Co-Adjuvant Intravenous Corticosteroids for Septic Arthritis (CICSA): A Proposal of a Multicenter Randomized Controlled Trial

Abstract

Background: Septic arthritis (SA) is a serious and rapidly progressive condition that can result in significant morbidity and mortality. Current clinical guidelines endorse a combination of surgical debridement and targeted antibiotic therapy as the gold standard treatment for adults with knee SA. Despite the effectiveness of this approach, patients often experience prolonged inflammation, leading to long-term complications such as cartilage degeneration and chronic pain. Since inflammatory cytokines contribute to cartilage destruction, it is considered to be possible that mitigating their levels through the use of steroids could potentially prevent cartilage damage. Methods: This study is designed as a multicenter, open-label, randomized controlled trial aimed at evaluating the efficacy of intravenous dexamethasone as an adjunctive therapy for adults diagnosed with knee joint SA. Participants aged 18 years and older will be randomized to receive either standard treatment (surgical debridement and antibiotics) or the same regimen with the addition of dexamethasone. The primary objective is to assess pain reduction at four days post-surgery using the EQ-VAS scale and knee joint effusion, while secondary objectives will include the evaluation of additional surgical interventions, pain control over time, joint function, normalization of inflammatory markers, and overall healthcare resource utilization. Discussion: While corticosteroids have demonstrated efficacy in pediatric populations with septic arthritis, the evidence for their use in adults remains limited. This trial aims to ascertain whether the anti-inflammatory effects of corticosteroids can mitigate complications and enhance clinical outcomes in adult patients with SA. The findings from this study could provide critical insights into optimizing treatment strategies for this complex condition, ultimately improving patient quality of life.

1. Introduction

Septic arthritis (SA) is a severe and rapidly progressive erosive disease [1]. It can be devastating and it can eventually cause a patient’s death [2]. Its incidence is one per 100,000 inhabitants per year in the general population, but this increases 70-fold in patients with multiple comorbidities. This condition is clearly distinguished from other osteoarticular infections involving implants, such as prosthetic joint infections and infections following anterior cruciate ligament reconstruction, where biofilm involvement leads to less frequent systemic involvement, as the immune system is less activated [3,4].

In the adult population, the knee is the most frequently affected joint in septic arthritis (60–70% of cases). There is wide consensus that gold standard treatment for SA should combine surgical debridement and lavage plus targeted antibiotic therapy according to the results of the intraoperative cultures (or considering the potential role of Staphylococcus aureus as a causative pathogen in culture-negative infections since this is the most common bacteria isolate) [5,6]. For the knee joint, arthroscopic debridement provides a similar cure rate to open debridement, with better recovery and functional outcomes. Therefore, it is generally the recommended approach for this joint [7,8].

In addition, it has to be considered that even in those cases with eradication of the infection, the inflammatory process may be prolonged, leading to a prolonged recovery and residual joint damage [9].

Whereas the management of native-joint infection is well established, sequelae after this disease might be devastating and impact patient’s function and quality of life. SA may also require several surgeries and prolonged hospitalization and antibiotic therapy scheduled for weeks to try to cure infection. The most feared complication after SA is cartilage degeneration ending in joint osteoarthritis in months or a few years [1]. Other related sequelae could be stiffness and chronic pain.

Corticosteroids are widely recognized as safe and effective medications utilized in the management of infectious diseases characterized by a significant inflammatory response, such as meningitis. In the context of treating native SA, the incorporation of corticosteroids into standard therapy has primarily been assessed in pediatric populations, yielding favorable outcomes. Evidence suggests that this approach is safe and results in significantly more rapid clinical improvement, ultimately reducing the length of hospitalization when compared to treatment with antibiotics alone [10,11].

In conclusion, there is limited evidence and a lack of clinical trials in adult populations assessing the impact of corticosteroids in the treatment of SA in adult patients. Investigating the addition of corticosteroids in the treatment of SA, as a means to reduce inflammation and long-term complications in native-joint infections, would be highly valuable.

The objective of this article is to outline the hypothesis, objectives, design, and procedures for a multicenter, open-label, randomized, controlled study that compares the use of corticosteroids in the treatment of SA in adult patients undergoing surgical debridement and antibiotic therapy.

2. Materials and Methods

2.1. Hypothesis and Objectives of the Study [12]

The hypothesis of the study is that in adult patients with SA of a native joint, the administration of intravenous (iv) dexamethasone in conjunction with antibiotic therapy and surgical debridement will enhance clinical and functional outcomes.

The primary objective of this study is to evaluate the efficacy of adding iv dexamethasone to standard antibiotic therapy and surgical debridement, measuring pain reduction using the EQ-VAS scale and knee joint effusion at four days post-surgery.

The secondary objectives are; (a) to evaluate the need for and type of additional surgeries during follow-up (either open surgery or arthroscopy) and to assess treatment failure, defined as the necessity for more than one surgery, death, or the initiation of a suppressive antibiotic regimen; (b) to assess pain control at one month, six months, and 12 months post-surgery using the EQ-VAS scale; (c) to evaluate joint function through range of motion (ROM), patient satisfaction, and functional joint scores (WOMAC), in addition to mobility and quality-of-life scores (EuroQol 5); (d) to assess the normalization of inflammatory markers, including C-reactive protein (CRP), erythrocyte sedimentation rate, and D-Dimer; (e) to determine specific bone inflammatory enzymes as markers of bone remodeling; and (f) to evaluate the duration of hospitalization, length of antibiotic therapy, rehabilitation requirements, and radiological assessments, including X-rays and magnetic resonance imaging (CUBE T2 sequence for volumetric calculation of joint effusion, T2 mapping for cartilage volume assessment, and evaluation of cartilage dehydration associated with degenerative changes).

2.2. Trial Design

Co-adjuvant Intravenous Corticosteroids for Septic Arthritis (CICSA) is designed as a prospective, multicenter, open-label, randomized, controlled study aimed at comparing the efficacy of iv corticosteroids in the treatment of SA in adult patients undergoing surgical debridement and antibiotic therapy.

The coordinating research center for this study will be Hospital Parc de Salut el Mar in Barcelona, with a planned recruitment period of 24 months.

The study protocol is in accordance with the SPIRIT 2025 guidelines for clinical trials, checklist can be found as Supplementary Materials.

2.3. Study Population

The study’s target population comprises individuals aged 18 years and older, diagnosed with SA of the knee, who have received debridement surgery and antibiotic therapy.

The definition of septic arthritis will be based on the criteria established by the European Bone and Joint Infection Society (EBJIS) guidelines, as referenced in this study [6]. These criteria include the presence of a painful knee and/or effusion and/or inflammation, in association with one of the following:

• Purulent joint fluid.
• Leukocyte count > 50,000 cells/μL or >90% polymorphonuclear cells.
• Positive microbiological cultures.

Inclusion criteria: Patients qualify for enrollment in the study if they meet all of the following criteria:

• Subject ≥ 18 years of age.
• Written informed consent has been obtained.
• Subject undergoing arthroscopic debridement due to knee SA.

Exclusion criteria: Study participants are not allowed to meet any of the listed following criteria:

• Subject is currently enrolled in another competitive study.
• Inability to read and understand the participant’s information.
• Age < 18 years old.
• Allergy to steroids.
• Unwillingness to participate.
• Medically unstable patient and/or unfit for surgical debridement.
• Pregnancy or breast feeding.
• Antibiotics treatment during the previous 48 h before surgery.
• Previous history of SA in the same or in the contralateral joint.
• Had received systemic steroids in the previous two months (except inhaled for asthma).
• History of a foreign body in the affected joint.
• Poorly controlled diabetes mellitus patients.
• Open debridement as first surgery for knee SA.
• Severe immunodeficiency or immunosuppression that prevents the administration of corticosteroids.

Subject withdrawal. Withdrawn subjects will be replaced with the additional inclusion of new patients. Patients will be withdrawn from the study if:

• The inclusion/exclusion criteria were not respected at time of inclusion.
• The patient withdraws consent.
• Patients in follow-up cannot be assured or managed.

2.4. Patient Selection and Enrolment

Potential participants will be identified through a systematic review of admissions to the Traumatology Units, including both Emergency Department cases and outpatient referrals, as well as during daily rounds in the Traumatology wards. The selection of eligible candidates will involve collaboration between the Traumatology and Infectious Diseases teams.

Patients admitted with SA of the knee will be included and closely monitored. Each participating study center will screen all patients (male and female) for eligibility, identifying potential participants during outpatient visits prior to hospitalization or after admission.

Informed consent will be obtained from all the participants by research personnel trained in Good Clinical Practice following a comprehensive review of the patient information sheet. Participation in this study is entirely voluntary, and the participants may withdraw their consent at any time without any impact on their clinical care. Upon obtaining informed consent, patients will be assigned to either the control or study group based on the criteria determined by the responsible physician.

2.5. Interventions and Study Treatment

In accordance with current clinical guidelines, all patients diagnosed with SA of the knee will undergo arthroscopic debridement. In rare instances where a patient’s medical condition renders them unfit for surgical intervention, such cases will be classified as exclusion criteria, as previously outlined.

The patients enrolled in the study will be randomly assigned to one of two treatment groups: The first group will receive standard treatment comprising surgical debridement and antibiotic therapy. The second group will receive a combination of surgical debridement, antibiotic therapy, and corticosteroids as adjunctive treatment.

In the latter group, the participants will be administered iv dexamethasone at a dosage of 4 mg every eight hours for a duration of 96 h.

To implement blinding, the pharmacy department of each hospital will provide containers that are labeled in the same manner and contain the same volume, which will be administered with the same dosage regimen. Specifically, intravenous saline injections will be used as a placebo, administered every 8 h for 96 h, following the same schedule as the corticosteroids.

2.6. Primary Variable of the Study

The primary variables of the study are the pain assessment using a visual analog scale EQ-VAS scale and knee joint effusion, measured using magnetic resonance imaging (MRI) with a General Electric Medical Systems SIGNA Explorer, 1.5 Tesla, on the fourth postoperative day (between 70 and 100 h post-surgery). These primary variables are considered a surrogate for the other secondary variables, as joint effusion correlates directly with increased intra-articular cytokine levels, indicating a higher risk of joint degeneration, increased pain, and poorer function. A joint effusion of 12 cm³ or greater will be considered clinically relevant [12].

The primary variable will be assessed using two sagittal plane sequences (CUBE T2) for volumetric calculations of the effusion in the suprapatellar, infrapatellar, and posterior intercondylar recesses. 2D sequences will generate isotropic, submillimeter, contiguous data, with subsequent reformatting, without gaps between slices and with the same resolution as the native plane. The signal-to-noise ratio will be optimized without partial volume effects. Images will be validated by two radiologists specialized in musculoskeletal imaging, with structured reports.

2.7. Secondary Variables of the Study

The most important secondary variable, which is a surrogate for the primary variable, will be the assessment of articular cartilage degeneration. This evaluation will be performed using a new MRI (General Electric Medical Systems SIGNA Explorer, 1.5 Tesla) conducted two years post-intervention. The T2-mapping protocol will be applied for calculating cartilage volume and assessing its hydration level. This sequence is sensitive to the T2 prolongation that occurs with cartilage degeneration. To minimize variations from physical activity, loading, or temperature on the cartilage, the patients will remain at rest for 30 min in a waiting area with stable, regulated temperature before accessing Nuclear Medicine. Images will be validated by two radiologists specialized in musculoskeletal imaging, with structured reports.

Other variables to be analyzed include:

• Treatment failure: defined as any readmission for additional surgical or antimicrobial treatment during follow-up. The need for suppressive antibiotic treatment will also be considered failure.
• Number of debridements: total surgical procedures (open or arthroscopic).
• Laboratory parameters: PCR, ESR, D-dimer and specific bone inflammatory enzymes.
• Quality of life: measured using the self-reported EuroQol 5.
• Function: assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) to evaluate function and degenerative symptoms.
• Range of motion: measured in degrees.
• Duration of antibiotic treatment: recorded in days, including both intravenous and oral treatments.
• Duration of hospitalization: recorded in days.
• Rehabilitation needs: recorded in days, with 0 days counted if rehabilitation is not required.
• Radiological evolution assessed by the Kellgren–Lawrence scale.
• Mortality (exitus).
• Hospitalization Visits.

Patients typically remain in the hospital for 1 to 2 weeks, depending on the surgical treatment and clinical course. During hospitalization, the patients will be clinically assessed by the study physician at 24 h post-surgery, on the fourth day, and weekly thereafter.

2.8. Follow-Up Visits Post-Discharge

The patients will return for follow-up visits at 6 weeks, 2 months, 6 months, 1 year, and 2 years post-surgery, as well as for any study-related events every 2 years. During these follow-up visits, infection outcomes and joint functionality will be evaluated. Any participant death will be reported, and the cause will be assessed by an external committee. Functional assessment will be performed using specific scoring systems (WOMAC), subjective pain evaluation using a pain scale (1–10), and quality-of-life assessment via EQ5D5L.

2.9. Unscheduled Visits

In cases of treatment failure or suspected treatment failure, an additional unscheduled visit will be arranged. During each follow-up or unscheduled visit (during and after hospitalization), clinical signs and symptoms of infection, adherence to antimicrobial treatment, and significant side effects of antimicrobials or steroids will be documented in case report forms. Plain radiographs and/or laboratory analyses may also be performed. Joint aspirations may be necessary according to usual clinical practice. Patients who miss scheduled visits will be actively contacted via phone (or through their treating physicians).

2.10. Efficacy Evaluation

During hospitalization and at 6 weeks, 6 months, 12 months, and 24 months post-inclusion in the study, the subjects will undergo clinical evaluations, along with assessments of laboratory and/or radiological parameters, function, and quality of life (as described above). In cases of treatment failure or suspicion of treatment failure, an additional unscheduled visit will be organized. During each follow-up or unscheduled visit (during and after hospitalization), clinical signs and symptoms of infection and potential significant side effects of corticosteroids will be documented in case report forms. Plain radiographs and/or blood tests will be conducted if deemed necessary according to standard clinical practice.

Healing will be defined as a knee with acceptable functionality and no pain, normal laboratory test results, and the absence of joint effusion. Treatment failure is defined as any readmission for additional surgical or antimicrobial treatment during follow-up. The need for suppressive antibiotic treatment will also be considered a treatment failure.

If the outcome assessment is unclear (symptom-free or not), the case will be discussed in periodic study meetings that include a multidisciplinary team from all study centers, as well as an external evaluation committee.

2.11. Sample Size

Accepting an alpha risk of 0.05 and a beta risk of 0.2 in a two-sided test, 70 subjects are necessary to assess a statistically significant difference greater or equal than 2 units in the EQ-VAS scale. The standard deviation is assumed to be 4. Drop-out and lost-to-follow-up are considered. A drop-out rate of 10% has been anticipated. A p-value < 0.05 is considered significant.

This sample size would also be appropriate for detecting a statistically significant difference of 30% between two proportions: the proportion of patients receiving corticosteroids that will normalize the value of CRP at day 7 after surgery (80%) and in those who not (50%).

2.12. Statistical Analysis

This is an explorative study. Categorical variables will be expressed as absolute (n), relative frequencies (%), whereas continuous variables as mean ± standard deviation or median (IQR). For group comparisons, Student’s t test will be used for normally distributed variables, and the Mann–Whitney U test for non-normally distributed variables.

A p-value < 0.05 is considered significant. To detect possible confounders related to baseline values and strata-like type, duration and route of antibiotic treatment, study center, type of surgery, type of joint, infecting microorganism and antimicrobial susceptibility will be tested for statistical significance, by using a Cox proportional-hazards regression model. The results will be expressed as hazard ratios and 95% confidence intervals (CI).

Primary and secondary endpoints will be analyzed using appropriate parametric and non-parametric statistical methods, depending on their scale and distribution. To assess whether a continuous variable follows a normal distribution, the Kolmogorov–Smirnov test will be used.

A 95% confidence interval (CI) will be calculated. Statistical analyses will be performed using IBM SPSS Statistics for Windows, version 26.0 (IBM Corp., Armonk, NY, USA).

2.13. Safety Evaluation and Monitoring

The safety of all drugs will be closely monitored throughout the study period, starting from the administration of the first dose of the investigational drug and continuing through outpatient follow-up visits for up to two years. Compliance will be maintained with Regulation (EU) No. 536/2014 and Royal Decree 1090/2015 [13]. Safety endpoints will include the frequency of adverse events (AEs) and serious adverse events (SAEs), laboratory analyses, temperature monitoring, concomitant medications, and physical examination findings. All treatment changes will be documented in the electronic Case Report Form (eCRF), and laboratory parameters will be routinely verified according to standard clinical practice to ensure optimal safety monitoring. In case of any uncertainties regarding treatment or follow-up details, the principal investigators, the designated pharmacist responsible for the study, and the external review committee will be contacted.

3. Results

The potential therapeutic benefits for the study participants may include outcomes demonstrated in pediatric populations, such as pain reduction, accelerated functional improvement, decreased inflammatory markers, enhanced functional outcomes, and reduced stiffness. The associated risks, primarily related to steroid infusion, will be documented.

No specific benefits or additional risks are anticipated for the control group, as they will receive standard treatment for septic arthritis in accordance with current clinical guidelines. All the treatments will align with standard medical practice.

4. Discussion

In native SA, hematogenous spread is the most usual origin of infection, while the injections and arthroscopy portal routes are rare. Once the organism is within the synovial fluid, adherence and infection occur due to the low fluid shear conditions. An influx of inflammatory cells follows synovial cell proliferation. The inflammatory cells are phagocytes (including neutrophils and macrophages) that migrate chemotactically in response to bacterial products and immune response mediators [9]. To try to eradicate bacteria, neutrophils phagocytose the organisms secreting the content of their granules, producing reactive oxygen species and antimicrobial peptides, and releasing neutrophil extracellular traps. Failure to eliminate the bacteria results in strong activation of the immune response which leads to the destruction of the joint. It is the exaggerated immune response of the host rather than the direct cytotoxicity of the bacteria that has the most detrimental effect [6].

It should be noted that steroids are commonly used for the management of other acute bacterial infections, e.g., in lung disease [14], the reason being the powerful anti-inflammatory effect of the steroids improves the patient’s lung function and wellbeing. Glucocorticoids, such as prednisolone, have powerful anti-inflammatory effects depressing the formation, release, and activity of endogenous mediators of inflammation, including the inflammatory cytokines, and modify the innate and adaptive immune responses [10,11,14,15].

Both host and bacterial factors may have important effects on an infected joint on the articular cartilage. In knock-out mouse studies, the loss of macrophage-derived cytokines, e.g., lymphotoxin α, tumor necrosis factor α, interleukin (IL) 1 receptor, and the absence of the anti-inflammatory cytokine IL 10, increases the morbidity and mortality of Staphylococcal aureus infections [9]. The virulence of the microorganism is also important, which has been investigated in vivo studies performed in mice using bacterial components.

Indeed, glucocorticoids have been used in pediatric SA and in many other inflammatory diseases. Two randomized controlled trials have been carried out in children with promising results: co-adjuvant steroids have been shown to be safe and to reduce pain, hospital stay, and joint stiffness and function impairment [10,11]. Moreover, in a meta-analysis including four articles, Qin et al. concluded that there was firm evidence to support the use of corticosteroids in treating children with native SA [16]. The evidence suggests that the use of steroids suppresses the adverse effects of the infective inflammatory response on the articular cartilage and bone. As a recent Cochrane study concluded, using corticosteroids as an adjunct to antibiotic therapy can be expected to shorten hospital stay, reduce the length of iv and subsequent oral antibiotic administration, and achieve a quicker normalization of the CRP [17].

The final aim of the present randomized controlled trial will be to find out if the same results obtained in children may be obtained in adults.

Limitations

The primary limitation of this study is the extrapolation of findings to joints other than the knee. However, it was decided to include only this joint, as it is the most frequently affected by native-joint septic arthritis (SA), allowing for the standardization of both surgical and antibiotic treatment. Another limitation is the inclusion of only arthroscopic debridements. This decision aims to unify and standardize the processes as uniformly as possible. Nevertheless, open surgical treatment is an accepted approach, and this study does not provide strong evidence to confirm whether the outcomes would be the same with open surgery. Finally, while joint effusion is utilized as the primary endpoint, articular cartilage degeneration remains the clinically most relevant sequela of knee septic arthritis. As previously explained in the methodology, we consider effusion to be a surrogate variable for joint degeneration, given that effusion is a result of the inflammatory response and there is a positive correlation between increased effusion and higher levels of cytokines.