Agnes M. Th. Boerbooms

Circulating soluble tumor necrosis factor receptors, interleukin‐2 receptors, tumor necrosis factor α, and interleukin‐6 levels in rheumatoid arthritis.

Objective. To assess whether circulating concentrations of soluble tumor necrosis factor receptors (sTNFR; p55 and p75), soluble interleukin-2 receptors (sIL-2R), tumor necrosis factor α (TNFα), and interleukin-6 (IL-6) reflect clinical response and whether changes are dependent on the drug used in rheumatoid arthritis (RA) patients taking methotrexate (MTX) or azathioprine (AZA). Methods. These cytokines and soluble receptors were assessed in 20 control subjects and serially for up to 48 weeks in 61 RA patients, by bioassay (IL-6) and immunoassays (sTNFR, sIL-2R, TNFα, and IL-6). Results. Concentrations of p55 and p75, sIL-2R, and TNFα (but not IL-6) were significantly higher in RA patients than in controls. Significant decreases in sIL-2R and p55 concentrations were associated with clinical improvement and were observed in patients treated with MTX, but not AZA. Both treatments induced decreases in IL-6 concentrations, but circulating AZA (or its metabolites) appears to interfere with the measurement of IL-6 bioactivity. TNFα and p75 levels did not show significant changes. Conclusion. Measurement of circulating sIL-2R, p55, and IL-6 may be useful in the evaluation of RA disease activity and response to therapy. Interference by circulating levels of drugs must be ruled out when bioassays are used to evaluate cytokine levels.

Infections during low-dose methotrexate treatment in rheumatoid arthritis

We studied the infection rate in patients with rheumatoid arthritis (RA) treated with low-dose methotrexate (MTX) in a 6-year open prospective study and in a 12-month randomized double blind trial comparing MTX with azathioprine (AZA) that was followed by a 3-year open prospective study. The literature on infections during low dose MTX in RA was reviewed. We also did a search for therapy-related opportunistic infections in RA and in MTX-treated psoriasis and psoriatic arthropathy patients. In our studies the infection rate during MTX treatment was higher in severe RA than in moderate RA. In severe RA there were often 2 infections simultaneously. The majority of the infections occurred in the first 1.5 years of treatment. There was no difference in the infection rate of MTX and AZA in the comparative trial. In the literature the infection rate was highest in short-term double-blind studies. Opportunistic infections are increasingly reported in RA treated with MTX and rarely with AZA, cyclosporine A, and cyclophosphamide or in MTX treated psoriasis and psoriatic arthropathy. In RA it appears that the initial period of treatment with MTX is the most vulnerable phase for infections, with the exception of opportunistic infections, which are not limited to a certain treatment period. Probably there are more MTX-associated infections in severe RA than in moderate RA.

Influence of Methotrexate and Azathioprine on Radiologic Progression in Rheumatoid Arthritis: A Randomized, Double-Blind Study

OBJECTIVE To compare the effects of azathioprine and methotrexate on progression of radiologic damage in patients with rheumatoid arthritis. DESIGN Double-blind, randomized 48-week trial. PATIENTS Sixty-four patients with active rheumatoid arthritis who either have not responded to or who have reacted with side effects to at least parenteral gold and D-penicillamine. INTERVENTIONS Either azathioprine, 100 mg daily, or methotrexate, 7.5 mg weekly, was administered orally. Depending on the clinical effect after 8 weeks, the dosage was increased to either azathioprine, 150 mg, or methotrexate, 15 mg. The dosages for nonsteroidal anti-inflammatory drugs and prednisone were held stable. MEASUREMENTS Clinical and laboratory assessments were done by the same physician every 4 weeks for the first 24 weeks and every 8 weeks thereafter. Radiographs of hands, wrists, and feet obtained at baseline and after 24 and 48 weeks were scored by one rheumatologist blinded to medication and clinical findings. MAIN RESULTS Initial radiologic scores were comparable in both groups and correlated with disease duration (r = 0.38). An intention-to-treat analysis after 24 and 48 weeks showed significantly fewer new erosions in the methotrexate group compared with the azathioprine group (difference, 2.0 [95% CI, 0.2 to 3.9] and 3.5 [CI, 1.3 to 5.8], respectively). The change in total joint score was also significantly less pronounced in the methotrexate group compared with the azathioprine group after 24 weeks (difference, 2.8 [CI, 0.2 to 5.2]) and after 48 weeks (difference, 3.9 [CI, 0.3 to 7.4]). Radiologic stabilization after 48 weeks was present in 10% of the azathioprine group compared with 29% of the methotrexate group. CONCLUSIONS Patients with rheumatoid arthritis treated with low-dose methotrexate showed significantly less radiologic progression than patients treated with azathioprine. This result suggests that methotrexate therapy is clinically superior in these patients.

Effects of antirheumatic agents on cytokines.

A review of the literature concerning the effects of traditional antirheumatic drugs on cytokines and the cytokine and anticytokine approaches already used in the therapy of rheumatoid arthritis (RA) is presented. Many antirheumatic drugs are capable of cytokine modulation in vitro. Corticosteroids inhibit the transcription of a broad spectrum of genes including those encoding monocyte, T cell-derived cytokines and several hemopoietic growth factors, whereas drugs such as cyclosporin A and D-penicillamine interfere with T cell activation more specifically by suppressing interleukin 2 (IL-2) production. The in vivo effects of drug therapy on cytokines in RA patients are less well established. Gold compounds reduce circulating IL-6 levels and the expression of monocyte-derived cytokines, such as IL-1, tumor necrosis factor (TNF), and IL-6, in the rheumatoid synovium. Decreases in circulating IL-6, soluble IL-2 (sIL-2R), and TNF receptors and in synovial fluid IL-1 levels have been reported with methotrexate. Reductions in circulating IL-6 and sIL-2R concentrations have also been observed with cyclosporin and corticosteroids, whereas azathioprine reduces IL-6 but not sIL-2R. Studies on sulfasalazine are conflicting and the in vivo effects of D-penicillamine and antimalarials have not been studied yet. Interferon gamma therapy is not effective in RA but may prove a useful antifibrotic for systemic sclerosis. Colony stimulating factors improve the granulocytopenia associated with Feltys syndrome or drug toxicities but can induce arthritis flares and should be reserved to treat infectious complications. Promising results are being obtained with selective antagonism of TNF and IL-1 in RA, and combinations of anticytokine strategies with traditional antirheumatic drugs have been already envisaged. These should preferably be based in a broader knowledge of the effects of antirheumatic agents on the cytokine network.

Radio-synovectomy in chronic synovitis of the knee joint in patients with rheumatoid arthritis

The influence of intra-articular (i.a.) colloidal 198Au (5 mCi) or 90Y-silicate (5 mCi) on synovitis of the knee joint in patients older than 45 years with rheumatoid arthritis (RA), who had been treated since 1970 in our hospital, was investigated. Of the 89 knee joints of 77 patients studied, 65 had no or minimal radiological abnormalities of the knee joint treated (group I), whereas 24 patients had moderate to severe changes (group II). Before and at regular intervals after radio-synovectomy the clinical response was scored using pain, hydrops and warmth as parameters. The results indicated that 1 year after treatment the percentage of knee joints with a favourable response was greater in group I than in group II (58% versus 25%, P=0.001). This difference was still present 3 years after treatment. Clinical response showed no correlation with initial inflammatory activity as measured by 99mTc-pertechnetate uptake measurements. However, in group I, those patients with an ESR below 60 mm/h, measured just before radio-synovectomy, more often had a favourable response than those with an ESR in excess of 60 mm/h (P=0.01). No or only slight complications of radio-synovectomy were noted, whereas leakage of radioactivity from the knee joints was minimal.It is concluded that radio-synovectomy is an effective and safe procedure in those patients with rheumatoid synovitis of the knee joint without the presence of significant radiological damage and the absence of active systemic disease.

Side effects of azathioprine treatment in Rheumatoid Arthritis: analysis of 10 years of experience

Our experience with azathioprine in the treatment of rheumatoid arthritis covers ten years, during which 91 rheumatoid patients (66 female and 25 male) received this drug, with a median treatment period of 36 months. Total follow-up experience, during and after treatment, was 399 person years. Twelve patients died. The principal causes of death were malignant neoplasm (six patients) and cardiovascular diseases (three patients). The mortality in our patients was compared to that of the general Dutch population by the Standardised Mortality Ratio (SMR). In the male patient group a significant excess of both total mortality and mortality from malignancy was observed. The female patients showed no differences from the general population. In this follow-up study, no lymphoreticular tumours occurred during or after azathioprine therapy.

Pancytopenia and methotrexate with trimethoprim-sulfamethoxazole.

Excerpt To the Editor:Kozarek and colleagues (1) found a dramatic clinical improvement in patients treated with methotrexate who had refractory Crohn colitis and an incomplete remission of chronic ...

Pancreatic carcinoma with polyarthritis, fat necrosis, and high serum lipase and trypsin activity.

A 46 year old white man presented with subcutaneous and intramedullary fat necrosis, destructive polyarthritis, and osteolytic bone lesions, complicating a poorly differentiated adenocarcinoma of the tail of the pancreas with metastases in the liver and omentum. There was a 100-fold increase in serum lipase and trypsin activity. His condition deteriorated rapidly, was characterised by rapid tumour growth, formation of ascites, a 20 kg weight loss, extensive subcutaneous fat necrosis, and fistula formation in the left calf. Treatment with 5-fluorouracil 300 mg/m2 on days 1-5 and doxorubicin 50 mg/m2 and cisplatin 100 mg/m2 on day 1, every three weeks, was well tolerated and resulted in rapid clinical improvement. After three courses of treatment a partial remission was seen and after seven courses further improvement occurred with a return to normal of serum lipase and trypsin activity. One year after starting chemotherapy the tumour relapsed but responded again to chemotherapy (epirubicin 40 mg/m2 and carboplatin 300 mg/m2 on day 1, every three weeks).

99MTC-Pertechnetate Uptake after Total Knee Replacement in Rheumatoid Arthritis

In 6 out of 48 non-hinged knee joint replacements in 35 patients, 99mTc04- uptake values were clearly increased compared with a control group. Measurements were performed an average of 3 years (range 9 months - 4 1/2 years) after operation. Four of the six cases showed loosening of the prosthesis at arthrotomy and one showed an infection. Tests for hypersensitivity to the different components of the prosthesis and cement were normal. Histology and immunofluorescence of the synovial membrane obtained at arthrotomy in the four operated patients showed no recurrence of the synovitis. This study indicates that there is no recurrence or only a slight recurrence of rheumatoid synovitis after total knee joint replacement of the geometric type.