Arthroscopic Guided Synovectomy, Synovial Biopsies, and Pathotype Identification in Refractory Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation, leading to joint destruction and significant disability¹. While advances in disease-modifying antirheumatic drugs (DMARDs) have improved outcomes, up to 30-40% of RA patients failed to respond to individual agents¹. Given the heterogeneity in treatment response, there is an increasing need for synovectomy and synovial biopsies in clinical practice to facilitate early diagnosis, guide personalized therapeutic strategies, and improve patient outcomes².

Synovectomy, the surgical removal of inflamed synovial tissue, can alleviate symptoms, delay joint destruction, and provide tissue for pathological analysis³. Synovial biopsy has been widely used for diagnostic purposes, allowing histopathological evaluation of the tissue to confirm the presence of rheumatoid synovitis⁴. This has enabled the detailed characterization of synovial pathotypes which are associated with varying disease mechanisms and responses to therapy⁵. Moreover, arthroscopic-guided techniques offer a minimally invasive approach with enhanced accuracy in tissue sampling, reducing patient morbidity compared to open surgical methods. However, the reports of integral procedures of the synovectomy and synovial biopsy in RA were still lacking, particularly in pre- and post-operative managements and assessments. A protocol for more effective clinical practice and minimizing postoperative complications is warranted.

While ultrasound-guided synovial biopsy is a less invasive alternative and has shown utility in many joints, arthroscopy allows for direct visualization, targeted sampling from multiple intra-articular regions, and concurrent therapeutic intervention when indicated. Therefore, this protocol focuses on the arthroscopic approach.

The overall goal of this study is to establish a comprehensive, standardized protocol for arthroscopic synovectomy and synovial biopsy in RA, with a focus on shoulder involvement. The rationale for this work stems from the unmet need for procedural consistency, which is essential for improving diagnostic accuracy, enabling reproducible research on synovial pathobiology, and enhancing patient care. Compared to alternative techniques (e.g., blind needle biopsy or open synovectomy), arthroscopy provides superior visualization, targeted tissue sampling, and lower complication rates, as evidenced by prior studies^6,7. Furthermore, this technique aligns with growing efforts to integrate synovial tissue analysis into RA management, as highlighted in recent consensus guidelines⁸.

This protocol contributes to the evolving framework of precision medicine in RA, where synovial tissue characterization is increasingly used to stratify patients for targeted therapies⁹. By detailing procedural steps, perioperative care, and pathological classifications, this work aims to help clinicians determine the method's applicability for their practice, particularly in cases of refractory RA or diagnostic uncertainty. Ultimately, this protocol may serve as a reference to standardize synovial tissue sampling, improve surgical outcomes, and advance research into RA heterogeneity.

Therefore, this paper aimed to describe a comprehensive procedure of synovectomy and synovial biopsies via arthroscopy in the shoulder for an RA patient, as well as the pathological classifications and treatments.

All procedures performed in the studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee, as well as with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. For the inclusion and exclusion criteria, refer to Supplementary File 1.

1. Preparation of the patient

1. Evaluate the patient to confirm readiness for the arthroscopic-guided synovectomy and synovial biopsy procedure.
2. Obtain informed consent and brief the patient on the procedure, including potential risks and expected outcomes.
3. Conduct clinical and biochemical assessments, including complete blood count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), anti-citrullinated peptide antibody (ACPA), liver and renal function tests, coagulation profile, and serology^10,11.
4. Advise the patient on preoperative fasting and adjust medications, discontinuing anticoagulants and antirheumatic drugs according to clinical guidelines¹².

2. Summary of medical history

1. Review the patient's medical history, focusing on the onset, duration, and severity of RA symptoms.
2. Document a history of joint swelling, stiffness, and pain, especially in the small joints of the hands and feet.
3. Record relevant comorbidities, such as cardiovascular disease, osteoporosis, and any previous joint surgeries.
4. Evaluate the patient's medication history, including disease-modifying antirheumatic drugs (DMARDs), biologics, and corticosteroids, due to their potential impact on synovial pathology and procedural outcomes.

3. Physical examination

1. Perform a focused musculoskeletal examination to evaluate joint tenderness, swelling, range of motion, and deformities.
2. Count the number of tender and swollen joints and assess for any extra-articular manifestations.
3. Calculate the Disease Activity Score 28 (DAS28) using tender and swollen joint counts, patient's global assessment, and ESR or CRP.
4. Examine nerve and vessel integrity, and inspect any surgical scars in the surgical region to identify possible anatomical changes.

4. Imaging assessment

1. Perform digital radiography pre-operatively to evaluate joint space narrowing or structural damage. In patients with refractory rheumatoid arthritis, perform preoperative magnetic resonance imaging (MRI) to rule out unrecognized concomitant conditions and to clearly delineate synovial hypertrophy, effusion, erosive changes, and the extent of joint pathology, thereby reducing the risk of iatrogenic damage during surgery.
2. Assess the anatomical relationship of the affected regions with adjacent nerves and blood vessels.
3. Utilize imaging findings to guide arthroscopy and select appropriate biopsy sites, focusing on the most affected areas for synovial biopsy.

5. Preparation for the surgery

1. Administer general anesthesia or regional nerve block depending on the joint involved, patient condition, and surgical complexity.
2. Assemble all required instruments and materials, including a standard surgical set for arthroscopic or open procedures, a 30° or 70° angled arthroscope, a motorized shaver system with full-radius resectors of varying diameters, a radiofrequency ablation system, synovial biopsy forceps in multiple sizes and angles, as well as sterile waterproof drapes and gowns to maintain a sterile field.
3. Collect necessary anesthetic agents (including those required by the anesthesiology team), sutures, and dressings for wound closure, ensuring all items are sterile and ready for use.

6. Patient preparation

1. Administer general anesthesia with or without neural blockade according to the anesthetic plan established by the anesthesia team.
2. Employ hypotensive anesthesia to minimize bleeding and enhance visualization during the procedure.
3. Position the patient in either a lateral decubitus or beach-chair position for shoulder synovectomy, based on the surgeon's preference.
4. Prepare and drape the shoulder area using sterile techniques to maintain a sterile field.

7. Procedure of the surgery (as an example of shoulder synovectomy)

1. Portals
   1. Establish a posterior mid-glenoid portal (PMGP), an anterior mid-glenoid portal (AMGP), and a lateral portal, which are generally sufficient for the procedure.
   2. Use an anterior-superior portal (ASP) to facilitate access to the subcoracoid space if required.
2. Inspection
   1. Perform an arthroscopic review of the anterior portion of the joint and the subcoracoid space using the scope in the PMGP.
   2. Switch the arthroscope to the AMGP to examine the posterior portion of the glenohumeral joint.
   3. After the procedure in the glenohumeral joint, use the PMGP and the lateral portals to conduct a subacromial bursoscopy, identifying synovial hypertrophy and other pathologies.
3. Biopsy
   1. Obtain a minimum of six samples from different regions of the glenohumeral joint¹³.
   2. Ensure that the samples are collected for subsequent histologic analysis.
4. Synovectomy
   1. Perform a global synovectomy using a power shaver.
   2. Debride the anterior portion of the glenohumeral joint with the shaver positioned in the AMGP while keeping the scope in the PMGP.
   3. Exchange the scope and shaver to complete the synovectomy in the glenohumeral joint.
   4. Resect the inflammatory and thickened bursal tissue in the subacromial and subdeltoid space with the shaver in the lateral portal.
   5. Using AMGP and PMGP, complete the subacromial and subdeltoid space with the shaver while keeping the scope in the lateral portal.
   6. Ensure meticulous hemostasis in each area using a radiofrequency ablation system.
5. Capsular release
   1. Perform a capsular release using a radiofrequency device or basket forceps for patients exhibiting significant stiffness under anesthesia, such as a forward flexion angle of less than 120°, an external rotation angle of less than 30° when the arm is placed at the side of the body, or an internal rotation angle below the fifth lumbar vertebra.
   2. Carefully assess the range of motion before and after the procedure to evaluate the effectiveness of the release.
6. Closure
   1. Close the wound using non-absorbable sutures.
   2. Cover the wound with a sterile dressing to ensure proper healing and prevent infection.
7. Tips and pitfalls
   1. Take care to preserve the rotator cuff tendons and the long head of the biceps.
   2. Keep the instruments lateral to the coracoid to avoid the iatrogenic injury of axillary vessels and brachial plexus.
   3. Ensure thorough hemostasis to reduce the risk of joint hematoma; consider the local injection of tranexamic acid as a beneficial adjunct.

8. Post-biopsy procedure

1. Administer immediate postoperative care, including pain management, and initiate structured physiotherapy with supervised active and passive range of motion exercises as early as possible following capsular release to preserve joint mobility and prevent postoperative stiffness..
2. Administer antibiotics according to protocol to prevent infection¹⁴.
3. Schedule suture removal after 14 days postoperatively.
4. Restart biologic therapy once the wound shows evidence of healing, all sutures have been removed, and there is no significant swelling, erythema, drainage, or evidence of non-surgical site infections¹⁵.
   NOTE: Synovectomy and capsular release are not routinely indicated and should be performed based on intraoperative findings and clinical necessity.

9. Pathological classification

1. Assess hematoxylin and eosin (HE) stained and immunohistochemistry (IHC) stained slides to evaluate the level of synovitis using the Krenn synovitis score¹⁶.
2. Identify synovial biopsies into histological patterns, also known as pathotypes, based on the following criteria¹⁷:
   Lympho-myeloid: Presence of score 2-3 CD20+ aggregates, CD20 ≥ 2 and/or CD138 ≥ 2;
   Diffuse-myeloid: CD68SL ≥ 2, CD20 ≤ 1 and/or CD3 ≥ 1 and CD138 ≤ 2;
   Pauci-immune-fibroid: CD68SL < 2 and CD3, CD20 and CD138 < 1.

10. Treatment and monitoring

1. Monitor the patient's progress closely through follow-up visits, imaging studies, and clinical assessments of joint function and disease activity.
2. Implement long-term management strategies that include optimizing pharmacologic treatment to prevent future joint damage and maintain functional capacity.
   NOTE: This protocol focuses on the technique of arthroscopic biopsy and synovial tissue classification. Therapeutic strategies are not included in the protocol, as pathotype-based treatment remains investigational and is not part of current clinical guidelines. However, a summary of proposed therapeutic approaches based on synovial pathotypes is provided in Table 1 for reference.

Arthroscopic synovial biopsy was performed in a patient with active shoulder synovitis and systemic inflammatory arthritis. On clinical examination, the shoulder exhibited a limited range of motion and localized tenderness, particularly in the anterior region. Inflammatory markers were elevated (CRP: 24.23 mg/L; ESR: 59 mm/h), while RA-related autoantibodies were negative. The DAS28 score for this patient was 5.81, indicating a high level of disease activity in RA.

Preoperative MRI demonstrated diffuse synovial hyperplasia, cartilage erosion, and joint space narrowing in the glenohumeral joint (Figure 1). During arthroscopy, synovial inflammation was confirmed, and areas of grade III-IV chondromalacia were observed on both the glenoid and humeral head. A total of six synovial tissue samples were collected from different intra-articular regions under direct visualization (Figure 2). Capsular release and joint debridement were also performed.

At 2 weeks postoperatively, the patient reported reduced pain and swelling, and the shoulder range of motion improved markedly. Histological analysis of the biopsy revealed a diffuse-myeloid pattern, characterized by high CD68 (3-4), moderate CD3 (3), and low CD20 and CD138 scores (both 1) (Figure 3). These findings illustrate the feasibility of using arthroscopic biopsy to obtain high-quality synovial tissue for immunohistochemical classification in inflamed joints.

Figure 1: T2-weighted images of the left rheumatoid shoulder. (A,B) Axial (A) and sagittal (B) T2-weighted images of the left rheumatoid shoulder demonstrated a diffuse synovial hyperplasia, especially in the subcoracoid space can be noted. A serious cartilage erosion and a narrow joint space were noted. Please click here to view a larger version of this figure.

Figure 2: Sample collection under direct visualization. (A) Hyperplastic inflamed synovial tissue in the subcoracoid space. Arthroscopic biopsy was performed with the scope in the PMGP. (B) Synovectomy was being performed with a power shaver in AMGP, with the scope in the PMGP. (C) Posterior capsular release was being performed with a radiofrequency probe, with the scope in the AMGP. Please click here to view a larger version of this figure.

Figure 3: Representative data. (A) HE staining: Synovium histopathology displayed diffuse-myeloid pathotype for the left shoulder, which revealed an "exuberant" view. IHC staining: (B) CD3 (partially reactive/mature T lymphocytes+, approximately 20% of the specimen area, semiquantitative score = 3); (C) CD20 (B lymphocytes+, approximately 1% of the specimen area, semiquantitative score = 1); (D) CD138 (scattered infiltrating reactive plasma cells+, approximately 1% of the specimen area, semiquantitative score = 1); (E) CD68 (histiocytes and/or multinucleated giant cells and megakaryocytes+, approximately 35% of the specimen area, semiquantitative score = 3-4); (F) CD117 (scattered or individual mast cells+, total count of 10 cells, approximately 1% of the specimen area). The left panels are shown at 40x magnification, while the right panels are shown at 100x magnification Please click here to view a larger version of this figure.

Table 1: Summary of synovial pathotypes and corresponding therapeutic implications in RA.

Supplementary File 1: Inclusion and exclusion criteria. Please click here to download this File.

This paper described a detailed procedure of synovectomy and synovial biopsy in the management of RA, particularly when performed in large joints like the shoulder. Synovectomy may offer symptomatic relief by removing inflamed synovial tissue, particularly in cases of joint-specific, treatment-refractory synovitis. It is typically considered an adjunct to pharmacologic therapy, rather than a primary intervention. Synovectomy is an important procedure for RA patients, particularly in cases where inflammation persists despite pharmacological intervention. However, the careful refinement of these techniques is required as unwanted complications after the surgery significantly impact patient outcomes and recovery.

In all cases, no significant postoperative complications were observed, and the results indicated only minimal side effects following synovectomy. This aligned with the literature suggesting that, with proper technique, synovectomy was a safe and effective treatment for managing RA symptoms^18,19. Previous reports have documented potential complications, including infection, joint swelling and hemarthrosis, and delayed wound healing following synovectomy^20,21. The results highlighted the importance of optimized perioperative protocols to reduce such risks and improve patient safety and long-term outcomes. These protocols included a thorough preoperative assessment, perioperative management of antirheumatic medication, an adequate preoperative preparation of surgical instruments, comprehensive anatomical knowledge, meticulous intraoperative maneuvers, thorough hemostasis, a rational perioperative antibiotic use, and an enhanced recovery after surgery.

The synovial biopsy plays a key role in identifying distinct pathological features of RA, which can vary greatly among patients. These pathological features, including the lympho-myeloid, diffuse-myeloid, and pauci-immune-fibroid patterns, offer valuable insights into the disease's progression and response to treatment²². Understanding these classifications is beneficial in tailoring personalized treatment for individual RA. In this representative case, synovial biopsies revealed a predominance of diffuse-myeloid pathotype, which could facilitate clinicians toward more targeted biologic therapies. Moreover, the application of pathotype classifications in treatment planning has been shown to improve clinical outcomes by allowing a more precise selection of disease-modifying therapies, reducing unnecessary exposure to relatively ineffective drugs¹⁷.

Despite the advantages, there are limitations associated with synovectomy and synovial biopsies. Firstly, the potential for incomplete resection of inflamed tissue during arthroscopic procedures might lead to recurrent inflammation and necessitate further intervention. This emphasizes the necessity of switching to the appropriate drug based on pathologic pattern postoperatively, to control the progression of the disease. Additionally, while arthroscopic synovectomy and synovial biopsy provide promising results and important diagnostic information, the invasive nature may cause infection, especially in patients with advanced RA or compromised immune systems. Anticoagulants and antirheumatic medication were discontinued in this case, and antibiotics were used perioperatively to prevent post-operative hemarthrosis and infection. Post procedure, there were no signs of infection. Thirdly, this paper presents a representative case involving synovectomy in one joint site and one pathological subtype. While this allows for illustrative demonstration of the procedural steps, it does not permit conclusions about generalizability or clinical efficacy. Future studies involving additional joint sites, pathotypes, and larger patient cohorts are needed to further validate the protocol's utility in diverse clinical contexts.

In conclusion, the arthroscopic synovectomy and synovial biopsy protocols outlined in this paper offered a reliable and minimally invasive approach for managing RA. Integrating the analysis of synovial pathotypes into clinical practice could be better for optimizing treatments for individual patients, improving outcomes, and minimizing unnecessary complications. Ongoing refinement of these techniques is essential to overcome existing limitations and enhance their role in the long-term management of RA.