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Background: Amyloid A (AA) amyloidosis is a serious complication of a wide range of chronic inflammatory, infectious and neoplastic diseases. A longstanding overproduction of the liver-synthesised cytokine-induced acute phase serum amyloid A (SAA) protein is a key event in the pathogenetic cascade leading to the deposition of AA amyloid in tissues and organs. Objective: The aim of the study was to critically review treatment strategies in AA amyloidosis. Methods: A systematic literature review was conducted based on PubMed (January 1980 – April 2008) and selected conference abstracts. Results/conclusions: The current strategy for the treatment of AA amyloidosis is firmly based on the knowledge of the underlying pathogenetic mechanism and aims at reducing the amyloid precursor (SAA) load by intensive anti-inflammatory/immunosuppressive therapy and, in selected instances, anticytokine (TNF-α, IL-1β or IL-6 blockade) therapy, or, when applicable, the eradication of an existing infectious focus (surgery, antimicrobial drugs). Emerging strategies focus on the dissolution of the amyloid deposits using small molecules that either interact with the glycosaminoglycans or the fibril component of the deposits, or deplete amyloid P component.

OBJECTIVE: To evaluate the role of serum osteoprotegerin (OPG) as a biochemical marker for disease activity assessment and drug monitoring in patients with rheumatoid arthritis (RA) treated with cyclical etidronate. DESIGN: Forty patients (35 women and 5 men) with RA of <5 years duration were randomized to receive intermittent cyclical etidronate therapy in conjunction with anti-rheumatic therapy or anti-rheumatic therapy alone (without etidronate) in a 2-year, open-label protocol. METHODS: Radiographs of hands and feet and serum samples for the determination of OPG, amino terminal propeptide (PINP), cross-linked C-telopeptide (ICTP) and amino terminal telopeptid of type I collagen were obtained at baseline and at 24 months. RESULTS: Etidronate treatment had no effect on circulating OPG levels, although the significant decline in PINP and ICTP (P=0.001 and P=0.04 respectively) reflected the efficacy of the anti-resorptive therapy. At baseline and at study termination, serum OPG correlated significantly with age (r=0.45; P=0.003 and r=0.56; P=0.0002 respectively). OPG was not related to biochemical markers of bone metabolism, indices of disease activity or radiographic disease progression. At baseline, the mean serum OPG was higher in patients receiving 5-10 mg/day prednisone (82.8+/-4.0 pg/ml, n=16) compared with those receiving <5 mg/day or with no prednisone (69.7+/-4.7 pg/ml, n=23) (P=0.05). CONCLUSIONS: Our results suggested that serum OPG measurement, perhaps because of the complexity of the regulation of the OPG, may be difficult to utilize in the evaluation of anti-resorptive therapy. Moreover, low dose corticosteroid-associated osteoporosis is probably not mediated by inhibition of OPG.

Objectives.Inflammatory arthritides/synovitides such as psoriatic (PsA), reactive (ReA) and rheumatoid (RA) arthritis share numerous immunopathological features, but develop different patterns of joint involvement. To investigate whether distinctive cell apoptosis may play a role in this context, we have assessed synovial cell apoptosis in situ in PsA and ReA, and compared it with RA and 'non-inflammatory' controls.Methods.TdT-mediated dUTP nick end-labelling (TUNEL) of DNA breaks complemented immunoperoxidase staining for CD68 or LCA as the specific cell markers.Results.The proportion of apoptotic synovial lining cells was high in PsA, ReA and RA arthritides in numbers of type of apoptotic lining cells. In RA, however, in contrast to PsA and ReA, apoptotic lining cells were clustered or, in a small subset of samples, were very low in number. Prominent apoptosis of inflammatory cells in the sublining in ReA has accounted for higher overall apoptotic cell numbers in synovial stroma (sublining + perivascular inflammatory cell infiltrates) in this condition than in RA or PsA (P<0.05).Conclusions.No disease-specific pattern in the phenotype of apoptotic synovial lining cells could be suggested in any of the inflammatory arthritides studied. However, topological differences in the lining and quantitative differences in the inflammatory cell apoptosis in synovial stroma may in part explain the occurrence of the prominent synovial lining cell hyperplasia distinguishing RA from ReA and PsA. On the other hand, relatively frequent inflammatory cell apoptosis may contribute both to the downregulation of synovial inflammation and to the control of synovial lining hyperplasia in ReA.Keywords:Psoriatic arthritis, Reactive arthritis, Rheumatoid arthritis, Synovial membrane, Apoptosis.

Two different classifications of discograms have been used in a prospective study of 279 injected discs in 100 patients. The five-stage classification of Adams, Dolan and Hutton (1986) showed increased degeneration in the lower lumbar discs and more degenerative changes in men than in women. Exact reproduction of the patient's pain on injection was more common in fissured or ruptured discs than in less degenerate discs, with 81% sensitivity and 64% specificity of the discogram for pain. The additional information obtained by comparing computerised tomography (CT) with discograms was minimal. Discography was found to be useful in the evaluation of chronic low back pain in patients whose ordinary CT scans, myelograms and flexion-extension radiographs were normal. In spondylolysis and spondylolisthesis, discography can disclose whether fusion needs to be extended above the lytic level, and it may show if the pain in patients who have had posterolateral fusion is discogenic. Thus, discography gives information which is useful in deciding whether to operate on patients with chronic low back pain.

We describe six patients with aggressive granulomatous lesions around cementless total hip prostheses. Two patients previously had a cemented prosthesis in the same hip. The Lord prosthesis was used in five patients, the PCA in one. Both prostheses were made of chrome-cobalt alloy. Pain on weight-bearing occurred on average 3.2 years after the cementless arthroplasty, and at that time radiography revealed aggressive granulomatosis around the proximal femoral stem and the acetabular component in five of the patients; one had a large solitary granuloma in the proximal femur. Revision was performed on average 4.8 years after the cementless arthroplasty. At that time all granulomas had grown large in size; while waiting for revision operation, two femoral stem components fractured. All the granulomas showed a uniform histopathology, which included histiocytosis; the cause for these lesions was thought to be plastic debris from the acetabular socket.

The extent of synovial cell proliferation in situ and its relationship to the destructive potential of rheumatoid arthritis (RA) is a matter of continuing debate. Notably, the situation has not been elucidated in other inflammatory arthritides [i.e. reactive (ReA) and psoriatic (PsA)], which, although they share some histopathological similarities with RA, develop different patterns of joint involvement. In order to estimate the proliferation of synovial cells in situ in PsA and ReA, and to compare this with RA and with 'non-inflammatory' joint lesions, we have utilized immunostaining of the Ki-67 antigen complemented with Ki-67/CD68 or Ki-67/leucocyte common antigen (LCA, clones 2B11 and PD7/226) double stainings to assess the extent of mononuclear inflammatory cell proliferation. Synovial samples analysed were from 33 patients: RA (n=8), PsA (n=13), ReA (n=6) and six 'non-inflammatory controls' (degenerative or traumatic joint lesions). Thickening of the synovial lining (in particular in RA) and perivascular accumulations of mononuclear inflammatory cells, predominantly lymphocytes, were characteristic features in all synovitides. In contrast to the thickened vascular synovial lining in RA, in 5/13 cases with PsA, blood vessels were observed in the lining. The percentage of lining cells expressing Ki-67 antigen was higher in RA (median=4.7, interquartile range [Q3-Q1]=3.9, mean [95% CI]=3.5[1.7-5.2], P=0.0063), PsA (median=1.2,[Q3-Q1]=1.9, mean [95% CI]=1.6 [0.7-2.5], P=0.007) and ReA (median=1.4, [Q3-Q1]=2.3, mean [95% CI]=1.6 [0.3-3.1], P=0.0235) than in controls (median=0.1, [Q3-Q1]=0.45, mean [95% CI]=0.2 [0.07-0.5]). In this respect, the differences between different forms of the inflammatory arthritides were not statistically significant (P<0.05). In RA, PsA and ReA, the percentage of labelled cells in the inflamatory mononuclear cell -rich areas was higher than in controls. The percentage of proliferating endothelial cells was also significantly higher in RA, PsA and ReA than in controls. However, in RA, endothelial expression of Ki-67 antigen was often seen in small blood vessels, whereas in PsA, Ki-67 antigen was prefreably expressed in the medium to large blood vessels. Synovial lining cells of the monocyte/macrophage lineage (type A synoviocytes), but not stromal monocytes, demonstrated modest proliferation in situ. These results indicate that although proliferation of synovial lining fibroblasts is a prominent feature in RA, the extents to which this, or in situ proliferation of lymphocytes, contribute to the histopathology of PsA, ReA and RA are comparable. Vascular involement is suggested by the proliferation of endothelial cells in RA, PsA and ReA in an overlapping manner, but based on topological differences, such a response may represent diverse pathological features, such as angiogenesis, vascular enlargement and reparative responses to injury.Key words: Psoriatic arthritis, Reactive arthritis, Rheumatoid arthritis, Cell proliferation, Ki-67 antigen.

Cytological analysis of material aspirated from the effusion which occasionally develops around a polyglycolic acid (PGA) osteosynthesis implant showed a predominance of inflammatory monocytes and in particular lymphocytes. In order to discover whether PGA implants are immunologically inert, density gradient-isolated peripheral blood mononuclear cells were cultured in 0.2 ml of 10% delta FCS-RPMI 1640 culture medium supplemented with 10 mg PGA. Phytohaemagglutinin (PHA) lectin, a purified protein derivate of tuberculin (PPD) antigen and culture medium alone were used as positive and negative controls. We studied lymphocyte activation kinetics on days 0, 1, 3 and 5. Major histocompatibility complex locus II antigen (MHC locus II antigen) and interleukin-2 receptor (IL-2R) expression were analysed using the avidin-biotin-peroxidase complex (ABC) method and lymphocyte DNA synthesis by using 3H-thymidine incorporation and beta-scintillation counting. Especially on culture days 0 and 1, lymphocytes and monocytes were seen by light microscopy to be attached to PGA particles. However, our results show no PGA-induced lymphocyte DNA synthesis, but PGA-induced MHC locus II antigen and IL-2R activation marker expression was seen, greater than in negative controls, but less than that seen in PPD antigen driven lymphocyte response. This suggests that PGA is an immunologically inert implant material, but it does seem to induce inflammatory mononuclear cell migration and adhesion, leading to a slight non-specific lymphocyte activation. This activation is lower than that seen in mitogen and antigen-driven lymphocyte responses.

The outcome of operations performed on 38 patients for rheumatoid disorders of the cervical spine were analysed 10 or more years later. The mean age of the patients at the time of operation was 56 years (35 to 77); 32 had seropositive disease. The mean duration of the disease was 17 years (four to 36). Twenty-seven patients had painful anterior atlanto-axial subluxation (AAS), nine had subaxial subluxation alone and two had severe cranial subluxation of the odontoid, one also with subaxial subluxation. One patient died from postoperative staphylococcal septicaemia and another 18 died during the follow-up period. Patients with coincident cardiac or other diseases, and those with cranial subluxation of the odontoid of more than 3 mm had an increased mortality. Neither the patients' age nor the magnitude of AAS correlated with mortality. Of the 37 patients with occipitocervical pain, 30 were relieved and all the six patients with tetraparesis were improved. Of the 24 Gallie fusions only 12 were solidly united; patients with long-term cortisone treatment were more likely to develop pseudarthrosis. There was no correlation between clinical outcome and radiological result. Four patients had further operations to treat subluxation which developed below the fused segments.

The membranes surrounding seven loose cementless acetabular implants were shown to contain polyethylene particles, birefringent in polarised light. Three of these implants were made of titanium alloy and the membranes around these contained titanium particles as well. There was no metallosis around the four implants made of chromium-cobalt-steel alloy. Both titanium and polyethylene particles caused migration, adherence and phagocytosis of CD11b-positive, peroxidase-negative macrophages. There were no histological signs of activation of the specific immune response; neither interleukin-2 receptor-positive activated T cells nor PCA-1 plasmablasts/plasma cells were present in the tissues. In cases of simple loosening, resident mesenchymal fibroblast-like cells were active. In aggressive granulomatosis, there were many macrophages and multinucleated giant cells but little fibroblast reaction. The clinical relevance of the findings is that the use of cementless prostheses is not a guarantee against adverse tissue reactions.

In 16 patients we used uncemented Lord prostheses at revision operations for aggressive granulomatosis after cemented hip arthroplasties; in 12 bone grafts also were used. In 13 hips the granulomatous lesions were multifocal, and in one the acetabular component was involved. There was no evidence of infection in any case: all the patients had normal ESR and CRP levels. The revision operation was performed on average 9.4 years after the primary replacement; the mean age at revision was 64 years. On radiographs, the bone around the prosthesis had consolidated by an average of 16 months. At follow-up, two to six years later (mean 3.5 years) there had been no recurrences, nine patients had an excellent Mayo hip score, five were good and two fair.

We reviewed 19 patients who presented with aggressive granulomatosis around the femoral stem after hip replacement. All had experienced stress pain and had required revision arthroplasty on average 8.8 years after the primary operation. Fifteen patients were men and four were women; none had rheumatoid arthritis. One patient had an uncemented Moore hemiprosthesis; the others all had cemented total hip replacements. When first detected, the granulomatous lesions were multifocal in 13 patients. The first granuloma was in the region of the lesser trochanter in 10, and near the tip of the stem in only two. Speed of growth varied but on average there was doubling of the area on anteroposterior films in 2.2 years (range 6 months to 4.6 years). Aggressive granulomatous lesions in replaced hips are a distinct condition, different from simple loosening or infection; the lesions may grow rapidly, so revision surgery is indicated soon after diagnosis.

We report the results of cementless total joint replacement in 18 patients with old tuberculosis of the hip, performed, on average, 34 years after the onset of infection. Mean follow-up was 3.5 years. Only seven of the patients had antituberculous drugs during or after the operation. Using the Mayo hip score, 15 patients had excellent or good results and two had a fair rating. One patient had the prosthesis removed more than one year postoperatively for late haematogenous staphylococcal infection and had a poor rating. All the patients had relief of hip-related pain. Despite the absence of any reactivation of tuberculosis in our series, we recommend the use of specific prophylaxis.

We have reviewed six patients with old tuberculosis of the knee treated by total replacement an average of 35 years after the primary infection. Three patients had no antituberculous prophylaxis and three had drugs for two to three weeks before and three weeks after the operation. One patient with a missed primary diagnosis had a relapse of the tuberculous arthritis 18 months after his arthroplasty and was successfully treated with antituberculous drugs for one year. At an average follow-up of 6.3 years all the patients were markedly improved. Old tuberculosis of the knee can be treated successfully with arthroplasty but there is a risk of reactivation of disease and prophylactic drugs are recommended.