Rheumatoid Arthritis: Harju A

Larsson P, Bratt J, Harju A, van Vollenhoven R, Klareskog L. · Reumatologiska kliniken, Karolinska sjukhuset, Stockholm. · Lakartidningen. · Pubmed #11265568 No free full text.

Abstract: 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).

Jonsdottir T, Forslid J, van Vollenhoven A, Harju A, Brannemark S, Klareskog L, van Vollenhoven RF. · Department of Rheumatology, Karolinska University Hospital, Stockholm, Sweden. · Ann Rheum Dis. · Pubmed #15066863 links to  free full text

Abstract: 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.

van Vollenhoven RF, Ernestam S, Harju A, Bratt J, Klareskog L. · Department of Rheumatology, Karolinska Hospital, Stockholm, Sweden. · Arthritis Res Ther. · Pubmed #14680509 links to  free full text

Abstract: Etanercept can be used both as monotherapy and in combination with methotrexate (MTX), but direct comparisons of these two options have not yet been reported. In order to compare the results seen in actual practice between these two options, clinical data on 97 patients followed in the Stockholm TNFalpha Follow-Up Registry were analysed. In 57 of these patients etanercept was added to previously started MTX while the others were treated with etanercept alone. The two groups had similar levels of disease activity at baseline. After 3 months, a significantly lower mean disease activity score (28-joint count-based disease activity score) was attained by the patients on etanercept plus MTX. In this group, the number of patients achieving European League Against Rheumatism-defined remission was also significantly greater. Other disease outcomes showed non-significant trends in the same direction. These data suggest that the combination of etanercept plus MTX is clinically more efficacious than etanercept alone.

van Vollenhoven R, Harju A, Brannemark S, Klareskog L. · Department of Rheumatology, Karolinska Hospital, 17176 Stockholm, Sweden. · Ann Rheum Dis. · Pubmed #14644858 links to  free full text

Abstract: 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.

Padyukov L, Lampa J, Heimbürger M, Ernestam S, Cederholm T, Lundkvist I, Andersson P, Hermansson Y, Harju A, Klareskog L, Bratt J. · Unit of Rheumatology, Karolinska Hospital, Karolinska Institutet, Stockholm, Sweden. · Ann Rheum Dis. · Pubmed #12759288 links to  free full text

Abstract: 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.