Leena Paimela

Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial

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.

Only high disease activity and positive rheumatoid factor indicate poor prognosis in patients with early rheumatoid arthritis treated with “sawtooth” strategy

OBJECTIVES To investigate the prognostic significance of clinical and genetic markers on the outcome of patients with recent-onset rheumatoid arthritis (RA) treated actively with slow acting antirheumatic drugs (SAARDs). METHODS A total of 142 consecutive patients with early RA (median disease duration of 7 months) were treated according to the “sawtooth” strategy and prospectively followed up for an average of 6.2 years. Several clinical parameters at start as well as genetic markers were related to the functional outcome (ARA Functional class and HAQ disability score) and radiographic joint damage (Larsen’s score) at the latest visit. RESULTS In logistic regression analysis only Mallya score (including morning stiffness, pain scale, grip strength, Ritchie’s articular index, haemoglobin, and erythrocyte sedimentation rate) at baseline, and Mallya score and rheumatoid factor (RF) positivity at one year were found to be of significance with respect to the radiographic outcome of the patients. Furthermore, at the latest visit HAQ score was related to radiographic score. At baseline the mean ages of the DR4 positive patients and the patients with RA associated DR alleles were statistically significantly lower than those without the above mentioned risk factors (44 v 49, p=0.03 and 41 v 53, p=0.04, respectively). However, these genetic markers had no prognostic significance on the functional or radiographic outcome of the patients. CONCLUSION High clinical disease activity at baseline and RF positivity especially at one year after the institution of SAARD treatment are the best predictors of poor prognosis in early RA. However, from the clinical point of view, the disease outcome of an individual patient with early RA, cannot be predicted accurately enough by present means.

Antikeratin antibodies: diagnostic and prognostic markers for early rheumatoid arthritis.

Antibodies to the stratum corneum of rat oesophagus (antikeratin antibodies) were assayed by indirect immunofluorescence in a prospective study of patients with early rheumatoid arthritis (RA). At the beginning of the study, antikeratin antibodies of IgG class were detected in serum samples from 27/71 (38%) patients compared with 1/20 (5%) control patients with reactive arthritis, and 1/38 (3%) healthy blood donors. At the end of the two year follow up, 27/67 (40%) patients with RA were positive for antikeratin antibodies. The patients with RA who were initially positive for antikeratin antibodies had a more active disease course than the patients negative for antikeratin antibodies as measured by clinical, laboratory, and radiological variables. The prevalence of positivity for antikeratin antibodies fluctuated during the follow up, the variation paralleling the disease activity. The occurrence of HLA-DR4 was similar in patients with RA who were positive and negative for antikeratin antibodies. Antikeratin antibodies were also found in seronegative patients with RA, confirming that antikeratin antibodies do not have rheumatoid factor activity. These results show that antikeratin antibodies are detectable at the time of the initial diagnosis of RA and that the positivity for antikeratin antibodies may have prognostic significance in early RA.

Mortality in patients with rheumatoid arthritis treated actively from the time of diagnosis.

Objectives: To evaluate the mortality rates among patients with early rheumatoid arthritis (RA) treated actively according to the “sawtooth” strategy. Methods: The study included 150 early, disease modifying antirheumatic drug (DMARD) naive patients with RA from two patient cohorts. The first cohort was assembled between 1986 and 1989 (87 patients, aged 19–65 years at onset) and the second between 1991 and 1993 (63 patients, aged 27–83 years at onset). The mean duration of symptoms at the time of diagnosis was 7.1 months (range 2–24). The clinical data and the use of DMARDs were systematically recorded. The causes of death were obtained from death certificates and medical records, if available. The data were collected up to 1 November 2000. Results: During a follow up time of 7–14 years, 24 patients died. The standardised mortality ratio was not increased (0.93 in the first cohort and 1.62 in the second cohort). Age adjusted mortality rates did not differ statistically significantly between the two patient cohorts. The causes of death included malignancy (8 patients); cardiovascular diseases (10); respiratory disease (4), including two patients with pneumonia; sepsis (one); and RA (one). High inflammatory activity, disease activity, and poor functional ability at study entry, and the presence of extra-articular features during the follow up were more common among the patients who had died. Conclusions: No statistically significant increase in mortality rates was seen in these actively treated early RA cohorts during the follow up. High disease activity at the onset and the development of extra-articular features seem to be associated with mortality.

Infliximab for 6 months added on combination therapy in early rheumatoid arthritis: 2-year results from an investigator-initiated, randomised, double-blind, placebo-controlled study (the NEO-RACo Study)

Objective Early treatment of patients with rheumatoid arthritis (RA) with combination treatment starting with methotrexate, sulfasalazine, hydroxychloroquine and prednisolone (FIN-RACo strategy) is superior to monotherapy. A study was undertaken to determine whether infliximab (INFL) added to intensified FIN-RACo treatment for the initial 6 months improves the 2-year outcome. Methods 99 patients with early untreated active RA were enrolled in an investigator-initiated, randomised, double-blind, multicentre, parallel-group trial. Primary outcomes were remission and radiological changes at 2 years. All patients started with FIN-RACo. In addition, they were randomised to receive INFL or placebo (Pla) from weeks 4 to 26. Results At 24 months, 66% and 53%, respectively, of the patients in the FIN-RACo+INFL and FIN-RACo+Pla groups were in remission according to the modified American College of Rheumatology (ACR) criteria (p=0.19), 26% and 10% were in sustained modified ACR remission (p=0.042) and 82% in both groups were in remission by 28-joint disease activity score (not significant). Mean changes in the total Sharp-van der Heijde score were 0.2 and 1.4, respectively (p=0.0058). Conclusions Most patients with early active RA achieve clinical remission and develop negligible joint damage with the intensified FIN-RACo regimen. Adding INFL for the first 6 months delays radiological progression.

Increased level of YKL-40 in sera from patients with early rheumatoid arthritis: a new marker for disease activity

Abstract. YKL-40 is a newly discovered major secretory protein of human chondrocytes and synoviocytes. We measured serum levels of YKL-40 in 52 patients with early onset rheumatoid arthritis (RA) by enzyme-linked immunosorbent assay (ELISA) during a 2-year prospective follow-up, correlating values with laboratory and clinical variables and radiographic progression. Levels at baseline before antirheumatic therapy were significantly higher in patients than in healthy controls. The levels of YKL-40 correlated with laboratory and clinical markers of disease activity both at baseline and during follow-up. Baseline YKL-40 values correlated with baseline Larsen scores but did not predict radiographic progression. Baseline and mean YKL-40 values did not differ between fast and slow radiological progressions. Mean YKL-40 levels correlated with the number of swollen joints but were not predictors of radiographic progression. These results suggest that in early RA, serum YKL-40 is an inflammatory marker correlating with disease activity. However, its levels do not predict clinical course or radiographic progression.

Amyloidosis is frequently undetected in patients with rheumatoid arthritis

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.

Functions of polymorphonuclear leukocytes in early rheumatoid arthritis

We carried out a prospective study on clinical variables and functions of polymorphonuclear leukocytes (PMNs) of 20 patients with early rheumatoid arthritis (RA) and compared the results with the presence of erosions before treatment and at a one-year follow-up. Migration of PMNs determined by agarose and filter assays and respiratory burst of PMNs determined by luminol-enhanced chemiluminescence (CL) test were studied both before starting RA-modifying treatment and 6–12 (mean 7.3) months later. PMNs of the patients without erosions at one year, as compared to the patients with erosions, showed significantly depressed migration into filter and significantly depressed CL responses toN-formyl-methionyl-leucyl-phenylalanine, both before starting the treatment and at 7.3 months. Although causality remains uncertain, the results suggest that depressed functional capacity of PMNs is associated with low risk of joint destruction in early RA.

The prognostic value of HLA DR4 and B27 antigens in early rheumatoid arthritis.

The prognostic significance of HLA DR4 and B27 antigens was investigated in a 3-year follow-up of 87 patients with early rheumatoid arthritis (RA). The frequencies of DR1, DR4 and also of B27 were increased and the frequencies of DR2, DR3 and DR7 decreased compared with the normal Finnish population. During the follow-up with antirheumatic treatment, a similar improvement in clinical variables and laboratory measure assessing disease activity was found in both DR4-positive and DR4-negative RA patients. Despite clinical improvement a fast radiological progression in peripheral joints was observed but the presence of DR4 or B27 had no impact on the progression of joint damage. In some patients cervical changes developed early in the course of RA but were not related to DR4 or B27 positivity. The earlier observation of increased prevalence of HLA B27 in the Finnish RA patients was confirmed but the presence of B27 did not modify the clinical picture of RA.

Can disease-modifying anti-rheumatic drugs be discontinued in long-standing rheumatoid arthritis? A 15-year follow-up

Objective: To investigate the 15-year outcome of patients with early rheumatoid arthritis (ERA) with respect to the continuity of treatment. Methods: We conducted a 15-year follow-up study of 87 patients with ERA treated since diagnosis with disease-modifying anti-rheumatic drugs (DMARDs) according to the ‘sawtooth’ strategy. The patients were divided into groups according to the continuity of treatment: (A) ‘continuous DMARDs’, (B) ‘discontinued and restarted DMARDs’, and (C) ‘permanently discontinued DMARDs’. The main outcome measurements included the Health Assessment Questionnaire (HAQ), the Larsen score, and clinical remission according to the American Rheumatism Association (ARA) criteria. Results: Seventy (80%) patients participated in the 15-year follow-up. DMARDs were discontinued in 20 (29%) patients due either to remission or to a symptom-free period of the disease. The disease flared up in nine (45%) of these patients, in some patients several years after the discontinuation. At the 15-year follow-up, 59 (84%) patients were on DMARDs; only three (4%) were using biologicals. Functional capacity remained good in all groups (mean HAQ score 0.52). The mean Larsen score was higher (54) in group A than in groups B (25) and C (12) (p =0.001). The remission rate was 64% in group C and considerably lower in groups A (6%) and B (0%) (p<0.001). Conclusions: Our results indicate that most of the patients with long-standing RA require continuous DMARD treatment. If the treatment is discontinued, patients should be followed-up closely and DMARDs readministered without delay if the disease flares up.