Reactivation of rheumatoid arthritis after pregnancy: increased phagocyte and recurring lymphocyte gene activity

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.

Interaction between rheumatoid arthritis and pregnancy: correlation of molecular data with clinical disease activity measures

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.

Pregnancy induces numerical and functional changes of CD4+CD25 high regulatory T cells in patients with rheumatoid arthritis

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.

Soluble tumour necrosis factor receptors sTNFR1 and sTNFR2 are produced at sites of inflammation and are markers of arthritis activity in Behçet's disease

OBJECTIVE: We analysed the production of soluble tumour necrosis factor receptors sTNFR1 and sTNFR2 at sites of inflammation and measured their plasma concentrations to evaluate them as biological markers of disease activity. METHODS: Plasma samples of 35 patients with Behçet's disease (BD) were collected prospectively at monthly intervals and grouped for inactive disease, active BD without arthritis, and active BD with arthritis. sTNFR1 and sTNFR2 concentrations were measured using immunoassays and compared with other biological disease activity parameters. Plasma sTNFR levels were compared to synovial fluid (SF) levels in seven patients. Sixteen tissue samples of mucocutaneous lesions were stained for TNFR2 expression by immunohistochemistry. RESULTS: sTNFR1 and sTNFR2 were found at increased plasma concentrations in active BD, with the highest concentration in active BD with arthritis (p<0.001). Concentrations of both sTNFRs were at least three times higher in SF of arthritic joints than in the corresponding plasma samples (p = 0.025). A change of more than 1 ng/mL of sTNFR2 plasma concentrations correlated with a concordant change in arthritic activity (96% confidence interval). Sensitivity to change was superior to that of sTNFR1, and other biological disease activity parameters such as erythrocyte sedimentation rate (ESR), immunoglobulin (Ig)G, IgA, and interleukin (IL)-10 plasma concentrations. A strong staining for TNFR2 was found in mucocutaneous lesions, where mast cells were identified as the major source for this receptor. CONCLUSIONS: This longitudinal study demonstrates that sTNFR2 plasma concentrations are closely linked with active BD, and especially with arthritis. Taken together with the expression of TNFR molecules in mast cells of mucocutaneous lesions, our results indicate a fundamental role for the TNF/TNFR pathway in BD.

Limited value of cyclosporine A for the treatment of patients with uveitis associated with juvenile idiopathic arthritis

AIMS: Juvenile idiopathic arthritis (JIA) is often associated with severe chronic anterior uveitis (CAU), and immunosuppressive therapy may be required. In this study, the value of cyclosporine A (CsA) as monotherapy or as combination therapy for treating uveitis was studied in a large cohort of JIA children. METHODS: Multicentre retrospective study including 82 JIA children (girls n=60) suffering from unilateral or bilateral (n=55) CAU. The indication for CsA was active uveitis, although patients were on topical or systemic corticosteroids, MTX, or other immunosuppressive drugs. RESULTS: Inactivity of uveitis during the entire treatment period (mean 3.9 years) was obtained with CsA monotherapy in 6 of 25 (24%) patients, but more often when CsA was combined with the immunosuppressives (35/72 patients; 48.6%, P=0.037), or MTX (18/37 patients, 48.6%, P=0.065), which had already been given. With CsA (mean dosage 2.9 mg/kg), systemic immunosuppressive drugs and steroids could be reduced by >or=50% (n=19) or topical steroids reduced to

High-resolution ultrasound confirms reduced synovial hyperplasia following rituximab treatment in rheumatoid arthritis

OBJECTIVE: To assess the response of RA patients to rituximab (RTX) treatment using a sensitive imaging technique for synovitis. METHODS: Twenty-three RA patients were treated with two 1000-mg infusions of the B-cell depleting antibody, RTX, in an observational protocol. Clinical response was assessed by the European League Against Rheumatism (EULAR) response criteria. High-resolution grey-scale and colour-coded power Doppler (PD) ultrasonography was performed at baseline and 6 months after RTX. The second to fifth MCP and PIP joints were bilaterally examined with joints in a neutral 0 position from a palmar view and scored from 0 to 3. RESULTS: Median disease activity score (DAS28) improved from 5.03 to 3.56 (P = 0.001), which corresponded to a EULAR moderate response in 11 of 23 patients and a EULAR good response in another 6 patients. Improved control of disease activity by RTX was also indicated by tapering of median daily corticosteroid doses from 10 to 5 mg, without flare ups. Mean grey-scale scores correlated with the swollen joint count at baseline (r = 0.484, P = 0.022) and month 6 (r = 0.519, P = 0.011). Mean grey-scale scores improved upon RTX from a 0.90 median (range 0.13-1.87) to 0.75 (range 0.19-1.50, P = 0.023). Frequency of PD positive joints was low (6.1%) at baseline and did not significantly change following RTX treatment. CONCLUSIONS: High-resolution grey-scale ultrasonography (US) examination confirmed reduced synovial hyperplasia, but the applied PD method displayed no significant changes. Therefore, only grey-scale US is recommended in follow-up examinations after RTX treatment.

Comparison of drug retention rates and causes of drug discontinuation between anti-tumor necrosis factor agents in rheumatoid arthritis

OBJECTIVE: Tumor necrosis factor (TNF) inhibitors have revolutionized the treatment of severe rheumatoid arthritis (RA), yet drug discontinuation is common. The aim of this study was to compare treatment retention rates and specific causes of anti-TNF discontinuation in a population-based RA cohort. METHODS: All patients treated with etanercept, infliximab, or adalimumab within the Swiss Clinical Quality Management RA cohort between 1997 and 2006 were included in the study. Causes of treatment discontinuation were broadly categorized as adverse events (AEs) or nontoxic causes, and further subdivided into specific categories. Specific causes of treatment interruption were analyzed using a Cox proportional hazards model and adjusted for potential confounders. RESULTS: A total of 2,364 anti-TNF treatment courses met the inclusion criteria. Treatment discontinuation was reported 803 times: 309 with etanercept, 249 with infliximab, and 245 with adalimumab. Drug inefficacy represented the largest single cause of treatment discontinuation (55.8% of cases). The median time of receiving anti-TNF therapy was 37 months, but discontinuation rates differed between the 3 anti-TNF agents (P < 0.001), with shorter retention rates for infliximab (hazard ratio [HR] 1.24, 99% confidence interval [99% CI] 1.01-1.51). The specific causes of treatment discontinuation revealed an increased risk of AEs with infliximab (HR 1.4, 99% CI 1.003-1.96), mostly due to an increased risk of infusion or allergic reactions (HR 2.11, 99% CI 1.23-3.62). Other discontinuation causes were equally distributed between the anti-TNF agents. CONCLUSION: In this population, infliximab was associated with higher overall discontinuation rates compared with etanercept and adalimumab, which is mainly due to an increased risk of infusion or allergic reactions.

Management of early aggressive rheumatoid arthritis during pregnancy and lactation

This survey outlines the problems of drug therapy in women with early aggressive rheumatoid arthritis (RA) who desire children, are pregnant, or are lactating. Solutions for treatment that benefit the mother and do not harm the fetus or the breast-fed child are discussed. The most effective immunosuppressive drugs alone or in combination are contraindicated during pregnancy and, to a lesser degree, also during lactation. Judicious timing of therapy is therefore necessary, aiming at fast remission of symptoms with the most effective therapy and maintaining quiescent disease with drugs compatible with pregnancy or lactation.

Early diagnosis of temporomandibular joint involvement in juvenile idiopathic arthritis: a pilot study comparing clinical examination and ultrasound to magnetic resonance imaging

OBJECTIVES: To study the validity of both rheumatological and orthodontic examinations and ultrasound (US) as screening methods for early diagnosis of TMJ arthritis against the gold standard MRI. METHODS: Thirty consecutive juvenile idiopathic arthritis (JIA) patients were included in this pilot study. Rheumatological and orthodontic examinations as well as US were performed within 1 month of the MRI in a blinded fashion. Joint effusion and/or increased contrast enhancement of synovium or bone were considered signs of active arthritis on MRI. RESULTS: A total of 19/30 (63%) patients and 33/60 (55%) joints had signs of TMJ involvement on MRI. This was associated with condylar deformity in 9/19 (47%) patients and 15/33 (45%) joints. Rheumatological, orthodontic and US examinations correctly diagnosed 11 (58%), 9 (47%) and 6 (33%) patients, respectively, with active TMJ arthritis, but misdiagnosed 8 (42%), 10 (53%) and 12 (67%) patients, respectively, as having no signs of inflammation. The best predictor for active arthritis on MRI was a reduced maximum mouth opening. CONCLUSION: None of the methods tested was able to reliably predict the presence or absence of MRI-proven inflammation in the TMJ in our cohort of JIA patients. US was the least useful of all methods tested to exclude active TMJ arthritis.

[Eye complications in chronic juvenile arthritis]

BACKGROUND: The relationship between uveitis anterior in childhood and juvenile chronic arthritis (JCA, respectively JRA) has been known since 1950. In a review, the clinical picture of uveitis anterior, its prevalence, pathogenesis, prognosis and current therapy of ocular complications are presented. In addition, we will report our results of a clinical study. PATIENTS AND METHODS: In a cross-sectional study, 64 patients with juvenile chronic arthritis (JCA) had an ophthalmological screening for eye complications either from the disease itself or from the treatment. RESULTS: In 16% of the patients, an iridocyclitis was found, in one case acute, in 9 cases chronic. The cases of chronic uveitis anterior showed in 43% a combination with the classic risk factors (ANA-positive, oligoarticular, female). At the beginning of uveitis, the patients had a mean age of 81 months, at the beginning of JCA disease a mean age of 37 months. Four of 10 patients (= 40%) had eye complications from uveitis (cataract, posterior synechiae, glaucoma). Complications from therapy were found in 27%, mostly cataract as a complication of systemic and topical steroid treatment. Eighteen % had a visual acuity of 0.4 or less. CONCLUSIONS: Because of the often asymptomatic progression of chronic uveitis anterior, the risk of severe undetected eye complications is high. Therefore, an intensive interdisciplinary cooperation between rheumatologists, pediatrics and ophthalmologists is required.

[Juvenile chronic arthritis: a rare disease with potentially serious consequences]

The term juvenile chronic arthritis covers several nosological entities with very different clinical presentation, course and prognosis. This review addresses non-rheumatologists and non-pediatricians. Diagnostic criteria, clinical presentation of the most common nosological subgroups and relevant investigations are spotlighted. Therapeutic guidelines are presented, bearing in mind, that for each child an individual interdisciplinary plan has to be elaborated. This would involve close cooperation between the pediatrician, the pediatric rheumatologist, the family doctor, parents and, if necessary, the physiotherapist, ergotherapist, social worker, ophthalmologist, orthopedic surgeon and school teachers. It is essential that each member of this therapeutic team reports regularly.

[Juvenile chronic arthritis: therapeutic strategy 1990]

Therapeutic strategies based on experience with 119 patients with juvenile chronic arthritis are reviewed. Therapeutic goals are formulated and the means of attaining them (NSAIDs, the so-called disease modifying drugs gold, chloroquine and penicillamine, the antimetabolite methotrexate, intra-articular and systemic corticosteroids, physio- and ergotherapy, technical and orthopedic measures, as well as vocational and medicosocial aspects) are discussed. As the individual prognosis normally depends less on drugs than on preventive and rehabilitative measures, the outcome is largely determined by the quality of a well-coordinated inter-disciplinary team approach.