Inhibitory effects of leflunomide therapy on the activity of matrixmetalloproteinase-9 and the release of cartilage oligomeric matrix protein in patients with rheumatoid arthritis.

OBJECTIVE: To determine the effects of the disease modifying antirheumatic drug (DMARD) leflunomide on the expression of the matrix metalloproteinase MMP-1 (collagenase) and the activity of MMP-9 that are believed to play a major role in cartilage destruction associated with inflammation in patients with rheumatoid arthritis (RA). Serum concentrations of cartilage oligomeric matrix protein (COMP) should offer promise for monitoring tissue degradation in the RA joints during a 6-month therapy with leflunomide. METHODS: Thirty-six patients with RA meeting the ACR-criteria were recruited for the study in a multicentre trial. A dose of 20 mg leflunomide/day (after a 3-day 100 mg/day loading dose), an isoxazole derivate and inhibitor of the "de novo" pyrimidine synthesis, was administered for a study period of 6 months. MMP-1, the activity of MMP-9 and COMP values were measured in serum by enzyme immuno assay. The very sensitive acute phase protein serum amyloid A (SAA) was also determined by EIA. The measurements were performed before and after 3 and 6 months of leflunomide therapy. RESULTS: High levels of active MMP-9, COMP and SAA were detected in the sera of the patients with RA prior to the start of the leflunomide therapy compared to normal control sera. A significant reduction of the MMP-9 activity levels was seen after 3 months immunomodulation with leflunomide and was maintained after 6 months (p < 0.01). The degradation marker COMP and the inflammation marker SAA decreased significantly after 6 months (p < 0.04, respectively p < 0.01). There was also an insignificant tendency of MMP-1 reduction in serum after 6 months. CONCLUSION: This study demonstrated that a DMARD therapy with leflunomide can cause positive effects on cartilage degradation and inflammation achieving reductions in the acute phase protein SAA, the enzymatic attack of MMPs and the loss of the cartilage matrix component COMP.

[Treatment of osteoarthritis of the knee joint. Efficacy and tolerance to acemetacin slow release in comparison to celecoxib]. / Behandlung der Gonarthrose. Wirksamkeit und Verträglichkeit von retardiertem Acemetacin im Vergleich zu Celecoxib.

OBJECTIVE: The aim of this trial was to compare acemetacin (ACE) with celecoxib (CEL) in terms of tolerability and efficacy in the treatment of osteoarthritis of the knee joint. METHODS: A total of 105 patients (26-64 years old) suffering from primary osteoarthritis (OA) of the knee were enrolled in this international, multicenter, randomized, double blind controlled trial. Fifty three patients were given ACE and 52 CEL. They were treated with either 90 mg bid of slow release ACE or 200 mg bid of CEL for 6 weeks. Additional gastroprotective therapy was not provided. Tolerability was assessed by physical examination, laboratory tests, vital signs and reports of side effects, as well as by patient and physician global assessments. Efficacy parameters comprised pain assessment by visual analogue scale (VAS) and ordinal scale, WOMAC, SF-36 and patient and physician global impressions of efficacy. In addition, acetaminophen consumption was recorded. RESULTS: In 21 ACE (39.6%) and 19 CEL patients (36.5%), the number of side effects totaled 56 (ACE n=29; CEL n=27) (ns). Mean pain reduction at week 6 was highly significant ( P<0.0001) in both groups and amounted to 38.7 mm (+/-20.3) in the ACE group and to 35.1 mm (+/-18.7) in the CEL group (ns). Very similar results were seen with respect to the other efficacy parameters. CONCLUSION: ACE is not inferior to CEL for the short-term treatment of knee OA in terms of tolerability and efficacy.

Visualization of non-Hodgkin's lymphoma by high dosed somatostatin receptor specific scintigraphy and extended single photon emission tomography.

The study aimed to increase the sensitivity of somatostatin receptor (SR) specific scintigraphy for the detection of non-Hodgkin's lymphoma (NHL). Ten selected patients presenting with histologically proven NHL and with 50% to 100% bone marrow involvement were injected with 20 micrograms octreotide labeled with a mean of 254 MBq 111In. The results were recorded with a double head gamma camera by long-time SPET (60 sec per frame, 3 interval) of neck/thorax and abdomen/pelvis. To show bone marrow displacement by lymphoma cells, SPET of the same regions (15 sec per frame, 3 interval) was recorded 3 to 7 days later after i.v. administration of 0.5-1 mg monoclonal anti-granulocyte antibody (Mab 250/183) labeled with a mean of 454 MBq 99mTc. This modality showed a person related sensitivity of 70%, a lesion related sensitivity of 48% (29/60), 60% (22/37) above and 30% (7/23) below the diaphragm. The sensitivity in detecting bone marrow involvement was 10%. Only 80% bone marrow infiltration with lymphoma cells in nodular configuration was shown by In-111-octreotide scintigraphy correlating with cold lesions in the anti-granulocyte scan. There was no false positive result; the smallest lesion correctly identified by SR scintigraphy had with a diameter of 1 cm, the largest lesion missed measured 3.5 cm. In conclusion, doubling the doses of octreotide and radiolabel and extended SPET recording improved to some extent the patient related sensitivity and visualized nodular bone marrow involvement in 10% of patients. The lesion related sensitivity improved mainly above but not below the diaphragm.

Cholestasis and liver cell damage due to hypersensitivity to erythromycin stearate--recurrence following therapy with erythromycin succinate.

Erythromycin is a frequently used antibiotic in patients with atypical respiratory infection and/or an allergy to penicillin. We report the case of a young woman who developed severe cholestasis and jaundice following treatment with erythromycin stearate. Two years later her general practitioner prescribed erythromycin succinate for pharyngitis. She experienced a severe second episode of jaundice and malaise. Different esters of erythromycin have been introduced to reduce side effects such as allergic reactions to erythromycin. The findings in our patient underline the fact that hypersensitivity is caused by the erythromycin molecule, independent from the type of esterification. Because of these side effects newer makrolides should be given preference over erythromycin.

Abnormal directed migration of blood polymorphonuclear leukocytes in rheumatoid arthritis. Potential role in increased susceptibility to bacterial infections.

Rheumatoid arthritis (RA) patients are at higher risks of bacterial infection than healthy subjects. Polymorphonuclear leukocytes (PMN) are the first line of nonspecific cellular defence against these infections. We tested the hypothesis that abnormal directed migration of PMN may be one reason for the increased infection rate of RA patients. PMN migration was investigated in 68 peripheral blood samples of 15 RA patients compared with 64 samples of healthy controls in a novel whole blood in vitro membrane filter assay. The migration of PMNs from RA patients and controls was stimulated using the bacterial chemoattractant N-formyl-methionyl-leucyl-phenylalanine (fMLP). Unstimulated PMN migration of RA patients was increased compared with healthy controls as measured by the following parameters: (a) absolute number of migrant PMNs (1954+/-87 vs. 1238 +/-58 PMN/mm2), (b) percentage of PMNs migrated into the filter (total migration index, TMI) (28.6+/-0.9 vs. 24.0+/-0.8%), (c) the distance half the migrating PMNs had covered (distribution characteristic, DC) (22.6+/-1.1 vs. 16.1+/-0.6 mm) and (d) the product of TMI and DC (neutrophil migratory activity, NMA) (669.0+/-45.0 vs. 389.0+/-18.9). fMLP stimulated PMNs of RA patients showed defective migration compared to unstimulated samples as shown by (a) a reduced number of migrant PMNs (1799+/-93 PMN/mm2), (b) lower TMI (26.1+/-0.9%), (c) unremarkable altered distribution characteristic (22.9+/-0.8 mm) and (d) significant reduced migratory activity (600.0+/-30.0). Our data suggest that the high incidence of infections in RA patients may partly be caused by defective migratory activity of PMNs to bacterial chemoattractants as demonstrated by fMLP.

[Results of efficacy study with diclofenac/orphenadrine infusions in patients with musculoskeletal diseases and functional disorders]. / Ergebnisse einer Anwendungsbeobachtung mit Diclofenac/Orphenadrin-Infusionen bei Patienten mit muskuloskelettalen Krankheiten und Funktionsstörungen.

During a post-marketing surveillance study, 641 patients (age range 18 to 86 years) with painful rheumatic diseases, mostly of vertebral etiology, were given ready-for-use infusions containing a combination of the non-steroid antiphlogistic agent diclofenac (75 mg) and the muscle relaxing agent orphenadrine (30 mg) parenterally for 7 days. The goal of the study was to investigate efficacy, tolerability, and acceptance of this intravenous therapy in wide use in physicians' practices. At the end of treatment, the global evaluation resulted in a score of 1.6 on a scale of 1 (very good) to 4 (insufficient). The tolerability score was 1.3 and the acceptability score was 1.5. Only 20 patients (3.1%) had adverse effects, most of which were of gastrointestinal nature. The medication proved appropriate for use in the treatment of painful spine syndromes, inflammatory osteoarthritis, painful osteoporosis, post-operative conditions, and extra-articular rheumatism and could represent a first step towards multi-factorial therapeutic management of these diseases.

[Diclofenac/orphenadrine infusion therapy in patients with active arthrosis]. / Diclofenac/Orphenadrin-Infusionstherapie bei Patienten mit aktivierten Arthrosen.

This study investigated the efficacy and safety of a diclofenac/orphenadrin infusion in 21 female and 1 male patients with clinically and radiologically diagnosed inflammatory osteoarthritis of the big joints, especially the knee and hip joints. The patients received 1 infusion per day over 2 h for 10 days. Efficacy and safety were assessed by measuring the subjective pain intensity at rest and during exercise on a visual analogue scale and on an ordinal rating scale before and after every infusion. The patients were interviewed daily for possible side effects. After the 10-days treatment course a 5% reduction of pain at rest and a 37.5% reduction of pain during exercise was observed. Subjective pain intensity was reduced by an average of 32.5%. In most cases relief was noticeable after the 4th infusion. 9 patients rated the medication safety as "very good", 11 patients as "good". A total of 12 patients reported mainly mild side effects such as vertigo, dry mouth, and temporarily reduced visual acuity. Based on its rapid onset of action and its efficacy, it can be stated that the investigated diclofenac/orphenadrin infusion is a valuable extension of the therapeutic methods in patients with inflammatory osteoarthritis.

Effect of steroid treatment on the migration behaviour of neutrophils in patients with early rheumatoid arthritis.

The influence of methylprednisolone on the migratory characteristics of neutrophil granulocytes was investigated in 10 patients with early rheumatoid arthritis (RA) and compared to 12 controls. The migration of neutrophils was measured with a whole-blood membrane filter assay with and without stimulation by the chemoattractant N-formyl-methionyl-leucyl-phenylalanine (fMLP). Total migration index (TMI), distribution characteristics (DC) and the product of TMI and DC (neutrophil migratory activity; NMA) served to characterize the migratory behaviour of neutrophils. The data demonstrated an increased polymorphonuclear leucocyte (PMN) migration in patients with early RA, indicating a bystander role of PMNs in inflammatory joint injury. Treatment with methylprednisolone reduced significantly the penetration depth (DC) of neutrophils, but did not influence the number of migrating cells (TMI). The unstimulated NMA was significantly reduced due to the marked DC reduction, whereas steroids did not influence the stimulated NMA of neutrophils. A significant reduction in PMN penetration depth was demonstrated only after a steroid therapy of at least 10 days, suggesting that a longer period of steroid therapy is necessary to provide effective inflammatory control.

[Possible diagnostic error of "Bechterew disease"]. / Mögliche Fehldiagnose "Morbus Bechterew".

A 41-year old caucasian male presented with limited range of motion of the entire spine and myogenous intermittent claudication. He was referred with the diagnosis "ankylosing spondylitis". The clinical picture mimicked ankylosing spondylitis, but there were no corresponding radiological abnormalities despite a 13-year history of his disease. Laboratory values showed markedly elevated levels of muscle enzymes. The diagnosis of rigid spine syndrome, a subtype of muscular dystrophy, was made from the clinical picture a normal EMG and degenerative changes on a biopsy from the muscle trapezius. We would like to draw attention to this rare cause of back pain.

Blood polymorphonuclear leukocyte migratory activities during rheumatoid arthritis.

Blood polymorphonuclear leukocyte (PMN) migratory activity was investigated in adult rheumatoid arthritis (RA) patients and in healthy control subjects using fresh whole blood in a novel membrane filter assay. The PMNs migrated under FMLP stimulation and under blank control conditions (spontaneous migration). Essential evaluation criteria were the percentage of PMNs that migrated from the entire blood sample into the filters (TMI) and the penetration depth of the migrating cell bulk into the filters (DC). PMNs from healthy subjects penetrate deeper under FMLP stimulation than under blank control conditions. Migration depends on age and sex: the TMI decreases, while the DC and the reactivity towards FMLP increase with age. FMLP triggers a stronger DC reaction in females than in males. Compared with healthy subjects, patients with RA develop an increased PMN reaction, whereas FMLP inhibits migration in comparison with the blank controls. There is no correlation between disease activity estimated by joint functions and PMN migratory activity, while there are strong correlations between disease activity and the classical RA laboratory parameters WBC, platelets, BSR, CRP, hemoglobin and rheumatoid factor. PMNs therefore probably do not play a major role in joint injury. Gold therapy inhibits DC reactivity. PMN migration in RA differs markedly from the reactions in juvenile rheumatoid arthritis, where high disease activity is associated with high PMN migratory activity, and the correlations between classical laboratory parameters and disease activity follow other patterns than in RA.

Sternoclavicular septic arthritis: a rare but serious complication of subclavian venous catheterization.

Sternoclavicular septic arthritis is a rare complication of subclavian venous catheterization. We estimate that septic involvement of this joint may be as common as one in 500 catheterizations. We report two patients with insidious onset of shoulder pain, chest discomfort, low-grade fever and slight but painful swelling of a sternoclavicular joint four weeks following subclavian venous catheterization. Positive blood cultures in the presence of abnormal bone scan and abnormal conventional X-ray examination or computed tomography of the sternoclavicular joint led to the diagnosis of septic arthritis. Both patients responded well to antibiotic treatment. Based on our observations and that reported in the literature, the earliest changes of sternoclavicular septic arthritis may be detected by bone scan while plain X-ray studies and CT become abnormal during advanced stages of this type of arthritis. We would like to alert physicians to this cause of fever and joint pain in patients who previously underwent subclavian venous catheterization.

Anticardiolipin antibodies in rheumatoid arthritis: their relation to rheumatoid nodules and cutaneous vascular manifestations.

One hundred and seventy-three consecutive patients with rheumatoid arthritis were examined for the presence of anticardiolipin antibodies (ACA), and for the clinical relevance and the relation of these antibodies to skin manifestations. Abnormally elevated IgG- and/or IgM-ACA levels were detected by an enzyme-linked immunosorbent assay in the sera of 55 (32%) patients. There was no statistical evidence of an association between ACA and a history of thrombosis in these patients. However, ACA were statistically significantly linked to the presence of rheumatoid nodules, which were found in 36 (21%) patients. In three patients, ACA were associated with vascular manifestations, including livedo reticularis, thrombophlebitis, and leucocytoclastic vasculitis. Our findings suggest that, although a subset of ACA may be linked to cutaneous vascular conditions, the major fraction of ACA in rheumatoid arthritis may have a different specificity than in other diseases, in which ACA are often linked to thrombotic events.

[Differential diagnostic considerations in eosinophilia with reference to a 19-year-old patients with Löffler endocarditis]. / Differentialdiagnostische Uberlegungen zur Eosinophilie anhand einer 19jährigen Patientin mit Löfflerscher Endokarditis.

In this case report a 19-year-old girl suffering from hypereosinophilia with 3500 cells/mm3 and involvement of the right lung, lymph nodes, skin, serosa and heart is described. Within 10 days of admission an infiltration of the right upper lung lobe disappeared spontaneously and was diagnosed as transient eosinophilic lung infiltration according to Löffler. Both lymph node needle biopsy and several skin biopsies revealed merely general reactive changes whereas a bronchial lavage produced a significant number of eosinophilic granulocytes. Autoimmunologic or infectious-toxic disorders were ruled out as etiologic causes. Within 4 weeks after admission severe mitral and tricuspidal insufficiency as well as AV-block second grade and protodiastolic galloping rhythm developed in addition to progressing polyserositis. The echocardiographic pattern was in accordance with restrictive endocarditis. Due to the greatly reduced left ventricular ejection fraction cortisone (125 mg prednison equivalent) was tentatively administered as therapy. Within 2 weeks heart-, serosa- and lymph-node-findings became normal as well as the eosinophilic count, the scaling skin rash being only partly improved. After 10 months of continuous cortisone therapy (10 mg prednison equivalent) the patient was without evidence of disease. However in conclusion, it may be said that such pattern of findings suggests a hypereosinophilic syndrome with Löffler endocarditis with an unknown future course of disease although generally survival prognosis may not be too high.