Nivelreumapotilaiden kuolinsyyt 40 vuoden aikana : ruumiinavauksen merkitys

Rheumatoid arthritis (RA) patients have premature mortality. Contrary to the general population, mortality in RA has not declined over time. This study aimed to evaluate determinants of mortality in RA by examining causes of death (CoDs) over time, accuracy of CoD diagnoses, and contribution of RA medication to CoDs. This study further evaluated detection rate of reactive systemic amyloid A amyloidosis, which is an important contributor to RA mortality. CoDs were examined in 960 RA patients between 1971 and 1991 (Study population A) and in 369 RA patients autopsied from 1952 to 1991, with non-RA patients serving as the reference cases (Study population B). In Study population B, CoDs by the clinician before autopsy were compared to those by the pathologist at autopsy to study accuracy of CoD diagnoses. In Study population B, autopsy tissue samples were re-examined systematically for amyloidosis (90% of patients) and clinical data for RA patients was studied from 1973. RA patients died most frequently of cardiovascular diseases (CVDs), infections, and RA. RA deaths declined over time. Coronary deaths showed no major change in Study population A, but, in Study population B, coronary deaths in RA patients increased from 1952 to 1991, while non-RA cases had a decrease in coronary deaths starting in the 1970s. Between CoD diagnoses by the clinician and those by the pathologist, RA patients had lower agreement than non-RA cases regarding cardiovascular (Kappa reliability measure: 0.31 vs. 0.51) and coronary deaths (0.33 vs. 0.46). Use of disease modifying anti-rheumatic drugs was not associated with any CoD. In RA patients, re-examination of autopsy tissue samples doubled the prevalence of amyloid compared with the original autopsy: from 18% to 30%. In the amyloid-positive RA patients, amyloidosis was diagnosed before autopsy in only 37%; and they had higher inflammatory levels and longer duration of RA than amyloid-negative RA patients. Of the RA patients with amyloid, only half had renal failure or proteinuria during lifetime. In RA, most important determinants of mortality were CVDs, RA, and infections. In RA patients, RA deaths decreased over time, but this was not true for coronary deaths. Coronary death being less accurately diagnosed in RA may indicate that coronary heart disease (CHD) often goes unrecognized during lifetime. Thus, active search for CHD and its effective treatment is important to reduce cardiovascular mortality. Reactive amyloidosis may often go undetected. In RA patients with proteinuria or renal failure, as well as with active and long-lasting RA, a systematic search for amyloid is important to enable early diagnosis and early enhancement of therapy. This is essential to prevent clinical manifestations of amyloidosis such as renal failure, which has a poor prognosis.Nivelreuma aiheuttaa nivelmuutoksia, mutta se myös lyhentää elinikää. Reumapotilaat kuolevat samoihin sairauksiin kuin väestö, mutta myös nivelreumaan. Vaikeassa reumassa toisinaan kehittyvä sekundaarinen amyloidoosi on tärkeä elinikää lyhentävä tekijä. Reumapotilaiden elinikä ei ole pidentynyt toisin kuin väestön keskimääräinen elinikä. Tämän väitöskirjatutkimuksen tavoitteena oli selvittää reumapotilaiden lisääntyneeseen kuolleisuuteen vaikuttavia tekijöitä tutkimalla reumapotilaiden kuolinsyitä pitkän ajanjakson aikana, kuolinsyydiagnoosien tarkkuutta, reumalääkityksen vaikutusta kuolinsyihin ja sitä kuinka kattavasti amyloidoosi oli diagnosoitu. Väitöskirjatyössä tutkittiin 960 reumapotilaan kuolinsyyt vuosilta 1971 - 1991 (aineisto A) ja 369 reumapotilaan ja verrokkien kuolinsyyt, jotka oli todettu ruumiinavauksessa vuosina 1952 - 1991 (aineisto B). Kuolinsyydiagnoosin osuvuutta tutkittiin vertaamalla ruumiinavauslähetteen oletettuja kuolinsyitä ruumiinavauksessa todettuihin kuolinsyihin (aineisto B). Ruumiinavauksessa otetut kudosnäytteet tutkittiin uudelleen 90%:lta potilaista amyloidoosin toteamiseksi ja sairaskertomustiedot kerättiin vuoden 1972 jälkeen kuolleilta reumapotilailta (aineisto B). Sydän- ja verisuonitaudit, reuma ja infektiot olivat reumapotilaiden tärkeimmät kuolinsyyt. Reuman aiheuttamat kuolemat vähenivät. Reumapotilaiden sepelvaltimotautikuolemat lisääntyivät 1952 - 1991 välillä. Verrokeilla ne kääntyivät laskuun 1970-luvulla (aineisto B). Reumapotilaiden sydän- ja verisuonitauti- ja sepelvaltimotautikuolemat olivat alidiagnosoituja. Reumalääkkeiden käyttö ei vaikuttanut kuolinsyihin. Amyloidoosi oli todettu elinaikana vain kolmasosalla reumapotilaista. Reumapotilaiden kudosnäytteiden uudelleentutkiminen lisäsi amyloidoosin määrän kaksinkertaiseksi ruumiinavauksessa todettuihin verrattuna. Näillä potilailla tulehdusarvot olivat olleet korkeammat ja reuma oli kestänyt pidempään. Heistä vain puolella oli elinaikana todettu munuaisten vajaatoiminta tai valkuaisvirtsaisuus. Reumapotilaiden tavallisimpia kuolinsyitä olivat sydän- ja verisuonitaudit, reuma ja infektiot. Reumapotilaiden sepelvaltimotauti näyttää olevan alidiagnosoitu. Sepelvaltimotaudin aktiivinen etsiminen ja tehokas hoito ovat tärkeitä kuolleisuuden vähentämisessä. Amyloidoosi myös voi jäädä toteamatta elinaikana. Amyloidoosia kannattaa etsiä etenkin reumapotilailta, joilla on munuaisten vajaatoiminta, valkuaisvirtsaisuus tai pitkään kestänyt ja aktiivi reuma. Amyloidoosin varhainen toteaminen on tärkeää, jotta voidaan estää sen eteneminen reuman hoitoa tehostamalla

Tulehdukselliset reumasairaudet sydän- ja verisuonitautien riskitekijänä

Vertaisarvioitu.Tulehduksellisia reumasairauksia sairastavat potilaat sairastuvat ja kuolevat muuta väestöä useammin sydän- ja verisuonitauteihin. Riski on lisääntynyt erityisesti nivelreumaa ja systeemistä lupus erythematosusta (SLE) sairastavilla potilailla, mutta se on myös jonkin verran lisääntynyt spondylartriittien, esimerkiksi selkärankareuman ja nivelpsoriaasin, sekä kihdin yhteydessä. Nivelreumapotilaan riski on verrattavissa diabetespotilaan riskiin. Sydän- ja verisuonitautiriskin taustalla vaikuttaa yleisten riskitekijöiden (tupakointi, dyslipidemia, verenpainetauti, diabetes ja insuliiniresistenssi, ylipaino, vähäinen liikunta ja parodontiitti) lisäksi myös krooninen tulehdus, ja yhdessä nämä johtavat ateroskleroosiin kiihtymiseen. Tulehdus pyritään kardiovaskulaaririskin vähentämiseksi hoitamaan tehokkaasti, tavoitteena on pysyvä remissio. Yksinään tulehduksen hoito ei kuitenkaan riitä, vaan tarvitaan myös tehokasta puuttumista yleisiin riskitekijöihin.Peer reviewe

Tulehdukselliset reumasairaudet sydän- ja verisuonitautien riskitekijänä

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STAT6 and STAT1 Pathway Activation in Circulating Lymphocytes and Monocytes as Predictor of Treatment Response in Rheumatoid Arthritis

Objective To find novel predictors of treatment response to disease-modifying antirheumatic drugs (DMARDs), we studied activation of STAT (signal transducers and activators of transcription) 6 and 1 in circulating leukocytes of patients with rheumatoid arthritis (RA). Methods 19 patients with untreated recent-onset RA, 16 patients with chronic RA irresponsive to synthetic DMARDs and 37 healthy volunteers provided blood samples for whole blood flow cytometric determination of intracellular STAT6 and STAT1 phosphorylation, expressed as relative fluorescence units, in response to IL-4 and IFN-gamma, respectively. Phosphorylation was restudied and treatment response (according to European League Against Rheumatism) determined after 1-year treatment with synthetic DMARDs in recent-onset RA and with biological DMARD in synthetic DMARD-irresponsive RA. Estimation-based exact logistic regression was used to investigate relation of baseline variables to treatment response. 95% confidence intervals of means were estimated by bias-corrected bootstrapping and the significance between baseline and follow-up values was calculated by permutation test. Results At baseline, levels of phosphorylated STAT6 (pSTAT6) induced by IL-4 in monocytes were higher in those who achieved good treatment response to synthetic DMARDs than in those who did not among patients with untreated RA (OR 2.74, 95% CI 1.05 to 9.47), and IFN-gamma-stimulated lymphocyte pSTAT1 levels were higher in those who achieved good treatment response to a biological drug than in those who did not among patients with chronic RA (OR 3.91, 95% CI 1.12 to 20.68). During follow-up, in recent-onset RA patients with good treatment response to synthetic DMARDS, the lymphocyte pSTAT6 levels decreased (p = 0.011), and, consequently, the ratio of pSTAT1/pSTAT6 in lymphocytes increased (p = 0.042). Conclusion Cytokine-stimulated STAT6 and STAT1 phosphorylation in circulating leukocytes was associated with treatment response to DMARDs in this pilot study. The result, if confirmed in larger studies, may aid in developing personalized medicine in RA.Peer reviewe

Periodontitis in early and chronic rheumatoid arthritis : a prospective follow-up study in Finnish population

Objectives To investigate the association between rheumatoid arthritis (RA) and periodontitis with special emphasis on the role of antirheumatic drugs in periodontal health. Design Prospective follow-up study. Patients with early untreated RA and chronic active RA were examined at baseline and 16months later. Controls were examined once. Settings and participants The study was conducted in Finland from September 2005 to May 2014 at the Helsinki University Hospital. Overall, 124 participants were recruited for dental and medical examinations: 53 were patients with early disease-modifying antirheumatic drug (DMARD) na1ve RA (ERA), 28 were patients with chronic RA (CRA) with insufficient response to conventional DMARDs. After baseline examination, patients with ERA started treatment with synthetic DMARDs and patients with CRA with biological DMARDs. Controls were 43 age-matched, gender-matched and community-matched participants. Outcome measures Degree of periodontitis (defined according to the Center for Disease Control and Prevention and the American Academy of Periodontology). Prevalence of periodontal bacteria (analysed from plaque samples), clinical rheumatological status by Disease Activity Score, 28-joint count (DAS28), function by Health Assessment Questionnaire (HAQ) and treatment response by European League Against Rheumatism (EULAR) criteria. Results Moderate periodontitis was present in 67.3% of patients with ERA, 64.3% of patients with CRA and 39.5% of control participants (p=0.001). Further, patients with RA had significantly more periodontal findings compared with controls, recorded with common periodontal indexes. In the re-examination, patients with RA still showed poor periodontal health in spite of treatment with DMARDs after baseline examination. The prevalence of Porphyromonas gingivalis was higher in patients with ERA with periodontal probing depth 4mm compared with patients with CRA and controls. Antirheumatic medication did not seem to affect the results. Conclusions Moderate periodontitis was more frequent in patients with RA than in controls. Patients with ERA and CRA exhibited poorer periodontal health parameters when compared with controls. There was no association between antirheumatic treatment and periodontal parameters.Peer reviewe

Inflammatory biomarkers in saliva and serum of patients with rheumatoid arthritis with respect to periodontal status

Objective: To study prospectively the association of salivary and serum matrix metalloproteinase (MMP)-8, tissue inhibitor of MMPs (TIMP)-1 and interleukin (IL)-6 with periodontal and systemic inflammation in rheumatoid arthritis (RA). We hypothesized that biomarker concentrations reflect inflammation. Methods: Fifty three early untreated RA (ERA) and 28 chronic RA (CRA) patients, underwent rheumatological and dental examinations at baseline and one year later after starting first conventional or biological disease modifying antirheumatic drug. We included 43 control subjects. Saliva and serum samples were analyzed for MMP-8, TIMP-1 and IL-6. Periodontal health was assessed by bleeding on probing (BOP), pocket depth (PD) and periodontal inflammatory burden index (PIBI); RA disease activity was assessed by disease activity score DAS28. Joint destruction was analyzed by the modified Sharp-van der Heijde (SHS) method. Results: Serum MMP-8 (p <.001; p <.001) and IL-6 (p <.001; p =.002) were significantly higher in CRA vs. other study groups during the study. Salivary MMP-8 (p =.010) and IL-6 (p =.010) were significantly higher in ERA vs. other study groups at baseline. Salivary MMP-8 was associated with periodontal parameters. Conclusion: Elevated serum concentrations of MMP-8 and IL-6 in CRA patients reflected chronic RA, while elevated salivary concentrations of MMP-8 levels in ERA patients reflected increased periodontal inflammation.Peer reviewe

Constitutive STAT3 Phosphorylation in Circulating CD4(+) T Lymphocytes Associates with Disease Activity and Treatment Response in Recent-Onset Rheumatoid Arthritis

The aim of the present study was to examine constitutive signal transducer and activator of transcription 3 (STAT3) phosphorylation in circulating leukocytes as a candidate biomarker in rheumatoid arthritis (RA). 25 patients with recent-onset, untreated RA provided samples for whole blood flow cytometric determination of intracellular STAT3 phosphorylation, expressed as relative fluorescence units. The occurrence of constitutive STAT3 phosphorylation was evaluated by determining proportion of STAT3-phosphorylated cells among different leukocyte subtypes. Plasma levels of interleukin (IL)-6, IL-17 and IL-21 were measured by immunoassay, radiographs of hands and feet were examined and disease activity score (DAS28) was determined. Biomarkers were restudied and treatment response (according to European League Against Rheumatism) was determined after 12 months of treatment with disease-modifying antirheumatic drugs. At baseline, constitutive phosphorylation of STAT3 occurred in CD4(+) T cells of 14 (56%) patients, CD8(+) T cells of 13 (52%) patients, in CD19+ B cells of 7 (28%) patients, and in CD14(+) monocytes of 12 (48%) patients. STAT3 phosphorylation levels of CD4(+) T cells associated with DAS28, and those of all leukocyte subtypes studied associated with erosive disease. The presence of constitutive STAT3 phosphorylation in CD4(+) T lymphocytes, pSTAT3 fluorescence intensity of CD4(+) and CD8(+) T cells and C-reactive protein (CRP) levels at baseline associated with good treatment response. In conclusion, constitutive STAT3 phosphorylation in circulating CD4(+) T cells is common in recent-onset untreated RA and associates with good treatment response in patients characterized by high disease activity and the presence of systemic inflammation.Peer reviewe

High Density Lipoprotein Structural Changes and Drug Response in Lipidomic Profiles following the Long-Term Fenofibrate Therapy in the FIELD Substudy

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Composition and lipid spatial distribution of HDL particles in subjects with low and high HDL-cholesterol

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Baseline JAK phosphorylation profile of peripheral blood leukocytes, studied by whole blood phosphospecific flow cytometry, is associated with 1-year treatment response in early rheumatoid arthritis

Background: We found recently that baseline signal transducer and activator of transcription 3 phosphorylation in peripheral blood CD4(+) T cells of patients with early rheumatoid arthritis (RA) is associated with treatment response to synthetic disease-modifying antirheumatic drugs (DMARDs). This prompted us to study the baseline phosphorylation profiles of Janus kinases (JAKs) in blood leukocytes with respect to treatment response in early RA. Methods: Thirty-five DMARD-naive patients with early RA provided blood samples for whole blood flow cytometric determination of phosphorylation of JAKs in CD4(+) and CD8(+) T cells, CD19(+) B cells, and CD14(+) monocytes. Treatment response was determined after 1 year of treatment with synthetic DMARDs, with remission defined as absence of tender and swollen joints and normal erythrocyte sedimentation rate. Exact logistic regression was used to investigate the association of baseline variables with treatment response. Ninety-five percent CIs of means were estimated by bias-corrected bootstrapping. Results: High JAK3 phosphorylation in CD4(+) and CD8(+) T cells, CD19(+) B cells, and CD14(+) monocytes and low JAK2 phosphorylation in CD14(+) monocytes were significantly associated with remission following treatment with synthetic DMARDs. Conclusions: Baseline JAK phosphorylation profile in peripheral blood leukocytes may provide a means to predict treatment response achieved by synthetic DMARDs among patients with early RA.Peer reviewe