MALDI MS imaging as a powerful tool for investigating synovial tissue.

OBJECTIVE: To identify and image protein biomarker candidates in the synovial tissue of patients with rheumatoid arthritis (RA) and patients with osteoarthritis (OA). METHODS: A novel matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) technique was applied to the analysis of synovial tissue. Patients were classified according to the American College of Rheumatology (ACR) criteria for RA. Frozen sections were stained to obtain morphological data. Serial sections were desiccated, and spotted with matrix for MALDI analysis. Ions generated by laser irradiation of the tissue were separated in time, based on their m/z ratio, and were subsequently detected. IMS was used in a 'profiling' mode to detect discrete spots for rapid evaluation of proteomic patterns in various tissue compartments. Photomicrographs of the stained tissue images were reviewed by a pathologist. Areas of interest (10 discrete areas/compartment) were marked digitally and the histology-annotated images were merged to form a photomicrograph of the section taken before the MALDI measurement. Pixel coordinates of these areas were transferred to a robotic spotter, the matrix was spotted, and the coordinates of the spots were transferred to a mass spectrometer for spectral acquisition. The data generated were then subjected to biocomputation analysis to reveal the biomarker candidates. RESULTS: Several peaks (m/z) consistent in mass with calgranulins, defensins, and thymosins were detected and their distribution in various synovial compartments (synovial lining and sublining layer) was demonstrated. CONCLUSION: MALDI IMS is a powerful tool for the rapid detection of numerous proteins (in situ proteomics) and was applied here for the analysis of the distribution of proteins in synovial tissue sections.

[Endoprosthetic replacement of the rheumatoid wrist]. / Endoprothetische Versorgung des Rheumatischen Handgelenks.

For patients with rheumatoid arthritis preventive and reconstructive surgery of the hand provide better functional results and higher patient satisfaction when surgery is done adequately before the inflammatory stage, especially when multiple joints are affected. Synovectomy, arthrodesis and prosthetic reconstruction are able to guarantee maintenance of function even in late stages and severe destruction, when modern drug therapy cannot prevent further inflammatory attacks and increasing destruction.

[Endoprosthetic replacement of rheumatoid finger joints]. / Endoprothetische Versorgung der Rheumatischen Fingergelenke.

Resection arthroplasty, arthrodesis and prosthetic reconstruction are able to guarantee the maintenance of good functional ability of finger joints even in late stages and with severe destruction. Destruction of soft tissues of the finger joints cannot be corrected by prosthetic measures alone. A stabile situation of the wrist joint is one of the most important prerequisites for a normal performance of daily life activities. Silastic endoprostheses are still the gold standard for finger replacement in rheumatoid arthritis.

[Applications of molecular pathology in the diagnosis of joint infections]. / Molekularpathologische Diagnostik von Gelenkinfektionen.

The diagnosis of infections in patients with arthritis and/or joint prostheses requires interdisciplinary cooperation and the use of up-to-date methods. Massive bacterial infection can be identified by bacterial culture, and minimal infection can be detected by molecular pathological methods. These processes include specific enrichment of bacterial and fungal DNA, amplification, and identification of the DNA by gel electrophoresis, sequencing techniques, and chip technologies.Anamnesis (enteral or urogenital infection), the clinical picture (oligoarthritis), and further parameters (e.g., HLA B27 status) are important for the diagnosis of reactive arthritis. In many cases of reactive arthritis, molecular methods allow detection of bacterial DNA or RNA in synovial fluid or tissue. Molecular pathological methods allow the fast and reliable differential diagnosis of granulomatous synovialitis without prior cultivation of bacteria or fungi. The development of new molecular pathological methods for detecting bacterial and fungal nucleic acids will increase diagnostic accuracy.

Colocalization of C4d deposits/CD68+ macrophages in rheumatoid nodule and granuloma annulare: immunohistochemical evidence of a complement-mediated mechanism in fibrinoid necrosis.

Rheumatoid nodule (RN) represents a palisading granuloma with central fibrinoid necrosis, which is not only a classical manifestation of rheumatoid arthritis (RA) and part of the American College of Rheumatology (ACR)-criteria, but also is its diagnostic hallmark. The pathogenesis of RN is still not fully understood. At present, only data on serum analyses indicating a complement-mediated pathogenesis in the development of RA are available. Equivalent examinations for RN have not yet been performed. Granuloma annulare (GA) represents another type of palisading granuloma. A special subtype of GA, subcutaneous GA (SGA), is an important differential diagnosis to RN. Therefore, our aim was to examine RN and SGA regarding the complement deposition (C4d) by immunohistochemical means. All RN and GA were stained by hematoxylin/eosin and different special stains. In addition, all specimens were stained immunohistochemically with antibodies against CD68. Five GA and five RN were analyzed immunohistochemically with antibodies against C4d and CD68, and evaluated using single- and doublestaining immunohistochemistry. All RN and GA displayed depositions of C4d within their central necroses and between the surrounding palisading macrophages. Most importantly, C4d/CD68 double staining was visible in the palisading macrophages next to the necroses, while macrophages in the periphery were negative for C4d but positive for CD68. The main difference between RN and GA was a quantitative phenomenon with less positively reacting macrophages in a more incomplete palisade in GA. The positive reactions of all central necroses to C4d and colocalization of CD68 and C4d suggest that a complement-mediated mechanism may be operative in the formation of fibrinoid necrosis. This mechanism may be involved in any form of "fibrinoid necrosis", since no different patterns of C4d/CD68 expression could be observed in GA. This may explain why RG/GA are not distinguishable morphologically.

[Differential therapy for the rheumatoid thumb]. / Differenzialtherapie des rheumatischen Daumens.

The thumb frequently is involved in rheumatoid arthritis and often is a source of significant functional loss, pain, and deformity. Surgical intervention in patients with rheumatoid arthritis of the thumb should be based on the degree of radiological destruction according to Larsen, the natural course of the rheumatoid hand, the nature and stage of deformity as well as the status of tendons, ligaments, and adjacent joints. The goals of surgery are to relieve pain, increase motion, and restore thumb function. The timing for shoulder surgery should be early in the course of the disease, since it determines the long-term prognosis and the remaining surgical options. Treatment options, alone or in combination, include synovectomy, arthrodesis, arthroplasty, and tendon repair or transfer. Joint-preserving surgery is indicated in the early stages of radiological destruction according to Larsen classification O-III, whereas the late stages of destruction (Larsen IV-V) require reconstructive surgery. Especially in hand and finger arthritis, the "wait and see" strategy should no longer be followed. Close interdisciplinary cooperation between surgeon and rheumatologist is necessary for early therapeutic strategy, taking into account the functional unit of the whole upper extremity. The ultimate aim is to provide pain relief, improve function, enhance appearance, and slow the progression of disease. When the pathogenesis and pathoanatomy of the impaired rheumatoid thumb are appreciated, and appropriate treatment is selected, surgical intervention is likely to provide a favorable outcome for the patient.

[Synovectomy of the rheumatoid elbow]. / Die Synovektomie des rheumatischen Ellenbogengelenks.

We present a comparative study of 120 elbow synovectomies with and without radial head resection performed between 1985 and 1993. Minimal radiological destruction according to Larsen stage 1-2 was present in 38 joints; 28 patients were followed postoperatively for an average period of 8.2 years. Synovectomy was combined with radial head resection in 70 patients (82 joints) where rheumatoid arthritis had radiologically proceeded to Larsen stage 3-4. Fifty patients were available for clinical and radiological follow-up. The follow-up period ranged from 6 to 15 years (average: 9.3 years). All patients in both groups were suffering from rheumatoid arthritis, and the proportion of females dominated. The mean age at the time of operation was 50 and 56 years, respectively. The results according to Inglis and Pellicci (16) were graded as good and excellent in 63.3% (19 joints) after elbow synovectomy. An average postoperative score result of 80.7 points (range: 43-96 points) was obtained. Synovectomy and radial head resection achieved comparable score results (75.7 points), representing 59.4% (35 joints) good and excellent ratings. Complete pain relief was obtained in 51.5%, and 27.1% complained of slight pain after elbow synovectomy. Of the patients who underwent radial head excision, 45.8% were pain free and 27.1% experienced slight pain. The range of motion of combined extension and flexion averaged 113 degrees and 110 degrees, respectively. A comparable improvement concerning pro/supination was maintained at final follow-up with an average gain of 20.4 degrees after synovectomy and 25.3 degrees for the latter group. We routinely noticed a moderate radiographic progression in both groups according to the criteria of the Larsen classification. The radiographic deterioration did not correlate with the clinical outcome. Synovectomy of the rheumatoid elbow is a valuable procedure in early as well as late stages of the disease. Our long-term results after synovectomy of the elbow prove significant pain relief and restoration of elbow function. The radiographic assessment revealed a moderate radiological deterioration. From the clinical viewpoint, the elbow function is maintained for a long time and valuable time is gained before reconstructive surgery may become necessary.

[Modular-physiological wrist arthroplasty in rheumatoid arthritis]. / Modularphysiologische Handgelenkprothese.

Silicone wrist arthroplasty has dominated reconstructive surgery of the rheumatoid wrist for a long time. The declining success rates of Swanson wrist arthroplasty has encouraged the development of new wrist devices. Modular physiological total wrist arthroplasty represents a new wrist prosthesis generation with anatomical reconstruction of carpal height and wrist pivot. This increases the efficiency of wrist and finger tendons. Modular physiological total wrist arthroplasty was developed in 1992 and has been in clinical application since 1993. A total of 46 total wrist arthroplasties in 39 patients were carried out between 1993 and 1999. All patients suffered from rheumatoid arthritis. The mean follow-up period was 4.6 years. The postoperative total wrist score averaged 77.3 points, representing 78% good and excellent scores. Patient satisfaction and pain relief were achieved in 86% of cases. The range of motion at last follow-up averaged 56 degrees of the combined extension and flexion and 27 degrees for combined ulnar and radial deviation were maintained. The radiographic analysis of MPH total wrist arthroplasty demonstrated a secure reconstruction of carpal height and restoration of joint pivot. Failures occurred in seven wrist arthroplasties. Malalignement of the carpal and radial component and soft-tissue dysbalance were the reasons for recurrent dislocation in four cases. Three wrists were fused and one exchange arthroplasty using a constrained revision prosthesis was performed. The remaining three revision cases were caused by one deep infection and two failures of the carpal implant.

[Differential therapy for the rheumatoid shoulder]. / Differentialtherapie der rheumatischen Schulter.

Despite frequent involvement, the rheumatoid shoulder is neglected in operative treatment of the upper extremities. The slow course of omarthritis, the compensation mechanism of scapulothoracic motion and neighbouring joints as well as dominating disabilities of the lower extremities and the rheumatoid hand are possible explanations. The pattern of destruction of the rheumatoid shoulder is characterized by progressive joint and soft tissue deterioration. Soft tissue involvement determines the course of the shoulder joint. The subacromial space is a common and early site for rheumatoid involvement, often leading to bursitis, tenosynovitis of the biceps tendon and rotator cuff rupture. Sonography and MRI enable the early detection of subacromial and glenohumeral pathology before deterioration is visible radiologically. Surgical intervention in patients with rheumatoid arthritis of the shoulder is based on the degree of radiological destruction according to Larsen, the natural course of the shoulder joint and the soft-tissue condition. The goals of surgery are to relieve pain, increase motion and restore shoulder function. Surgery should be carried out early in the course of the disease, thus determining the long-term prognosis and the remaining surgical options. Depending on the pattern of destruction of the rheumatoid shoulder, the options for treatment can be divided into early and late procedures.Joint-preserving surgery is indicated in the early stages of radiological destruction according to Larsen classification O-III, whereas the late stages of destruction (Larsen IV-V) require reconstructive surgery. The introduction of arthroscopic and semiarthroscopic techniques has improved the acceptance of early synovectomy for the rheumatoid shoulder, but there is still a place for open synovectomy in patients with extensive soft-tissue repair and bone-remodelling procedures. Arthroscopic and open synovectomy are supplementary and noncompetitive surgical procedures for the rheumatoid shoulder. With proceeding bone and soft-tissue destruction corresponding to Larsen stage IV and V, synovectomy is not successful and reconstructive surgery is necessary. Resection-interposition-arthroplasty (RAIP) remains a controversial alternative to arthroplasty in young patients with sufficient bone stock and a reconstructable rotator cuff. The success of cup-replacement will additionally restrict the indications for RAIP. RIAP remains a possible salvage procedure after aseptic and septic loosening of shoulder arthroplasty. Glenohumeral replacement arthroplasty has become the procedure of choice in reconstructive surgery of the shoulder. The severity of soft-tissue and bone destruction determines the choice of shoulder prosthesis. Current modular shoulder systems with increased numbers of humeral-head stem combinations are calculated to achieve a better adjustment of the soft-tissue tension and to optimize the adaptation between head geometry and the natural shape of the glenoid.The surrounding soft-tissue structure, especially the condition of the rotator cuff, is very important for the functional recovery after shoulder arthroplasty. We prefer a hemiarthroplasty of the rheumatoid shoulder joint to avoid critical glenoid fixation. Patients with irreparable rotator cuff tears and severe glenohumeral arthritis remain a difficult challenge in shoulder surgery and the ideal procedure has not yet been found.Pain relief and a modest increase in active motion are the main goals in operative treatment. Bipolar shoulder arthroplasty represents an adequate alternative to currently favoured hemiarthroplasty in patients with cuff-deficient shoulders.

[Radiolunate arthrodesis of the rheumatoid wrist - mid- and long-term results]. / Die radioulnäre Teilarthrodese zur Stabilisierung des rheumatischen Handgelenkes Mittel-langfristige Ergebnisse.

Late Synovectomy of the rheumatoid wrist combined with ulna head resection and dorsal wrist stabilization will not prevent carpal instability and dislocation. Depending on the radiological destruction pattern and the natural course of the wrist according to Simmen, dorsal wrist synovectomy is combined with soft-tissue or osseus stabilization procedures.This article describes the mid- and long-term results of radio-lunate arthrodesis in patients with rheumatoid arthritis. We present a retrospective study of 69 radiolunate arthrodesis performed from 1988 to 1994. Fifty patients with 57 wrists were available for clinical and radiological follow-up. All patients were suffering from rheumatoid arthritis (dominating female). The average length of R.A. illness was 9.6 years. The mean age at operation was 54.4 years. Postoperative results were reviewed with the Clayton score. The radiographic analysis included measurement of the carpal height index and ulnar translation of the carpus. The follow-up period ranged from 4 to 10.8 years (average: 7 years). The postoperative Clayton score averaged 74.2 points, representing 70% good or excellent results. Twelve wrists achieved satisfactory results and five were judged poor. The most benefit was achieved in pain relief and restoration of wrist function and extensor strength. Complete pain relief was achieved in 36 wrists, while 16 reported slight pain from loads. Five patients still complained about pain with daily wrist activity. We noticed a moderate decrease for extension-flexion (-39 degrees ) and for combined ulnar-radial deviation (-10 degrees ). The radiographic analysis proved stabilization of ulnar translocation in most cases. We routinely noticed a moderate radiographic progression according to the Larsen classification (+0.7) with reduction of the carpal height ratio. In conclusion radioulnate arthrodesis proved satisfactory pain relief and maintenance of functional wrist motion. Despite radiographic deterioration, partial wrist arthrodesis restrains ulnar translocation, while stabilization of the rheumatoid wrist is achieved.

[Long-term outcome of Swanson prosthesis management of the rheumatic wrist joint]. / Langzeitergebnisse nach Swanson-Prothesenversorgung des rheumatischen Handgelenks.

Silicone-wrist arthroplasty has dominated reconstructive surgery of the rheumatoid wrist for a long time. Silicone interposition wrist arthroplasty yielded good clinical results in short and midterm studies. The durability and longevity of the prosthesis however is limited and progressive X-ray deterioration and silicone synovialitis are the main shortcomings. We present the ten-year follow-up results of 102 rheumatoid wrists operated between 1984 and 1992. 72 patients with 82 wrist arthroplasties were clinically and radiologically examined. The mean age at operation was 56.9 years. The average onset of R.A. was 16.1 years. Each wrist was rated on a 100-point scale, with points based on wrist balance, range of motion, pain relief and extensor strength. The postoperative Clayton score averaged 69.4 points. Including revision cases, 51% of the Swanson implants were rated good or excellent, 16% fair, and 33% were judged poor because of pain or prosthesis breakage. Patient satisfaction and pain relief were achieved in 68.2%. Active motion with unrevised implants was 21 degrees extension and 31 degrees flexion. We noticed a moderate increase (7 degrees) for ulnar-radial deviation. There was a progressive deterioration in the radiographic appearance. Implant fracture occurred in 31% of the patients. Subsidence of the implant and significant reduction of carpal height was noticed in 82.5% of the prosthesis. Revision procedures were performed in eleven cases. We conclude that the clinical and radiological results of Swanson silicone interposition arthroplasty will deteriorate with the passage of time. Beyond the potential deleterious effects of silicone, long-term radiological complications such as implant fracture, subsidence and carpal collapse are the main disadvantages of Swanson arthroplasty of the wrist. We therefore currently recommend the MPH-total wrist design in patients with rheumatoid arthritis.

Cobalt-specific T lymphocytes in synovial tissue after an allergic reaction to a cobalt alloy joint prosthesis.

Metals such as cobalt and nickel are common contact allergens. We studied the mechanisms underlying an allergic reaction with marked synovial inflammation in a patient with a cobalt alloy arthroplasty. After removing the joint prosthesis the adjacent synovial tissue was examined for cobalt-specific T lymphocytes. Synovial membrane mononuclear cells were expanded in interleukin 2 and cloned using a representative cloning protocol. T cell clones were tested for their proliferative response to cobalt and further characterized with regard to cytokine secretion, phenotype, and HLA restriction. Additionally, synovial fibroblasts were tested for their function as antigen presenting cells (APC). Almost 30% of the T cell clones reacted to cobalt, but not to the control nickel. All these T cell clones were CD4 positive. The cobalt induced proliferative response could be blocked by anticlass II antibodies. Also, synovial fibroblasts expressing class II molecules induced by interferon-gamma were able to serve as APC. However, when testing a panel of APC of HLA class II mismatched donors, no requirement for a certain HLA class II molecule could be defined. Further studies are necessary to determine mechanisms of presentation and recognition of cobalt by T lymphocytes, a prerequisite for improved prevention and treatment of metal induced allergic reactions.

[Ankle prostheses. Mid-term results after Thompson-Richards and STAR prostheses]. / Prothetische Versorgung des Sprunggelenks. Mittelfristige Ergebnisse nach Thompson-Richards- und STAR-Prothesen.

Thirty-seven patients with 20 cemented Thompson-Richards prostheses and 19 cementless S.T.A.R. prostheses (2 bilateral cases) were followed up after 1-12 years. Rheumatoid arthritis was the main diagnosis in both populations, with females dominating. The investigation was based on the Kofoed ankle score. At follow-up the total scoring improved to 86.9 pts. in S.T.A.R. and to 77.7 pts. in T.R.P. replacement. The radiological examination showed a high rate of radiolucency for the tibial component (53.3%) in cemented T.R.P.; subsidence of talar component was seen in 3 cases with T.R.P. In cementless S.T.A.R. prothesis only 3 cases showed small radiolucent lines of the flat tibial component. Talar subsidence was not seen at all. In T.R.P. we had two revisions due to prothesis loosening and one maleollar fracture, giving a cumulative estimated survival rate of 87% at 12 years. In the S.T.A.R. prosthesis group two revisions had to be performed because of one meniscal breakage and correction of meniscal height. The estimated survival rate at 6 years was 94.3%.

Ankle prostheses. Mid-term results after Thompson-Richards and STAR prostheses.

Thirty-seven patients with 20 cemented Thompson-Richards prostheses and 19 cementless S. T. A. R. prostheses (2 bilateral cases) were followed up after 1-12 years. Rheumatoid arthritis was the main diagnosis in both populations, with females dominating. The investigation was based on the Kofoed ankle score. At follow-up the total scoring improved to 86.9 pts. in S. T. A. R. and to 77.7 pts. in T. R. P. replacement. The radiological examination showed a high rate of radiolucency for the tibial component (53.3 %) in cemented T. R. P.; subsidence of talar component was seen in 3 cases with T. R. P. In cementless S. T. A. R. prosthesis only 3 cases showed small radiolucent lines of the flat tibial component. Talar subsidence was not seen at all. In T. R. P. we had two revisions due to prosthesis loosening and one maleollar fracture, giving a cumulative estimated survival rate of 87 % at 12 years. In the S. T. A. R. prosthesis group two revisions had to be performed because of one meniscal breakage and correction of meniscal height. The estimated survival rate at 6 years was 94.3 %.

[Medium-term results using the cement-free link endoprosthesis. Ribbed shaft V socket]. / Mittelfristige Ergebnisse mit der zementfreien "link"-Endoprothese. Rippenschaft-Typ V Schraubring.

Since 3/84 340 primary implantations with the uncemented "Link" hip system (Rib-Type V socket) were done. The results with an average follow up of 3.2 years are published. Only 2.17% revision had to be suffered in the rib stem, while 0.77% socket revision had to be done. According to the score of Merle d'Aubigné the values of pain increased from 2.87% to 5.38%, walking ability from 3.68% to 5.27% and the range of motion from 133 degrees to 199 degrees. A high rate of good and satisfying results proved this anatomical implant system to be a good alternative in total hip replacement in younger patients.

The transsynovial distribution of oxaprozin.

Oxaprozin (Wy-21743) is a novel and unique compound among NSAIDs: it bears an aliphatic propionic acid function as a side chain in contrast to the large group of acetic acids and profens. The transsynovial distribution was studied in 18 RA-patients, who required articular surgery. Following a wash-out period of 7 days they were treated with 2 x 600 mg of oxaprozin. The patients were assigned to four different groups representing different treatment duration (2, 3, 4 and 5 days). 12 hours after the last dose during surgery synovial fluid and synovial tissue specimen were removed. Blood samples were taken simultaneously and analysed for oxaprozin employing HPLC. In the synovial tissue samples concentrations of 27 micrograms/g were detected. The concentrations were considerably higher than blood (10-17 micrograms/ml) or synovial fluid (4.9-7.6 micrograms/ml) levels. Oxaprozin shows a different pattern of transsynovial distribution and tissue affinity as compared to other NSAIDs.

[Initial results following implantation of silastic wrist joint prostheses in patients with chronic polyarthritis with additional use of titanium grommets]. / Erste Ergebnisse nach Implantation von Silastik-Handgelenkprothesen bei Patienten mit chronischer Polyarthritis unter zusätzlicher Verwendung von Titan-Schalen (Grommets).

Implantation of titanium grommets should protect the flexible implant from the sharp bone edges and avoid fracture of the implant. In case of bone cysts and thin corticalis they should provide further support against countersinking. Swanson et al. (1982) reported bone remodeling phenomena around the grommets and the implant. Eight patients suffering rheumatoid arthritis have been reviewed at an average of 18 months (12 to 24 months) following operation with the flexible implant and additional grommets. The following results were observed: 1. No fractured implants were noted in any patient. 2. In two cases resorption was noted around the proximal grommet. 3. In no case was new bone formation noted. 4. In one case the flexible implant and the grommets became countersunk into bone.