Triple therapy in early active rheumatoid arthritis: a randomized, single-blind, controlled trial comparing step-up and parallel treatment strategies.

OBJECTIVE: The Tight Control of Rheumatoid Arthritis study previously demonstrated that an intensive step-up disease-modifying antirheumatic drug (DMARD) treatment strategy targeting persistent disease activity was superior to routine care in the management of early rheumatoid arthritis (RA). We undertook this study to test the hypothesis that early parallel triple therapy achieves better outcomes than step-up therapy within an intensive disease management regimen. METHODS: Ninety-six patients with early RA (mean disease duration 11.5 months) were randomized to receive step-up therapy (sulfasalazine [SSZ] monotherapy, then after 3 months, methotrexate [MTX] was added, and when the maximum tolerated dosage of MTX was reached, hydroxychloroquine [HCQ] was added) or parallel triple therapy (SSZ/MTX/HCQ). All patients were assessed monthly for 12 months. If their disease activity score in 28 joints (DAS28) was > or =3.2, the dosage of DMARDs was increased according to protocol, and swollen joints were injected with triamcinolone acetonide (maximum dosage 80 mg per month). A metrologist who was blinded to the treatment allocation performed assessments every 3 months. The primary outcome measure was the mean decrease in the DAS28 score at 12 months. RESULTS: Both groups showed substantial improvements in disease activity and functional outcome. At 12 months, the mean decrease in the DAS28 score was -4.0 (step-up therapy group) versus -3.3 (parallel therapy group) (P = 0.163). No significant differences in the percentages of patients with DAS28 remission (step-up therapy group 45% versus parallel triple therapy group 33%), DAS28 good response (60% versus 41%, respectively), or American College of Rheumatology criteria for 20% improvement (ACR20) (77% versus 76%, respectively), ACR50 (60% versus 51%, respectively), or ACR70 (30% versus 20%, respectively) responses were seen. Radiologic progression was similar in both groups. CONCLUSION: This study confirms that highly effective control of disease activity can be achieved using conventional DMARDs as part of an intensive disease management strategy. Within this setting, step-up therapy is at least as effective as parallel triple therapy.

Variation to cause host injury between Russian wheat aphid (Homoptera: Aphididae) clones virulent to Dn4 wheat.

Biotypes are infraspecific classifications based on biological rather than morphological characteristics. Cereal aphids are managed primarily by host plant resistance, and they often develop biotypes that injure or kill previously resistant plants. Although molecular genetic variation within aphid biotypes has been well documented, little is known about phenotypic variation, especially virulence or the biotype's ability to cause injury to cultivars with specific resistance genes. Five clones (single maternal lineages) of Russian wheat aphid, Diuraphis noxia (Kurdjumov) (Homoptera: Aphididae), determined to be injurious to wheat, Triticum aestivum L., with the Dn4 gene, were evaluated on resistant and susceptible wheat and barley, Hordeum vulgare L., for their ability to cause chlorosis, reduction in plant height, and reduction in shoot dry weight. Variation to cause injury on resistant 'Halt' wheat, susceptible 'Jagger' wheat, and resistant 'STARS-9301B' barley was found among the Dn4 virulent clones. One clone caused up to 30.0 and 59.5% more reduction in plant height and shoot dry weight, respectively, on resistant Halt than other clones. It also caused up to 29.9 and 55.5% more reduction in plant height and shoot dry weight, respectively, on susceptible Jagger wheat. Although STARS-9301B barley exhibited an equal resistant response to feeding by all five clones based on chlorosis, two clones caused approximately 20% more reduction in plant height and shoot dry weight than three other clones. The most injurious clones on wheat were not the most injurious clones on barley. This is the first report of variation to cause varying degrees of plant damage within an aphid biotype virulent to a single host resistance gene. A single aphid clone may not accurately represent the true virulent nature of a biotype population in the field.

Efficacy of pyramiding greenbug (Homoptera: Aphididae) resistance genes in wheat.

Durable resistance to greenbug, Schizaphis graminum (Rondani), in wheat is a goal of wheat improvement teams, and one that has been complicated by the regular occurrence of damaging biotypes. Simulation modeling studies suggest that pyramiding resistance genes, i.e., combining more than one resistance gene in a single cultivar or hybrid, may provide more durable resistance than sequential releases of single genes. We examined this theory by pyramiding resistance genes in wheat and testing a series of greenbug biotypes. Resistance genes Gb2, Gb3, and Gb6, and pyramided genes Gb2/Gb3, Gb2/Gb6, and Gb3/Gb6 were tested for effectiveness against biotypes E, F, G, H, and I. By comparing reactions of plants with pyramided genes to those with single resistance genes, we found that pyramiding provided no additional protection over that conferred by the single resistance genes. Based on the results of this test, we concluded that the sequential release of single resistance genes, combined with careful monitoring of greenbug population biotypes, is the most effective gene deployment strategy for greenbug resistance in wheat.

Plant resistance components of two greenbug (Homoptera: Aphididae) resistant wheats.

Several biotypes of the greenbug, Schizaphis graminum (Rondani), attack winter wheat, Triticum aestivum L., on the Southern Plains every year. Two wheat germplasm sources of resistance ('Largo' and 'GRS 1201') have been developed that provide protection against the three predominant greenbug biotypes (E, I, and K). Each source has agronomic and end-use quality advantages and disadvantages for the breeder to consider in choosing a greenbug-resistant breeding line. We compared these two germplasms to determine their levels of resistance against biotype E. Components of resistance (i.e., antibiosis, antixenosis, and tolerance) were measured on seedlings of GRS 1201, Largo, and 'TAM W-101' (a susceptible control). Several aphid and plant measurements (e.g., total number of aphids produced per plant, aphid selection preferences, and plant damage ratings) were recorded for each plant entry. Select data recorded for each resistance component were normalized and combined to derive a plant resistance index for each wheat entry. Results indicated that GRS 1201 had a higher level of combined resistance components than did Largo, followed by TAM W-101, the susceptible control. These data provide additional information for the breeder to consider in selecting a greenbug-resistant breeding line.

Does sulphasalazine cause drug induced systemic lupus erythematosus? No effect evident in a prospective randomised trial of 200 rheumatoid patients treated with sulphasalazine or auranofin over five years.

BACKGROUND: Sulphasalazine (SSZ) has been reported to cause drug induced systemic lupus erythematosus (SLE), but diagnosis of this complication in the context of rheumatoid arthritis (RA) is difficult. OBJECTIVE: To determine prospectively: (1) if patients become seropositive for antinuclear antibodies (ANA) during prolonged treatment with SSZ without clinical evidence of SLE; (2) if ANA positive patients develop more adverse reactions than ANA negative patients; (3) if drug induced SLE was identified in this cohort. METHODS: 200 patients enrolled in a randomised prospective trial of SSZ and auranofin (AUR) were followed up for five years. Baseline and annual ANA results were collected along with information on drug toxicity and reasons for discontinuation of treatment. RESULTS: Over five years 24 patients stopped taking SSZ and 49 AUR because of side effects. Of the features common to SLE, rash developed in nine SSZ patients and 11 AUR treated patients and mouth ulcers in three and four patients respectively. Six SSZ treated patients and three treated with AUR developed leucopenia, which promptly resolved with drug withdrawal. No adverse event was ascribed to drug induced SLE. Of the 72 SSZ treated patients who were ANA negative or weakly positive at outset, 14 (19%) became strongly ANA positive compared with 11 (14%) of 80 AUR patients. Patients ANA positive at baseline or who became ANA positive were not more likely to develop drug toxicity or to withdraw from treatment than those ANA negative throughout. CONCLUSION: ANA positivity is common in patients with RA, but the presence or development of ANA did not increase the likelihood of withdrawing from treatment. No case of drug induced SLE was seen over five years in this study.

Is rheumatoid arthritis becoming a milder disease? Or are we starting second-line therapy in patients with milder disease?

The aim of the study was to see whether rheumatoid arthritis (RA) is becoming a milder disease. Information on the initial disease activity and patient function (modified Health Assessment Questionnaire-HAQ) was collected in all RA patients enrolled into studies of sulphasalazine since 1980 in two Glasgow teaching hospitals. Patients (352) were enrolled in trials in the decade 1980-1989, and were compared to 374 patients enrolled in 1990-1994. Patients recruited in the 1980s were significantly younger, but had a similar disease duration to the 1990s patients. The 1980s patients had more active disease as measured by erythrocyte sedimentation rate (61 vs 44, P < 0.0001) and C-reactive protein (40 vs 26, P < 0.0001), and significantly worse function (HAQ 2.3 vs 1.9, P < 0.001). The response to sulphasalazine was very similar in the two cohorts, in terms of the percentage of patients remaining on therapy for 6 months, and the percentage improvement in measures of disease activity. Patients with milder disease were enrolled into the more recent trials of sulphasalazine. This may be because RA is becoming a milder disease, but other possible explanations are discussed.

Outcome of second line therapy in rheumatoid arthritis.

OBJECTIVES: To study the functional outcome in patients with rheumatoid arthritis (RA) who tolerate second line drug therapy for five years. METHODS: We enrolled into prospective controlled trials, 190 patients with rheumatoid arthritis who tolerated 'disease modifying' antirheumatic drug therapy for five years. Demographic data were recorded. Disease activity was measured every six months for two years and annually thereafter, using clinical and laboratory variables. Patient function was measured using the modified Health Assessment Questionnaire. The change in each variable was analysed using paired Wilcoxon tests. RESULTS: Patient function improved significantly compared with baseline. The improvement was maximal after one to two years, and thereafter function started to decline slowly. After five years of treatment the patients' function was still significantly better than before treatment had started. There were highly significant improvements in all variables measured to assess disease activity, which remained well controlled throughout the five year period. CONCLUSION: Good control of disease activity and improved function can be achieved long term in approximately 30% of RA patients treated with injectable gold, sulphasalazine or penicillamine.

An Early Indicator of Resistance in Barley to Russian Wheat Aphid.

During early stages of infestation by Russian wheat aphids (Diuraphis noxia [Mordvilko]; RWAs), barley (Hordeum vulgare L.) leaf cells collapsed and showed autofluorescence in the mesophyll and bundle sheath adjacent to the RWA stylet sheath. The response was visually similar to the hypersensitive cell death response, typical of resistance to microbial pathogens. Resistant barley produced significantly more collapsed, autofluorescent cells (CAC) than did susceptible barley. RWA stylet entry sites and sheath paths also fluoresced, making them easy to observe in whole leaf sections. The number of CAC increased with the number of RWAs and with the number of days of feeding in resistant plants. The CAC could be observed 1 d following infestation, making this the most rapid plant response toward the RWAs known to date. The response may be useful in screening for resistant plants and may provide insight into resistance mechanisms in barley.

The use of serum ferritin estimation in the investigation of anaemia in patients with rheumatoid arthritis.

We report a retrospective study of 101 patients with rheumatoid arthritis and anaemia undergoing investigation in a teaching hospital rheumatology unit. Patients with anaemia of chronic disorder had significantly higher serum ferritin (p < 0.0001), mean corpuscular volume (p < 0.05), and acute phase reactants (p < 0.001). The sensitivity, predictive value and validity of measuring serum ferritin to predict the absence of bone marrow iron stores was studied. Maximum validity (89%) was achieved by defining iron deficiency as occurring when serum ferritin was < 75 ng/ml. 93% of patients with ferritin < 50 ng/ml were iron deficient on bone marrow examination. 91% of patients with ferritin > 100 ng/ml were iron replete on bone marrow examination. 86% of patients had ferritin < 50 or > 100 ng/ml. Age was not a significant confounding factor. Serum ferritin concentration is an informative investigation in rheumatoid patients with anaemia. Correct interpretation of the results eliminates the need for bone marrow aspiration in the majority of cases.

The 'natural' history of active rheumatoid arthritis over 3-6 months--an analysis of patients enrolled into trials of potential disease-modifying anti-rheumatic drugs, and treated with placebo.

The natural history of RA over a period of 6 months is not known, but this is of central importance to the design and interpretation of drug trials of possible DMARDs. We analysed the disease activity of 142 rheumatoid patients who were randomized to receive placebo in five double blind, placebo-controlled trials of possible disease-modifying drugs conducted in a single unit. There was no significant change in ESR, duration of morning stiffness or platelet count over a period of 6 months; the mean change in ESR at 3 months was an increase of 2 mm/h (99% C.I. -3, +7), and only 5% of patients more than halved their ESR over 6 months. There was a small significant fall in articular index over 6 months of placebo treatment. There is no measurable placebo effect on ESR, morning stiffness or platelet count when these are used as measures of disease activity in trials of drug therapy in RA. ESR is an informative, stable measure of disease activity; the duration of morning stiffness may be more useful than the articular index. The use of these results as the basis of a historical cohort to help design future placebo-controlled trials, and to interpret uncontrolled trials of putative anti-rheumatic drugs is discussed.

Second line (disease modifying) treatment in rheumatoid arthritis: which drug for which patient?

OBJECTIVES: The objectives were to assess (a) the comparative merits of commonly used disease modifying drugs in the treatment of rheumatoid arthritis (RA) and (b) the influence of age, gender, and disease duration on the outcome of treatment. METHODS: Collected analysis (meta-analysis) was performed on results obtained during the first year of treatment in 1140 patients with RA treated with gold, penicillamine, sulphasalazine, or auranofin from a single centre. RESULTS: Gold, penicillamine, and sulphasalazine performed similarly, with about 60% of patients continuing to receive each of these drugs for at least one year. Neither gender nor age had an influence on the response to treatment, but patients with a longer disease duration showed a greater tendency to stop treatment. The median percentage improvement was 33% in visual analogue pain score and 50% in erythrocyte sedimentation rate. CONCLUSIONS: Routine use of these drugs should at least equal these results. Any new drug should either be substantially less toxic or at least as efficacious.

Combination therapy in rheumatoid arthritis--no benefit of addition of hydroxychloroquine to patients with a suboptimal response to intramuscular gold therapy.

OBJECTIVE: To determine if there is any advantage in adding hydroxychloroquine to intramuscular gold therapy in patients with rheumatoid arthritis (RA) with a suboptimal response to gold after 6 months of treatment. METHODS: Prospective double blind placebo controlled study at the Centre for Rheumatic Diseases, Glasgow Royal Infirmary and Gartnavel General Hospital, Glasgow. Patients--440 patients with RA began intramuscular gold therapy. One hundred forty-two patients with a suboptimal response at 6 months were randomized to receive additional treatment with hydroxychloroquine (400 mg/day) or placebo, and followed for a further 6 months. Outcome measures were erythrocyte sedimentation rate, C-reactive protein, Ritchie articular index, grip strength, visual analog pain score, duration of morning stiffness, health assessment questionnaire, and rate of side effects. RESULTS: There was no difference in outcome in terms of efficacy or toxicity. CONCLUSION: There is no justification for using a combination of intramuscular gold and hydroxychloroquine in patients with RA with a partial response to gold.