Rheumatoid Arthritis: Leirisalo-Repo M

Helenius M, Leirisalo-Repo M. · HUS:n kirurgian klinikka, suu- ja leukakirurgian yksikkö. · Duodecim. · Pubmed #16457118 No free full text.

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Leirisalo-Repo M. · Helsinki University Central Hospital, Department of Medicine, Division of Rheumatology, Helsinki, Finland. · Curr Opin Rheumatol. · Pubmed #15956840 No free full text.

Abstract: PURPOSE OF REVIEW: To summarize the recent literature on the association of infection with early arthritis, and to discuss the possible role of such infections with respect to the development of chronic rheumatic complications. RECENT FINDINGS: Viral infections are frequently associated with arthritis. Alphaviruses belong to mosquito-borne viruses, one form of which (Sindbis virus) can in Scandinavia and Karelia cause acute arthritis with typical rash. The role of this infection leading to chronic erosive arthritis needs further prospective studies. Patients infected with HIV can have various forms of arthritis. The role of HIV virus as an arthritogenic agent is still debated. On the basis of population studies, Campylobacter infections seem to be increasing as causative infections in reactive arthritis. There is no role for prolonged antibiotic therapy to shorten the duration of acute reactive arthritis, but the possibility that such a treatment might reduce the development of chronic sequelae needs to be examined in a larger study. The role of preceding infection initiating the process of rheumatoid arthritis is still an option, the association being observed in about 20% of patients studied in the early phase of arthritis. SUMMARY: Viral and microbial infections play a role in acute arthritis. The role of these infections in the development of chronic arthritis needs further prospective controlled studies.

Kuuliala A, Leirisalo-Repo M, Möttönen T, Hannonen P, Nissilä M, Kautiainen H, Korpela M, Julkunen H, Hakola M, Repo H, Anonymous00299. · Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland. · Clin Exp Rheumatol. · Pubmed #15895898 No free full text.

Abstract: OBJECTIVE: To study the value of baseline serum levels of circulating soluble interleukin-2 receptor (sIL-2R) and soluble E-selectin as predictors of early remission in patients with recent-onset rheumatoid arthritis (RA) receiving a single disease-modifying anti-rheumatic drug (DMARD) (SINGLE) or therapy with a combination of DMARDs (COMBI). METHODS: Baseline (n = 157) serum samples originate from the FIN-RACo (FINnish Rheumatoid Arthritis Combination therapy) trial, in which 195 patients with early and clinically active RA were randomly assigned to receive either SINGLE (initially sulfasalazine) with or without prednisolone, or COMBI therapy (sulfasalazine, methotrexate, hydroxychloroquine, and prednisolone). Of the samples, 76 were from SINGLE patients and 81 from COMBI patients. sIL-2R was measured by automated immunoassay analyzer and sE-selectin by enzyme-linked immunosorbent assay. RESULTS: At six months, 7 (9% [95% CI: 4 to 18]) SINGLE and 19 (23% [95% CI: 15 to 34]) COMBI patients were in remission. In multivariate logistic regression analysis, sIL-2R <442 U/ml and COMBI therapy were the only predictors of remission. The area under receiver operating characteristic curve for sIL-2R level was 0.86 (95% CI: 0.62 to 0.95) in SINGLE and 0.57 (95% CI: 0.42 to 0.71) in COMBI (p = 0.006). In SINGLE, the optimal cut offpoint was 442 U/ml, lower levels predicting remission with sensitivity of 83% (95% CI: 73% to 91%) and specificity of 86% (95% CI: 42% to 100%). Likelihood ratio for positive test was 5.9 (95% CI: 1.6 to 32.8). In multivariate logistic regression analysis, sIL-2R <442 U/ml and COMBI therapy were the only predictors of remission. CONCLUSION: Low baseline serum sIL-2R level predicts early remission of patients with active early RA treated with a single DMARD.

Puolakka K, Kautiainen H, Möttönen T, Hannonen P, Korpela M, Hakala M, Järvinen P, Ahonen J, Forsberg S, Leirisalo-Repo M, Anonymous00147. · Department of Medicine, Lappeenranta Central Hospital, Valto Käkelän katu 1, Lappeenranta FIN-53130, Finland. · Arthritis Rheum. · Pubmed #15641055 links to  free full text

Abstract: OBJECTIVE: To explore the impact of an early treatment response on maintenance of work capacity in patients with early, active rheumatoid arthritis (RA). METHODS: In the Finnish Rheumatoid Arthritis Combination Therapy trial, 195 patients with recent-onset RA were randomized to receive either a combination of disease-modifying antirheumatic drugs (DMARDs) with prednisolone or a single DMARD with or without prednisolone for 2 years. Treatment responses were evaluated according to the American College of Rheumatology (ACR) criteria. After a 5-year followup, the cumulative number of days of sick leave and RA-related permanent work disability was calculated for each of the 162 patients who were available for the active work force at baseline. RESULTS: Of the 159 patients assessed at 6 months, 29 were in clinical remission, 66 achieved an ACR50 response but not remission, 29 achieved an ACR20 response but not an ACR50 response, and 35 failed to achieve an ACR20 response. In these 4 groups, the median numbers of work disability days per patient-year from 6 months through 60 months of followup were 0 (interquartile range [IQR] 0-3), 4 (IQR 0-131), 16 (IQR 0-170), and 352 (16-365), respectively (P < 0.001). Pairwise multiple comparisons showed a statistically significant difference between all groups except the ACR50 and ACR20 groups. At 12 months, 30 patients were in remission. None of the 44 patients in remission at 6 or 12 months became permanently work disabled over the 5-year followup, as compared with 15 patients in the ACR50 group (23%), 6 in the ACR20 group (21%), and 19 without an ACR20 response at 6 months (56%). CONCLUSION: Prompt induction of remission translates into maintenance of work capacity. At 6 months, an ACR50 response is no better than an ACR20 response with regard to future productivity, while failure to achieve an ACR20 response carries a high risk for work disability.

Puolakka K, Kautiainen H, Möttönen T, Hannonen P, Hakala M, Korpela M, Ilva K, Yli-Kerttula U, Piirainen H, Leirisalo-Repo M, Anonymous00040. · Department of Medicine, Lappeenranta Central Hospital, Valto Käkelän katu 1, FIN-53130 Lappeenranta, Finland. · Ann Rheum Dis. · Pubmed #15608311 links to  free full text

Abstract: OBJECTIVE: To explore baseline risk factors for productivity loss and work disability over 5 years in patients with early, active RA. PATIENTS AND METHODS: In the FIN-RACo trial, 195 patients with recent onset RA were randomised to receive either a combination of DMARDs with prednisolone or a single DMARD for 2 years. At baseline, 162 patients were working or available for work. After 5 years' follow up, data on sick leave and retirement were obtained from social insurance registers or case records. The cumulative duration of sick leaves and RA related disability pensions was counted for each patient. To analyse predictors of productivity loss, the patients were divided into four groups according to duration of work disability per patient year. RESULTS: Patient's and physician's global assessment of RA severity > or =50 and HAQ score > or =1.0 were risk factors for extension of productivity loss (OR (95% (CI) 1.77 (1.00 to 3.16), 1.85 (1.03 to 3.32), and 1.78 (1.01 to 3.14), respectively). Additional risk factors were low education level (2.40 (1.18 to 4.88)) and older age (1.03 (1.00 to 1.06)); combination treatment was a protective factor (0.59 (0.35 to 0.99)). CONCLUSION: At baseline, the risk of future productivity loss is best predicted by education level, age, global assessments of RA severity, and HAQ score.

Korpela M, Laasonen L, Hannonen P, Kautiainen H, Leirisalo-Repo M, Hakala M, Paimela L, Blåfield H, Puolakka K, Möttönen T, Anonymous00438. · Tampere University Hospital, Tampere, Finland. · Arthritis Rheum. · Pubmed #15248204 links to  free full text

Abstract: OBJECTIVE: To evaluate the long-term frequency of disease remissions and the progression of joint damage in patients with early rheumatoid arthritis (RA) who were initially randomized to 2 years of treatment with either a combination of 3 disease-modifying antirheumatic drugs (DMARDs) or a single DMARD. METHODS: In this multicenter prospective followup study, a cohort of 195 patients with early, clinically active RA was randomly assigned to treatment with a combination of methotrexate, sulfasalazine, hydroxychloroquine, and prednisolone or with a single DMARD (initially, sulfasalazine) with or without prednisolone. After 2 years, the DMARD and prednisolone treatments became unrestricted, but were still targeted toward remission. The long-term effectiveness was assessed by recording the frequency of remissions and the extent of joint damage seen on radiographs of the hands and feet obtained annually up to 5 years. Radiographs were assessed by the Larsen score. RESULTS: A total of 160 patients (78 in the combination group and 82 in the single group) completed the 5-year extension study. At 2 years, 40% of the patients in the combination-DMARD group and 18% in the single-DMARD group had achieved remission (P < 0.009). At 5 years, the corresponding percentages were 28% and 22% (P not significant). The median Larsen radiologic damage scores at baseline, 2 years, and 5 years in the combination-DMARD and single-DMARD groups were 0 and 2 (P = 0.50), 4 and 12 (P = 0.005), and 11 and 24 (P = 0.001), respectively. CONCLUSION: Aggressive initial treatment of early RA with the combination of 3 DMARDs for the first 2 years limits the peripheral joint damage for at least 5 years. Our results confirm the earlier concept that triple therapy with combinations of DMARDs contributes to an improved long-term radiologic outcome in patients with early and clinically active RA.

Kirwan JR, Hällgren R, Mielants H, Wollheim F, Bjorck E, Persson T, Book C, Bowman S, Byron M, Cox N, Field M, Kanerud L, Leirisalo-Repo M, Malaise M, Mohammad A, Palmer R, Petersson IF, Ringertz B, Sheldon P, Simonsson M, Snowden N, Van den Bosch F. · Academic Rheumatology Unit, University Division of Medicine, Bristol Royal Infirmary, Bristol BS2 8HW, UK. · Ann Rheum Dis. · Pubmed #15140776 links to  free full text

Abstract: OBJECTIVES: To compare budesonide, a locally acting glucocorticoid with minimal systemic exposure, with conventional glucocorticoid treatment and placebo in rheumatoid arthritis. METHODS: A double blind, randomised, controlled trial over 12 weeks in 143 patients with active rheumatoid arthritis, comparing budesonide 3 mg daily, budesonide 9 mg daily, prednisolone 7.5 mg daily, and placebo. Particular attention was paid to the pattern of clinical response and to changes in the four week period following discontinuation of treatment. RESULTS: There were improvements in tender joint count and swollen joint count on budesonide 9 mg compared with placebo (28% for tender and 34% for swollen joint counts, p<0.05). Prednisolone 7.5 mg gave similar results, while budesonide 3 mg was less effective. ACR20 response criteria were met by 25% of patients on placebo, 22% on budesonide 3 mg, 42% on budesonide 9 mg, and 56% on prednisolone 7.5 mg. A rapid and significant reduction in symptoms and signs in response to budesonide 9 mg and prednisolone 7.5 mg was evident by two weeks and maximal at eight weeks. There was no evidence that budesonide provided a different pattern of symptom control from prednisolone, or that symptoms became worse than placebo treatment levels after discontinuation of glucocorticoid treatment. Adverse effects attributable to glucocorticoids were equally common in all groups. CONCLUSIONS: The symptomatic benefits of budesonide 9 mg and prednisolone 7.5 mg are achieved within a short time of initiating treatment, are maintained for three months, and are not associated with any rebound in symptoms after stopping treatment.

Puolakka K, Kautiainen H, Möttönen T, Hannonen P, Korpela M, Julkunen H, Luukkainen R, Vuori K, Paimela L, Blåfield H, Hakala M, Leirisalo-Repo M. · Lappeenranta Central Hospital, Lappeenranta, Finland. · Arthritis Rheum. · Pubmed #14730599 links to  free full text

Abstract: OBJECTIVE: To compare the efficacy of therapy with a combination of disease-modifying antirheumatic drugs (DMARDs) versus therapy with a single DMARD in the prevention of work disability in patients with early rheumatoid arthritis (RA). METHODS: In the Finnish Rheumatoid Arthritis Combination Therapy trial, 195 patients with recent-onset RA were randomly assigned to receive either combination therapy with DMARDs (sulfasalazine, methotrexate, hydroxychloroquine) plus prednisolone or single therapy with a DMARD with or without prednisolone. After 2 years, the drug treatment strategy was no longer restricted. At baseline, 162 patients (80 in the combination-treatment group and 82 in the single-treatment group) were still working or at least available for work. After 5 years of followup, data on all sick leave and retirement were obtained from social insurance registers or case records. The main outcome for each patient was the cumulative duration of all sick leaves and RA-related disability pensions, divided by the observation period during which the patient was not retired because of another disease or because of age. RESULTS: The cumulative duration of work disability per patient-observation year was significantly lower in those randomized to combination therapy than in those randomized to single therapy: median 12.4 days (interquartile range [IQR] 0-54) versus 32.2 days (IQR 6-293) (P = 0.008, sex- and age-adjusted P = 0.009). This was mainly due to the difference in sick leaves (i.e., work disability periods </=300 days): median 11.7 days (IQR 0-44) per patient-observation year in those treated with combination therapy and 30.0 days (IQR 6-68) in those treated with single therapy (P = 0.002). No statistically significant difference was seen in RA-related disability pensions. CONCLUSION: Aggressive initial treatment of RA with a combination of DMARDs improves 5-year outcome in terms of lost productivity in patients with RA of recent onset.

Laasila K, Laasonen L, Leirisalo-Repo M. · Division of Rheumatology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland. · Ann Rheum Dis. · Pubmed #12810429 links to  free full text

Abstract: OBJECTIVE: To evaluate whether a three month course of lymecycline has an effect on the long term prognosis of reactive arthritis (ReA). METHODS: In 1987-88 a double-blind controlled study with three month course of lymecycline/placebo was conducted. 17 of 23 patients treated at the outpatient department of Helsinki University Central Hospital volunteered to take part in a follow up study, where a physical examination were performed, and erythrocyte sedimentation rate, C reactive protein, rheumatoid factor, and radiographs of the lumbosacral spine and sacroiliac joints and of symptomatic peripheral joints were examined. RESULTS: 16/17 (94%) patients reported some kind of back pain and 10/17 (59%) peripheral joint symptoms during the follow up. Two patients had unilateral grade 1 sacroiliitis, one patient grade 4 sacroiliitis, and one patient bilateral grade 2 sacroiliitis. In one patient the disease had progressed to ankylosing spondylitis (AS), and in another to chronic spondyloarthropathy. In addition, two patients had small erosions in radiocarpal joints. No statistically significant differences were found between placebo and lymecycline groups in the development of chronic arthritis, sacroiliitis, or AS. CONCLUSION: The results of the initial study showed that long term treatment with lymecycline in patients with acute ReA decreased the duration of arthritis in those with Chlamydia trachomatis triggered ReA, but not in other patients with ReA. Ten years after the acute arthritis one patient had developed AS, and three had radiological sacroiliitis, three patients had radiological changes at peripheral joints. Long term lymecycline treatment did not change the natural history of the disease.

Kvien TK, Zeidler HK, Hannonen P, Wollheim FA, Førre O, Hafström I, Kaltwasser JP, Leirisalo-Repo M, Manger B, Laasonen L, Prestele H, Kurki P. · Oslo City Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway. · Ann Rheum Dis. · Pubmed #12006323 links to  free full text

Abstract: OBJECTIVE: To compare the three year safety and efficacy of cyclosporin and parenteral gold in the treatment of early, active, severe rheumatoid arthritis (RA), and to study the reversibility of cyclosporin associated renal dysfunction in patients who discontinued cyclosporin treatment. METHODS: The patients continued to receive cyclosporin or parenteral gold in an 18 month open extension to an 18 month randomised, parallel group study. The main efficacy variable was blinded evaluation of radiographic progression of joint damage. Safety variables included serum creatinine, calculated creatinine clearance, and blood pressure. RESULTS: Radiographic progression during follow up was similar in both groups. About 60% of the patients in the intention to treat groups (n=272) and about half of the patients in the completer groups (n=114) had definite radiographic progression in joint damage (increases >6 in the Larsen-Dale score), and about one in three also had substantial progression (>18 increase in Larsen-Dale score). Both systolic and diastolic blood pressure were significantly increased in the cyclosporin group compared with the gold group, and 12/139 (9%) versus 3/139 (2%) (p=0.03) had notably raised blood pressure. The mean serum creatinine increased by 28% at the treatment end point in the cyclosporin group as compared with 7% in the gold group. The mean calculated creatinine clearance was reduced by 16% and increased by 1% in the cyclosporin and gold groups, respectively, at the end of the study. At the final follow up visit after discontinuation of cyclosporin (at least three months after treatment was stopped) the mean serum creatinine was increased by 15% and creatinine clearance reduced by 16%. Sustained increases in serum creatinine at this post-treatment end point were mostly seen in patients with a raised serum creatinine during treatment of at least 50%. CONCLUSION: Three year changes in radiographic damage during cyclosporin and parenteral gold were similar in patients with early, active RA. Abnormal renal function and raised blood pressure were often seen in the cyclosporin treated patients.

Möttönen T, Hannonen P, Korpela M, Nissilä M, Kautiainen H, Ilonen J, Laasonen L, Kaipiainen-Seppänen O, Franzen P, Helve T, Koski J, Gripenberg-Gahmberg M, Myllykangas-Luosujärvi R, Leirisalo-Repo M, Anonymous00036. · Department of Medicine, Turku University Central Hospital, Turku, Finland. · Arthritis Rheum. · Pubmed #11953964 No free full text.

Abstract: OBJECTIVE: To study the impacts of 1) the delay from the onset of symptoms to the institution of disease-modifying antirheumatic drug (DMARD) therapy, 2) two treatment strategies (treatment with a combination of DMARDs or with a single drug), and 3) the presence of HLA-DRB1 alleles (shared epitope) on the prediction of disease remission after 2 years in patients with early rheumatoid arthritis (RA). METHODS: In the FIN-RACo (FINnish Rheumatoid Arthritis Combination therapy) trial, 195 patients with recent-onset RA (median duration 6 months) were randomly assigned to receive either 1) a combination of DMARDs (sulfasalazine, methotrexate, hydroxychloroquine, and prednisolone) or 2) a single DMARD with or without prednisolone. The presence of a shared epitope was tested for in 165 of the 178 patients completing the study. The additional variables of age, sex, presence of rheumatoid factor, number of fulfilled American College of Rheumatology criteria for the classification of RA, and length of delay from onset of symptoms to institution of therapy were entered into a logistic regression model to determine the significant predictors for remission at 2 years. RESULTS: The delay to therapy (cut point of 4 months) was the only significant predictor for remission in patients treated using the single-DMARD strategy, while no variable was a significant predictor for remission in those treated using the combination-DMARD strategy. The frequency of achieving remission in the combination-DMARD group after 2 years was similar in patients with short (0-4 months) and long (>4 months) delay periods (11 of 26 patients and 22 of 53 patients, respectively [approximately 42% in each group]), while the corresponding frequencies in the single-DMARD group were 8 of 23 patients (35%) and 7 of 63 patients (11%) (P = 0.021). The presence of a shared epitope was not related to the induction of remission. CONCLUSION: The delay of a few months from the onset of symptoms to institution of therapy decreases the ability of the traditional single-drug strategy to induce remission in early RA.

Neva MH, Kauppi MJ, Kautiainen H, Luukkainen R, Hannonen P, Leirisalo-Repo M, Nissilä M, Möttönen T, Anonymous00034. · Jyväskylä Central Hospital, Finland. · Arthritis Rheum. · Pubmed #11083260 links to  free full text

Abstract: OBJECTIVE: To compare the efficacy of combination therapy with disease-modifying antirheumatic drugs (DMARDs) versus single therapy with DMARDs in the prevention of early cervical spine changes in patients with rheumatoid arthritis (RA). METHODS: One hundred ninety-five patients with recent-onset RA (mean disease duration 8 months) were randomly assigned to receive a combination of DMARDs (sulfasalazine, methotrexate, hydroxychloroquine, and prednisolone) or a single DMARD with or without prednisolone. After 2 years of followup, cervical spine radiographs were taken of 176 of these patients (85 in the combination-therapy group and 91 in the single-therapy group). These radiographs were evaluated, and the findings were correlated with the therapy strategies as well as with peripheral joint destruction and clinical and laboratory variables describing the disease activity. RESULTS: Anterior atlantoaxial subluxation (aAAS), atlantoaxial impaction (AAI; i.e., vertical subluxation), and subaxial subluxation (SAS) were found in only 6 (3.4%), 2 (1.1%), and 5 (2.8%) of the patients, respectively. Interestingly, none of the patients in the combination-therapy group had aAAS or AAI. The incidences of aAAS and AAI in the single-therapy group were 6.6% and 2.2%, respectively. SAS was present in 2 patients (2.2%) in the single-therapy group and in 3 patients (3.5%) in the combination-therapy group. The difference in the incidence of aAAS between the treatment groups was statistically significant (P = 0.029). None of the patients with cervical spine changes achieved remission of RA during the study. CONCLUSION: In the present study, the incidence of cervical spine subluxations in patients treated with single-drug therapy was in accord with findings of previous studies. However, none of the patients in the combination-therapy group had aAAS or AAI. These findings suggest that early, aggressive combination-DMARD therapy with sulfasalazine, methotrexate, hydroxychloroquine, and prednisolone can prevent or retard the development of rheumatoid atlantoaxial disorders.

Leirisalo-Repo M, Hernandez-Munoz HE, Rook GA. · Department of Medicine, Helsinki University Central Hospital, Hyks, Finland. · Rheumatol Int. · Pubmed #10399791 No free full text.

Abstract: Patients with rheumatoid arthritis or with Crohn's disease have deficient galactosylation of serum IgG [Gal(0)]. To study whether such deviation occurs in patients with spondyloarthropathy (SPA), we studied the percentage incidence of Gal(0) corrected for age [Gal(0)corr] in 47 SPA patients undergoing ileocolonoscopy and correlated the findings with clinical variables and prognosis of the patients. Gal(0)corr was elevated in 36% of the patients. Such patients had a higher number of inflamed joints (P < 0.02), higher ESR (P < 0.001) and CRP (P < 0.001). Elevated Gal(0)corr was also of prognostic significance: at 6-month follow-up those with elevated levels had a higher number of inflamed joints (P < 0.02) and ESR (P < 0.05). The presence of high Gal(0)corr did not associate with gut inflammation. In conclusion, a proportion of SPA patients has elevated levels of Gal(0), the amount of which correlates with severity of the disease and is a prognostic marker for chronicity of the disease.

Dougados M, Combe B, Cantagrel A, Goupille P, Olive P, Schattenkirchner M, Meusser S, Paimela L, Rau R, Zeidler H, Leirisalo-Repo M, Peldan K. · Institut de Rhumatologie, Hardy B, Hôpital Cochin, Paris, France. · Ann Rheum Dis. · Pubmed #10364900 links to  free full text

Abstract: OBJECTIVES: To investigate the potential clinical benefit of a combination therapy. METHODS: 205 patients fulfilling the ACR criteria for rheumatoid arthritis (RA), not treated with disease modifying antirheumatoid drugs previously, with an early (< or = 1 year duration), active (Disease Activity Score (DAS) > 3.0), rheumatoid factor and/or HLA DR 1/4 positive disease were randomised between sulphasalazine (SASP) 2000 (maximum 3000) mg daily (n = 68), or methotrexate (MTX) 7.5 (maximum 15) mg weekly (n = 69) or the combination (SASP + MTX) of both (n = 68). RESULTS: The mean changes in the DAS during the one year follow up of the study was -1.15, -0.87, -1.26 in the SASP, MTX, and SASP + MTX group respectively (p = 0.019). However, there was no statistically significant difference in terms of either EULAR good responders 34%, 38%, 38% or ACR criteria responders 59%, 59%, 65% in the SASP, MTX, and SASP + MTX group respectively. Radiological progression evaluated by the modified Sharp score was very modest in the three groups: mean changes in erosion score: +2.4, +2.4, +1.9, in narrowing score: +2.3, +2.1, +1.6 and in total damage score: +4.6, +4.5, +3.5, in the SASP, MTX, and SASP + MTX groups respectively. Adverse events occurred more frequently in the SASP + MTX group 91% versus 75% in the SASP and MTX group (p = 0.025). Nausea was the most frequent side effect: 32%, 23%, 49% in the SASP, MTX, and SASP + MTX groups respectively (p = 0.007). CONCLUSION: This study suggests that an early initiation therapy of disease modifying drug seems to be of benefit. However, this study was unable to demonstrate a clinically relevant superiority of the combination therapy although several outcomes were in favour of this observation. The tolerability of the three treatment modalities seems acceptable.

Möttönen T, Hannonen P, Leirisalo-Repo M, Nissilä M, Kautiainen H, Korpela M, Laasonen L, Julkunen H, Luukkainen R, Vuori K, Paimela L, Blåfield H, Hakala M, Ilva K, Yli-Kerttula U, Puolakka K, Järvinen P, Hakola M, Piirainen H, Ahonen J, Pälvimäki I, Forsberg S, Koota K, Friman C. · Division of Rheumatology, Turku University Central Hospital, Finland. · Lancet. · Pubmed #10334255 No free full text.

Abstract: BACKGROUND: The treatment of rheumatoid arthritis should aim at clinical remission. This multicentre, randomised trial with 2-year follow-up sought evidence on the efficacy and tolerability of combination therapy (sulphasalazine, methotrexate, hydroxychloroquine, and prednisolone) compared with treatment with a single disease-modifying antirheumatic drug, with or without prednisolone, in the treatment of early rheumatoid arthritis. METHODS: 199 patients were randomly assigned to two treatment groups. 195 started the treatment (97 received combination and 98 single drug therapy). Single-drug therapy in all patients started with sulphasalazine; in 51 patients methotrexate was later substituted. Oral prednisolone was required by 63 patients. The primary outcome measure was induction of remission. Analyses were intention to treat. FINDINGS: 87 patients in the combination group and 91 in the single-therapy group completed the trial. After a year, remission was achieved in 24 of 97 patients with combination therapy, and 11 of 98 with single-drug therapy (p=0.011). The remission frequencies at 2 years were 36 of 97 and 18 of 98 (p=0.003). Clinical improvement (American College of Rheumatology criteria of 50% clinical response) was achieved after 1 year in 68 (75%) patients with combination therapy, and in 56 (60%) using single-drug therapy (p=0.028), while at the 2-year visit 69 and 57 respectively (71% vs 58%, p=0.058) had clinically improved. The frequencies of adverse events were similar in both treatment groups. INTERPRETATION: Combination therapy was better and not more hazardous than single treatment in induction of remission in early rheumatoid arthritis. The combination strategy as an initial therapy seems to increase the efficacy of the treatment in at least a proportion of patients with early rheumatoid arthritis.

Anderson IF, Helve T, Hannonen P, Leirisalo-Repo M, Gilboe IM, Nissilä M, Keystone EC, Kraag GR, Bjørneboe O, Chalmers A, Dovland H, Mueller E, Richard F, Whatmough I, Schmidt AG, Kovarik JM. · Pretoria Rheumatology Institute, Pretoria Academic Hospital, South Africa. · J Rheumatol. · Pubmed #10090162 No free full text.

Abstract: OBJECTIVE: To assess whether patients with rheumatoid arthritis (RA) may be converted, on a milligram-to-milligram basis, from conventional cyclosporin A (CyA, Sandimmun) to the microemulsion formulation (Neoral) with maintenance of longterm safety, and to compare cyclosporin A (CyA) pharmacokinetics between formulations. METHODS: In this double blind, multicenter, parallel group study, 51 patients receiving stable conventional CyA maintenance treatment were randomized to continue conventional CyA (n = 27) or to convert to CyA microemulsion (n = 24) and were monitored for 52 weeks. Trough blood CyA levels were measured before and at intervals after conversion. CyA steady-state area under the curve was assessed one week before and 2 and 6 weeks after randomization in 15 patients in each treatment arm. CyA trough levels and pharmacokinetic results remained unknown to investigators throughout the study. CyA doses were titrated as necessary on the basis of clinical evaluation and disease activity assessments. RESULTS: Initial mean daily doses were 3.5 mg/kg/day (conventional CyA) and 3.3 mg/kg/day (CyA microemulsion) and did not change significantly during the study. The mean bioavailability of CyA from the microemulsion formulation was 23% higher than from conventional CyA. Replicate assessments indicated a more reproducible pharmacokinetic profile with CyA microemulsion. The overall incidence and nature of adverse events and changes in vital signs and laboratory variables were similar in both groups. No clinically relevant differences in efficacy were found between treatments. No loss of efficacy and no tolerability problems occurred after conversion from conventional to microemulsion CyA. CONCLUSION: Existing CyA dosing guidelines, formulated for conventional CyA, are suitable for longterm CyA microemulsion therapy of patients with RA. These results indicate the pharmacokinetic advantages of the microemulsion formulation.

Puolakka K, Kautiainen H, Möttönen T, Hannonen P, Korpela M, Hakala M, Viikari-Juntura E, Solovieva S, Arkela-Kautiainen M, Leirisalo-Repo M. · Department of Medicine, Lappeenranta Central Hospital, Lappeenranta, Finland. · Clin Exp Rheumatol. · Pubmed #19604434 No free full text.

Abstract: OBJECTIVE:To explore the combination of data on functioning and work load for early identification of patients at risk for diminished work productivity in rheumatoid arthritis (RA).PATIENTS AND METHODS:In the FIN-RACo trial, 162 patients with recent onset RA and available for the workforce were treated with either a combination of disease-modifying antirheumatic drugs (DMARDs) or a single DMARD for 2 years. Otherwise, they received routine care and were followed up for 5 years. Data on their individual income and lost work days came from official registers. Loss of productivity was computed by the human capital approach. Self-reported data on physical work demand (Finnish Institute for Occupational Health Questionnaire) at baseline and on functioning (HAQ) at 6 months were linked according to the International Classification of Functioning, Disability and Health. RESULTS:Data on 112 patients were analyzable at 6 months; 35 (31%) of them had diminished capacity in functions required at paid work. Any mismatch between perceived abilities and requirements predicted future (7 through 60 months) loss of productivity - on average Euro 14,040 (95% confidence interval (CI): 9,143-20,511) per year in patients with the mismatch compared to Euro 3,043 (1,623-5,534) in those without any mismatch - and was associated with RA-related permanent work disability (hazard ratio: 11.6; 95%CI: 4.0-33.4).CONCLUSION:Linking together self-reported data about functioning and work load helps in early identification of the RA patients at risk for loss of working days.

Laas K, Peltomaa R, Puolakka K, Kautiainen H, Leirisalo-Repo M. · Division of Rheumatology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland. · Clin Exp Rheumatol. · Pubmed #19473574 No free full text.

Abstract: OBJECTIVES: To assess health-related quality of life (HRQoL) in patients with rheumatoid arthritis (RA) treated with etanercept or adalimumab in routine clinical practice. METHODS: Patients with RA who started etanercept or adalimumab at Helsinki University Central Hospital or Lappeenranta Central Hospital during 2003-2006 were asked to participate in the study. In 97 patients, HRQoL was measured by the RAND 36-Item Health Survey 1.0 (RAND-36) at baseline and after three months of the treatment. HRQoL of the RA patients was compared to the Finnish age- and sex-matched general population values. In addition, changes in clinical parameters and disability index measured by the health assessment questionnaire (HAQ) were recorded. RESULTS: Treatment with etanercept and adalimumab increased the values in all domains of the RAND-36 during the first three months in routine practice. The improvement in both groups was statistically significant: with etanercept p=0.041 and with adalimumab p=0.019. The efficacy of etanercept and adalimumab in improving HRQoL during the first three months was comparable. The patients reported their best improvement in the subscales of bodily pain, role functioning/physical, energy, social functioning, and role functioning/emotional. Compared to the Finnish age- and sex-matched general population values, the HRQoL of the patients with RA was significantly lower at baseline and remained low at follow-up. The change in clinical parameters and the HAQ paralleled the improvement in HRQoL. CONCLUSION: Treatment of patients with RA with etanercept and adalimumab in routine clinical practice provides clinically important and statistically significant improvement in HRQoL already in the first three months.

Rantalaiho V, Korpela M, Hannonen P, Kautiainen H, Järvenpää S, Leirisalo-Repo M, Hakala M, Puolakka K, Julkunen H, Luosujärvi R, Möttönen T, Anonymous00066. · Department of Internal Medicine, Centre for Rheumatic Diseases, Tampere University Hospital, Tampere, Finland. · Arthritis Rheum. · Pubmed #19404945 No free full text.

Abstract: OBJECTIVE: To evaluate the evolution of functional and clinical outcomes over 11 years in patients with early rheumatoid arthritis (RA) initially treated with a combination of 3 disease-modifying antirheumatic drugs (DMARDs) or with a single DMARD. METHODS: A cohort of 199 patients with early active RA were initially randomized to receive treatment with a combination of methotrexate, sulfasalazine, and hydroxychloroquine with prednisolone or treatment with a single DMARD (initially, sulfasalazine) with or without prednisolone. After 2 years, the drug treatment strategy became unrestricted, but still targeted remission. At 11 years, function was assessed with the Health Assessment Questionnaire (HAQ), and clinical outcomes were assessed with the modified Minimal Disease Activity (MDA) measure and the American College of Rheumatology (ACR) criteria for remission. RESULTS: At 11 years, 138 patients were assessed (68 in the combination-DMARD group and 70 in the single-DMARD group). The mean+/-SD HAQ scores were 0.34+/-0.54 in the combination-DMARD group and 0.38+/-0.58 in the single-DMARD group (P=0.88). Modified MDA was achieved by 63% (95% confidence interval [95% CI] 51, 77) and by 43% (95% CI 32, 55) (P=0.016) of the combination-DMARD group and the single-DMARD group, respectively, and ACR remission by 37% (95% CI 26, 49) and by 19% (95% CI 11, 29) (P=0.017), respectively. CONCLUSION: Initial therapy with a combination of DMARDs in early RA results in higher rates of patients achieving modified MDA and strict ACR remission even over the long term than initial single-DMARD therapy. Targeting remission with tight clinical controls results in good functional and clinical outcomes in most RA patients.

Puolakka K, Kautiainen H, Mottonen T, Hannonen P, Korpela M, Hakala M, Luukkainen R, Vuori K, Blåfield H, Leirisalo-Repo M. · Lappeenranta Central Hospital, Lappeenranta, Finland. · Scand J Rheumatol. · Pubmed #19274516 No free full text.

Abstract: OBJECTIVE: To evaluate the utility of the Stanford Health Assessment Questionnaire (HAQ) in the estimation of loss of productivity due to early rheumatoid arthritis (RA) and to develop a simple model for analysis of the cost-benefit of therapies. METHODS: In the Finnish Rheumatoid Arthritis Combination Therapy (FIN-RACo) trial, 162 patients with recent-onset RA who were available for the workforce were randomized to receive either a combination of three disease-modifying anti-rheumatic drugs (DMARDs) or a single DMARD for 2 years and were followed up for 5 years. No biological drugs were used. Data on sick leave and RA-related disability pensions came from official register records. Loss of productivity was computed by both the human capital approach (HCA) and the friction cost approach (FCA). Functional capacity was assessed by the HAQ at baseline and at 6 months. RESULTS: Over 5 years, mean loss of productivity per year was EUR 8344 by the HCA and EUR 1928 by the FCA. The level of the HAQ index at 6 months, but not the change in HAQ from baseline, determined productivity costs. With the HCA, a monotonous association between annual loss of productivity and the 6-month HAQ was found: EUR 2087 [95% confidence interval (CI) 1340-2903] per one step (0.13) on the HAQ scale from 0 to 1.88. With the FCA, the increase in loss of productivity was cut at the HAQ level of 0.5 to 0.75 (EUR 17 740 in 5 years). CONCLUSION: The HAQ index at 6 months may serve as a determinant of long-term RA-related indirect costs in economic analyses in early RA.

Kauppi MJ, Neva MH, Laiho K, Kautiainen H, Luukkainen R, Karjalainen A, Hannonen PJ, Leirisalo-Repo M, Korpela M, Ilva K, Möttönen T, Anonymous00063. · Rheumatism Foundation Hospital, 18120 Heinola, Finland. · J Rheumatol. · Pubmed #19132793 No free full text.

Abstract: OBJECTIVE: To evaluate the 5-year incidence of cervical spine disorders in patients with early rheumatoid arthritis (RA) treated by 2 different disease modifying antirheumatic drug (DMARD) strategies. METHODS: In a national, multicenter, prospective FIN-RACo-trial, a cohort of 199 patients with early, clinically active RA was randomly assigned to treatment with a combination of 3 DMARD and prednisolone (Combi group) or with a single DMARD (Single group) with or without prednisolone, aiming to induce remission. After 2 years, the DMARD therapy was unrestricted. Lateral view cervical spine radiographs during full flexion and extension were taken at the 5-year followup visits. The presence of anterior atlantoaxial subluxation (aAAS), atlantoaxial impaction (AAI), and subaxial subluxation (SAS) was assessed in the 149 patients with radiographs available (80 Single and 69 Combi). RESULTS: At the 5-year visits, aAAS, AAI, and SAS were found in 13 (9%), 6 (4%), and 9 (6%) patients, respectively. The corresponding Single/Combi group ratios were 11/2, 5/1, and 5/4. Of the baseline data, only poor physical function [Health Assessment Questionnaire (HAQ); p = 0.024] and Single treatment strategy (p = 0.019) were significantly associated with aAAS. Worse HAQ scores and Disease Activity Score 28 values were found in patients who developed aAAS during the 5-year followup. CONCLUSION: RA patients with sustained clinical disease activity and poor HAQ are at increased risk of developing aAAS. The development of aAAS during the first 5 years of RA was rare among the patients treated with a combination of DMARD for at least 2 years from the diagnosis. Intensive treatment with traditional DMARD prevents or retards the development of aAAS in patients with recent-onset RA.

Koivuniemi R, Paimela L, Suomalainen R, Tornroth T, Leirisalo-Repo M. · Division of Rheumatology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland. · Amyloid. · Pubmed #19065298 No free full text.

Abstract: Prevalence of AA amyloid in rheumatoid arthritis (RA) is still unclear. The objective of this retrospective study was whether dedicated re-examination of autopsy tissues from RA patients increases the detection rate of amyloid compared to routine examination. Amyloid was re-examined in tissue samples and detection rate compared with original reports of 369 consecutively autopsied RA patients and 370 non-RA patients matched for sex, age, and year of autopsy between 1952 and 1991. Re-examination of 90% of the 739 cases showed doubling of the prevalence of amyloid compared with the original reports: from 18 to 30% in RA and from 2 to 4% in non-RA patients. In RA patients, cardiac amyloid was as frequent as renal amyloid. In RA patients with amyloid at re-examination, amyloidosis had been diagnosed before autopsy in 37%, and these patients had more inflammation and longer disease duration than RA patients without amyloid. Only 56% of RA patients with renal amyloid were known to have proteinuria. In conclusion, this autopsy study shows that amyloid in RA is a common finding which remains frequently undetected. In patients with active and long-lasting RA, a systematic search for amyloid may enable early diagnosis of amyloidosis, which will require effective suppression of inflammation.

Koivuniemi R, Paimela L, Suomalainen R, Piirainen H, Karesoja M, Helve T, Leirisalo-Repo M. · Division of Rheumatology, Department of Medicine, Helsinki University Central Hospital, PO BOX 263, 00029 HUS, Helsinki, Finland. · Rheumatol Int. · Pubmed #18716780 No free full text.

Abstract: We studied causes of death (CoDs) between 1952 and 1991 assessed by a clinician before autopsy and then determined at autopsy by a pathologist in 369 subjects with rheumatoid arthritis (RA) and 370 subjects without RA (non-RA). We analysed clinical data for RA subjects between 1973 and 1991. In RA subjects, leading autopsy-based CoDs were RA, cardiovascular diseases and infections. Between diagnoses of CoDs by the clinician and those determined by the pathologist, RA subjects had lower agreement than did the non-RA regarding coronary deaths (Kappa reliability measure: 0.33 vs. 0.46). In non-RA subjects, autopsy-based coronary deaths showed a decline since the 1970s with no such decline in RA. Between subjects treated at any time during RA with disease-modifying anti-rheumatic drugs and those without, autopsy-based CoDs were similar. Coronary death being less accurately diagnosed in RA subjects may indicate that coronary heart disease in RA patients often remains unrecognized.

Laas K, Roine R, Räsänen P, Sintonen H, Leirisalo-Repo M, Anonymous00012. · Division of Rheumatology, Department of Medicine, Helsinki University Central Hospital, Kasarmikatu 11-13, HUS, P. O. Box 263, 00029, Helsinki, Finland. · Rheumatol Int. · Pubmed #18682951 No free full text.

Abstract: The aim of the present study was to assess the health-related quality of life (HRQoL) in patients with common rheumatic diseases referred to a rheumatology clinic and to compare it to the HRQoL of the general population. All patients with a new referral to the Department of Rheumatology of the Helsinki University Central Hospital were asked to participate in the study during the period from May 2002 to April 2003. A total of 295 patients with various rheumatic diseases were included in the analysis: 99 patients with rheumatoid arthritis (RA), 47 with arthralgia and fibromyalgia, 43 with other chronic arthritis (spondyloarthritis, psoriatic arthritis, enteropathic arthritis), 44 with osteoarthritis (OA), 22 with active reactive arthritis (ReA), 17 with systemic rheumatic diseases, 9 adults with juvenile idiopathic arthritis (JIA) and 14 with other diagnoses. HRQoL was measured by a disease specific instrument, the Stanford health assessment questionnaire (HAQ) and by a generic instrument, 15D. The mean baseline 15D score of the 295 included patients (0.822, SD 0.114) was significantly lower than of the general population (0.903, SD 0.098). Patients with OA and chronic arthritis reported the poorest HRQoL scores (both 0.810 on a 0-1 scale). In patients with RA and ReA the 15D score improved in a statistically significant and clinically important manner during the 8-month follow-up. Discomfort and symptoms caused by the disease were alleviated in a statistically significant manner in patients with RA as well as in those with arthralgia and fibromyalgia, chronic arthritis, ReA and systemic rheumatic diseases. HAQ score improved significantly in patients with RA, arthralgia and fibromyalgia, and ReA. The HRQoL of patients with common rheumatic diseases at referral to rheumatology clinic is significantly lower than the HRQoL of age-standardized general population. The most affected patients are those with OA, chronic arthritis and RA. A significant improvement in HRQoL with conventional interventions was achieved in patients with RA and ReA.

Koivuniemi R, Paimela L, Suomalainen R, Leirisalo-Repo M. · Division of Rheumatology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland. · Clin Exp Rheumatol. · Pubmed #18578961 No free full text.

Abstract: OBJECTIVE: To study amyloidosis as a cause of death along with associated factors and frequency of pre-mortem diagnosis in patients with rheumatoid arthritis (RA) autopsied between 1952 and 1991. METHODS: We studied causes of death in 369 consecutively autopsied RA and 370 autopsied non-RA patients of the same sex, age at death, and year of autopsy. In those RA patients who died from 1973 onwards, we were also able to analyse clinical data: pre-mortem diagnosis of amyloidosis, clinical features of RA, and treatment. RESULTS: Based on autopsy, amyloidosis was determined as a cause of death in 9.5% of RA and in none of the non-RA patients (p<0.001). In our RA patients, we detected no trend in deaths from amyloidosis between 1952 and 1991. The RA patients dying of amyloidosis died younger than those dying of other causes (p=0.001). During the course of the disease, the RA patients with amyloidosis had: higher erythrocyte sedimentation rate (p=0.002), lower haemoglobin (p<0.001), more frequently proteinuria (p<0.001) and renal failure (p<0.001) than did the rest of the RA patients. Pre-mortem, amyloidosis was diagnosed by biopsy in 65% of the RA patients with amyloidosis as their cause of death. CONCLUSION: Amyloidosis may be undetected during the course of RA. Thus, it should be actively searched for in the patients with long-lasting and active disease, especially, if they have proteinuria or renal failure.