanges and increased range of motion in the hip joints, while muscle strength and tension were normal.

In results of blood laboratory tests performed during this hospitalization compared to the results before treatment modification showed leukocytes was decreased and within reference value at 6440/μL (reference value 4190–9430/μL), normal CRP value <5 mg/L (reference value <10 mg/L), erythrocytes increased to 3 830 000/μL (reference value 4 100 000–5 100 000/μL), hemoglobin to 9.9 g/dL (reference value 10.8–13.3 g/dL), hematocrit to 30.3% (reference value 33.4–40.4%), and platelets decreased to 346 000/μL (reference value 194 000–345 000/μL). Liver and kidney parameters remained normal: blood urea nitrogen was 4.08 mmol/L (reference value 2.7–7 mmol/L), creatinine was 63.3 μmol/L (reference value 40–69 μmol/L), aspartate aminotransferase was 23 U/L (reference value 15–45 U/L), and alanine aminotransferase was 21 IU/mL (reference value 10–40 IU/mL).

An orthopedic consultation revealed remission of CNO and active bilateral sacroiliac arthritis. Therefore, it was decided to modify the treatment again. Bisphosphonate was discontinued, methotrexate was reduced to 15 mg once a week, folic acid was maintained at a dose of 15 mg once a week, vitamin D3 was increased to 4000 units a day, sulfasalazine was increased to 1 g twice a day, and etoricoxib was added at a dose of 60 mg once a day for 4 weeks.

The patient was discharged from the hospital in good general condition with recommendations for follow-up at the Rheumatology and Orthopedic Clinics.

Discussion

CNO is a disease that is diagnosed based on the clinical presentation, imaging findings, and bone biopsy [21]. Correct diagnosis is of great importance to avoid unnecessary surgery. For this reason, it was essential to perform a wide panel of tests, including invasive examinations, which resulted in the diagnosis of CNO in the presented case and allowed the patient to be provided with effective treatment. The primary management of a CNO patient is conservative treatment and mainly involves the administration of drugs such as disease-modifying anti-rheumatic drugs (DMARDs) and bisphosphonates [22]. This standardized treatment targeted particularly at patients with active inflammatory lesions in the spine resulted in resolution of clinical symptoms of CNO in our patient. In this particular case, the confirmation of the CNO diagnosis required an entire year of different diagnostic procedures, including X-rays, CT scans, MRI, skeletal scintigraphy, and 2 invasive bone biopsies. It was challenging to differentiate CNO from the proliferative process that may have been present in the involved bones. The first treatment with an antibiotic initiated following the suspicion of CNO was inadequate and is not mentioned in the published CNO treatment strategies [23]. However, the patient was referred to the Orthopedic Outpatient Clinic of the University Children’s Hospital in Cracow, which specializes in treatment of CNO and where appropriate therapy with bisphosphonates was instituted, resulting in remission. By managing the patient in a specialized orthopedic institution, it was possible to quickly react when the overlap of sacroiliac arthritis appeared and transfer the patient to the Rheumatology Department. CNO is one of the major causes of sacroiliitis in children [4,24,25]. The present case illustrates the importance of cooperation between physicians of various specializations, which is particularly important in management of patients with rare diseases, who usually require multidisciplinary consultations.

MRI is essential for the diagnosis of sacroiliac arthritis [26–28], and in our patient revealed inflammatory lesions despite no significant elevation of inflammatory markers in laboratory tests. This highlights the importance of MRI in the early diagnosis of sacroiliac arthritis, which allowed the immediate addition of meloxicam and sulfasalazine to the existing treatment [29]. As a result, resolution of symptoms was achieved. In addition, an increase in erythrocyte count and hemoglobin was obtained; therefore, it was decided that the patient did not require further hematological consultation. The prognosis of patients with CNO and an extraosseous manifestation such as sacroiliitis is worse than in patients with bone-limited CNO and may require escalation of therapy to DMARDs and biologic agents [25,30], as in our patient.

Another point of interest in this case is that despite the patient’s numerous hospitalizations, the symptoms of hypermobility, the presence of reticular rash on the skin of the mandible, and difficult-to-heal scars from diagnostic biopsies were not noticed until 2022, when the 17.5-year-old patient was hospitalized in our department. It is not known when the above symptoms first appeared. In addition, the patient developed gastritis and colitis after oral antibiotic and diclofenac treatment, which may also be related to a proven predisposition to gastrointestinal diseases in patients with EDS [31–33] and CNO [25]. According to the literature, the diagnosis of EDS is made an average of 14 years after the appearance of the first clinical manifestations [34]. This may be related to the common physicians’ perception of EDS as a rare disease. However, it is essential to quickly establish an appropriate diagnosis to prevent later complications, such as through appropriate pain management, physical therapy [35], and patients’ self-management [36]. In the presented case, the diagnosis of EDS did not change the treatment, as the patient had already received multiple medications due to previously diagnosed rheumatic diseases, which were sufficient to deal with her condition.

Each patient with coexisting inflammatory diseases, sacroiliac arthritis, and CNO with genetic diseases poses a diagnostic challenge. These diseases have similar clinical manifestations [37]; therefore, it is crucial to constantly observe such patients and detect any new, often untypical symptoms emerging. There are a few case reports in the literature of patients with a CNO diagnosis and coexisting sacroiliitis [38,39]. There are also data in the literature on the co-occurrence of EDS and CNO [40], and there is little evidence that EDS is associated with complicated rheumatological conditions [20]. The coexistence of these 3 diseases in the same patient has not been previously reported.

Conclusions

The co-occurrence of CNO, sacroiliac arthritis, and EDS is very rare and requires extensive investigations. Imaging examinations such as MRI of the musculoskeletal system and bone scintigraphy are particularly important in CNO and sacroiliac arthritis; however, in certain cases, a bone biopsy is needed to exclude proliferative diseases. Increased attention should be paid to patients with joint hypermobility, as EDS is often diagnosed several years after the first symptoms appeared. The multi-speciality therapeutic management of patients with complicated medical histories is essential to provide an appropriate diagnosis and initiate suitable treatment to achieve remission.