Health-Related Quality of Life, Costs and Treatment of Inflammatory Rheumatic Diseases in Routine Practice : With special emphasis on biological drugs

Rheumatoid arthritis (RA) and other chronic inflammatory joint diseases already begin to affect patients health-related quality of life (HRQoL) in the earliest phases of these diseases. In treatment of inflammatory joint diseases, the last two decades have seen new strategies and treatment options introduced. Treatment is started at an earlier phase; combinations of disease-modifying anti-rheumatic drugs (DMARDs) and corticosteroids are used; and in refractory cases new drugs such as tumour necrosis factor (TNF) inhibitors or other biologicals can be started. In patients with new referrals to the Department of Rheumatology of the Helsinki University Central Hospital, we evaluated the 15D and the Stanford Health Assessment Questionnaire (HAQ) results at baseline and approximately 8 months after their first visit. Altogether the analysis included 295 patients with various rheumatic diseases. The mean baseline 15D score (0.822, SD 0.114) was significantly lower than for the age-matched general population (0.903, SD 0.098). Patients with osteoarthritis (OA) and spondyloarthropathies (SPA) reported the poorest HRQoL. In patients with RA and reactive arthritis (ReA) the HRQoL improved in a statistically significant manner during the 8-month follow-up. In addition, a clinically important change appeared in patients with systemic rheumatic diseases. HAQ score improved significantly in patients with RA, arthralgia and fibromyalgia, and ReA. In a study of 97 RA patients treated either with etanercept or adalimumab, we assessed their HRQoL with the RAND 36-Item Health Survey 1.0 (RAND-36) questionnaire. We also analysed changes in clinical parameters and the HAQ. With etanercept and adalimumab, the values of all domains in the RAND-36 questionnaire increased during the first 3 months. The efficacy of each in improving HRQoL was statistically significant, and the drug effects were comparable. Compared to Finnish age- and sex-matched general population values, the HRQoL of the RA patients was significantly lower at baseline and, despite the improvement, remained lower also at follow-up. Our RA patients had long-standing and severe disease that can explain the low HRQoL also at follow-up. In a pharmacoeconomic study of patients treated with infliximab we evaluated medical and work disability costs for patients with chronic inflammatory joint disease during one year before and one year after institution of infliximab treatment. Clinical and economic data for 96 patients with different arthritis diagnoses showed, in all patients, significantly improved clinical and laboratory variables. However, the medical costs increased significantly during the second period by 12 015 (95% confidence interval, 6 496 to 18 076). Only a minimal decrease in work disability costs occurred mean decrease 130 (-1 268 to 1 072). In a study involving a switch from infliximab to etanercept, we investigated the clinical outcome in 49 patients with RA. Reasons for switching were in 42% failure to respond by American College of Rheumatology (ACR) 50% criteria; in 12% adverse event; and in 46% non-medical reasons although the patients had responded to infliximab. The Disease Activity Score with 28 joints examined (DAS28) allowed us to measure patients disease activity and compare outcome between groups based on the reason for switching. In the patients in whom infliximab was switched to etanercept for nonmedical reasons, etanercept continued to suppress disease activity effectively, and 1-year drug survival for etanercept was 77% (95% CI, 62 to 97). In patients in the infliximab failure and adverse event groups, DAS28 values improved significantly during etanercept therapy. However, the 1-year drug survival of etanercept was only 43% (95% CI, 26 to 70) and 50% (95% CI, 33 to 100), respectively. Although the HRQoL of patients with inflammatory joint diseases is significantly lower than that of the general population, use of early and aggressive treatment strategies including TNF-inhibitors can improve patients HRQoL effectively. Further research is needed in finding new treatment strategies for those patients who fail to respond or lose their response to TNF-inhibitors.

Infections in lung and heart transplant recipients : Studies on the impact of bronchoscopy in the diagnosis of respiratory infections and detection of viral infections in blood and bronchoalveolar lavage fluid

Infection is a major cause of mortality and morbidity after thoracic organ transplantation. The aim of the present study was to evaluate the infectious complications after lung and heart transplantation, with a special emphasis on the usefulness of bronchoscopy and the demonstration of cytomegalovirus (CMV), human herpes virus (HHV)-6, and HHV-7. We reviewed all the consecutive bronchoscopies performed on heart transplant recipients (HTRs) from May 1988 to December 2001 (n = 44) and lung transplant recipients (LTRs) from February 1994 to November 2002 (n = 472). To compare different assays in the detection of CMV, a total of 21 thoracic organ transplant recipients were prospectively monitored by CMV pp65-antigenemia, DNAemia (PCR), and mRNAemia (NASBA) tests. The antigenemia test was the reference assay for therapeutic intervention. In addition to CMV antigenemia, 22 LTRs were monitored for HHV-6 and HHV-7 antigenemia. The diagnostic yield of the clinically indicated bronchoscopies was 41 % in the HTRs and 61 % in the LTRs. The utility of the bronchoscopy was highest from one to six months after transplantation. In contrast, the findings from the surveillance bronchoscopies performed on LTRs led to a change in the previous treatment in only 6 % of the cases. Pneumocystis carinii and CMV were the most commonly detected pathogens. Furthermore, 15 (65 %) of the P. carinii infections in the LTRs were detected during chemoprophylaxis. None of the complications of the bronchoscopies were fatal. Antigenemia, DNAemia, and mRNAemia were present in 98 %, 72 %, and 43 % of the CMV infections, respectively. The optimal DNAemia cut-off levels (sensitivity/specificity) were 400 (75.9/92.7 %), 850 (91.3/91.3 %), and 1250 (100/91.5 %) copies/ml for the antigenemia of 2, 5, and 10 pp65-positive leukocytes/50 000 leukocytes, respectively. The sensitivities of the NASBA were 25.9, 43.5, and 56.3 % in detecting the same cut-off levels. CMV DNAemia was detected in 93 % and mRNAemia in 61 % of the CMV antigenemias requiring antiviral therapy. HHV-6, HHV-7, and CMV antigenemia was detected in 20 (91 %), 11 (50 %), and 12 (55 %) of the 22 LTRs (median 16, 31, and 165 days), respectively. HHV-6 appeared in 15 (79 %), HHV-7 in seven (37 %), and CMV in one (7 %) of these patients during ganciclovir or valganciclovir prophylaxis. One case of pneumonitis and another of encephalitis were associated with HHV-6. In conclusion, bronchoscopy is a safe and useful diagnostic tool in LTRs and HTRs with a suspected respiratory infection, but the role of surveillance bronchoscopy in LTRs remains controversial. The PCR assay acts comparably with the antigenemia test in guiding the pre-emptive therapy against CMV when threshold levels of over 5 pp65-antigen positive leukocytes are used. In contrast, the low sensitivity of NASBA limits its usefulness. HHV-6 and HHV-7 activation is common after lung transplantation despite ganciclovir or valganciclovir prophylaxis, but clinical manifestations are infrequently linked to them.

Tumour necrosis factor receptor-associated periodic syndrome (TRAPS) : Identification of novel TNFRSF1A mutations and intracellular signalling defects

The systemic autoinflammatory disorders are a group of rare diseases characterized by periodically recurring episodes of acute inflammation and a rise in serum acute phase proteins, but with no signs of autoimmunity. At present eight hereditary syndromes are categorized as autoinflammatory, although the definition has also occasionally been extended to other inflammatory disorders, such as Crohn s disease. One of the autoinflammatory disorders is the autosomally dominantly inherited tumour necrosis factor receptor-associated periodic syndrome (TRAPS), which is caused by mutations in the gene encoding the tumour necrosis factor type 1 receptor (TNFRSF1A). In patients of Nordic descent, cases of TRAPS and of three other hereditary fevers, hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), chronic infantile neurologic, cutaneous and articular syndrome (CINCA) and familial cold autoinflammatory syndrome (FCAS), have been reported, TRAPS being the most common of the four. Clinical characteristics of TRAPS are recurrent attacks of high spiking fever, associated with inflammation of serosal membranes and joints, myalgia, migratory rash and conjunctivitis or periorbital cellulitis. Systemic AA amyloidosis may occur as a sequel of the systemic inflammation. The aim of this study was to investigate the genetic background of hereditary periodically occurring fever syndromes in Finnish patients, to explore the reliability of determining serum concentrations of soluble TNFRSF1A and metalloproteinase-induced TNFRSF1A shedding as helpful tools in differential diagnostics, as well as to study intracellular NF-κB signalling in an attempt to widen the knowledge of the pathomechanisms underlying TRAPS. Genomic sequencing revealed two novel TNFRSF1A mutations, F112I and C73R, in two Finnish families. F112I was the first TNFRSF1A mutation to be reported in the third extracellular cysteine-rich domain of the gene and C73R was the third novel mutation to be reported in a Finnish family, with only one other TNFRSF1A mutation having been reported in the Nordic countries. We also presented a differential diagnostic problem in a TRAPS patient, emphasizing for the clinician the importance of differential diagnostic vigiliance in dealing with rare hereditary disorders. The underlying genetic disease of the patient both served as a misleading factor, which possibly postponed arrival at the correct diagnosis, but may also have predisposed to the pathologic condition, which led to a critical state of the patient. Using a method of flow cytometric analysis modified for the use on fresh whole blood, we studied intracellular signalling pathways in three Finnish TRAPS families with the F112I, C73R and the previously reported C88Y mutations. Evaluation of TNF-induced phosphorylation of NF-κB and p38, revealed low phosphorylation profiles in nine out of ten TRAPS patients in comparison to healthy control subjects. This study shows that TRAPS is a diagnostic possibility in patients of Nordic descent, with symptoms of periodically recurring fever and inflammation of the serosa and joints. In particular in the case of a family history of febrile episodes, the possibility of TRAPS should be considered, if an etiology of autoimmune or infectious nature is excluded. The discovery of three different mutations in a population as small as the Finnish, reinforces the notion that the extracellular domain of TNFRSF1A is prone to be mutated at the entire stretch of its cysteine-rich domains and not only at a limited number of sites, suggesting the absence of a founder effect in TRAPS. This study also demonstrates the challenges of clinical work in differentiating the symptoms of rare genetic disorders from those of other pathologic conditions and presents the possibility of an autoinflammatory disorder as being the underlying cause of severe clinical complications. Furthermore, functional studies of fresh blood leukocytes show that TRAPS is often associated with a low NF-κB and p38 phosphorylation profile, although low phosphorylation levels are not a requirement for the development of TRAPS. The aberrant signalling would suggest that the hyperinflammatory phenotype of TRAPS is the result of compensatory NF-κB-mediated regulatory mechanisms triggered by a deficiency of the innate immune response.

Infliximabi-infuusioiden akuuttien haittavaikutusten esto asetyylisalisyylihapolla lapsipotilaiden IBD- ja reumasairauksien hoidossa

IBD- ja reumasairaudet ovat elämänlaatua merkittävästi heikentäviä, kroonisia tulehduksellisia sairauksia, joiden keskivaikeiden ja vakavien muotojen hoidossa suoneen annettava biologinen TNF-alfa -tulehdustekijän vasta-aine infliksimabi (Remicade®) on vankassa asemassa. Infliksimabin hyvän tehon kääntöpuolena esiintyy yleisesti haittoja, joista infuusion aikana tai pian sen jälkeen ilmenevät allergistyyppiset reaktiot ovat hoitoa hankaloittava ja jopa vaarallinen alaluokka. Infuusioreaktioiden estoon ei nykyisellään ole todistettavasti tehokkaita keinoja. Parasetamoli ja setiritsiini osoittautuivat tässä käyttötarkoituksessa tehottomiksi. HUS:n Lasten ja nuorten sairaalassa aloitettiin 11.3.2009 hoitokokeilu asetosalisyylihapolla (ASA, Disperin®), annosteltuna painonmukaisesti per os, päämääränä selvittää prospektiivisesti ASA:n käyttömahdollisuudet infuusioreaktioiden ehkäisyssä. Tämän tutkielman aineisto kerättiin esilääkekokeilun alun ja 24.6.2010 välisellä ajalla (yhteensä 67 viikkoa) infliksimabi-infuusiossa Lasten ja nuorten sairaalan osasto 2:lla käyneiden IBD- ja reumapotilaiden asiakirjoista. Vain 1 (0,2 %) ASA:n kanssa annetuista infuusioista johti infuusioreaktioon kun aiemmin parasetamolin ja setiritsiinin kanssa todettiin 11 (2,9 %) reaktiota. GraphPad Prism 5 -ohjelmistolla tehdyn tilastoanalyysin perusteella tulokset osoittavat ASA:n olevan erittäin lupaava infuusioreaktioiden estolääke.

Simplified Treatment of Childhood Acute Bone and Joint Infections

Acute childhood osteomyelitis (OM), septic arthritis (SA), and their combination osteomyelitis with adjacent septic arthritis (OM+SA), are treated with long courses of antimicrobials and immediate surgery. We conducted a prospective multi-center randomized trial among Finnish children at age 3 months to 15 years in 1983-2005. According to the two-by-two factorial study design, children with OM or OM+SA received 20 or 30 days of antimicrobials, whereas those with SA were treated for 10 or 30 days. In addition, the whole series was randomized to be treated with clindamycin or a first-generation cephalosporin. Cases were included only if the causative agent was isolated. The treatment was instituted intravenously, but only for the first 2-4 days. Percutaneous aspiration was done to obtain a representative sample for bacteriology, but all other surgical intervention was kept at a minimum. A total of 265 patients fulfilled our strict inclusion criteria and were analyzed; 106 children had OM, 134 SA, and 25 OM+SA. In the OM group, one child in the long and one child in the short-term treatment group developed sequelae. One child with SA twice developed a late re-infection of the same joint, but the causative agents differed. Regarding surgery, diagnostic arthrocentesis or corticotomy was the only surgical procedure performed in most cases. Routine arthrotomy was not required even in hip arthritis. Serum C-reactive protein (CRP) proved to be a reliable laboratory index in the diagnosis and monitoring of osteoarticular infections. The recovery rate was similar regardless of whether clindamycin or a first-generation cephalosporin was used. We conclude that a course of 20 days of these well-absorbing antimicrobials is sufficient for OM or OM+SA, and 10 days for SA in most cases beyond the neonatal age. A short intravenous phase of only 2-5 days often suffices. CRP gives valuable information in monitoring the course of illness. Besides diagnostic aspiration, surgery should be reserved for selected cases.

Makrodomeeni-inhibiittorit antiviraalisina yhdisteinä

Alfavirukset ovat positiivissäkeisiä RNA-viruksia, jotka kuuluvat Togaviridea –heimoon. Alfaviruksia levittävät Aedes –suvun hyttyset ja niitä esiintyy Etelämanteretta lukuunottamatta kaikilla mantereilla. Alfaviruksia on tähän mennessä löydetty 29 lajia ja ne voidaan jakaa uuden ja vanhan maailman viruksiin niiden maantieteellisen esiintyvyyden ja taudinaiheuttamiskyvyn mukaan. Chikunkunyavirus (CHIKV) on yksi vanhan maailman alfaviruksista, jota esiintyy muun muassa Afrikassa ja Aasiassa. Ilmaston lämmettyä se on leviämässä myös eteläiseen Eurooppaan. Ihmisessä se aiheuttaa muun muassa kuumetta, päänsärkyä, ihottumaa ja niveltulehdusta, joka voi kestää useita vuosia ja ne voivat olla hyvinkin kivuliaita. Pienillä lapsilla chikungunya on todettu aiheuttavan myös neurologisia oireita kuten aivotulehdusta. Alfaviruksen genomi koodaa neljää rakenneproteiinia ja neljää replikaatioproteiinia. Replikaatioproteiineista nsP3 sisältää makrodomeeniosan. Makrodomeeniproteiinit ovat eliökunnassa konservoituneita, mutta makrodomeeniproteiinien tarkkaa merkitystä ei vielä tunneta. Makrodomeenien on osoitettu sitovan ADP-riboosia ja sen johdannaisia ja alfaviruksen nsP3-proteiinin on osoitettu olevan tärkeä osa viruksen replikaatiossa. Tutkimuksen tavoitteena oli tutkia makrodomeeniproteiiniin sitoutuvien yhdisteiden käyttöä antiviraalisena yhdisteinä. Tietokonemallinnuksella valittiin antiviraalitutkimuksiin 45 yhdistettä, joiden oletettiin sitoutuvan makrodomeeniproteiiniin. Kilpailevassa sitoutumiskokeessa viisi yhdistettä esti yli 50 % poly-ADP-riboosia (PAR) sitoutumasta MDO1-makrodomeeniproteiiniin, jolla tietokonemallinnus oli tehty. SFV-makrodomeeniproteiinilla tehdyssä kokeessa vain yksi yhdiste esti yli 50 % poly-ADP-riboosin sitoutumisen. SFV-antiviraalikokeessa seitsemällä yhdisteellä inhibitioprosentti oli yli 50 %. Näillä yhdisteillä ei kuitenkaan ollut merkittävää vaikutusta poly-ADP-riboosin sitoutumisen estossa. CHIKV-replikonikokeessa yli 50 % inhibitioprosentti oli viidellä yhdisteellä. Muiden mahdollisia vaikutusmekanismeja tutkittiin selvittämällä estävätkö yhdisteet virusta pääsemästä solun sisään. Tässä kokeessa tutkituista yhdisteistä lähes kaikilla oli vaikutusta viruksen soluun pääsyn estossa. Yleisesti ottaen kyky estää PAR:n sitoutuminen makrodomeeniproteiineihin ja antiviraaliset vaikutukset eivät korreloineet keskenään tutkittavilla yhdisteillä. Vaikka antiviraalista vaikutusta omaavat yhdisteet eivät osoittaneetkaan makrodomeeni-inhibiitiota, työssä löydettiin potentiaalisia antiviraalisia yhdisteitä joiden käyttö viruksen soluun pääsyn estäjinä antaa aihetta jatkotutkimuksille.