[Skin ulcerations due to CINCA syndrome and its successful treatment with prostaglandin E1]. / Kutane Ulzerationen bei CINCA­Syndrom und ihre erfolgreiche Behandlung durch Prostaglandin E1.

Chronic infantile neurological cutaneous and articular syndrome (CINCA) is a disorder with a defect in the CIAS1 (NLRP3) gene and the altered gene product cryopyrin leads to inflammasome activation with increased IL-1beta synthesis. The activation pathway of the transcription factor NF-κB is also affected, which plays a role in angiogenesis. With respect to the angiogenesis stimulating ability of prostaglandin E1, we treated a female patient with CINCA syndrome and conventionally non-responsive skin ulcers with prostaglandin E1 infusions (6 µg/kg bw/24 h/5 day) followed by wound healing lasting over 3 weeks. After 1 year of periodic infusions, the skin defects were permanently closed.

[Significance of clinically latent bacterial arthritis]. / Die Bedeutung der klinisch latenten bakteriellen Arthritis.

The classical septic bacterial arthritis is a rare event, but can be distinguished by unequivocal signs such as fibrin exudation and neutrophilic masses (pus). For a long time we have been observing an abortive form of bacterial arthritis in biopsies which subsides spontaneously without antibiotic intervention. Only very early during the course can Staphyolcoccus aureus or epidermidis be detected. Despite the brief presence of bacteria, enzymes from the neutrophils can destroy cartilage and bone. The fact that the attending physician had suspected a bacterial infection in only 7% of these patients highlights the diagnostic complexity. We have termed this form clinically latent bacterial arthritis (CLBA). Structural changes in the synovial membrane, e.g. in rheumatoid arthritis or osteoarthritis, predispose for a hematogenous seeding of endogenous staphylococci and trigger clinically unapparent, temporary infections. This clinically latent bacterial superinfection (CLSI) is also self-limiting, but the high degrading potential of the neutrophilic proteases makes CLSI a very probable contributing factor in joint destruction.

[Differential diagnosis of rheumatoid granuloma]. / Differenzialdiagnostik des rheumatoiden Granuloms.

Rheumatoid granuloma (RG) is histomorphologically defined as a subcutaneous palisading granuloma with central fibrinoid necrosis. Clinically, it presents as a nodule typically localized at pressure points near the joints. From the rheumatic pathological point of view, the main diagnostic challenge is the differentiation of RG from granuloma anulare, especially if clinical information on the site of removal, known diseases, duration of illness, medication and existing American College of Rheumatology (ACR) criteria are missing. Other granulomatous lesions, such as mycobacterial infections, foreign body granulomas, necrobiosis lipoidica or sarcoidosis, can be differentiated from RG by histopathological criteria or by additional examinations such as pathogen specification or PCR. An immunohistochemical marker for the differential diagnosis of granulomas is not yet available. Diagnosis is based on conventional H-E staining, alcian blue-PAS staining, polarizing analysis or PCR. In the following article, the most important granulomatous entities in the differential diagnosis of RG are introduced and the main diagnostic characteristics are discussed.

Proposal for a histopathological consensus classification of the periprosthetic interface membrane.

AIMS: The introduction of clearly defined histopathological criteria for a standardised evaluation of the periprosthetic membrane, which can appear in cases of total joint arthroplasty revision surgery. METHODS: Based on histomorphological criteria, four types of periprosthetic membrane were defined: wear particle induced type (detection of foreign body particles; macrophages and multinucleated giant cells occupy at least 20% of the area; type I); infectious type (granulation tissue with neutrophilic granulocytes, plasma cells and few, if any, wear particles; type II); combined type (aspects of type I and type II occur simultaneously; type III); and indeterminate type (neither criteria for type I nor type II are fulfilled; type IV). The periprosthetic membranes of 370 patients (217 women, 153 men; mean age 67.6 years, mean period until revision surgery 7.4 years) were analysed according to the defined criteria. RESULTS: Frequency of histopathological membrane types was: type I 54.3%, type II 19.7%, type III 5.4%, type IV 15.4%, and not assessable 5.1%. The mean period between primary arthroplasty and revision surgery was 10.1 years for type I, 3.2 years for type II, 4.5 years for type III and 5.4 years for type IV. The correlation between histopathological and microbiological diagnosis was high (89.7%), and the inter-observer reproducibility sufficient (85%). CONCLUSION: The classification proposed enables standardised typing of periprosthetic membranes and may serve as a tool for further research on the pathogenesis of the loosening of total joint replacement. The study highlights the importance of non-infectious, non-particle induced loosening of prosthetic devices in orthopaedic surgery (membrane type IV), which was observed in 15.4% of patients.

Expression pattern of cell cycle-related gene products in synovial stroma and synovial lining in active and quiescent stages of rheumatoid arthritis.

OBJECTIVE: To investigate the expression pattern of cell cycle related gene products in active and quiescent Rheumatoid arthritis (RA). METHODS: Synovial tissue from 20 patients with active proliferative RA and 28 patients with RA in remission was immunohistochemically examined for expression of p53, p63, p21, p27, p16, cyclin D1, CDK4, RB, E2F, Ki-67 on tissue microarrays and by DNA flow cytometry for cell cycle phases. RESULTS: Elevated expression of p53 and p27 was found in synovial lining and in stromal cells in proliferative active RA. In the remission stage this finding was confined to the synovial lining. Most of the cells were in the G0-phase. Ki-67 proliferation index was maximum 10% in synovial cells. CONCLUSION: The p53 pathway is activated in synovial cells in active RA as well as in quiescent stage of disease. Differences in the spatial expression pattern of proteins involved in the p53 pathway in RA in remission compared to actively proliferating RA reflect the phasic nature of the disease and support in our opinion the concept of adaptive role of p53 pathway in RA.

[Proposal for the classification of the periprosthetic membrane from loosened hip and knee endoprostheses]. / Vorschlag für eine Konsensus-Klassifikation der periprothetischen Membran gelockerter Hüft- und Knieendoprothesen.

After 10 years, loosening of total joint endoprostheses occurs in about 3 to 10 percent of all patients, requiring elaborate revision surgery. A periprosthetic membrane is routinely found between bone and loosened prosthesis. Further histomorphological examination allows determination of the etiology of the loosening process. Aim of this study is the introduction of clearly defined histopathological criteria for a standardized evaluation of the periprosthetic membrane. Based on histomorphological criteria and polarized light microscopy, four types of the periprosthetic membrane were defined: periprosthetic membrane of wear particle type (type I), periprosthetic membrane of infectious type (type II), periprosthetic membrane of combined type (type III), periprosthetic membrane of indifferent type (type IV). Periprosthetic membranes of 268 patients were analyzed according to the defined criteria. The correlation between histopathological and microbiological diagnosis was high (89%, p<0,001), the inter-observer reproducibility was sufficient (95%). This classification system enables a standardized diagnostic procedure and therefore is a basis for further studies concerning the etiology of and pathogenesis of prosthesis loosening.

Subtyping of osteoarthritic synoviopathy.

OBJECTIVE: Osteoarthritis research is traditionally concentrating on events within the degenerated articular cartilage. Changes in the synovial membrane are largely neglected. In fact, they are generally interpreted as secondary to the cartilage changes and not pathogenetically involved in the disease process. In this study, we present a systematic analysis of the synovial reaction pattern in early and late stages of the osteoarthritic disease process. METHODS: A large series of synovial specimens derived from early and late stage osteoarthritic cartilage disease were investigated by histological and immunohistochemical means for tissue architecture and inflammatory cell infiltrates. For comparison, also samples with rheumatoid arthritis, seronegative arthritis, and septic arthritis were included as well as normal synovial membrane specimens. RESULTS: In all specimens derived from patients with diagnosed osteoarthritis alterations of the synovial tissue were observed. A large spectrum of alterations was found in different stages of osteoarthritic joint disease and four different basic pattern of synovial reactions could be identified: (i) hyperplastic, (ii) inflammatory, (iii) fibrotic, and (iv) detritus-rich synoviopathy. CONCLUSION: We show that in all cases of clinically overt osteoarthritic joint disease significant synovial pathology is associated. Furthermore, our study clearly documents that in osteoarthritic synovium significant inflammation can occur. This is suggestive of a distinct pathogenetic role of the synovium also in osteoarthritic cartilage degeneration at least in a subset of cases.

Recurring synovitis as a possible reason for aseptic loosening of knee endoprostheses in patients with rheumatoid arthritis.

We evaluated histologically samples of synovial tissue from the knees of 50 patients with rheumatoid arthritis (RA). The samples were taken during revision for aseptic loosening. The findings were compared with those in 64 knees with osteoarthritis (OA) and aseptic loosening and in 18 knees with RA without loosening. The last group had been revised because of failure of the inlay or the coupling system of a constrained prosthesis. All the patients had had a total ventral synovectomy before implantation of the primary prosthesis. In all three groups a foreign-body reaction and lymphocellular infiltration were seen in more than 80% of the tissue samples. Deposits of fibrin were observed in about one-third to one-half of the knees in all groups. Typical signs of the reactivation of RA such as rheumatoid necrosis and/or proliferation of synovial stromal cells were found in 26% of knees with RA and loosening, but not in those with OA and loosening and in those with RA without loosening. Our findings show that reactivation of rheumatoid synovitis occurs after total knee replacement and may be a cofactor in aseptic loosening in patients with RA.

Cell populations involved in pigmented villonodular synovitis of the knee.

OBJECTIVE: Pigmented villonodular synovitis (PVNS) of the knee is a tumor-like process of uncertain nature. We analyzed the involved cell populations, iron deposition, and cell proliferation in PVNS to propose a pathogenetic concept of this still elusive disease entity. METHODS: The study was performed on a series of 14 cases of localized PVNS of the knee. Histology and histochemistry were used to evaluate basic morphology and iron deposit distribution. Immunohistochemistry was performed to characterize the inflammatory cell infiltrate and to identify the proliferating cell compartments. In situ hybridization analysis using a cDNA probe against type I collagen was utilized to further characterize the mononuclear cell infiltrate. RESULTS: In addition to the classic features (mononuclear cell infiltrate, multinuclear giant cells, iron deposits, and stromal fibrosis) we observed a chronic inflammatory cell infiltrate in all PVNS samples, in which CD8 positive T cells were conspicuous. A high portion of non-phagocytotic cells resorbed iron and became CD68 positive. A proportion of mononuclear cells expressed type I collagen, thus resembling B synoviocytes. CONCLUSION: Our results suggest that preexisting chronic inflammation plays an important pathogenetic role in the PVNS disease process. Chronic inflammation increases the risk of articular bleeding and probably deranges the iron processing capacity of local synovial macrophages. The resulting iron overload could lead to a shift of iron storing cells from synovial macrophages to B synoviocytes and fibroblasts. A perpetuated proliferation and activation of these cells can explain why PVNS behaves like a neoplastic process.