Musculoskeletal symptoms and their impact on health-related quality of life in chronic nonbacterial osteomyelitis patients

To the best of our knowledge, this is the first detailed study encountered by CNO patients that utilizes a Nordic MSK questionnaire to evaluate MSK symptoms among these patients. The study includes those diagnosed with CNO and provides data on MSK manifestations and their relation to HRQoL in CNO patients. The present study revealed that CNO patients had a heavy MSK symptom burden, which was associated with worse scores of HRQoL either in their physical, psychological, or rheumatological aspects.

CNO seems to be the standard term for long-lasting bone inflammation, no matter where it shows up (single or multiple sites) or how it progresses (self-limiting, persistently active vs. recurring) [20]. Previously considered a mild and self-limiting condition, CNO is now considered a severe and, in some instances, fatal condition due to chronic and severe pain as well as possible complications, including vertebral body fractures [21]. Despite the fact that the incidence of CNO has been reported to be as low as 4 cases per million children [22], various centers have witnessed an increase in the number of cases as awareness has been raised [23, 24].

In this study, the median age of the included CNO patients was 14 years; most of them (86.8%) were below the age of 20 years, and about two-thirds (66.2%) were females. In general, it appears that girls and young women are afflicted more commonly than boys and men (about 2:1) [25], and the majority of patients show symptoms between the ages of 7 and 9 years old [21]. CNO is infrequently observed in adults but can manifest in individuals of all age groups [9]. Females are more likely to be affected than males, and the progression of the disease varies greatly from case to case [26, 27]. Within European cohorts, there is a higher likelihood of females being affected [6, 28, 29]. while a male preponderance is reported in the Latin American and Indian series [30, 31].Obtaining a diagnosis for this condition often requires a year, on average, due to its uncommonness. However, 7% of patients experience a delay of over 5 years before receiving a diagnosis [32].

In our cohort, most of the CNO participants had MSK manifestations in the last month before the study. Pain is the most prevalent and prominent symptom of CNO [33]. It is typical for complaints to wax and wane, and an acute onset of pain may occur, necessitating a rapid diagnostic workup and prompt treatment [29]. Nocturnal exacerbations of discomfort and potential disruption of sleep are commonly observed, accompanied by localized tenderness at the affected area in the child [21].

When we questioned our cohort about additionalcomorbidities, we discovered that about one-half (54.4%) had associated comorbidities; the most common one was psoriasis (17.6%), followed by juvenile idiopathic arthritis (8.8%). When any autoimmune or autoinflammatory condition was taken into consideration, 50% of children diagnosed with CNO had at least one inflammatory comorbidity [34]. Pustular skin disease is a significant aspect or coexisting condition of CNO [29]. The prevalence of pustulosis/acne-like skin illness remains constant over time, whereas the incidence of inflammatory bowel disease (IBD) increases with the course of the disease [35]. According to the findings of other studies that investigated the connection between CNO and various auto-inflammatory diseases, there was a correlation between CNO and palmoplantar pustulosis, IBD, and psoriasis, as well as relatives who had chronic arthritis [22, 23, 36].

In this study, MSK manifestations were more prevalent in females (p = 0.005). Also, psoriasis was statistically significantly present in those with MSK manifestations (p = 0.048). In this regard, Girschick et al. described a cohort of 486 patients from around the world, which revealed that females (64%) are predominantly afflicted by CNO [29]. CNO patients with severe and multiple major bone lesions have been found to have a higher occurrence of concurrent arthritis or psoriasis [34, 37]. Also, recent data suggest that around 50% of individuals with CNO exhibit additional involvement outside of the bones, primarily in the form of psoriasis and palmoplantar pustulosis, IBD, and arthritis. However, the prevalence of specific co-morbidities varies considerably among the cohorts that have been studied [29, 34, 36, 38].

Regarding treatment used for our CNO cohort, NSAIDs were the most administered drugs (76.5%), followed by physical therapy (41.2%), MTX (41.2%), and bisphosphonates (35.3%). While NSAIDs are often recommended, particularly for children, their effectiveness is generally considered to be modest [30]. According to the current understanding of the pathophysiology of CNO, NSAIDs can potentially address the excessive activity of osteoclasts by reducing the generation of prostaglandins through the inhibition of cyclooxygenase enzymes. Prostaglandins play a crucial role in the process of osteoclast differentiation and activation. Moreover, NSAIDs influence the processing of pain, which accounts for their prompt analgesic effects [2].

In this study, patients with MSK manifestations significantly used bisphosphonates (p = 0.006) and pain medications (p = 0.005). Bisphosphonates have emerged as a highly efficacious second-line therapy for CNO subsequent to the failure of NSAIDs [39]. As second-line treatments for CNO, tumor necrosis factor alpha (TNF-α) inhibitors and the bisphosphonate pamidronate are frequently prescribed in Europe [40]. A multicenter study conducted by Bhat et al. found that bisphosphonate treatment was effective in 68.5% of all cases involving patients [6]. Although bisphosphonates do affect bone remodeling, they do not cause damage to developing skeletons or impede normal growth [41]. Various treatment modalities have been deliberated for patients who do not exhibit a favorable response to NSAIDs or who have predominant vertebral involvement. These alternatives consist of MTX, sulfasalazine (SSZ), biopharmaceutical drugs, specifically TNF-α inhibitors, and bisphosphonates [40].

In this study, about two-thirds (63.2%) did not administer any of the bDMARDs, while 27.9% administered at least 1 agent, 5.9% administered at least 2 agents, and only one patient received 3 agents and another one received 4 agents. Notwithstanding the growing recognition of CNO over the last few decades, the lack of evidence-based treatments continues to pose a challenge to clinical management [42]. Currently, there are no approved therapies available for the treatment of CNO. NSAIDs, MTX, sulfasalazine, pamidronate (PAM), anti-IL1 agents, and TNFα inhibitors have all been shown to work in many studies [29, 34].

According to the body regions, the maximum number of patients encountered pain in the last month in the right and left ankle/foot (26.5%) and right shoulder (25%), while the neck (8.8%) and ribs (5.9%) were the least affected body areas. The distribution of lesions has been exhaustively studied, typically utilizing whole body MRI at presentation and throughout the course of the disease, and typically affects the metaphyses of long bones, particularly in the lower extremities close to the knees and ankles [43].CNO can be found in all bones, but it is more frequently seen in the metaphyses and epiphyses of the long bones in children. However, it is not unusual to find CNO in the pelvis, shoulder girdle, and spine of both children and adults. The presentation of CNO in the jaw is one that is frequently overlooked [33, 44, 45].

According to the Nordic MSK questionnaire, most of the studied patients (66%) reported MSK symptoms in the last month; 22% described at least 1 site of discomfort;12% had at least 2; while 6% had at least 3; and 26% had > 3 body sites of MSK discomfort. Similar to other systemic inflammatory diseases, increased MSK pain can be a substantial comorbidity or consequence with a notable psychosocial impact [46].

The concept of HRQoL has gained significant recognition in recent years as an outcome that is useful to patients, as it reflects the effects of chronic illness on different health conditions [47]. In the present study, CNO patients with MSK symptoms had statistically significantly lower scores than did patients without in all domains of HRQoL. Although the treatment is advanced, patients with CNO still experience poor HRQoL [48]. In a study that comprised 18 CNO patients from a single center in Turkey, the authors discovered that the HRQoL of CNO patients was negatively affected, even though the treatment was effective [48]. These adverse consequences of CNO were detected not only in the patients’ physical activities but also in their social lives, emotional lives, and academic lives as well [48]. Another study demonstrated comparable deterioration in the physical and academic performance of patients with CNO, as assessed through the utilization of PedsQL-4. Similarly, the aforementioned study documented the presence of anxiety and difficulties in communication among individuals with CNO [49].

There are some limitations to this study that need to be addressed. One limitation of this study is that no matter who filled out the questionnaires, the patient and parent-reported measurements were analyzed together. This was done regardless of who completed the questionnaires. Even though this combination maximizes the total sample size, there may be differences in perceptions between children and proxies, particularly for children who are older. It is necessary to evaluate our HRQoL findings with respect to the treatments that were administered to the children who were included in this cohort. Children who are treated in a significantly different manner may experience varying patterns of HRQoL. We included six patients with JIA who were diagnosed after the onset of CNO in the study, which could potentially have a substantial impact on the study’s results. Due to the fact that CNO is an uncommon disease, we were compelled to do so, as it was somewhat challenging to collect a sufficient number of cases. Specifically, the inclusion of these JIA patients potentially confounded the analysis of both pain and medication parameters. Finally, our findings lend credence to the necessity of conducting additional research to further explain the nature and etiology of MSK symptoms, as well as their impact on HRQoL, and to identify the most effective treatment techniques for patients who are experiencing these symptoms.