Rheumatoid Arthritis: Østensen M

Østensen M, Motta M. · Center for Women with Rheumatic Disease, Department of Rheumatology, University Hospital of Bern, Bern, Switzerland. · Nat Clin Pract Rheumatol. · Pubmed #17599074 No free full text.

Abstract: In 90% of cases, women with rheumatoid arthritis suffer a disease flare within 3 months of delivery of their baby. Drug treatment is, therefore, required; however, such therapies have implications for mothers who decide to nurse their infants. Unfortunately, because of a paucity of data, little is known about the transfer of antirheumatic drugs into breast milk, and even less is known about whether small amounts of these agents ingested during nursing could harm the infant. Our review of the literature indicates that paracetamol, prednisone, antimalarial agents, sulfasalazine and most NSAIDs can safely be used by lactating mothers. Expert opinions differ regarding the use of azathioprine, ciclosporin, and methotrexate during lactation because of varying views on the potential for short-term and long-term adverse effects. Evidence regarding the transfer of leflunomide and biologic drugs into breast milk is insufficient; therefore, until more studies are conducted, the use of these drugs in breastfeeding mothers should be restricted. At present, many patients feel they have to choose between postpartum disease control and lactation. Extended studies of the transfer of antirheumatic drugs into breast milk and the resulting consequences are, therefore, urgently needed.

Østensen M, Förger F, Villiger PM. · Department of Rheumatology and Clinical Immunology and Allergy, University Hospital, CH-3010 Bern, Switzerland. · Ann N Y Acad Sci. · Pubmed #16855162 No free full text.

Abstract: Cytokines are important mediators involved in the successful outcome of pregnancy. The concept of pregnancy as biased toward a Th2 immune response states that Th1 type cytokines are associated with pregnancy failure and that Th2 cytokines are protective and counteract pregnancy-related disorders. Studies at the level of the maternal-fetal interface, in the maternal circulation and in cells of peripheral blood have shown that the Th2 concept of pregnancy is an oversimplification. Both Th1 and Th2 type cytokines play a role at different stages of pregnancy and are adapted to the localization and function of cells and tissues. The changes of local and systemic cytokine patterns during pregnancy correspond to neuroendocrine changes with hormones as powerful modulators of cytokine expression. Several autoimmune disorders show a modulation of disease activity during and after pregnancy. In rheumatic diseases with a predominance of a Th1 immune response, a shift to a Th2 type immune response during pregnancy has been regarded as beneficial. Studies of pregnant patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) have shown a cytokine expression similar to that found in healthy pregnant women. Significant differences were present only for a few cytokines and seemed related to the activity of the underlying disease. Interestingly, a gestational increase of cytokine inhibitors interleukin 1 receptor antagonist (IL-1ra) and soluble tumor necrosis factor receptor (sTNFR) in the circulation corresponded to low disease activity in RA. The influence of hormones and cytokines on autoimmune disease is an issue for further study.

Haga HJ, Johnsen V, Østensen M, Mikkelsen K, Gulseth HC, Kvien TK, Nordvåg BY. · Revmatologisk avdeling Haukeland Sykehus 5021 Bergen. · Tidsskr Nor Laegeforen. · Pubmed #11187194 No free full text.

Abstract: The polymyalgic syndrome may be the presenting clinical feature for several diseases such as polymyalgia rheumatica, temporal arteritis, malignancy, rheumatoid arthritis, virus infections, connective tissue diseases, and myositis. In this review we present the various diagnostic options seen from a rheumatological point of view, with emphasis on polymyalgia rheumatica, temporal arteritis and the paraneoplastic syndrome. We are of the opinion that polymyalgia rheumatica is overdiagnosed in general practice, and steroid treatment may delay diagnosis and treatment of other differential diagnosis presenting as the polymyalgic syndrome. Several recently published Norwegian epidemiological studies offer new information on various aspects of the polymyalgic syndrome, which will be discussed.

Østensen M, Förger F. · Department of Rheumatology, Clinical Immunology and Allergology, University Hospital Bern, Bern, Switzerland. · Nat Rev Rheumatol. · Pubmed #19506586 No free full text.

Abstract: A desire for children or the presence of pregnancy limits the drug therapy options for a woman with rheumatoid arthritis. Combination therapies that include methotrexate or new drugs that have not been studied or used in pregnant patients must be excluded, even though they might be highly efficacious. With few exceptions, the reason for this exclusion is not the proven teratogenicity of the drugs, but the absence of proven safety for the fetus. Whereas methotrexate, leflunomide, abatacept and rituximab must be withdrawn before a planned pregnancy, tumor necrosis factor inhibitors and bisphosphonates can be continued until conception. Antimalarial agents, sulfasalazine, azathioprine and ciclosporin are compatible with pregnancy, and so can be administered until birth. Corticosteroids and analgesics such as paracetamol (acetaminophen) can also be used throughout pregnancy. NSAIDs can be safely administered until gestational week 32. The most important consideration when managing rheumatoid arthritis medications during pregnancy is that therapy must be tailored for the individual patient according to disease activity.

Häupl T, Østensen M, Grützkau A, Radbruch A, Burmester GR, Villiger PM. · Department of Rheumatology and Clinical Immunology, Charité-University Medicine, Berlin, Germany. · Arthritis Rheum. · Pubmed #18821679 No free full text.

Abstract: OBJECTIVE: Pregnancy is associated with reduced disease activity in rheumatoid arthritis (RA) and frequently with disease exacerbation after delivery. This study was undertaken to generate a systematic overview of the molecular mechanisms related to disease remission and postpartum reactivation. METHODS: Transcriptomes of peripheral blood mononuclear cells (PBMCs) were generated from RA patients and healthy women by transcription profiling during the third trimester and 24 weeks after delivery. For functional interpretation, signatures of highly purified immune cells as well as Kyoto Encyclopedia of Genes and Genomes pathway annotations were used as a reference. RESULTS: Only minor differences in gene expression in PBMCs during pregnancy were found between RA patients and controls. In contrast, RA postpartum profiles presented the most dominant changes. Systematic comparison with expression signatures of monocytes, T cells, and B cells in healthy donors revealed reduced lymphocyte and elevated monocyte gene activity during pregnancy in patients with RA and in controls. Monocyte activity decreased after delivery in controls but persisted in RA patients. Furthermore, analysis of 32 immunologically relevant cellular pathways demonstrated a significant additional activation of genes related to adhesion, migration, defense of pathogens, and cell activation, including Notch, phosphatidylinositol, mTOR, Wnt, and MAPK signaling, in RA patients postpartum. CONCLUSION: Our findings indicate that innate immune functions play an important role in postpartum reactivation of arthritis. However, this may depend not only on the monocyte itself, but also on the recurrence of lymphocyte functions postpartum and thus on a critical interaction between both arms of the immune system.

Häupl T, Østensen M, Grützkau A, Burmester GR, Villiger PM. · Department of Rheumatology and Clinical Immunology, Charité-University Medicine, Tucholskystr. 2, 10117 Berlin, Germany. · Rheumatology (Oxford). · Pubmed #18504279 No free full text.

Abstract: OBJECTIVE: The factors that induce remission of RA during pregnancy and the relapse occurring after delivery remain an enigma. In a previous study, we investigated gene-expression profiles of peripheral blood mononuclear cells (PBMC) in patients with RA and healthy women in late pregnancy and postpartum. Profiles of samples from both groups were similar in late pregnancy with elevated monocyte and decreased lymphocyte signatures. Postpartum, in RA PBMC the high level of monocyte transcripts persisted. Further increase was observed in adhesion, migration and signalling processes related to monocytes but also in lymphocytes despite similar clinical activity due to intensified drug treatment. This prompted us to investigate correlations between clinical parameters of disease activity and gene profiles. METHODS: Transcriptome data were correlated with RADAI, CRP, monocyte and lymphocyte counts. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotations, monocytes and lymphocytes signatures were used as reference information. RESULTS: Comparative analysis of PBMC expression profiles from RA patients during and after pregnancy with RADAI and CRP revealed a correlation of these disease activity parameters predominantly with monocyte transcripts. Genes related to cellular programs of adhesion, migration and response to infections were upregulated. Comparing clinically active and not-active RA patients postpartum revealed a cluster of 19 genes that could also identify active disease during pregnancy. CONCLUSION: The data suggest that an increase of the RADAI and an elevation of CRP is a consequence of molecular activation of monocytes. Furthermore, they indicate that molecular activation of T lymphocytes may remain clinically unrecognized postpartum. It is conceivable that a set of 19 genes may qualify as molecular disease activity marker.

Förger F, Marcoli N, Gadola S, Möller B, Villiger PM, Østensen M. · Department of Rheumatology and Clinical Immunology and Allergology, Inselspital, University of Bern, Bern, Switzerland. · Ann Rheum Dis. · Pubmed #17971458 No free full text.

Abstract: OBJECTIVE: In a prospective study we investigated whether numerical and functional changes of CD4+CD25(high) regulatory T cells (Treg) were associated with changes of disease activity observed during pregnancy and post partum in patients with rheumatoid arthritis (RA). METHODS: The frequency of CD4+CD25(high) T cells was determined by flow cytometry in 12 patients with RA and 14 healthy women during and after pregnancy. Fluorescence-activated cell sorting (FACS) was used to sort CD4+CD25(high) T cells and CD4+CD25- T cells were stimulated with anti-CD3 and anti-CD28 monoclonal antibodies alone or in co-culture to investigate proliferation and cytokine secretion. RESULTS: Frequencies of CD4+CD25(high) Treg were significantly higher in the third trimester compared to 8 weeks post partum in patients and controls. Numbers of CD4+CD25(high) Treg inversely correlated with disease activity in the third trimester and post partum. In co-culture experiments significantly higher amounts of IL10 and lowered levels of tumour necrosis factor (TNF)alpha and interferon (IFN)gamma were found in supernatants of the third trimester compared to postpartum samples. These findings were independent from health or disease in pregnancy, however postpartum TNFalpha and IFN gamma levels were higher in patients with disease flares. CONCLUSION: The amelioration of disease activity in the third trimester corresponded to the increased number of Treg that induced a pronounced anti-inflammatory cytokine milieu. The pregnancy related quantitative and qualitative changes of Treg suggest a beneficial effect of Treg on disease activity.

Østensen M, Raio L. · Department of Rheumatology and Clinical Immunology and Allergology, University of Berne, Switzerland. · Nat Clin Pract Rheumatol. · Pubmed #16932640 No free full text.

Abstract: BACKGROUND: A 25-year-old woman with a 3-year history of rheumatoid arthritis presented 6 months before her first planned pregnancy. At the time of presentation, she was being successfully treated with infliximab and methotrexate. During her pregnancy, the patient discontinued infliximab and methotrexate and her arthritis relapsed. She was treated with low-dose prednisone, sulfasalazine, nimesulide, and intra-articular corticosteroid injections. Oligohydramnios developed at gestational week 18. INVESTIGATIONS: Laboratory testing, ultrasonography of the fetus and of the patient's affected joints. DIAGNOSIS: Active arthritis during pregnancy and oligohydramnios suspected to be caused by nimesulide. MANAGEMENT: Low-dose oral prednisone, sulfasalazine, repeated intra-articular corticosteroid injections. Infliximab and methotrexate were restarted immediately after delivery.

Förger F, Østensen M, Schumacher A, Villiger PM. · Department of Rheumatology and Clinical Immunology and Allergology, University Hospital, CH-3010 Bern, Switzerland. · Ann Rheum Dis. · Pubmed #15778241 links to  free full text

Abstract: OBJECTIVE: To gain insight into patient experience of the disease course and health related quality of life during and after pregnancy in women with rheumatoid arthritis and ankylosing spondylitis. METHODS: 10 patients with rheumatoid arthritis, 10 patients with ankylosing spondylitis, and 29 age matched healthy pregnant controls were evaluated by the medical outcomes study short form 36 (SF-36) health survey once at each trimester and at 6, 12, and 24 weeks postpartum. A group of non-pregnant age matched female patients (40 rheumatoid arthritis, 16 ankylosing spondylitis) was studied for comparison. RESULTS: Impaired physical dimensions as well as increased bodily pain was observed in healthy women in late pregnancy. Patients with rheumatoid arthritis showed improved physical functioning scores in the second trimester and reduced pain in the third trimester. Among pregnant patients, those with ankylosing spondylitis suffered the greatest impairment of health related quality of life during pregnancy. In all patient groups the physical impairment in the third trimester was less pronounced than in healthy controls. Mental health scores remained stable even with persisting active disease during pregnancy, or with a postpartum flare. CONCLUSIONS: Pregnancy reduced physical functioning in healthy women and patients, but had no impact on mental and emotional health, even at times of disease aggravation. The pregnancy experience documented in our patients may be helpful when counselling patients contemplating pregnancy.

Østensen M, Sicher P, Förger F, Villiger PM. · Department of Rheumatology and Clinical Immunology, University Hospital, CH-3010 Bern, Switzerland. · Ann Rheum Dis. · Pubmed #15647441 links to  free full text

Abstract: OBJECTIVE: To study the putative shift of a Th1 to a Th2 immune response in pregnancy and its reversal post partum in healthy women and patients with rheumatoid arthritis (RA). METHODS: Peripheral blood mononuclear cells (PBMC) were examined by FACS analysis for the expression of activation markers CD25 and HLA-DR and chemokine receptors CXCR3 and CCR4 on CD4+ and CD8+ T cells in four healthy women and four patients with RA. Samples were analysed once in the third trimester and six and 12 weeks post partum. Eight healthy non-pregnant women served as controls. RESULTS: No reduction of CD25 and HLA-DR+ T cells occurred in the third trimester, but a significant increase was observed post partum in healthy women and an even greater increase in patients. Proportions of T cells expressing the CXCR3 or CCR4 marker were similar in patients and controls during pregnancy, whereas a significant increase occurred post partum. The ratio of CXCR3+ to CCR4+ cells remained unchanged during the observation period and did not differ significantly from that in non-pregnant controls. CONCLUSION: A shift from a Th1 to a Th2 immune response was not detected in the circulation of healthy pregnant women or pregnant patients. The significant increase of T cell activation after pregnancy warrants further investigation into the mechanisms of adjustment of the immune system post partum and its clinical correlates in rheumatic patients.

Østensen M, Förger F, Nelson JL, Schuhmacher A, Hebisch G, Villiger PM. · Department of Rheumatology and Clinical Immunology and Allergy, University Hospital, CH-3010 Bern, Switzerland. · Ann Rheum Dis. · Pubmed #15539410 links to  free full text

Abstract: OBJECTIVE: To investigate changes in the levels of circulating cytokines with a focus on the Th1/Th2 balance during and after pregnancy in patients with rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), and ankylosing spondylitis (AS). METHODS: Plasma and serum samples of 34 pregnant patients, 19 with RA, 6 with JIA, and 9 with AS, and of 30 healthy pregnant women, 20 non-pregnant patients, and 10 non-pregnant healthy women were analysed for levels of interferon gamma (IFNgamma), interleukin (IL) 1beta, IL10, IL1 receptor antagonist (IL1Ra), soluble tumour necrosis factor receptor (sTNFR), and soluble CD30 (sCD30) by ELISA. Clinical assessment and blood sampling in pregnant women was done once in each trimester and 6, 12, and 24 weeks post partum. Disease activity in the patients was evaluated by validated clinical instruments and correlated with circulating levels of cytokines. RESULTS: Low levels of IL10 were found sporadically, whereas IFNgamma and IL1beta were below detection level in the samples tested. Significantly higher concentrations of sTNFR and IL1Ra were measured in pregnant than in non-pregnant subjects. An increase of IL1Ra from the second to the third trimester correlated with improvement of disease activity in patients with RA and AS. Compared with non-pregnant patients and the other pregnant women, patients with RA showed markedly raised levels of sCD30 during pregnancy. CONCLUSIONS: IFNgamma and IL10, markers of a Th1 and Th2 response, respectively, were either low or undetectable in the cohorts analysed. The increase of cytokine inhibitors IL1Ra and sTNFR was related to pregnancy and was independent of an underlying disease. These anti-inflammatory mediators seem to affect disease activity.

Østensen M, Fuhrer L, Mathieu R, Seitz M, Villiger PM. · Department of Rheumatology and Clinical Immunology and Allergy, University Hospital, CH-3010 Bern, Switzerland. · Ann Rheum Dis. · Pubmed #15361373 links to  free full text

Abstract: OBJECTIVE: : To analyse the disease course of patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) during and after pregnancy by validated clinical instruments for measurement of disease activity, and assess their usefulness in pregnant patients. METHODS: Included were 10 patients with RA and 9 with AS (10 pregnancies). Clinical examination and blood/urine sampling was performed before conception, at each trimester, and weeks 6, 12, and 24 post partum. Assessment of RA was by the RA Disease Activity Index (RADAI), the 44 joint count, and the Health Assessment Questionnaire; assessment of AS by the Bath Ankylosing Spondylitis Activity Index (BASDAI), the Dougados Functional and Articular Index, and a night pain index. Common for all patients were the patient's and physician's global assessment. RESULTS: : Most patients with RA showed sustained or increased improvement of disease activity during pregnancy. Higher disease activity scores were found in the patients with AS with a frequent increase of disease activity in the second trimester and mitigation of symptoms in the third trimester. Analysis specifically for the patient's assessment of pain showed continuously higher pain scores in the patients with AS than in those with RA. Rank correlation showed good to moderate correlation between most clinical measurements and RADAI or BASDAI, respectively. Functional indices were confounded by physiological changes of late pregnancy. CONCLUSION: RA can be monitored during and after pregnancy by the swollen joint count and RADAI without interference from pregnancy related symptoms, whereas usual measures of disease activity are not always applicable in pregnant patients with AS.