Treatment with tumour necrosis factor alpha antagonists in patients with rheumatoid arthritis induces anticardiolipin antibodies.

OBJECTIVE: To determine the frequency and clinical impact of anticardiolipin antibodies (aCL) in patients with rheumatoid arthritis treated with infliximab and etanercept. METHODS: 121 patients from the Stockholm tumour necrosis factor alpha (TNFalpha) follow up registry (STURE) treated with infliximab or etanercept were studied. RESULTS: At baseline 9/65 (14%) infliximab and 10/56 (18%) etanercept treated patients had positive aCL. After 3 months the frequencies of aCL positivity were 29% (p<0.05 compared with baseline) and 27%, respectively, and after 6 months 28% and 25%. Increases were seen for both IgG and IgM aCL. Increasing age, a higher number of prior DMARDs, and higher DAS28 were predictors for the development of aCL. In the infliximab treated patients, 26/30 (87%) aCL(-) but only 7/14 (50%) aCL(+) patients met the ACR20 criteria (p<0.05), and the frequency of treatment limiting infusion reactions in the aCL(+) patients was higher than expected (17%). aCL positivity in the etanercept treated patients did not show such a clinical correlate. Four patients had thromboembolic events, of whom two were aCL(+) and two aCL(-). CONCLUSION: Frequencies of both IgM and IgG aCL positivity increase in patients treated with these TNFalpha antagonists for 3 months or longer. Increasing age, a greater number of prior DMARDs and a greater disease activity at baseline are predictors for the development of aCL. The development of aCL during treatment with infliximab, but not etanercept, is associated with worse clinical results and more frequent serious infusion reactions. aCL are an important class of autoantibodies associated with TNFalpha blocking therapy.

Treatment with infliximab (Remicade) when etanercept (Enbrel) has failed or vice versa: data from the STURE registry showing that switching tumour necrosis factor alpha blockers can make sense.

OBJECTIVE: When one TNFalpha blocker (etanercept or infliximab) has failed, to determine whether it makes sense to treat patients with the other. PATIENTS AND METHODS: Since 1999 patients treated with etanercept or infliximab have been systematically followed up at our institution in the STURE database. We identified 31 patients who had received both agents. RESULTS: Eighteen patients received etanercept first; discontinuation was mostly due to lack of efficacy. DAS28 values had improved only slightly with etanercept, with a mean (SEM) best DAS28 value of 4.8 (0.6). After switching to infliximab, the mean best DAS28 was 3.6 (0.6)-significantly better than the previous result (p<0.05). Similarly, the mean best ACR-N during etanercept treatment was 17.2 (6.65) and during subsequent infliximab treatment 40.4 (10.6) (p = 0.08). Thirteen patients received infliximab first; discontinuation was mainly due to adverse events. The best DAS28 value achieved during etanercept was 3.6 (0.4) compared with 4.1 (0.4) for infliximab (p<0.05), but the change in DAS28 was not different and ACR-N were similar for infliximab and etanercept in this group. CONCLUSION: For patients with insufficient efficacy from etanercept, treatment with infliximab provided better results, suggesting that a trial of infliximab is reasonable for such patients. For patients who discontinued infliximab owing to adverse events, treatment with etanercept gave at least similar clinical efficacy. Taken together, these data provide support for a trial of the reciprocal TNFalpha blocker in patients when one such agent has failed.

Genetic markers for the efficacy of tumour necrosis factor blocking therapy in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a genetically complex disease where the response to different treatments varies greatly between different patients. This is the case with the tumour necrosis factor (TNF) blocking agents, where 20-40% of patients have been described as non-responders. No predictive markers exist as yet for the prognosis of response. OBJECTIVE: To analyse whether polymorphisms of several cytokine genes are associated with the responsiveness to TNF blockade with etanercept. METHODS: 123 patients with active RA were treated with etanercept and response rates were determined after three months using American College of Rheumatology (ACR)20 and disease activity score (DAS)28 response criteria. Genotyping was done for TNF (-308 TNFA), interleukin (IL)10 (-1087 IL10), transforming growth factor (TGF)beta1 (codon 25 TGFB1), and IL1 receptor antagonist (intron 2 IL1RN). RESULTS: 24 patients (20%) were defined as non-responders owing to their failure to fulfil any of the ACR20 or DAS28 response criteria. None of the recorded alleles was alone significantly associated with responsiveness to treatment. However, a certain combination of alleles (-308 TNF1/TNF1 and -1087 G/G) was associated with good responsiveness to etanercept (p<0.05). In addition, a combination of alleles influencing interleukin 1 receptor antagonist (IL1Ra) and TGFbeta1 production (A2 allele for IL1RN and rare C allele in codon 25 of TGFB1 gene) was associated with non-responsiveness (p<0.05). CONCLUSION: Genetic polymorphisms, which may influence the balance of pro- and anti-inflammatory cytokines of relevance for the course of RA, are associated with clinical responsiveness to etanercept treatment.

Development of a pharmaceutical apotransferrin product for iron binding therapy.

High-dose chemotherapy of patients with haematological malignancies results in extracellular iron accumulation and appearance of non-transferrin-bound iron, which is thought to predispose the patients to septic infections and contribute to organ toxicity. We describe the development of a human plasma-derived apotransferrin product for iron binding therapy. The product is purified from Cohn fraction IV of human plasma by two ion exchange chromatography steps and ultrafiltration. The process comprises solvent detergent treatment as the main virus inactivation step and 15 nm virus filtration and polyethylene glycol precipitation as removal steps for physico-chemically resistant infectious agents. Product characterization by electrospray and MALDI-TOF mass spectrometry indicated no other chemical modifications than N-linked glycan chains and disulphide bonds, except minor oxidation. The purity of the product was more than 98%, main impurities being IgG, IgA and hemopexin. The product had intact iron binding capacity and native conformation. A stable liquid formulation for the finished product was developed. The product has proved safe and well tolerated in early clinical trials in iron binding therapy.

[Blockade of TNFalpha--new therapeutic principle in severe rheumatoid arthritis]. / Blockad av TNF alpha--ny behandlingsprincip vid svår reumatoid artrit.

TNF-alpha is a proinflammatory cytokine. It has a key function in the inflammatory cascade both systemically and locally in the inflamed joints of patients affected by rheumatoid arthritis (RA). Treatment with two different "biological" drugs that block the proinflammatory capacity of TNF-alpha has recently been approved by the European drug authorities. This paper discusses experience gained in clinical trials and during the first year of treatment in Sweden using infliximab (anti-TNF-alpha monoclonal antibodies) and etanercept (recombinant TNF-alpha receptor fusion protein).

Rotator cuff calcifications: treatment with ultrasound-guided percutaneous needle aspiration and lavage.

OBJECTIVE: To analyze the results of ultrasound (US)-guided needle puncture, aspiration and lavage in the treatment of symptomatic calcific tendinitis of the rotator cuff. DESIGN AND PATIENTS: Atraumatic pain in 61 shoulders of 58 patients was resistant to conservative therapy. The average age of the treated patients was 42 years (range 26-49 years), follow-up was 12 months, and the mean diameter of the calcifications was 1.6 cm (range 1.1-2.9 cm). With US guidance and local anesthesia, two needles were placed within each calcification. The calcification was punctured 10-15 times and saline solution injected and aspirated using the needles until the aspirate was free of calcific particles. RESULTS AND CONCLUSIONS: Based on radiographs at 1 year follow-up. 74% (45 of 61) of the calcifications decreased, including 28% (17 of 61) which disappeared totally, and 26% (16 of 61) were unchanged. Calcifications with a faint or absent shadow on US proved to be nearly liquid (slurry calcification in 93% (14 of 15) of cases and could be aspirated. Clinical results were excellent in 74% (45 of 61), moderate in 16% (10 of 61) and poor in 10% (6 of 61) of cases. US offers technical advantages over fluoroscopy, and the typical US image of a slurry calcification helps to select the most suitable patients for aspiration treatment. The results are comparable with those using fluoroscopic guidance.

Hill-Sachs lesion: sonographic detection.

OBJECTIVE: To determine the value of ultrasonography (US) in the detection of Hill-Sachs lesion of the humerus in comparison with double-contrast computed tomographic arthrography (CTA) and with arthroscopy. DESIGN AND PATIENTS: US and CTA were performed on 92 patients, 86 of whom subsequently underwent arthroscopy. The findings of US, CTA and arthroscopy in these 86 patients in the diagnosis of Hill-Sachs lesion were analyzed. RESULTS AND CONCLUSIONS: In the detection of Hill-Sachs lesion US showed a sensitivity of 91% (21 of 23), a specificity of 95% (60 of 63) and an accuracy of 94% (81 of 86) when compared with CTA, and a sensitivity of 94% (18 of 19), specificity of 91% (61 of 67) and accuracy of 91% (79 of 86) when compared with arthroscopy. In only 2% (2 of 86) of patients was there reduced visualization because of restriction of movement. Hill-Sachs lesion and its relationship to the humeral head can be reliably diagnosed with US.

Medial displacement of the biceps brachii tendon: evaluation with dynamic sonography during maximal external shoulder rotation.

PURPOSE: To determine the value of the sonographic subluxation test--dynamic scanning of a shoulder during maximal external rotation--in the evaluation of medial displacement of the biceps tendon. MATERIALS AND METHODS: The subluxation test was performed during shoulder sonography in 1,210 patients, 284 of whom subsequently underwent surgery (152 men and 132 women aged 24-77 years [mean, 52 years]). Subluxation or displacement of the biceps tendon was surgically confirmed in 21 of the 284 patients (16 men and five women aged 35-57 years [mean, 48 years]). The sonographic and surgical findings in these 21 patients were analyzed. RESULTS: The subluxation test helped detect 12 of 14 (86%) cases of subluxation. Static scanning (without the subluxation test) depicted six of seven (86%) cases of dislocation. The test failed or could not be performed in 18 of the 284 (6%) patients; however, no false-positive findings occurred. CONCLUSION: The subluxation test is reliable in the diagnosis of subluxation of the biceps tendon and should be performed during shoulder sonography.

Dupuytren's contracture: the long-term results after day surgery.

220 operations in 211 hands in 160 consecutive patients suffering from Dupuytren's contracture were performed from 1976 through 1984 at the Kuopio University Central Hospital in Finland. 179 operations were carried out as day cases. The mean follow-up was 3.2 years. Sub-total fasciectomy resulted in good immediate and long-term improvement in 86% of patients. The recurrence rate was 27%. Surgical treatment of Dupuytren's contracture was well-suited to day surgery. A properly planned follow-up programme is suggested because of the relatively high rate of recurrence, which usually appeared within two years after operation.