INTRODUCTION
Chronic recurrent multifocal osteomyelitis (CRMO), which is the most serious type of chronic nonbacterial osteomyelitis (CNO), is a chronic noninfectious autoinflammatory disease characterized by multiple sites of painful swelling of bones, most often in the metaphysis of the long bones or the pelvis, the shoulder girdle and the spine, although every bone can be involved (1). This little-known inflammatory bone disease appears mainly in children, and the mean age at its onset is approximately 10 years of age. The epidemiology of the disease depends on the studies, and its prevalence is estimated to be between 1/160 000 and 1/2 000 000, while its incidence is estimated to be between 1/250 000 and 1/1 000 000. Females are more affected by this disease than males, in a ratio of 4:1 (2).
Even though the exact mechanism of CRMO is unknown, several studies have made assumptions about its etiology and pathophysiology. It has a complex genetic background related to innate immunity combined with the effects of many epigenetic mechanisms, such as intestinal dysbiosis and stressor exposure (3). Also, similarities with juvenile spondyloarthritis were reported, moreover the fact that the evolution from one disease to another is not impossible (3). The cases can be divided into sporadic form and syndromic form. In syndromic forms CRMO is linked with Majeed syndrome which is an autosomal recessive hereditary disease. It is characterized by CRMO in early age and dyserythropoietic anemia which is often followed by recurrent fever. Furthermore, it is connected with an absence of the Interleukin-1 Receptor Antagonist (DIRA) that is an autosomal recessive disorder which occurs in newborns with osteitis, generalized pustulosis, periostitis and systemic inflammation as a consequence of mutations in the interleukin-1 receptor antagonist (IL1RN) (4, 5). In sporadic forms of CRMO a genetic component is suspected, particularly in the dysregulation of immune pathways of the anti-inflammatory cytokine interleukin-10 and pro-inflammatory cytokine interleukin-1 (5). It is worth mentioning that several adult-onset forms of this disease have been reported. These disease types simulate the SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis and osteitis) (5). It is not clear whether the SAPHO syndrome and CRMO are two separate entities or if they are part of the same disease spectrum with CRMO being the pediatric parallel of the SAPHO syndrome (6).
A typical symptom of CRMO is bone pain which is worse during the night and is often accompanied by fever (7). From one to approximately 20 locations can be entangled at the same time. The metaphysis of the long bones, the clavicles, and the vertebral bodies are the most common sites. Moreover, other locations, such as the pelvis, the mandible, and the small bones of the hands and feet can also be involved (8). Clinical signs include standard sings of inflammation: rubor, tumor, calor, dolor and functio laesa of the affected bone. These signs can also be found on the skin above the affected bone. Optional symptoms can be precipitated by paraosseous inflammation, involving peripheral nerves and vessels. A few other inflammatory conditions are often associated with CRMO such as psoriasis and palmoplantar pustulosis (8%), inflammatory bowel disease (10%), severe acne (10%), ankylosing spondylitis (25%) and the aforementioned juvenile spondyloarthritis (3, 4). Infectious osteomyelitis, malignancy (osteosarcoma, Ewing’s sarcoma, leukemia, non-Hodgkin lymphoma), benign bone lesion (such as osteoid osteoma) and Langerhans cells histiocytosis (LCH) are the most common differential diagnoses (9). In diagnosis, a combination of clinical, radiological and histological findings are used. Due to the absence of disease biomarkers or widely used criteria, CRMO still remains a diagnosis of exclusion. Laboratory tests often reveal modest leukocytosis, faster erythrocyte sedimentation rate (ESR) and slightly elevated other inflammation parameters, but normal findings are also possible. Cultures of bone and hemocultures are almost never positive. Imaging techniques are significant for the diagnosis of CRMO and the exclusion of other differential diagnoses. The first approach includes plain radiographs (X-ray) through which bone changes can be seen as radiolucent, osteolytic, or sclerotic lesions, with the possibility of no changes being detected in the early stages of the disease. Magnetic resonance imaging (MRI) is the golden standard technique with high sensitivity, especially in the early stages of the disease. Typical findings include bone oedema, which is also the first sign of the disease, which is most commonly followed by osteolytic or sclerotic, and hyperostotic bone lesions, as well as periosteal and soft tissue reactions, if present. Infectious osteomyelitis and malignant bone tumors are ruled out by bone biopsy (10, 11).
Non-steroidal anti-inflammatory drugs (NSAIDs) are the first-line treatment, with reported response rates of up to 80% (12). Oral steroids, methotrexate, sulfasalazine, colchicine, bisphosphonates and tumor necrosis factor (TNF)-alpha inhibitors can be used as an alternative treatment in cases in which patients are unresponsive to NSAIDs, during exacerbations and in order to prevent relapses. The anti-inflammatory action of azithromycin may also contribute to a positive clinical therapeutic effect (13). In this paper, we present a case of a 13-year-old boy who suffered from pain in the lumbar spine and who has received the final diagnosis of CRMO at the University Hospital Center (UHC) Zagreb. Our aim is to contribute to the avoidance of misdiagnoses and late diagnoses of this disease.
CASE REPORT
We were introduced to a case of a 13-year-old boy, suffering from pain projecting into the lumbosacral region of his spine since the age of 7. The pain was precipitated by a trauma which happened in 2013, during a physical education class (PE) (forward roll). When it comes to the patient’s anamnesis vitae it can be noted that there were no difficulties reported during his birth, and the APGAR score at birth was 9/10. Before this event, the boy did not suffer from any diseases until the age of 7. In 2013, the patient was hospitalized because of pain in the lumbar spine. After an MRI showed a minimal discontinuation of the left mass of the lateral sacral bone in the level of S1 without significant displacement and with the presence of bone oedema, the fracture of sacral bone was suspected (Figure 1, 2A, 2B, 3). He was discharged under the diagnosis of unknown etiology back pain and pharmacotherapy in terms of analgesia and physical therapy were prescribed. Because of the presence of mild pain, which did not progress to severe or limiting levels, the patient underwent physical therapy at least once a year until 2017, when the diagnosis of scoliosis was made after general medical examination. During that period, the exacerbation of pain also occurred.
After five years, the boy was hospitalized due to anaemia and malnutrition and after a short period he was discharged with a recommendation of taking iron and enteral nutrition therapy. Shortly afterwards, while looking for a second opinion, the patient was taken in by another department and processed by an orthopaedic surgeon and a paediatric rheumatologist. At that time, the patient underwent all standard immunological tests, which were all negative. The complement component C4 was normal as was the total complement activity, but there was a slight elevation in the C3 component. Moreover, the initial inflammatory parameters were elevated in 2018 (Erythrocyte sedimentation rate (ESR) 80/1h, C-reactive protein (CRP) 48 mg/L, fibrinogen 5.6 g/L), no leucocytosis was observed (L 8.67 [1e9]/L).
In September 2018, a control MRI was made which showed significant progression of the disease since 2013. Zones of high intensity signal in turbo inversion recovery magnitude (TIRM) and T2 techniques of vertebral bodies L5, S1, S2 and S3 were found with signs of high intensity signals extending from the pedicle of vertebral arch of the L5 vertebral body to the spinous process. There were also signs of regional oedema of the soft tissue and oedematous changes of the anterior adipose tissue inside the lumbar and sacral region of the spinal canal. Moreover, signs of bone destruction of the ventral segment of the L1 vertebral body were observed. Biopsy was recommended. Bone scintigraphy findings from November 2018 showed very intensive bone remodeling and expressed vascular space in the sacral bone and pelvis on the left side. On the CT scan from December 2018 changes of bone structure of the L5 vertebral body, the sacral bone (mainly S1, S2 and S3 vertebral bodies, more notable to the paramedian left) and the wings of the iliac bone on the left side were depicted. Furthermore, the inhomogeneous and reduced bone structure of the mentioned part of the skeleton with erosive, osteolytic and osteoblastic changes was shown, in addition to the fragmentation of the bone in the region of the left sacroiliac joint. These changes were also present at the cranial segment of the right sacroiliac joint (SI) joint with pseudo-enlargement at the cranial parts of both SI joints. The enlarged wing of the iliac bone with sclerotic and lytic lesions was found (Figure 4). Changes in the adipose tissue were also described, mainly around the mentioned part of the skeleton and in the region of the neural foramen from the L5 to the S1 segment and sacral foramen of the S1 segment on the left side. Irregular curves of the anterior cortex of the sacral bone from the S1 to the S3 vertebral body, along with the adipose tissue changes and a small portion of liquid in the anterior sacral region were also described. Given all of these pathological findings, the patient was diagnosed with chronic active osteomyelitis and referred to a rheumatologist and an orthopaedic surgeon for consultation.
In January 2019, the patient was admitted at the UHC Zagreb, the Department of Orthopaedic Surgery. At that time, the patient did not experience severe pain. Nothing significant was found in the patient’s clinical status, except for the low body mass index (BMI) (14.4 kg/m2). In terms of his locomotor status, the boy showed perturbations when performing repeated forward bending tasks, Thomayer’s test (fingertips-floor in forward bending) value was 41 cm, Schober’s test value was 1.5 cm, Mennell’s clinical test for sacroiliac joints was negative, sacroiliac distraction test was negative, Gowers’ sign was positive, the sagittal profile of the spine was at level, and the Lasègue’s (straight-leg) test showed no irritation on either side of the spinal roots. However, the left leg was 1.5 cm shorter and finally, the shortened and tense tendons of the hamstrings on both sides were found. The human leukocyte antigen (HLA) test was positive for HLA B27, while the interferon-gamma release assay (IGRA) was negative. The patient was indicated for bone biopsy. After histopathologic findings of the bone tissue, which showed reactive changes in the bone marrow with newly-formed connective tissue, the final diagnosis of CRMO of the pelvis and spine with a positive HLA B 27 result has been established. The patient was monitored by a paediatric rheumatologist and following therapy with indomethacin and bisphosphonate, the pain subsided. Bisphosphonate therapy was initiated in September 2020, and a maximal dose was administered throughout treatment. Shortly after that, the treatment was continued with NSAIDs. The patient responded well to bisphosphonate therapy and not only did he experience less pain, but this also resulted in a reduction of the inflammation parameters, an improvement of the patient’s general condition, and an improvement of the patient’s locomotor status and his clinical findings. Finally, at that time, the complications of CRMO such as pathological fractures and neurologic deficits were prevented.
At a follow-up examination in September 2021, a pelvis MRI without and with contrast was performed. In comparison with the previous MRI examination, this did not show significant changes in the distribution and the extent of the previously described bone lesions in the area of the lower lumbar segments, sacral bone, and pelvic bones. The urinary bladder, soft tissue and pelvic structures show normal morphology and signal intensity. There was no enlargement of the lymph nodes in the scanned area with normal large blood vessels. There was no free fluid in the pelvis, but there was still minimal effusion in the left coxofemoral joint.
In April 2022, a clinical and radiological worsening of the findings had occurred. The patient started to experience morning stiffness. After the examination, the diagnosis of juvenile spondyloarthritis on the base of CRMO was established. In addition to that, vitiligo was diagnosed by a paediatric dermatologist shorty after. Considering the stated facts, biological therapy was indicated, and from May 2022 treatment with Humira (adalimumab) was initiated. The most recent control MRI done in March 2023 showed a significant improvement in the radiological findings which was the same as before, followed by an improvement in the clinical findings and a reduction of the mentioned symptoms.
DISCUSSION
CRMO is a rare disease which happens to be often misdiagnosed or diagnosed at a late stage. With its subtle onset of symptoms, periods of partial remission and exacerbation and an unclear etiology and pathophysiology, CRMO presents complications in diagnosis. Sites that are most often involved include the metaphysis of the long bones, the clavicles, and the vertebral bodies. According to Guariento et al., most commonly the vertebral bodies of the thoracic spine are involved (58%) with sclerosis and endplate abnormality present in 13% of cases (14). The mandible, pelvis, and small bones of the hands and feet, can also be involved (8). Furthermore, Stojkic et al. reported a case of an adolescent male patient who presented with recurrent swelling of the temporal region of skull as a uncommon clinical presentation of CRMO (15). In our patient, lumbosacral vertebral bodies and pelvis were affected. Generally, CRMO presents with unspecific symptoms, laboratory and X-ray findings. Laboratory findings often show slightly elevated inflammatory parameters. Roderick et al. reported in their study that CRP findings were slightly elevated in 14 out of 28 patients and ESR was raised in 16 out of 19 patients (10). Our patient had elevated inflammatory parameters during exacerbation periods. The golden standard for diagnosis is MRI. Indeed, in the case of our patient, the suspicion of an unconventional diagnosis was made after an MRI scan. However, CRMO still remains a diagnosis of exclusion. The diagnosis is most often established based on a combination of clinical, radiological and histological exams in addition to symptoms and clinical signs (16). Jansson et al. suggested the diagnostic criteria which included two major criteria or one major and three minor criteria, with the major ones being: radiologically proven osteolytic/-sclerotic bone lesion, multifocal bone lesions, palmoplantar pustulosis or psoriasis, sterile bone biopsy with signs of inflammation and/or fibrosis, sclerosis and the minor being: normal blood count and good general state of health, CRP and ESR mildly-to-moderately elevated, observation time longer than 6 months, hyperostosis, associated with other autoimmune diseases apart from palmoplantar pustulosis or psoriasis, grade I or II relatives with autoimmune or autoinflammatory disease, or with NBO (17). Bristol diagnostic criteria for CRMO use similar combination of criteria (10). Infectious osteomyelitis, malignancy (osteosarcoma, Ewing’s sarcoma, leukemia, non-Hodgkin lymphoma), benign bone lesion (such as osteoid osteoma) and Langerhans cells histiocytosis (LCH) are the most common differential diagnoses (9). In addition to that, similarities with juvenile spondyloarthritis were reported, moreover the fact that the evolution from one disease to another is not impossible (3). This reported evolution occurred in the case of our patient, who was diagnosed with juvenile spondyloarthritis on the base of CRMO after he started experiencing morning stiffness. NSAIDs are the first-line therapy, with reported response rates of up to 80% (12). Oral steroids, methotrexate, sulphasalazine, colchicine, bisphosphonates and TNF-α blockers can be used as an alternative treatment in cases in which the patients are unresponsive to NSAIDs, during exacerbations and in order to prevent relapses. Furthermore, Hug et al. reported the role of paediatric spine surgery interventions in patients with spine involvement with the aim of preventing disease complications such as neurological deficits, pain, deformity or instability, although there are no current guidelines for such management (18). Our patient responded well to the treatment with a combination of indomethacin and bisphosphonates, but eventually, due to the worsening of symptoms, radiological findings and the evolution of juvenile spondyloarthritis on the base of CRMO, biological therapy was indicated. After the treatment with adalimumab, there was an improvement of both clinical and radiological findings in the case of our patient.
In a child with chronic and recurrent bone pain, elevated inflammatory parameters, osteolytic and osteosclerotic lesions found on X-ray, long-lasting bone oedema found on MRI on multiple sites and excluded infectious or malignant etiology, CRMO should always be suspected. Proper diagnosis improves the quality of life for children in multiple ways. Most notably, it puts an end to an incorrect, difficult and prolonged antibiotic therapy and frequent exposure to radiation (by recurrent X-ray and CT imaging). Another significant benefit of applying the right treatment is the reduction of symptoms as well as avoidance of complications from CRMO, like bone damage and bone deformities. Frequent MRI controls and early HLA typing are suggested for the purpose of avoiding misdiagnoses. Moreover, bone oedema on radiological findings, if present, should indicate a possible rheumatic and immunological origin of the condition. We hope that this case report will prove to be helpful in in establishing a proper diagnosis and treatment of patients with CRMO and we look forward to new studies about this rare and serious disease.
Acknowledgments: The authors report no acknowledgments.
Funding: For this work authors did not receive any funding.
Conflict of interest statement: The authors declare no conflict of interest.
REFERENCES / LITERATURA
<jrn>3. Koné-Paut I, Mannes I, Dusser P. Chronic recurrent multifocal osteomyelitis (CRMO) and juvenile spondyloarthritis (JSpA): to what extent are they related? J Clin Med. 2023 January 5;12(2):453.PubMedhttps://doi.org/10.3390/jcm12020453</jrn>
<jrn>18. Hug NF, Purger DA, Li D, Rinsky L, Hong DS. Neurosurgical management of vertebral lesions in pediatric chronic recurrent multifocal osteomyelitis: patient series. J Neurosurg Case Lessons. 2023 January 23;5(4):CASE22179.PubMedhttps://doi.org/10.3171/CASE22179</jrn>
Figure 1 Lumbosacral MRI – STIR sagittal view Caption / Opis slike: Bone and soft tissue oedema of S1, minimal discontinuation of the left mass of the lateral sacral bone in the level of S1 without significant displacement and with the presence of bone oedema. / Edem kosti i mekog tkiva u segmentu S1, minimalni diskontinuitet lijeve mase u lateralnom dijelu križne kosti u razini S1 bez značajnijeg pomaka uz prisutnost edema kosti.
Figure 2A T2 MRI transversal view (S1) Caption / Opis slike: Hypointense signal in the left lateral mass of the sacral bone representing bone oedema. / Hipointenzivni signal u lijevoj lateralnoj masi križne kosti predstavlja edem kosti.
Figure 2B Postcontrast T1 MRI (S1) Caption / Opis slike: Postcontrast enhancement of the oedema. / Postkontrastno povećanje edema.
Figure 3 MSCT scan, axillary view (Dec 14, 2018) Caption / Opis slike: Sclerosis of the affected bone (sacral bone, iliac bone, vertebral body). / Skleroza zahvaćene kosti (križna kost, ilijakalna kost, trup kralješka).
Figure 4 Control finding of postcontrast T1 FS MRI (May 4, 2020) Caption / Opis slike: Unchanged mass on the left side of the affected vertebra. / Nepromijenjena lijeva masa na zahvaćenom kralješku.