Fibroblast activation and inflammation in frozen shoulder.

INTRODUCTION: Frozen shoulder is a common, fibro-proliferative disease characterised by the insidious onset of pain and progressively restricted range of shoulder movement. Despite the prevalence of this disease, there is limited understanding of the molecular mechanisms underpinning the pathogenesis of this debilitating disease. Previous studies have identified increased myofibroblast differentiation and proliferation, immune cell influx and dysregulated cytokine production. We hypothesised that subpopulations within the fibroblast compartment may take on an activated phenotype, thus initiating the inflammatory processes observed in frozen shoulder. Therefore, we sought to evaluate the presence and possible pathogenic role of known stromal activation proteins in Frozen shoulder. METHODS: Shoulder capsule samples were collected from 10 patients with idiopathic frozen shoulder and 10 patients undergoing shoulder stabilisation surgery. Fibroblast activation marker expression (CD248, CD146, VCAM and PDPN, FAP) was quantified using immunohistochemistry. Control and diseased fibroblasts were cultured for in vitro studies from capsule biopsies from instability and frozen shoulder surgeries, respectively. The inflammatory profile and effects of IL-1ß upon diseased and control fibroblasts was assessed using ELISA, immunohistochemistry and qPCR. RESULTS: Immunohistochemistry demonstrated increased expression of fibroblast activation markers CD248, CD146, VCAM and PDPN in the frozen shoulder group compared with control (p < 0.05). Fibroblasts cultured from diseased capsule produced elevated levels of inflammatory protein (IL-6, IL-8 & CCL-20) in comparison to control fibroblasts. Exposing control fibroblasts to an inflammatory stimuli, (IL-1ß) significantly increased stromal activation marker transcript and protein expression (CD248, PDPN and VCAM). CONCLUSIONS: These results show that fibroblasts have an activated phenotype in frozen shoulder and this is associated with inflammatory cytokine dysregulation. Furthermore, it supports the hypothesis that activated fibroblasts may be involved in regulating the inflammatory and fibrotic processes involved in this disease.

Biological Aspect of Pathophysiology for Frozen Shoulder.

It is fairly well understood that frozen shoulder involves several stages, which reflect the series of process from capsular inflammation and fibrosis to spontaneous resolution of this fibrosis. However, the underlying pathophysiologic process remains poorly determined. For this reason, management of frozen shoulder remains controversial. Determining the pathophysiological processes of frozen shoulder is a pivotal milestone in the development of novel treatment for patients with frozen shoulder. This article reviews what is known to date about the biological pathophysiology of frozen shoulder. Although articles for the pathophysiology of frozen shoulder provide inconsistent and inconclusive results, they have suggested both inflammation and fibrosis mediated by cytokines, growth factors, matrix metalloproteinases, and immune cells. Proinflammatory cytokines and growth factors released from immune cells control the action of fibroblast and matrix remodeling is regulated by the matrix metalloproteinases and their inhibitors. To improve our understanding of the disease continuum, better characterizing the biology of these processes at clearly defined stages will be needed. Further basic studies that use standardized protocols are required to more narrowly identify the role of cytokines, growth factors, matrix metalloproteinases, and immune cells. The results of these studies will provide needed clarity into the control mechanism of the pathogenesis of frozen shoulder and help identify new therapeutic targets for its treatment.

Adhesive capsulitis: An age related symptom of metabolic syndrome and chronic low-grade inflammation?

Adhesive capsulitis (AC) is very poorly understood, particularly it's underlying etiology. Obesity and metabolic syndrome, which are strongly associated with chronic low grade inflammation, are becoming increasingly understood to underlie a raft of morbid states including upper limb pain syndromes, diabetes (DM), cardiovascular disease (CVD), cancer and central nervous system dysfunction and degeneration. Notwithstanding age, two of the strongest established risk factors for AC are DM and CVD. The hypothesis argues that similar to DM and CVD, the inflammation and capsular fibrosis seen in AC is precipitated by metabolic syndrome and chronic low grade inflammation. These pathophysiological mechanisms are highly likely to be perpetuated by upregulation of pro-inflammatory cytokine production, sympathetic dominance of autonomic balance, and neuro-immune activation. The hypothesis predicts and describes how these processes may etiologically underpin and induce each sub-classification of AC. An improved understanding of the etiology of AC may lead to more accurate diagnosis, improved management, treatment outcomes, and reduce or prevent pain, disability and suffering associated with the disease. The paper follows on with a discussion of similarities between the pathophysiology of AC to general systemic inflammatory control mechanisms whereby connective tissue (CT) fibrosis is induced as a storage depot for leukocytes and chronic inflammatory cells. The potential role of hyaluronic acid (HA), the primary component of the extracellular matrix (ECM) and CT, in the pathophysiology of AC is also discussed with potential treatment implications. Lastly, a biochemical link between physical and mental health through the ECM is described and the concept of a periventricular-limbic central driver of CT dysfunction is introduced.

Candida glabrata olecranon bursitis treated with bursectomy and intravenous caspofungin.

Orthopedic surgeons are becoming more involved in the care of patients with septic arthritis and bursitis caused by yeast species. This case report involves a middle-aged immunocompromised female who developed a Candida glabrata septic olecranon bursitis that developed after she received a corticosteroid injection in the olecranon bursa for presumed aseptic bursitis. Candida (Torulopsis) glabrata is the second most frequently isolated Candida species from the bloodstream in the United States. Increased use of fluconazole and other azole antifungal agents as a prophylactic treatment for recurrent Candida albicans infections in immunocompromised individuals is one reason why there appears to be increased resistance of C. glabrata and other nonalbicans Candida (NAC) species to fluconazole. In this patient, this infection was treated with surgery (bursectomy) and intravenous caspofungin, an echinocandin. This rare infectious etiology coupled with this intravenous antifungal treatment makes this case novel among cases of olecranon bursitis caused by yeasts.

Comparison between NSAID and intra-articular corticosteroid injection in frozen shoulder of diabetic patients; a randomized clinical trial.

INTRODUCTION: Frozen shoulder or adhesive capsulitis is a relatively common encountered musculo-skeletal disease in which arouses following soft tissue involvement of glenohumeral joint and presents with pain and limitation of shoulder' active and passive motions. The incidence of frozen shoulder among diabetic patients is about 10-20%, stiffness in such patients is more severe and should be managed actively. Local Glucocorticoid injection, NSAIDs and physiotherapy each can relief the symptoms. The aim of this study was to compare the efficacy of glenohumeral injection of Glucocorticoid with NSAIDs in frozen shoulder of diabetic patients. METHOD: The randomized clinical trial study conducted during Feb 2009-Aug 2010 on diabetic patients with frozen shoulder that were referred to rheumatology and endocrinology clinics, Yazd, Iran. Diagnostic criteria of capsulitis were pain of shoulder and range of motion limitation in all directions. The patients were divided into 2 groups, patients of first group received NSAID while the latter group were undergone intra-articular corticosteroid injection. After 1 week, home exercise was done for both group and evaluation of the patients after first visit was done likewise 2nd, 6th, 12th and 24th weeks. All registered data were transformed into SPSS-15 software and analyzed. RESULTS: Totally 57 patients (19 males (33.3%) and 38 females (66.7%) were included in the analysis. There was no significant difference between sex (P=0.4) and age (P=0.19) of patients. No significant relation was detected between 2 groups after 24 weeks according to range of motion in flexion (P=0.51), abduction (P=0.76), external rotation (0.12) and internal rotation (P=0.91). Also any significant difference in pain score was not detected (P=0.91). CONCLUSION: Based on our study, both intra-articular corticosteroid and NSAID are effective in treatment of adhesive capsulitis and there is no significant difference between efficacies of these 2 treatment modalities in diabetic patients.

Infrapatellar bursitis with Mycobacterium malmoense related to immune reconstitution inflammatory syndrome in an HIV-positive patient.

The immune reconstitution inflammatory syndrome (IRIS) after starting antiretroviral treatment for HIV infection can be caused by a great variety of pathogens. Among these are non-tuberculous mycobacteria (NTM), with Mycobacterium avium complex being the most commonly described finding. Antimycobacterial treatment of NTM in cases of IRIS is controversial. We report the case of a 39-year-old man diagnosed with HIV-1 infection during admission to hospital with Pneumocystis jirovecii pneumonia (PCP) and a CD4 cell count of 60/µl. The patient started antiretroviral treatment and made an uneventful recovery from the PCP diagnosis, but was readmitted after 2.5 months with a purulent infrapatellar bursitis on the left knee. A surgical procedure was performed and Mycobacterium malmoense was grown from the pus from the bursa. The patient recovered without supplemental antimycobacterial treatment. To our knowledge, this is the first report on IRIS caused by M malmoense.

Bursitis trocantérea tuberculosa en mujer joven inmunocompetente / Trochanteric bursitis due to tuberculosis in an immunocompetent young woman

La infección de tejidos blandos por Mycobacterium tuberculosis puede afectar al músculo, tendones, fascia, bursa y tejido sinovial. La bursitis trocantérea de origen tuberculoso es una entidad infrecuente, que suele afectar a pacientes inmunocomprometidos. Se manifiesta habitualmente de forma insidiosa, lo que dificulta el diagnóstico y retrasa el tratamiento. Se presenta el caso de una mujer joven, inmunocompetente, que acudió a nuestro servicio por dolor crónico de cadera izquierda. El estudio realizado confirmó el diagnóstico de bursitis trocantérea tuberculosa. Este caso demuestra la importancia de considerar el posible origen infeccioso de las bursitis en pacientes inmunocompetentes (AU)

Soft tissue infection due to Mycobacterium tuberculosis can affect muscle, tendons, fascia, bursa and synovial tissue. Tuberculous trochanteric bursitis is a rare entity that usually affects immunocompromised patients. Manifestations usually occur insidiously, which delays diagnosis and treatment. We present the case of an immunocompetent young woman who came to our department for chronic left hip pain. The study confirms the diagnosis of tuberculous trochanteric bursitis. This case demonstrates the importance of considering a possible infectious origin of bursitis in immunocompetent patients (AU)

Atraumatic osteonecrosis of the humeral head after influenza A-(H1N1) v-2009 vaccination.

In the recent pandemic influenza A-(H1N1) v-2009 vaccination campaign, adjuvanted vaccines have been used because of their antigen-sparing effect. According to available reports, the rate of severe vaccination reactions has not increased, as compared with previous seasonal influenza vaccinations. Here we describe an adult female patient who was vaccinated with an AS03 adjuvanted split-virus vaccine injected into the left arm. She experienced a prolonged and painful local reaction for 4 weeks. During this time, persistent incapacitating pain shifted into the left shoulder. Magnetic resonance imaging (MRI) at the injection site detected atraumatic humeral head osteonecrosis in conjunction with bursitis of the rotator cuff region. Clinical and laboratory examination revealed no other underlying disease. Using analgetic medication and physical therapy, resting pain completely remitted within the following 14 weeks. Pain on exertion declined within the following 6 months. Atraumatic osteonecrosis, a relatively rare disorder which initially presents non-specific clinical symptoms, has never been associated with parenteral influenza vaccination. Although the available data cannot establish a causal relationship, our patient's clinical course - with a continuous transition from increased local post-vaccination reactions to symptoms of a severe shoulder lesion with osteonecrosis - raises the question of a pathogenetic link. Considering the vascular pathogenesis of osteonecrosis, we hypothesize that our patient's enhanced local immunologic reaction may have led to regional vasculitis as the cause of bone destruction. As mild forms of osteonecrosis may have escaped previous clinical attention, it is the purpose of our report to increase awareness of this exceptional event as a possible side effect of parenteral adjuvanted vaccination.

Interleukin-1ß stimulates stromal-derived factor-1α expression in human subacromial bursa.

Chemokines produced by synoviocytes of the subacromial bursa are up-regulated in subacromial bursitis and rotator cuff disease. We hypothesized that SDF-1α production in bursal synoviocytes may be induced by local cytokines such as interleukin IL-1ß and IL-6. Subacromial bursa specimens were obtained from patients undergoing shoulder surgery. Bursal specimens were stained with anti-human antibodies to IL-1, IL-6, and SDF-1α by immunohistochemistry and compared to normal and rheumatoid controls. Bursal cells were also isolated from specimens and cultured. Early passaged cells were then treated with cytokines (IL-1ß and IL-6) and SDF-1α expression was measured by ELISA and RT-PCR. SDF-1α, IL-1ß, and IL-6 were expressed at high levels in bursitis specimens from human subacromial bursa compared to normal controls. In cultured bursal synoviocytes, there was a dose-dependent increase in SDF-1α production in the supernatants of cells treated with IL-1ß. SDF-1α mRNA expression was also increased in bursal cells treated with IL-1ß. IL-6 caused a minimal but not statistically significant increase in SDF-1α expression. SDF-1α, IL-1ß, and IL-6 are expressed in the inflamed human subacromial bursal tissues in patients with subacromial bursitis. In cultured bursal synoviocytes, SDF-1α gene expression and protein production are stimulated by IL-1ß. IL-1ß produced by bursal syvoviocytes and inflammatory cells in the human subacromial bursa is an important signal in the inflammatory response that occurs in subacromial bursitis and rotator cuff disease.

Olecranon bursitis secondary to Mycobacterium kansasii infection in a patient receiving infliximab for Behcet's disease.

We present a case of Mycobacterium kansasii olecranon bursitis in a woman with known immunosuppression secondary to the treatment received for her Behçet's disease. We found only one other case report of olecranon bursitis caused by M. kansasii in the literature, which, unlike our case, presented in an immunocompetent adult following trauma. This case extends the range of opportunistic mycobacterial infections that are associated with anti-tumour necrosis factor therapy.

Trochanteric bursitis: refuting the myth of inflammation.

BACKGROUND AND OBJECTIVES: Greater trochanteric (GT) bursitis is a common cause of hip pain. Previously, the etiology of the trochanteric pain syndrome was thought to be caused by inflammation of the subgluteus maximus bursa (i.e., bursitis). Recently, MRI and ultrasound studies have brought into serious doubt the idea that bursitis is the etiology for trochanteric pain. To our knowledge, no histologic study of GT bursitis has been reported to date. The purpose of this study is to evaluate the histopathology of patients with and without the clinical syndrome of GT bursitis to assess for the presence of bursal inflammation. DESIGN AND METHODS: This is a prospective, case-controlled, blinded study of the histopathologic features of controls and patients with GT bursitis. We recruited patients who required total hip arthroplasty (THA) for rheumatoid or osteoarthritis. Inclusion criteria for the study consisted of the following: needing THA as standard of care; THA secondary to OA or RA; age greater than 18; and minimal risk for surgery by the American Heart Association Criteria. We excluded anyone who received a GT bursa injection 9 months before surgery. Eligible participants were then stratified as cases or controls using the 1985 clinical criteria for GT bursitis. The harvesting of the bursa required no modification of the surgical procedure. The specimens were then examined by 2 independent pathologists who were blinded as to the patients' clinical status. RESULTS: Six bursal specimens were evaluated by 2 blinded surgical pathologists revealing primarily fibroadipose tissue with no signs of acute or chronic inflammation. There were 3 bursas in the control group and 2 specimens with clinical GT bursitis. No significant differences were found between the specimens of the 2 groups. CONCLUSIONS: The results of this small prospective observational histologic study, along with recent MRI and ultrasound studies on the topic, strongly suggest that there is no etiologic role of bursal inflammation in the trochanteric pain syndrome.

Stromal cell-derived factor 1 (SDF-1, CXCL12) is increased in subacromial bursitis and downregulated by steroid and nonsteroidal anti-inflammatory agents.

Several studies have demonstrated that inflammation in the subacromial bursa is an important component in the pathogenesis of impingement syndrome. We have demonstrated in a previous study that many inflammatory cytokines, including stromal cell-derived factor 1 (SDF-1, CXCL12), are increased in the subacromial bursa [Blaine et al. 2005. J Shoulder Elbow Surg 14(Suppl 1):84S-89S]. SDF-1 is a potent chemotactic and angiogenic factor that stimulates recruitment of inflammatory cells. In the current study, we proposed that the resident cells in subacromial bursal tissue produce SDF-1, which can play a role in the inflammatory reponse of bursal tissue, and that this chemokine can be regulated by steroid (dexamethasone) and nonsteroidal anti-inflammatory medications (NSAIDs). Twenty-two subacromial bursa tissues (18 bursitis and 4 normal bursa) were obtained intraoperatively from patients during shoulder surgery and analyzed using the cDNA Array technique in accordance with an IRB approved protocol. cDNA array results were confirmed with real-time reverse transcription-polymerase chain reaction (RT-PCR). Bursal cells (from 4 normal bursa, 3 bursitis) and two normal bone marrow with whole tissue explants were cultured for one passage. Cell culture supernatants were collected and SDF-1 protein was detected with enzyme-linked immunosorbent assay (ELISA). Cultured bursal cells were treated with a COX-2 inhibitor and dexamethasone, and cells was harvested at 1-day and 4-day intervals. SDF-1 expression was evaluated by real-time RT-PCR and ELISA. cDNA Array analysis demonstrated that the gene expression of SDF-1 was increased in patients with subacromial bursitis compared to controls (p < 0.05). Real-time RT-PCR also revealed that the mRNA expression of SDF-1 in bursitis tissue is increased 10-fold over control tissue. While the normal bursal cells produced negligible amounts of SDF-1 protein, cultured cells derived from bursitis lesion released as much SDF-1 protein (235 pg/100,000 cells) as normal bone marrow stromal cells (283 pg/100,000 cells) as measured by ELISA. The addition of a COX-2 inhibitor and dexamethasone to bursitis cell lines led to decreased SDF-1 expression levels compared to untreated bursitis cell lines. These studies demonstrate that there is a significant elevation of SDF-1 expression in the subacromial bursa of patients with rotator cuff disease. Furthermore, this chemokine can be downregulated by COX-2 inhibitors and steroids. These results provide biologic evidence for the use of steroid and NSAIDs in the treatment of subacromial bursitis. In the future, targeted inhibition of molecules such as SDF-1 in the subacromial bursa may present a therapeutic strategy that may avoid the side effects of these other (steroid and NSAID) medications.

Inflamed shoulder structures in polymyalgia rheumatica with normal erythrocyte sedimentation rate.

OBJECTIVE: To investigate the inflammatory involvement of shoulder articular and extraarticular structures in polymyalgia rheumatica (PMR) patients with a normal erythrocyte sedimentation rate (ESR) at diagnosis. METHODS: This was a case-control study. All consecutive, untreated new outpatients diagnosed as having PMR with a normal ESR (<40 mm/hour) during a 6-month period were included in the study (case patients). Controls were 12 consecutive, untreated PMR outpatients with an ESR of >40 mm/hour who were observed after the case patients. Before starting corticosteroid therapy, all case patients and controls underwent bilateral shoulder ultrasonography (US) and magnetic resonance imaging (MRI). US and MRI scans were evaluated independently by two radiologists who were blinded to the reciprocal results. RESULTS: Six case patients (4 men and 2 women) and 12 controls (4 men and 8 women) were studied. Both US and MRI demonstrated bilateral subacromial/subdeltoid bursitis in all 6 case patients and in 11 of the 12 (92%) controls (P not significant [NS]). One control had unilateral bursitis. Glenohumeral joint synovitis was found in 4 of 6 case patients (67%) by MRI and in 3 of 6 case patients (50%) by US (P NS), as well as in 8 of 12 controls (67%) by MRI and in 7 of 12 controls (58%) by US (P NS). Both MRI and US detected biceps tenosynovitis in 5 of 6 case patients (83%) and in 8 of 12 controls (67%) (P NS). The severity of bursitis did not differ significantly between the groups. US was as effective as MRI in detecting inflammatory changes of the shoulder. CONCLUSION: MRI and US studies showed that PMR patients with normal or high ESRs have similar inflammatory shoulder lesions. Moreover, bilateral subacromial/subdeltoid bursitis represents the imaging hallmark in PMR patients with a high or normal ESR. MRI or US of the shoulder may facilitate the proper diagnosis in patients with the typical proximal symptoms of PMR who also have normal ESRs.

Matrix metalloproteinase-19 in capillary endothelial cells: expression in acutely, but not in chronically, inflamed synovium.

Matrix metalloproteinase-19 (MMP-19), originally isolated as an autoantigen from the synovium of a patient suffering from rheumatoid arthritis (RA), is expressed in smooth muscle cells of the tunica media of large blood vessels of an RA patient, but not in the endothelial cell layer. By contrast, in acutely inflamed tissue, synovial capillaries strongly express MMP-19 in the cytoplasm, as shown by immunofluorescence of cryostat sections. In MMP-19-producing capillaries the beta3 integrin chain was found at the endothelial cell surface, as was the vascular endothelial cell growth factor receptor-2 (KDR). The specific tissue inhibitor of metalloproteinases TIMP-1 was absent or faintly stained in MMP-19-expressing capillaries, whereas TIMP-1, but not TIMP-2, was strongly expressed in large vessels and in MMP-19-negative capillaries of RA synovia. In the spontaneously transformed human umbilical vein endothelial cell line ECV304 neither MMP-19 transcripts nor protein could be detected. By contrast, primary cultures of human endothelial cells of either dermal or adipose tissue origin produced MMP-19 mRNA and protein. The results strongly suggest the regulated induction of matrix metalloproteinase-19 in capillary endothelial cells during acute inflammation and hint at a role of MMP-19 in angiogenesis.

Immunocytologic characteristics of mononuclear cell populations found in nonseptic olecranon bursitis.

OBJECTIVE: To determine the immunocytologic characteristics of the various subsets of nonseptic olecranon bursal fluid mononuclear cells. METHODS: Twenty consecutive patients with culture negative olecranon bursitis had immunocytochemical and flow cytometric analysis performed using a panel of monoclonal antibodies to determine lymphocyte and monocyte/macrophage population subtypes and proportions. RESULTS: In traumatic bursitis (n = 9), the mean (+/- SD) white blood cell (WBC) count/mm3 was 1,368 +/- 1,559; WBC mononuclear differential count was 29.5 +/- 19% lymphocytes and 55 +/- 26% monocyte/macrophages. In idiopathic bursitis (n = 11), the mean WBC/mm3 was 376 +/- 515; WBC mononuclear differential count was 28.5 +/- 16% lymphocytes and 52 +/- 27% monocytes/macrophages. Flow cytometry revealed 88% CD2+ T lymphocytes in the lymphocyte population, 3% B lymphocytes and CD4/CD8 T cell mean ratio of 2.5 +/- 1.5 for traumatic bursitis and 88% CD2+ T lymphocytes, 4% B lymphocytes and CD4/Cd8 ratio of 1.4 +/- 0.6 for idiopathic bursitis (p < 0.05, t test). Both groups contained increased proportions of lymphocyte subtypes expressing activation markers: CD25+, CD26+ and HLA DR+ compared to normal peripheral blood. In traumatic bursitis, the mean percent of CD14+ cells (monocyte/macrophages) was 62 +/- 24; in idiopathic bursitis, the mean percent was 51 +/- 28. The vast majority expressed high levels of HLA-DR indicating activation. CONCLUSION: We observed a preponderance of activated T cell subpopulations and monocyte/macrophages suggesting an immunologic role for these cell populations in the development and perpetuation of nonseptic bursitis.

Inflammation of the subacromial bursa in chronic shoulder pain.

Subacromial bursal tissue was studied in 12 patients operated on for painful (10 patients with constant pain and 2 patients with pain on motion) rotator cuff tendinitis/impingement syndrome. The Neer acromioplasty technique was used. Six patients had moderate inflammatory changes and one had a slight inflammation. In three of the five remaining patients, the subacromial bursa did not show any signs of inflammatory involvement, but patients experienced pain at rest and at night, reflecting clinical inflammation in tissues other than the bursa. The two patients with pain only on strain did not show inflammation of the bursa. Immunohistochemical typing of the bursal tissue disclosed a typical chronic mononuclear cell infiltrate consisting mainly of CD2-positive T lymphocytes (50-80% of all inflammatory cells), accompanied by less frequent CD11b (C3bi receptor)-positive monocyte/macrophages (10-40%). The relative paucity of plasmablasts/plasma cells expressing PCA-1 suggests this to be an inflammatory rather than an immune response. Active involvement of some of the local cells is suggested to be the source of algogenic and hyperalgesic substances contributing to pain in chronic shoulder pain syndromes.