Monoarticular transfer of adjuvant arthritis by intraarticular injection with sensitized lymphocytes.
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The authors report their experience of 61 injections of osmic acid into the knee during the course of rheumatoid polyarthritis. The results stated to be very good and good, are classified by the disappearance of pain, swelling and stiffness, or a improvement in any one of these criteria. As observed in 67% of cases at the third month the result following changed with time. While these favourable results persisted into the fifth month, there was a remarkable maintenance of them to the 30th month in those patients who it was able to follow so long. The most distinct and lasting results were seen in those joints which showed the least radiological change. Tolerance of the injection of osmic acid was satisfactory apart from several painful reactions which improved in the 24 hours following injection. Two cases of thrombo-phlebitis were seen and one case of rupture of the synovium. If the results obtained with osmic acid appear less impressive than those obtained with isotopes, the simplicity of the method attracts attention as it needs no complicated equipment and is applicable to young invalids.
The terms erosive or inflammatory osteoarthritis refer to an inflammatory condition of the interphalangeal joints of the hand. In this report, observations of 15 patients with erosive osteoarthritis are described. The principal clinical features are symmetrical synovitis of the interphalangeal joints of the hand, the knees, and the first carpometacarpal, interphalangeal, and metacarpophalangeal joints. The principal roentgenographic features are productive and destructive osseous changes. These changes, found particularly at the interphalangeal joints of the hand, consist of both central and peripheral articular erosions and cysts associated with adjacent osteophyte formation. Serologic abnormalities commonly found in rheumatoid arthritis are rarely encountered. In two thirds of the patients, the synovial fluid is noninflammatory; in the remainder, it is mildly to severely inflammatory. The injection of intra-articular corticosteroids predictably results in decreased synovitis but does not seem to affect the subsequent development of erosions.
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The experimental investigation is divided into 3 parts: Firstly, it was assessed that cyclophosphamide (Cp) in different dosages was well tolerated locally when injected into the knee joint of normal rabbits as compared to saline controls on the basis of histology and cell count determination of the injected joints. In a second series of experiments a hyperimmune arthritis (HIA) was produced in rabbits by systemic administration of albumin, complete Freund's adjuvant and intraarticular stimulus by ovalbumin. Histological examination of synovial membranes reveal alterations similar to those of human rheumatoid arthritis on the 7th day after stimulus. Further experiments were aimed at assessing if Cp exerted an inhibitory effect on the 7 day old HIA. Cp in a dosage of 10 mg has been applied intraarticularly in various intervals prior, simultaneously and after the elicitation of HIA. It could be demonstrated that Cp led to a reduction of the number of lymphocytes, plasma cells and fibroblasts in the synovial membrane, the inhibitory effect on fibroblasts was bound to its administration around the point of HIA elicitation, an even stronger inhibition of lymphocytes and plasma-cells was only to be expected when Cp was applied 48 hours after ovalbumin challenge. Unwanted reactions in the course of Cp administration such as superficial and deep necrosis as well as damage of blood vessels in the synovial membrane combined with minor inhibition of lymphocytes and plasma cells were encountered when Cp was injected 120 hours after HIA elicitation. These new experimental results lead to the conclusion that efficacy and unwanted reactions during Cp administration are related to a local activation of the substance in the inflammatory milieu of HIA. Furthermore we were able to demonstrate that even the sole application of Cp if injected shortly before immigration of lymphocytes into the synovial tissue led to a marked suppression of almost all histological parameters of HIA. Our experimental findings strongly support the importance of lymphocytes and plasma cells being inactivated for the successful treatment of adult rheumatoid arthritis. They grow to consider the formation of necrosis and damage of blood vessels as sequelae of too fast a local activation of Cp in the inflammatory tissue.
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A comparison of intra-articular methotrexate and intra-articular triamcinolone hexacetonide was made in 42 arthritic patients with persistent bilateral knee effusions. One knee was injected with either 5 mg methotrexate (two injections of 2.5 mg a week apart) or a single injection of 20 mg triamcinolone. An objective assessment of both knees was made by quantitative thermography at 0,3,7,14 and 21 days. Joints injected with triamcinolone showed a greater fall in thermographic index (T.I) than the joints injected with methotrexate, which showed similar change to the non-injected knee joints in both groups. Four patients received larger doses of methotrexate, up to 20 mg, though the fall in T.I. was still less than the mean fall for triamcinolone injected joints. Peak venous blood levels of methotrexate were reached 1 hour after intra-articular injection, and a sphygmomanometer cuff inflated around the leg above the injected knee for periods of up to 1 hour did not appreciably delay this. Methotrexate had no immediate anti-inflammatory effect, even in psoriatic arthropathy, and did not give the relief of intra-articular steroid.
To determine the possible relevance of intra-articular pressure in the production of ulnar drift, metacarpophalangeal joints of fresh cadaver specimens were injected with water to increase the intra-articular pressure. Of the thirty-two joints tested, ulnar deviation was produced in twenty-three, flexion in twenty-four, and simultaneous ulnar deviation and flexion (ulnar drift) in nineteen. In two or three instances, the displacement was in extension or radial deviation. These results suggest that elevated intra-articular pressure may be a factor in the initiation of ulnar drift in patients with rheumatoid arthritis.
Full-grown rabbits were injected in the knee joints with solutions of trypsin of various concentrations. The animals were sacrificed 2 weeks after the trypsin injection. Twenty-four hours before sacrifice they received 40 muCi 3H-thymidine intra-articularly. The changes in the knee joints were then studied by histological and autoradiographical methods. The injection of trypsin did not result in the development of osteoarthritis. However, autoradiography revealed that the chondrocytes started to divide after the injection. The mitosis of the chondrocytes can thus not be due to degeneration of the cartilage. The explanation put forward is that the mitosis of the chondrocytes may be the result of a decrease in the concentration of a growth controlling factor (chalone) initiated by the administration of trypsin.
Nine inflamed knee joints out of eight patients were examined before and after intraarticular injection of yttrium-90 silicate colloid, in order to find out the effect of radiation synovectomy on the perfusion of the joints. These joints and the untreated contralateral knee joints were examined as to the clinical status and the fast component Tf of the xenon-133 clearance was determined as a means of the perfusion of the synovium. A linear correlation exists between the clinical status of the knee joint and the perfusion as determined by Tf measured three months before and after injection of yttrium-90. Also the joints without any radiation synovectomy showed this correlation. Three months after radiation synovectomy with yttrium-90 there was still no therapeutic effect apparent in the majority of the inflamed knee joints (seven out of nine). At this stage there still existed a hyperaemia. Therefore, it seems that on the whole three months are too short a period to judge the therapeutic effect.
Cholesterol crystals were identified in 16 synovial fluids from 12 patients who were seen over the 14-year period 1964 through 1977. Ten of the 12 patients had rheumatoid arthritis of a median duration of 12 years. One patient had ankylosing spondylitis and another had iliopectineal bursitis without other joint disease. The fluids were usually turbid, white, or yellow in color and of thick consistency. When the synovial fluid concentration of cholesterol was determined, it was higher than the serum level. The swollen joints and bursae did not respond favorably to simple aspiration or corticosteroid injections but did to surgical synovectomy. No relationship was found between synovial fluid accumulation of cholesterol crystal and previous intra-articular corticosteroid therapy, serum lipoprotein abnormalities, intra-articular hemorrhage, or generalized arteriosclerosis. The results suggest that local factors are most important in the development of synovial fluid cholesterol crystals, but the exact mechanisms are unknown. The presence of cholesterol crystals in synovial fluid should suggest a severe persistent synovitis, knowledge of which may be helpful in diagnosis and planning therapy.
1 Three intra-articular prednisolone analogues have been studied in a group of forty-six rheumatoid arthritic subjects. Each compound was tested at 50 mg and 100 mg dose over 3 weeks. 2 The anti-inflammatory effect was assessed by quantitative thermography. Systemic escape of the drug was monitored by plasma prednisolone and cortisol levels. 3 Both the systemic escape from the joint and the duration of effect on injected and uninjected knees were related to drug solubility. 4 Depression of plasma cortisol occurred with all three preparations and was most prolonged with the long-acting preparation. 5 Increasing the dose from 50 mg to 100 mg increased the antiflammatory effect only with the soluble acetate preparation.
The effects of varying intra-articular (ia) doses of bovine serum albumin (BSA) antigen on immune synovitis in rabbits have been investigated. Chronic synovitis, characterized by mononuclear cell infiltration in synovial tissues, was induced by a single ia challenge with BSA in sensitized rabbits. However, cartilage and bone erosions and pannus formation were rarely observed. By varying the number and magnitude of the BSA challenges, lesions with different characteristics were observed at different times of analysis of joint pathology. In 3- to 10-week studies, multiple ia challenges with BSA produced lesions characterized by severe cartilage and bone changes; polymorphonuclear leukocyte (PMN) exudates; and mononuclear cells and, sometimes, PMNs in synovial tissues. Substantial increases in knee widths and synovial tissue weights also observed. By increasing the frequency of ia injections, more severe changes were produced more rapidly, so that within a 3-week period, the animals also experienced pain and were unable to fully extend their antigen-challenged knees. Some of the lesions observed in immune synovis resembled those in rheumatoid arthritis (RA). However, the presence of large numbers of PMNs in synovial tissue under certain conditions suggests some possible differences between the pathogenesis of experimental synovitis and RA.