Effectiveness of janus kinase inhibitors in relapsing giant cell arteritis in real-world clinical practice and review of the literature.

BACKGROUND: A substantial proportion of patients with giant cell arteritis (GCA) relapse despite standard therapy with glucocorticoids, methotrexate and tocilizumab. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway is involved in the pathogenesis of GCA and JAK inhibitors (JAKi) could be a therapeutic alternative. We evaluated the effectiveness of JAKi in relapsing GCA patients in a real-world setting and reviewed available literature. METHODS: Retrospective analysis of GCA patients treated with JAKi for relapsing disease at thirteen centers in Spain and one center in United States (01/2017-12/2022). Outcomes assessed included clinical remission, complete remission and safety. Clinical remission was defined as the absence of GCA signs and symptoms regardless of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) values. Complete remission was defined as the absence of GCA signs and symptoms along with normal ESR and CRP values. A systematic literature search for other JAKi-treated GCA cases was conducted. RESULTS: Thirty-five patients (86% females, mean age 72.3) with relapsing GCA received JAKi therapy (baricitinib, n = 15; tofacitinib, n = 10; upadacitinib, n = 10). Before JAKi therapy, 22 (63%) patients had received conventional synthetic immunosuppressants (e.g., methotrexate), and 30 (86%) biologics (e.g., tocilizumab). After a median (IQR) follow-up of 11 (6-15.5) months, 20 (57%) patients achieved and maintained clinical remission, 16 (46%) patients achieved and maintained complete remission, and 15 (43%) patients discontinued the initial JAKi due to relapse (n = 11 [31%]) or serious adverse events (n = 4 [11%]). A literature search identified another 36 JAKi-treated GCA cases with clinical improvement reported for the majority of them. CONCLUSIONS: This real-world analysis and literature review suggest that JAKi could be effective in GCA, including in patients failing established glucocorticoid-sparing therapies such as tocilizumab and methotrexate. A phase III randomized controlled trial of upadacitinib is currently ongoing (ClinicalTrials.gov ID NCT03725202).

Long-Term Outcomes of an International Cooperative Study of Intraoperative Radiotherapy Upfront Boost With Low Energy X-Rays in Breast Cancer.

Purpose: The purpose of this study was to assess the effectivity of upfront kilovoltage intraoperative radiotherapy (IORT) as a boost in high-risk early-stage breast cancer patients from an international pooled cohort. Materials/Methods: Patients from four centers in three different countries were retrospectively screened. Those with a minimum 1-year follow-up were included. Cumulative local (LR), regional (RR), and distant metastasis rates (DM) were analyzed. Additionally, the estimated overall survival (OS) was assessed. The Cox regression analysis was performed to identify failure predicting factors. Results: A total of 653 patients from centers in Peru, Spain, and Germany were included. The median follow-up was 55 (12-180) months, and age was 58 (27-86) years. Clinical tumor (T) staging was T1 65.85%, T2 30.17%, and T3 3.98%. Positive margins were found in 7.9% and in-situ component in 20.06%. The median IORT dose was 20 (6-20). The median time from IORT to EBRT was 74.5 (13-364) days. An overall 3.4% (n = 22) of patients developed local recurrence at some point during follow-up. The 12-, 60-, and 120-month cumulative LR were 0.3%, 2.3%, and 7.9%, respectively. After multivariate analysis, only age <50 remained to be a significant prognostic factor for local recurrence (HR 0.19, 95% CI 0.08-0.47; p < 0.05). The 10-year estimated OS was 81.2%. Conclusion: Upfront boost with IORT yields similar local control outcomes to those EBRT-based reports. Results from prospective trials, regarding toxicity, cosmesis, and effectivity are awaited to confirm these findings.

Biologic therapy in refractory neurobehçet's disease: a multicentre study of 41 patients and literature review.

OBJECTIVES: To assess efficacy and safety of biologic therapy (BT) in neurobehçet's disease (NBD) refractory to glucocorticoids and at least one conventional immunosuppressive drug. METHODS: Open-label, national, multicentre study. NBD diagnosis was based on the International Consensus Recommendation criteria. Outcome variables were efficacy and safety. Main efficacy outcome was clinical remission. Other outcome variables analysed were glucocorticoid-sparing effect and improvement in laboratory parameters. RESULTS: We studied 41 patients [21 women; age 40.6 (10.8) years]. Neurological damage was parenchymal (n = 33, 80.5%) and non-parenchymal (n = 17, 41.5%). First BTs used were infliximab (n = 19), adalimumab (n = 14), golimumab (n = 3), tocilizumab (n = 3) and etanercept (n = 2). After 6 months of BT, neurological remission was complete (n = 23, 56.1%), partial (n = 15, 37.6%) and no response (n = 3, 7.3%). In addition, median (IQR) dose of oral prednisone decreased from 60 (30-60) mg/day at the initial visit to 5 (3.8-10) mg/day after 6 months (P < 0.001). It was also the case for mean erythrocyte sedimentation rate [31.5 (25.6)-15.3 (11.9) mm/1st h, P = 0.011] and median (IQR) C-reactive protein [1.4 (0.2-12.8) to 0.3 (0.1-3) mg/dl, P = 0.001]. After a mean follow-up of 57.5 months, partial or complete neurological remission persisted in 37 patients (90.2%). BT was switched in 22 cases (53.6%) due to inefficacy (n = 16) or adverse events (AEs) (n = 6) and discontinued due to complete prolonged remission (n = 3) or severe AE (n = 1). Serious AEs were observed in two patients under infliximab treatment. CONCLUSIONS: BT appears to be effective and relatively safe in refractory NBD.

Suprascapular Nerve Release: Technique Based on Anatomic Landmarks.

Dysfunction of the suprascapular nerve (SSN) is closely related to rotator cuff pathology; nerve dysfunction can lead to cuff disease and vice versa. Owing to repetitive microtrauma during overhead sports or massive cuff tears with significant tendon retraction, the SSN may suffer compression or traction neuropathy at the suprascapular notch. The SSN release technique has already been described. However, on the basis of the many hands-on cadaveric laboratories in which we have participated in the past 20 years, only a few instructors and almost none of the attendants have shown the experience and skill set needed to release the SSN at the suprascapular notch. Therefore, a review of the surgical technique following the anatomic descriptions of an expert anatomist (P.G.) of the shoulder girdle is quite valuable.

Footprint preparation with nanofractures in a supraspinatus repair cuts in half the retear rate at 1-year follow-up. A randomized controlled trial.

PURPOSE: To evaluate if adding nanofractures to the footprint of a supraspinatus tear repair would have any effect in the outcomes at one-year follow-up. METHODS: Multicentric, triple-blinded, randomized trial with 12-months follow-up. Subjects with isolated symptomatic reparable supraspinatus tears smaller than 3 cm and without grade 4 fatty infiltration were included. These were randomized to two groups: In the Control group an arthroscopic supraspinatus repair was performed; in the Nanofracture group the footprint was additionally prepared with nanofractures (1 mm wide, 9 mm deep microfractures). Clinical evaluation was done with Constant score, EQ-5D-3L, and Brief Pain Inventory. The primary outcome was the retear rate in MRI at 12-months follow-up. Secondary outcomes were: characteristics of the retear (at the footprint or at the musculotendinous junction) and clinical outcomes. RESULTS: Seventy-one subjects were randomized. Two were lost to follow-up, leaving 69 participants available for assessment at 12-months follow-up (33 in the Control group and 36 in the Nanofracture Group). The Nanofracture group had lower retear rates than the Control group (7/36 [19.4%] vs 14/33 [42.4%], differences significant, p = 0.038). Retear rates at the musculotendinous junction were similar but the Nanofracture group had better tendon healing rates to the bone (34/36 [94.4%] vs. 24/33 [66.71%], p = 0.014). Clinically both groups had significant improvements, but no differences were found between groups. CONCLUSION: Adding nanofractures at the footprint during an isolated supraspinatus repair lowers in half the retear rate at 12-months follow-up. This is due to improved healing at the footprint. LEVEL OF EVIDENCE: Level I.

Biomechanical analysis of acromioclavicular joint dislocation repair using coracoclavicular suspension devices in two different configurations.

BACKGROUND: The best treatment option for some acromioclavicular (AC) joint dislocations is controversial. For this reason, the aim of this study was to evaluate the vertical biomechanical behavior of two techniques for the anatomic repair of coracoclavicular (CC) ligaments after an AC injury. MATERIALS AND METHODS: Eighteen human cadaveric shoulders in which repair using a coracoclavicular suspension device was initiated after injury to the acromioclavicular joint were included in the study. Three groups were formed; group I (n = 6): control; group II (n = 6): repair with a double tunnel in the clavicle and in the coracoid (with two CC suspension devices); group III (n = 6): repair in a "V" configuration with two tunnels in the clavicle and one in the coracoid (with one CC suspension device). The biomechanical study was performed with a universal testing machine (Electro Puls 3000, Instron, Boulder, MA, USA), with the clamping jaws set in a vertical position. The force required for acromioclavicular reconstruction system failure was analyzed for each cadaveric piece. RESULTS: Group I reached a maximum force to failure of 635.59 N (mean 444.0 N). The corresponding force was 939.37 N (mean 495.6 N) for group II and 533.11 N (mean 343.9 N) for group III. A comparison of the three groups did not find any significant difference despite the loss of resistance presented by group III. CONCLUSION: Anatomic repair of coracoclavicular ligaments with a double system (double tunnel in the clavicle and in the coracoid) permits vertical translation that is more like that of the acromioclavicular joint. Acromioclavicular repair in a "V" configuration does not seem to be biomechanically sufficient.

Long-term follow-up of allograft reconstruction of segmental defects of the humeral head associated with posterior dislocation of the shoulder.

The purpose of this study is to report the long-term follow-up result of allograft reconstruction of segmental defect of the humeral head associated with posterior dislocation of the shoulder. Six men underwent operative management of defects of the humeral head involving 40% of the articular surface, following posterior dislocation of the humeral head. The period of time between dislocation and surgery ranged from 7 to 8 weeks. The defect in the head was filled with an allogeneic segment of humeral head contoured to restore the spherical shape. All the patients returned to their occupation 4 months later. All the cases were evaluated clinically and by radiographs and computed tomography (CT) scan at a mean of 122 (96-144) months after the operative procedure. Three men had no complaints of pain, instability, clicking or catching, whereas three had pain, clicking, catching and stiffness. The three patients with good clinical result showed also good radiographic result. The computed tomography (CT) confirmed incorporation of the allograft and no osteoarthrosis. Another patient had a good clinical and radiographic result until the eighth postoperative year. At 8-year follow-up examination, this patient developed shoulder osteoarthrosis and he had pain and stiffness. He needed an arthroplasty 10 years after the operation. The other two patients developed collapse of the graft and osteoarthrosis that were yet evident at 4-year follow-up. These patients required a shoulder arthroplasty 8 years after the procedure. We conclude that the treatment of segmental defects of the humeral head associated with posterior dislocations of the shoulder by allograft reconstruction has a good long-term follow-up result in 50% of the patients.

Single-row versus double-row arthroscopic repair in the treatment of rotator cuff tears: a prospective randomized clinical study.

PURPOSE: The purpose of this study was to compare arthroscopic rotator cuff repair with single-row and double-row techniques because research has demonstrated the superiority of double-row repair from a biological and mechanical point of view but there is no evidence of clinical superiority. METHODS: A total of 160 patients with a full-thickness rotator cuff tear underwent arthroscopic repair with suture anchors. They were randomised into two groups of 80 patients according to the repair technique: single-row (group 1) and double-row (group 2). Results were evaluated by use of the University of California, Los Angeles (UCLA), American Shoulder and Elbow Surgeons (ASES) and Constant questionnaires, the Shoulder Strength Index (SSI) and range of motion. Follow-up time was two years. Magnetic resonance imaging (MRI) studies were performed on each shoulder preoperatively and two years after repair. RESULTS: One hundred per cent of the patients were followed up. All measurements showed significant improvement compared with the preoperative status. The UCLA score showed significant improvement in group 2. In over 30-mm tears UCLA and ASES showed significant differences. SSI showed significant improvement in group 2. Range of motion showed significant improvements in flexion and abduction in group 2. In under 30-mm tears group 2 showed also significant improvement in internal and external rotation. In MRI studies there were no significant differences. CONCLUSIONS: At two years follow-up the double-row repair technique showed a significant difference in clinical outcome compared with single-row repair and this was even more significative in over 30-mm tears. No MRI differences were observed.

The use of the Lima reverse shoulder arthroplasty for the treatment of fracture sequelae of the proximal humerus.

BACKGROUND: Experience treating proximal humerus fracture sequelae with reverse total shoulder arthroplasty is limited. We report our results. PATIENTS: Forty-four patients with sequelae of a proximal humeral fracture were treated with a reverse total shoulder prosthesis. There were 26 women and 18 men, with a mean age of 77 years (range, 74-84 years). The mean follow-up after reverse arthroplasty was 48 months (range, 40-84 months). RESULTS: The mean Constant score increased from 28 preoperatively to 58 postoperatively (p < 0.0001). The average anterior elevation increased from 40° to 100° (p < 0.0001), abduction from 41° to 95° (p < 0.0001), external rotation from 15° to 35° (p < 0.0001) and internal rotation from 25° to 60° (p < 0.0001). The average subjective shoulder score increased from 13% preoperatively to 56% postoperatively (p < 0.0001). All but six patients would undergo the same procedure again if faced with the same problem. Twenty-four patients were very satisfied, 14 satisfied and 6 unhappy with the operation. Six prosthetic dislocations occurred (13.6%). Two of them were successfully treated by adding an extension to the humeral neck component to increase the offset and tension. In the other four dislocations this procedure failed, and the prosthesis was revised and converted to a hemiarthroplasty. There was one case of glenoid component loosening that was converted to a hemiarthroplasty. CONCLUSIONS: The reverse total shoulder arthroplasty improves function and motion in patients with proximal humeral fracture sequelae. However, the dislocation rate is high.

Internal fixation and strut allograft augmentation for periprosthetic humeral fractures.

PURPOSE: To report 6 patients with periprosthetic humeral fractures treated with open reduction and internal fixation with plate and strut allograft augmentation. METHODS: 6 women aged 69 to 79 (mean, 73) years underwent open reduction and internal fixation with plate and strut allograft augmentation for periprosthetic humeral fractures (type C) after a fall. They had undergone reverse shoulder arthroplasty for rotator cuff arthropathy. The mean interval between the initial arthroplasty and the fracture was 17 (range, 11-21) months. RESULTS: The mean follow-up period was 14 (range, 12-16) months. The mean time to union was 5.4 (range, 4-6) months. All fractures united without complications. The mean Constant score at the last follow-up was 64 (range, 56-80). The range of shoulder movement and patient satisfaction were restored to pre-fracture status in all patients, except for one who had more pain in the lateral area of the arm (probably because of soft-tissue irritation by the plate and wires). Three patients had evidence of graft-to-host union and 3 others had graft resorption. CONCLUSION: Internal fixation with plate, cable wires and strut allogaft augmentation achieves satisfactory results for periprosthetic humeral fractures.

Liberacion endoscopica del nervio supraescapular: aportaciones anatomicas / Endoscopic release of the suprascapular nerve: anatomical considerations

En la práctica artro-endoscópica del aparato locomotor, se desarrollan constantemente nuevas opciones terapéuticas, en ocasiones insospechadas. En general, estas nuevas técnicas requieren de una gran habilidad y de un nuevo conocimiento anatómico, la anatomía artro-endoscópica. El objetivo de esta publicación es proporcionar un recuerdo anatómico útil para la realización de la liberación endoscópiea del nervio supraescapular.

Liberacion endoscopica del nervio supraescapular: aportaciones anatomicas / Endoscopic release of the suprascapular nerve: anatomical considerations

En la práctica artro-endoscópica del aparato locomotor, se desarrollan constantemente nuevas opciones terapéuticas, en ocasiones insospechadas. En general, estas nuevas técnicas requieren de una gran habilidad y de un nuevo conocimiento anatómico, la anatomía artro-endoscópica. El objetivo de esta publicación es proporcionar un recuerdo anatómico útil para la realización de la liberación endoscópiea del nervio supraescapular.(AU)

Arthroscopic treatment for malunions of the proximal humeral greater tuberosity.

The purpose of this article was to report an arthroscopic treatment method for greater tuberosity malunion. Eight patients with malunion of the greater tuberosity were treated by arthroscopic acromioplasty, detachment of rotator cuff, tuberoplasty of the greater tuberosity and repair of the rotator cuff. On the basis of the UCLA rating scale, the overall score increased from 11.1 (range 9-14) to 30.2 (range 25-35) postoperatively, with one excellent result, six good results, and one poor result. All patients had less pain than preoperatively. Full activity level was achieved in two patients, five patients had only slight functional restriction, and one patient had mild limitation in activities of daily living. Seven patients returned to their previous occupations without restrictions. One patient did not return to work because of residual upper extremity weakness. We conclude that arthroscopic tuberoplasty is a good method for the treatment of greater tuberosity malunion.

Allograft reconstruction of segmental defects of the humeral head associated with posterior dislocations of the shoulder.

Six men underwent operative management of defects of the humeral head involving at least 40% of the articular surface, following posterior dislocation of the humeral head. The cause of dislocation was a grand mal seizure in three and a fall in three cases. In five cases the dislocation was reduced under general anaesthesia, and in all the posterior dislocation recurred early. Time between dislocation and surgery ranged from 7 to 8 weeks. The defect in the head, revealed by CT, was filled with an allogeneic segment of humeral head contoured to restore the spherical shape. All the patients returned to their occupation 4 months later. The mean duration of follow-up was 62.6 (60-68) months. At discharge, four of the men had no complaints of pain, instability, clicking or catching; two had pain, clicking, catching and stiffness. Radiographs and CT revealed no failures of fixation or of incorporation of the allograft. In four cases the contour and volume of the graft were maintained, but in the two with a bad clinical result, flattening and collapse of the graft and osteoarthrosis were observed. If the procedure fails, prosthetic reconstruction should be simple because the skeletal anatomy has not been distorted.

Rotator interval closure after arthroscopic capsulolabral repair: a technical variation.

Rotator interval tear is one of the lesions identified in patients with glenohumeral instability. We present our technique for arthroscopic interval capsule repair. After having performed Bankart reconstruction, we pull the anterosuperior cannula back some millimeters and introduce a Penetrator suture retriever forceps (Arthrex, Naples, FL) through the upper interval capsule into the joint. Then we also remove some millimeters of the anterior cannula and introduce a suture passer (Spectrum; Linvatec, Largo, FL) loaded with a monofilament suture through the lower interval capsule. The suture is pushed into the joint and, using the Penetrator suture retriever forceps, we retrieve it out of the joint. This suture is replaced if desired by a permanent braided suture. Next, a suture passer (Arthrex) advances the end of the suture from the anterosuperior portal into the joint. The suture is retrieved out of the joint from the anterior cannula with a crochet hook. We tie the suture down the anterior cannula to close the anterior capsule. Because we use cannulas, we can use a sliding knot. The degree of tightening can be observed directly under arthroscopic view but the knot is outside of the capsule. We believe that this method is easy, effective, and reproducible.

Evidence of a cross-talk regulation of a GA 20-oxidase (FsGA20ox1) by gibberellins and ethylene during the breaking of dormancy in Fagus sylvatica seeds.

Gibberellin 20-oxidase (GA 20-oxidase) is an enzyme that catalyses the last three steps in the synthesis of active GAs and is a potential control point in the regulation of GA biosynthesis. Reverse transcriptase-polymerase chain reaction with degenerated oligonucleotides conserved among GA 20-oxidases was used to isolate a cDNA clone for this enzyme in Fagus sylvatica L. seeds. This clone contains all the features and exhibits homology to GA 20 oxidases from several plant species. Expression of this clone, named FsGA20ox1, as a fusion protein expressed in Escherichia coli confirmed that it was able to metabolize [(14)C]GA(12) to [(14)C]GA(9) and [(14)C]GA(53) to [(14)C]GA(20). Analysis of FsGA20ox1 transcript levels showed similar low expression during stratification at 4 degrees C and in the presence of gibberellic acid or ethephon (compound that releases ethylene in solution), treatments proved to be efficient in breaking the dormancy of beech seeds. However, there was a drastic increase of FsGA20ox1 transcript levels in the presence of paclobutrazol (PCB), a well-known GAs biosynthesis inhibitor, or of 2-aminoxyacetic acid (AOA), an inhibitor of ethylene biosynthesis. Furthermore, the effect of AOA was reversed by the addition of GA(3) and that of PCB by ethephon. This indicates that the gene product is subjected to down-regulation by GA and ethylene, and further suggests a cross-talk gene regulation by these two hormones during the transition from seed dormancy to germination.

Activation of the fatty acid alpha-dioxygenase pathway during bacterial infection of tobacco leaves. Formation of oxylipins protecting against cell death.

A pathogen-induced oxygenase showing homology to prostaglandin endoperoxide synthases-1 and -2 was recently characterized by in vitro experiments as a fatty acid alpha-dioxygenase catalyzing formation of unstable 2(R)-hydroperoxy fatty acids. To study the activity of this enzyme under in vivo conditions and to elucidate the fate of enzymatically produced 2-hydroperoxides, leaves of tobacco were analyzed for the presence of alpha-dioxygenase-generated compounds as well as for lipoxygenase (LOX) products and free fatty acids. Low basal levels of 2-hydroxylinolenic acid (0.4 nmol/g leaves fresh weight) and 8,11,14-heptadecatrienoic acid (0.1 nmol/g) could be demonstrated. These levels increased strongly upon infection with the bacterium Pseudomonas syringae pv syringae (548 and 47 nmol/g, respectively). Transgenic tobacco plants overexpressing alpha-dioxygenase were developed, and incompatible infection of such plants led to a dramatic elevation of 2-hydroxylinolenic acid (1778 nmol/g) and 8,11,14-heptadecatrienoic acid (86 nmol/g), whereas the levels of LOX products were strongly decreased. Further analysis of oxylipins in infected leaves revealed the presence of a number of 2-hydroxy fatty acids differing with respect to chain length and degree of unsaturation as well as two new doubly oxygenated oxylipins identified as 2(R),9(S)-dihydroxy-10(E),12(Z),15(Z)-octadecatrienoic acid and 2(R),9(S)-dihydroxy-10(E),12(Z)-octadecadienoic acid. alpha-Dioxygenase-generated 2-hydroxylinolenic acid, and to a lesser extent lipoxygenase-generated 9-hydroxyoctadecatrienoic acid, exerted a tissue-protective effect in bacterially infected tobacco leaves.