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To investigate the ablative effectiveness of microbubble-mediated ultrasonic cavitation for treating synovial pannus and to determine a potential mechanism using the antigen-induced arthritis model (AIA). Ultrasonic ablation was performed on the knee joints of AIA rabbits using optimal ultrasonic ablative parameters. Rabbits with antigen-induced arthritis were randomly assigned to 4 groups: (1) the ultrasound (US) + microbubble group; (2) the US only group; (3) the microbubble only group, and (4) the control group. At 1 h and 14 days after the first ablation, contrast-enhanced ultrasonography (CEUS) monitoring and pathology synovitis score were used to evaluate the therapeutic effects. Synovial necrosis and microvascular changes were also measured. After the ablation treatment, the thickness of synovium and parameters of time intensity curve including derived peak intensity and area under curve were measured using CEUS, and the pathology synovitis score in the ultrasound + microbubble group was significantly lower than that found in the remaining groups. No damage was observed in the surrounding normal tissues. The mechanism underlying the ultrasonic ablation was related to microthrombosis and microvascular rupture that resulted in synovial necrosis. The results suggest that microbubble-mediated ultrasonic cavitation should be applied as a non-invasive strategy for the treatment of synovial pannus in arthritis under optimal conditions.

A 14-year-old boy presented with a 10-year history of the "sicca" form of seronegative juvenile idiopathic polyarthritis. Severely limited range of motion, pain, and capsular swelling in both small and large weight-bearing joints left him wheelchair-bound. Erythrocyte sedimentation rate and C-reactive protein were normal. Two-phase bone scan revealed tracer uptake of almost every joint at both early and late time points, indicating pathologic exudation and enhanced bone metabolism consistent with severe arthritis. However, radiographic studies revealed no erosive arthropathy but severe osteopenia, dysplastic bone changes, mega os trigonum, and platyspondylia. A magnetic resonance imaging (MRI) scan of the hips showed no signs of synovitis, pannus, or effusion but cartilage irregularities and subchondral cysts. These findings strongly suggested the diagnosis of progressive pseudorheumatoid dysplasia of childhood, an autosomal-recessive disorder of cartilage homeostasis. The patient carries a novel homozygous two-nucleotide deletion in exon 4 of the WISP3 gene. This genetic disorder is an important differential diagnosis of sicca polyarthritis.

When rheumatoid articular cartilage samples were incubated with normal peripheral blood monocytes and cultured synovial cells in the presence of recombinant human interleukin-1 (IL-1) in vitro, large numbers of monocytes were seen to be attached to the articular surface. Significant numbers of monocytes invaded the cartilage tissue when the rheumatoid cartilage samples were pre-incubated with 10 U/ml of IL-1. Considerable numbers of monocytes were also attached to normal cartilage when these were pre-incubated with IL-1. It is of interest that recombinant human gamma interferon (gamma-IFN) did not enhance monocyte attachment. However, there was a significantly greater attachment of monocytes to rheumatoid than to normal cartilage. When normal cartilage was exposed to collagenase and then incubated with monocytes or synovial cells in the presence of 10 U/ml of IL-1, large numbers of cells were attached to the natural cartilage surface but not to the cut surface. These phenomena were much more intense when the rheumatoid cartilage was pre-incubated with collagenase. These results indicate that increased levels of IL-1 in the rheumatoid joint may play an important role in joint destruction by stimulation of pannus formation by inducing synovial cell attachment to the articular surface.

A 44-year-old man with intermittent asymmetric migratory oligoarthritis lasting the recent decade was admitted to our hospital. Considerable specific biomarkers for rheumatoid arthritis such as anti-agalactosyl IgG antibody are all negative. He was diagnosed as palindromic rheumatism (PR). Although hand X-rays showed no remarkable findings, hand magnetic resonance imaging (MRI) detected pannus and bone erosion. PR is defined as the disease characterized by short-lasting attacks of acute oligoarthritis, without radiographic changes. To our knowledge, the findings of MRI for PR have not been previously described. We propose that MRI findings in patients with PR is useful tool to distinguish PR from rheumatoid arthritis (RA) or other RA related diseases.

We report a rare case of cervical cord compression caused by intraspinal pannus formation at C6 in a patient with long-term rheumatoid arthritis. No atlantoaxial abnormalities were seen. The imaging findings are presented and the pathology discussed.

We would like to draw attention to the relatively new concept of ALVAL prosthetic failure, illustrated by the following clinical case. Whilst currently very topical and familiar to orthopaedic surgeons, it may not be as familiar to rheumatologists. A 58-year-old woman underwent a successful resurfacing procedure of the right hip in September 2003. She underwent a similar procedure for the left hip in April 2007. At the time of this surgery, a dislocation of the right prosthesis occurred which hampered recovery. She presented to A and E in April 2009 with difficulty weight bearing and painful movements of the right hip. She was apyrexial, had a WBC of 19.9 and a CRP of 96.3. A radiograph showed bilateral hip prostheses. On the right, there was thinning of the inferior femoral neck and a soft tissue mass was visible in the same region (Fig. 1). An ultrasound showed pannus around the right hip joint and a collection in the right psoas bursa. An aspirate revealed white cells and no organisms, with no growth on culture. A CT scan confirmed bony erosion at the inferior aspect of the femoral neck along with the soft tissue mass. The prosthesis was successfully revised to a total hip replacement, with a ceramic on ceramic bearing in May 2009. Significant amounts of stained and necrotic tissue were removed from around the original prosthesis. Histology showed fibrovascular connective tissue with extensive dystrophic calcification, chronic inflammatory infiltrate and hemosiderin-laden macrophages. Analysis of the removed prosthesis showed excessive wear of both the acetabular and the femoral components. She was diagnosed with Aseptic Lymphocytic-Vasculitis-Associated Lesion (ALVAL). The use of large metal on metal (MoM) bearings in hip replacement has been gaining in popularity. The superior wear characteristics, improved motion and stability have attractive benefits, especially in young active patients. The materials currently used are high carbon cobalt chromium alloys. Reports of problematic painful MoM hips associated with soft tissue masses have been increasing. They can be destructive and lead to infiltration and destruction of soft tissues, pain, dislocation, nerve irritation or palsy, or cause local bone resorption leading to component loosening or fracture [1]. Willerts et al. first reported patients undergoing revision for non-infected, painful MoM implants with histological findings of diffuse perivascular lymphocytic infiltrates with accumulation of macrophages and eosinophilic granulocytes with tissue necrosis and termed it ALVAL [2]. Later reports found similar histological findings [1, 3]. The underlying cellular reaction appears similar to a type IV hypersensitivity response [2], (sometimes referred to as metal hypersensitivity), though exact causation remains unclear [4]. The trigger appears to be an increased local concentration of metal ions, to which an excessive reaction is initiated in certain patients. Blood levels of metal ions are elevated with all MoM bearings [5]. The extent appears to be related to the orientation of the components [6–8], with the resulting abnormal biomechanics in malaligned prostheses leading to focal regions of increased wear. This is especially noticeable in women, where the smaller J. R. B. Hutt (&) 6 Nevis Road, Tooting, London SW17 7QX, UK e-mail: drhutt@hotmail.com

The effect of running activity on normal and inflamed knees was determined by light microscopic (LM) and scanning electron microscopic (SEM) observations on hamster articular cartilage. Animals were split into two groups; one housed in standard cages and one given free access to running wheels. Twenty-one days prior to analysis, half of each group was given an intra-articular injection of lipopolysaccharide (LPS) to cause an inflammation, the other half were uninjected. No remarkable changes were observed by LM in either the control running or nonrunning groups. In contrast, cartilage proteoglycan depletion, and pannus and synovial hyperplasia were equally observed in both groups of LPS-injected animals. SEM observations on the patellae from control animals found them to be free from damage to the articular cartilage. The joints of both the LPS nonrunning and running animals contained synovial hypertrophy with villus projection from the synovial lining. However, only the LPS-injected running hamsters had cartilage fraying over large areas of the articular surface, as well as areas in which the villus projections had been flattened. These results demonstrated that mechanical stress applied to a proteoglycan-depleted cartilage enhances the breakdown of the collagen matrix as judged by fibrillation, and may aggravate the inflammation by crushing the swollen synovial lining where it encroaches on the joint space.

Rheumatoid arthritis (RA) is an inflammatory disease of the synovial membrane, which results in the destruction of joints by inflammatory pannus. The synovial membrane shows proliferation and cellular infiltrates on microscopy with signs of chronic and acute inflammation. Macrophages are thought to play a central role in the pathogenesis of RA. We examined synovial membrane specimens of 21 RA patients using morphological, immunohistological and enzyme histochemical methods for number and distribution of macrophages. We were able to identify 41.5 +/- 8.8% of lining cells as macrophages, depending on the method used. In abundant diffuse lymphocellular infiltrates, 23.4 +/- 11.1% of mononuclear cells were macrophages. In addition, most cells in the region of tumorlike proliferation and a stromal population of fibroblastlike cells were detected by macrophage markers. Although cell number in synovial membrane increases drastically, we did not find correlations between the relative amount of macrophages in these regions and basic activity. Basic activity includes proliferative reaction as well as lymphoplasmacellular and mononuclear infiltration--both signs of an immunopathological process. In contrast, using enzymes or activation markers, there was a clear correlation. We consider that a constant high percentage of macrophages in RA synovial membrane is present regardless of any actual inflammatory process.

During inflammation the rheumatoid synovial membrane is invaded by a number of different cell types. When activated most of these cells produce cytokines including tumor necrosis factor alpha (TNF alpha) and interleukin-1 beta (IL-1 beta). These cytokines are believed to stimulate production of degradative enzymes and disturb the equilibrium between such enzymes and their inhibitors resulting in tissue damage. In this study we investigated the localisation of TNF alpha and IL-1 beta at the cartilage-pannus junction (CPJ). Here, cytokines are well placed to influence the integrity of articular cartilage. Tissue was derived from advanced rheumatoid (RA) and, as a comparison, osteoarthritic (OA) joints at the time of replacement surgery (arthroplasty). Antibody staining of fixed serial sections of tissue localised cells that were associated with IL-1 beta and TNF alpha. Cell markers for macrophages and endothelial cells were included to provide positive identification of the cytokine-associated cells. Analysis of these sections revealed that both TNF alpha and IL-1 beta were associated with macrophages, particularly those in the synovium overlying cartilage (pannus) and endothelial cells. Positive staining was seen at the CPJ in RA and in similarly located tissue in OA. The similar distribution of cytokines in OA was unexpected even if the overall numbers of tissue and infiltrating cells in the CPJ were different in the two diseases. This highlights the possible role played by endogenous inhibitors [1, 2] in influencing the degree of cytokine activity necessary to explain the different pathogenic mechanisms in RA and OA.

Immunoperoxidase studies were carried out on the pannus-cartilage junction (PCJ) of patients with rheumatoid arthritis (RA) and psoriatic arthritis to investigate the distribution of the enzyme inhibitors alpha 2 macroglobulin (alpha 2 M) and alpha 1 antitrypsin (alpha 1 AT). Comparisons were made with the equivalent synovial cartilage junctional area in osteoarthritis (OA). In all 12 patients with RA, prominent deposits of alpha 2 M and alpha 1 AT were found within the PCJ whereas in OA patients and the case of psoriatic arthritis fewer or no deposits were seen. Inhibitors were localised in pannus synovial lining cells, perivascular inflammatory cells, macrophage and fibroblast-like cells invading the cartilage as well as along the junctional cartilage matrix and in the adjacent pannus-free cartilage. Deposits of immunoglobulins were found in similar areas to enzyme inhibitors. The presence of enzyme inhibitors at the PCJ suggests that this area is not unprotected against enzymatic attack. Thus the concept that pannus is a prime area for cartilage damage because aggressive, invasive cells release destructive enzymes in an environment free from inhibitors should be reviewed.

Proliferation of pannus tissue cells has been investigated under in vitro conditions after labeling of joint tissues with 3H-thymidine. It was demonstrated that there is only a minimal proliferation of chondrocytes as well as of pannus tissue cells. Slight increased proliferation was observed in granulation tissue poor in lymphocytes and plasma cells, and perhaps in those areas of destroying pannus tissue that exhibited polymorphonuclear granulocytes (PMNs) at the pannus-cartilage junction. These results are in contrast to the idea that pannus tissue is a tumor-like lesion, for the present observations, even within the limits of autoradiographic investigations on a heterogeneous tissue, and indicate that pannus tissue has to be regarded as an inflammatory granulation tissue.

The cartilage-pannus junction in joints from patients with active rheumatoid arthritis was studied by means of immunohistochemical analysis of frozen sections, using monoclonal antibodies directed against HLA-DR, HLA-DQ class II transplantation antigens, against the transferrin receptor and against T-lymphocyte subpopulations. Expression of HLA-DR antigens was seen on a large number of synovial cells in immediate contact with the cartilage, whereas the expression of HLA-DQ antigens was only seen on a subfraction of the HLA-DR-positive cells. Most of the cells in close contact with the cartilage expressed the transferrin receptor, indicating a proliferative state of these cells. It is suggested that class II antigen-expressing synovial cells in immediate contact with the cartilage in rheumatoid joints might, in addition to their potential role in the destructive process, also serve functions in the elicitation of immune reactions against molecules released from the cartilage.

Immuno-electron microscopy has been utilised to examine the cartilage-pannus junction in seven patients with rheumatoid arthritis. Using a monoclonal antibody, keratan sulphate was localised to cells with the ultra-structural appearance of fibroblasts within a transitional fibroblastic zone in the pannus in two cases. This confirms previous light microscopy evidence that this area (which is clearly separate from articular cartilage) contains cells which produce keratan sulphate, and strengthens the hypothesis that these cells are derived from cartilage rather than from the adjacent synovial membrane.

The occurrence of the S-100 protein was studied in normal and pathological cartilage from patients with osteoarthrosis and rheumatoid arthritis. In normal cartilage all cells of the different zones exhibit immunoreactivity for this protein. An identical distribution is observed in cases of osteoarthrosis and rheumatoid arthritis. Cellular pannus tissue usually is devoid of the S-100 protein. However, if chondroid metaplasia occurs in this tissue the cells become positive for the S-100 protein. From these results it is concluded that a chondroid metaplasia not only leads to a matrix comparable to cartilage but also contains cells that gain further characteristics of original chondrocytes.

Peroxidase-anti-peroxidase (PAP) staining and specific antibodies against cathepsin G and elastase from polymorphonuclear leukocytes (PMN) were applied to pannus-free and microscopically intact superficial articular cartilage. Restricted local deposits containing cathepsin G and elastase were found in three of ten patients with seropositive rheumatoid arthritis (RA), in one of three patients with seronegative RA and in one patient with juvenile chronic arthritis (JCA). Similarly, localized deposits of IgG and C3 were found in the patients with seropositive RA and JCA, but not in the patient with seronegative RA. Adjacent sections exhibited esterase activity in and around the PMN. In proteinase-positive areas from patients with seropositive RA the inhibitors α1-proteinase inhibitor (α1-PI) and α2-macroglobulin (α2-MG) were present in two of three and one of three patients, respectively. In JCA only α1-proteinase inhibitor was present, and in seronegative RA no inhibitors were found. No staining of articular cartilage was observed in a patient with psoriatic arthritis. One of three cases with osteoarthritis exhibited patchy superficial staining for IgG only. In articular cartilage covered by pannus, in three patients with seropositive RA, in one with seronegative RA and in the patient with JCA a few regions with variably dense PMN infiltrates were observed. Cathepsin G, elastase and esterase activity were found in and around the PMN. In one of the three patients with seropositive RA the adjacent cartilage-pannus junction exhibited distinct staining for cathepsin G and elastase, but not for IgG/C3 and proteinase inhibitors. The findings suggest that cathepsin G and elastase from PMN are involved in the breakdown of rheumatoid articular cartilage in the presence, as well as in the absence, of entrapped immune-complex-like material, and that proteinase inhibitors are often lacking in such regions.

Using a specific substrate, no leucocyte elastase activity could be detected in 55 synovial fluids, including 29 from patients with rheumatoid arthritis (RA). However, a high percentage of samples contained phagocytic inclusions of elastase, alpha 1-proteinase inhibitor (alpha 1-PI) and alpha 2-macroglobulin (alpha 2-MG) in both the polymorphonuclear (PMN) and mononuclear phagocytes. Immunofluorescence and indirect peroxidase-antiperoxidase staining of articular cartilage (ACA) from 52% of 21 patients with RA and one with juvenile RA (JRA) showed presence of elastase in the superficial layer of microscopically intact but proteoglycan depleted pannus-free ACA. In histologically altered pannus-free RA-ACA superficial elastase deposits were found in 24% of the cases. Adjacent ACA sections contained IgG, C3, alpha 1-PI and rarely alpha 2-MG. RA-ACA below or surrounded by pannus showed close contact with intact and decaying PMN in 62% and 48% of the cases, respectively. ACA specimens from patients with degenerative disease and systemic lupus were negative. These findings strongly suggest that PMN leucocyte elastase is operative in the degradation of RA-ACA and JRA-ACA, and that this activity is largely dependent upon the presence of entrapped immune complexes in such cartilage.

In the cartilage-pannus junction of 14 patients with rheumatoid arthritis (RA) and seven patients with osteoarthritis (OA), monoclonal antibodies to keratan sulphate (KS) and chondroitin sulphate (CS) stained a transitional fibroblastic zone (TFZ) within the pannus in nine RA patients and one OA patient. In three patients this was clearly localised to the cytoplasm of cells in this zone, but in all remaining cases KS and CS could be demonstrated in the surrounding matrix. This area was distinguished from adjacent pannus which contained many blood vessels and cells positive for MHC Class II antigen. Specific markers for glycosaminoglycans have been employed to demonstrate that chondrocyte-derived cells and matrix contribute to the changes seen at the cartilage-pannus junction in RA-affected joints.