Rheumatoid Arthritis: Markusse HM

Landewé RB, Boers M, Verhoeven AC, Westhovens R, van de Laar MA, Markusse HM, van Denderen JC, Westedt ML, Peeters AJ, Dijkmans BA, Jacobs P, Boonen A, van der Heijde DM, van der Linden S. · Department of Internal Medicine/Rheumatology, PO Box 5800, University Hospital Maastricht, 6202 AZ Maastricht, The Netherlands. · Arthritis Rheum. · Pubmed #11840436 No free full text.

Abstract: OBJECTIVE: The Combinatietherapie Bij Reumatoide Artritis (COBRA) trial demonstrated that step-down combination therapy with prednisolone, methotrexate, and sulfasalazine (SSZ) was superior to SSZ monotherapy for suppressing disease activity and radiologic progression of rheumatoid arthritis (RA). The current study was conducted to investigate whether the benefits of COBRA therapy were sustained over time, and to determine which baseline factors could predict outcome. METHODS: All patients had participated in the 56-week COBRA trial. During followup, they were seen by their own rheumatologists and were also assessed regularly by study nurses; no treatment protocol was specified. Disease activity, radiologic damage, and functional ability were the primary outcome domains. Two independent assessors scored radiographs in sequence according to the Sharp/van der Heijde method. Outcomes were analyzed by generalized estimating equations on the basis of intent-to-treat, starting with data obtained at the last visit of the COBRA trial (56 weeks after baseline). RESULTS: At the beginning of followup, patients in the COBRA group had a significantly lower mean time-averaged 28-joint disease activity score (DAS28) and a significantly lower median radiologic damage (Sharp) score compared with those in the SSZ monotherapy group. The functional ability score (Health Assessment Questionnaire [HAQ]) was similar in both groups. During the 4-5 year followup period, the time-averaged DAS28 decreased 0.17 points per year in the SSZ group and 0.07 in the COBRA group. The Sharp progression rate was 8.6 points per year in the SSZ group and 5.6 in the COBRA group. After adjustment for differences in treatment and disease activity during followup, the between-group difference in the rate of radiologic progression was 3.7 points per year. The HAQ score did not change significantly over time. Independent baseline predictors of radiologic progression over time (apart from treatment allocation) were rheumatoid factor positivity, Sharp score, and DAS28. CONCLUSION: An initial 6-month cycle of intensive combination treatment that includes high-dose corticosteroids results in sustained suppression of the rate of radiologic progression in patients with early RA, independent of subsequent antirheumatic therapy.

Verhoeven AC, Boers M, te Koppele JM, van der Laan WH, Markusse HM, Geusens P, van der Linden S. · Internal Medicine/Rheumatology Department, Maastricht University Hospital, Maastricht, The Netherlands. · Rheumatology (Oxford). · Pubmed #11709606 links to  free full text

Abstract: OBJECTIVES: Exploration of bone metabolism changes at different levels of disease activity, both with and without oral corticosteroid therapy, and prediction of changes in joint damage and bone density from the observed changes in markers of bone turnover. METHODS: Data analysis from a randomized clinical trial with 155 rheumatoid arthritis (RA) patients; median age 50 yr, early and active disease (diagnosis < 2 yr); one group treated with a combination of sulphasalazine (SSZ; 2000 mg/day), methotrexate (MTX; 7.5 mg/week) and prednisolone (initially 60 mg/day, tapered in six weekly steps to 7.5 mg/day), the other group with SSZ alone. Prednisolone and MTX were tapered and stopped after weeks 28 and 40, respectively, while SSZ was continued. Urine and serum samples were collected at baseline and weeks 16, 28, 40 and 56. Measurements of urinary pyridinoline (PYD) and deoxypyridinoline (DPD) and serum alkaline phosphatase (tAP) and osteocalcin (OC) were performed, as well as standard clinimetry and bone densitometry. RESULTS: Over time and in both treatment groups, bone formation and bone resorption markers showed a pattern similar to erythrocyte sedimentation rate (ESR): a significant decrease compared with baseline and a larger decrease with combined treatment at weeks 16 and 28. PYD excretion, tAP, OC, and joint damage scores were significantly lower in the combined treatment group. Changes in bone density (of spine and hips) did not significantly differ between treatment groups. Mainly cumulative ESR explained progression of joint damage. CONCLUSIONS: Prednisolone and disease-modifying anti-rheumatic drug therapy in patients with early and active RA are both independently associated with decreased levels of urinary excretion of bone collagen resorption markers PYD and DPD. Markers of bone formation and resorption closely followed changes in ESR in both treatment groups. Reduced bone resorption together with reduced bone formation-initially at a somewhat faster pace-resulted in less bone turnover and explain the observed (non-significant and partially reversible) extra bone loss in the lumbar spine associated with prednisolone (combined treatment).

Levin MD, van t Veer MB, de Veld JC, Markusse HM. · Department of Haematology, Erasmus Medical Centre, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands. · Neth J Med. · Pubmed #13677318 links to  free full text

Abstract: Thrombocytopenia is a well-known side effect following intramuscular gold therapy in patients with rheumatoid arthritis. Thrombocytopenia may occur at any time and it can be irreversible and sometimes fatal despite cytotoxic or immunosuppressive therapy. We describe two patients who presented with haemorrhagic diathesis on the day after the administration of aurothioglucose. The thrombocytopenia in these patients was caused by aurothioglucose-induced antibody-mediated platelet destruction. Both patients made an uneventful recovery and the platelet count returned to normal within several weeks without further treatment. Antibody-detecting tests were repeated five years later and could not demonstrate the presence of antibodies. Also after incubation with aurothioglucose no antibodies could be demonstrated.

Barendregt PJ, Tulen JH, van den Meiracker AH, Markusse HM. · Department of Rheumatology, Medisch Centrum Rijnmond Zuid, Rotterdam, The Netherlands. · Ann Rheum Dis. · Pubmed #11830428 links to  free full text

Abstract: BACKGROUND: Autonomic dysfunction has been described in primary Sjögren's syndrome (SS). OBJECTIVE: To investigate the circulatory autonomic regulation in patients with primary SS by power spectral analysis of heart rate and blood pressure variability. METHODS: Forty three (42 female) patients with primary SS, mean age 52 years (range 23-80), with a mean disease duration of eight years (range 1-30) and 30 (15 female) healthy controls, mean age 43 years (range 21-68) were studied. In each patient blood pressure, heart rate, and respiration were measured continuously during supine rest and orthostatic challenge (60 degrees head-up tilt). Power spectral analysis was performed to determine possible differences in short term sympathetic and parasympathetic autonomic regulation between patients and controls. Furthermore, spectral parameters were studied in relation to illness severity and disease duration of the patients with primary SS. RESULTS: After controlling for differences in age, heart rate variability of the mid-frequency band and the variation coefficient of systolic blood pressure were significantly lower in patients with primary SS than in controls during supine rest. During 60 degrees tilt patients with primary SS showed a significantly higher mean heart rate, mean systolic blood pressure, and variation coefficient of diastolic blood pressure, and a significantly lower baroreflex index than controls. After controlling for age, no differences were found either in heart rate variability, blood pressure results, and baroreflex sensitivity during supine rest and tilt between the subgroups divided according to disease duration, Schirmer test results, or between the subgroups with different fatigue scores. No differences were found in spectral data between the groups with and without positive antinuclear antibody serology. CONCLUSION: For the group no differences in sympathetic and parasympathetic cardiac control were seen between patients with primary SS and controls, as assessed by spectral techniques, although some cardiovascular differences were found, particularly during orthostatic challenge.

Barendregt PJ, van den Bent MJ, van Raaij-van den Aarssen VJ, van den Meiracker AH, Vecht CJ, van der Heijde GL, Markusse HM. · Department of Rheumatology, Zuiderziekenhuis, Rotterdam, The Netherlands. · Ann Rheum Dis. · Pubmed #11502615 links to  free full text

Abstract: BACKGROUND: Involvement of the peripheral nervous system in patients with primary Sjögren's syndrome (SS) has been reported, but its prevalence in neurologically asymptomatic patients is not well known. OBJECTIVE: To assess clinical and neurophysiological features of the peripheral nervous system in patients with primary SS. PATIENTS AND METHODS: 39 (38 female) consecutive patients with primary SS, aged 20-81 years (mean 50), with a disease duration of 1-30 years (mean 8) were studied. The peripheral nervous system was evaluated by a questionnaire, physical examination, quantified sensory neurological examination, and neurophysiological measurements (nerve conduction studies). To assess autonomic cardiovascular function an orthostatic challenge test, a Valsalva manoeuvre, a forced respiration test, and pupillography were done. RESULTS: Abnormalities as indicated in the questionnaire were found in 8/39 (21%) patients, while an abnormal neurological examination was found in 7/39 (18%) patients. Abnormalities in quantified sensory neurological examination were found in 22/38 (58%) patients. In 9/39 (23%) patients, neurophysiological signs compatible with a sensory polyneuropathy were found. No differences were found in the autonomic test results, disease duration, serological parameters, or erythrocyte sedimentation rate between the patients with primary SS with and those without evidence of peripheral nervous involvement. CONCLUSION: Subclinical abnormalities of the peripheral nervous system may occur in patients with primary SS selected from a department of rheumatology, but clinically relevant involvement of the peripheral nervous system in this patient group is rare.

Schrijver IA, Melief MJ, Markusse HM, Van Aelst I, Opdenakker G, Hazenberg MP, Laman JD. · Department of Immunology, Erasmus University Rotterdam, The Netherlands. · Rheumatology (Oxford). · Pubmed #11312384 links to  free full text

Abstract: OBJECTIVES: Peptidoglycan (PG), a component of Gram-positive bacteria, may be involved in rheumatoid arthritis (RA) because of its ability to induce production of proinflammatory cytokines, to induce arthritis in rodents, and its presence in antigen-presenting cells in RA joints. METHODS: In the present study, physiologically relevant PG was able to induce T-cell proliferation in peripheral blood and synovial fluid samples of RA patients, but the magnitude of the response did not differ from that of cells from healthy subjects. In addition, production of cytokines associated with RA (interleukins (IL)-1beta, IL-6, IL-8, IL-10, IL-12 and tumour necrosis factor alpha) and of the matrix metalloproteinase, gelatinase B (MMP-9), was induced in blood and synovial fluid cultures of RA patients. CONCLUSION: The fact that PG, which can be found in synovial tissues of RA patients is able to induce the production of inflammatory mediators supports the hypothesis that PG plays a role in the pathogenesis of RA by influencing the inflammatory microenvironment of the joint.

Schrijver IA, De Man YA, Melief MJ, Van Laar JM, Markusse HM, Klasen IS, Hazenberg MP, Laman JD. · Department of Immunology, Erasmus University Rotterdam and University Hospital-Dijkzigt Rotterdam, The Netherlands. · Clin Exp Immunol. · Pubmed #11168011 links to  free full text

Abstract: The gut flora is believed to play a role in the pathogenesis of RA. Peptidoglycan, a major cell wall component of Gram-positive bacteria, is a candidate antigen because of its capability to trigger production of proinflammatory cytokines, to induce arthritis in rodents, and because of its presence in antigen-presenting cells in RA joints. We investigated whether the systemic and local antibody levels against a peptidoglycan-polysaccharide (PG-PS) are related to the presence and disease activity of RA. Significantly lower levels of systemic IgG directed against PG-PS were found in healthy females compared with healthy males, and systemic IgA levels specific for PG-PS were negatively correlated with age. Levels of systemic IgG directed against PG-PS were significantly reduced in RA patients compared with sex- and age-matched healthy controls. Local (synovial fluid) levels of IgG did not correlate with disease activity whereas synovial fluid levels of IgA correlated positively with disease activity. These data suggest that IgG in healthy people mediates protection against spreading of PG to non-mucosal sites.

Barendregt PJ, van Den Meiracker AH, Markusse HM, Tulen JH, Boomsma F, van Der Heijde GL, Veld AJ. · Department of Rheumatology, Zuiderziekenhuis, Rotterdam, the Netherlands. · Ann Rheum Dis. · Pubmed #10577960 links to  free full text

Abstract: OBJECTIVE: To investigate the sympathetic and parasympathetic cardiovascular function in primary Sjögren's syndrome (SS) and to investigate the possible relation with ocular dryness. METHODS: 41 (40 women) patients with primary SS, mean age 50 years (range 20-80) with a mean disease duration of eight years (range 1-30), were studied. In each patient direct arterial blood pressure (BP), heart rate (HR) and respiration were measured continuously for two hours. The function of the autonomic circulatory regulation was evaluated by measuring the heart rate response to deep breathing (6 cycles/min) and by means of the Valsalva manoeuvre and the responses of BP, HR and plasma noradrenaline (norepinephrine) concentrations to a 10 minute 60 degree head up tilt test. Pupillography was done to evaluate ocular autonomic function. RESULTS: The HR-Valsalva ratio was abnormal in 24% of the patients, and the HR variability during forced respiration was abnormal in 56% of the patients. The HR responses to both the Valsalva manoeuvre and deep breathing, as indicators of parasympathetic function, were abnormally low in 6 of 41 (15%) patients. In only two patients the decrease in systolic BP in response to the head up tilt test, as indicator of sympathetic function, was more than 20 mm Hg. However, increment of plasma noradrenaline concentration during head up tilt test and the overshoot of BP in phase IV of the Valsalva manoeuvre, as indicators of sympathetic function, were normal in both patients. Thus, no evidence for sympathetic dysfunction was found, whereas evidence for parasympathetic failure occurred sometimes. Autonomic pupillary function in patients with primary SS and healthy controls, as well as the Schirmer test in patients with or without evidence for parasympathetic dysfunction as based on the results of the Valsalva and deep breathing tests, were not significantly different. CONCLUSION: Parasympathetic, but not sympathetic dysfunction seems to occur in a subgroup of primary SS. Results show that this does not necessarily contribute to the typical ocular dryness in this condition.

Levin MD, Zoet-Nugteren SK, Markusse HM. · No affiliation provided · Lancet. · Pubmed #10408493 No free full text.

Abstract: We describe congestive heart failure caused by autoimmune myocarditis in a patient with primary Sjögren's syndrome. Only after corticosteroids were given did the symptoms and laboratory abnormalities disappear.