Effects of naproxen and sulphasalazine or methotrexate on hypothalamic-pituitary-adrenal axis activity in patients with rheumatoid arthritis.

OBJECTIVES: To study the effects of antirheumatic drugs on hypothalamic-pituitary-adrenal (HPA) axis activity in patients with rheumatoid arthritis (RA). METHODS: Twenty patients with recent-onset active RA were studied before antirheumatic treatment, after 2 weeks of naproxen, and after 5½ months of additional treatment with sulphasalazine or methotrexate. The results before treatment were compared with those obtained in 20 age and sex-matched healthy controls (HC). Activity of the HPA-axis was assessed under basal conditions and during insulin tolerance tests (ITT). The ex-vivo production of interleukin (IL)-1ß, tumour necrosis factor-α (TNF-α) and IL-6 in whole blood samples was measured with and without stimulation by LPS. RESULTS: At baseline, plasma ACTH and cortisol levels were not different between patients with RA and HC. The unstimulated production of IL-6 was significantly higher in RA patients than in HC. After 2 weeks of treatment with naproxen, urinary cortisol excretion decreased significantly (p=0.03), and the area under the curve for plasma cortisol during the ITT was significantly lower (p=0.015). The LPS stimulated production of IL-1ß was significantly lower compared with baseline. After 6 months, basal plasma, salivary and urinary cortisol levels, and plasma cortisol and ACTH levels during the ITT, were all unchanged in comparison to the pre-treatment period. The unstimulated ex-vivo production of IL-1ß was significantly lower than before treatment. CONCLUSIONS: Our results suggest that the non-steroidal anti-inflammatory drug naproxen suppresses the HPA-axis in the first weeks of treatment. After 6 months, this suppressive effect is no longer present, suggesting the existence of adaptive mechanisms.

Intranasal administration of recombinant human cartilage glycoprotein-39 as a treatment for rheumatoid arthritis: a phase II, multicentre, double-blind, randomised, placebo-controlled, parallel-group, dose-finding trial.

BACKGROUND: Autoantigen-specific immunotherapy by mucosal tolerance induction via the intranasal route is an attractive therapeutic option for the treatment of autoimmune diseases, including rheumatoid arthritis (RA). Human cartilage glycoprotein-39 (HC gp-39) has been identified as a potential key autoantigen in RA. Based on animal studies, intranasal administration of the autoantigen is hypothesised to induce immunological tolerance in patients with RA and to ameliorate disease activity. In a phase I/IIA clinical trial in patients with RA, intranasal application of HC gp-39 was safe and well tolerated. OBJECTIVE: To investigate the efficacy of intranasally administered fully human, recombinant HC gp-39 (Org 39141) by a large clinical study. METHODS: In a 13-week multicentre, double-blind, randomised, placebo-controlled, parallel-group, dose-finding, proof-of-concept trial, patients with RA (disease-modifying antirheumatic drug (DMARD) naive or after washout of DMARD treatment) were randomised to receive either intranasal applications of placebo or HC gp-39 in doses of 30, 150, 300 or 600 microg, once a week. The primary efficacy variable was the 28 joint count Disease Activity Score (DAS28). RESULTS: During the treatment period the DAS28 decreased similarly for all treatment groups-including placebo-indicating lack of efficacy of intranasal HC gp-39 treatment in the current setting. Safety variables were similar for all study groups. CONCLUSION: It was concluded that with the treatment protocol used (dose levels and frequency of dosing), intranasal treatment with Org 39141 was safe but did not result in more clinical improvement than in placebo-treated patients.

Effect of naproxen on the hypothalamic-pituitary-adrenal axis in healthy volunteers.

AIM: To study the effect of the nonsteroidal anti-inflammatory drug naproxen on the activity of the hypothalamic-pituitary-adrenal (HPA) axis in healthy volunteers. METHODS: A double-blind, randomized study in two groups of 20 healthy volunteers was performed. The activity of the HPA axis was measured before and after the use of naproxen or placebo during a period of 2 weeks. Basal plasma adrenocorticotropic hormone (ACTH) and cortisol, 24-h urinary cortisol, and circadian cortisol rhythm in saliva were determined. Plasma ACTH and cortisol were also measured during submaximal physical exercise. RESULTS: There were no significant differences between the placebo and naproxen groups in basal plasma ACTH [09.00 h 3.1 pmol l(-1), 95% confidence interval (CI) 2.0, 4.2, and 2.8 pmol l(-1), 95% CI 1.9, 3.7, respectively], cortisol levels (09.00 h 0.45 micromol l(-1), 95% CI 0.39, 0.51, and 0.40 micromol l(-1), 95% CI 0.35, 0.44, respectively), 24 h urinary cortisol excretion (67.5 nmol 24 h(-1), 95% CI 54.3, 80.7, and 86.8 nmol 24 h(-1), 95% CI 54.4, 119.2, respectively), circadian cortisol rhythm measured in salivary samples, or ACTH and cortisol concentrations after physical exercise. After the use of placebo or naproxen for 2 weeks, no significant change in any of the parameters occurred (ACTH 09.00 h 3.0 pmol l(-1), 95% CI 2.0, 3.9, and 3.0 pmol l(-1), 95% CI 2.2, 3.8, respectively; cortisol 09.00 h 0.45 micromol l(-1), 95% CI 0.37, 0.52, and 0.39 micromol l(-1), 95% CI 0.34, 0.44, respectively; cortisol urine 79.5 nmol 24 h(-1), 95% CI 59.5, 99.4, and 81.7 nmol 24 h(-1), 95% CI 64.0, 99.4, respectively), and no significant differences were found in these parameters between the placebo and naproxen groups. CONCLUSIONS: The use of naproxen does not influence the activity of the HPA axis in healthy volunteers under basal circumstances or in response to physical stress.

Key randomized trials of single agents in early rheumatoid arthritis.

Disease modifying antirheumatic drugs (DMARD) for treatment of rheumatoid arthritis (RA) are well established. As evidence has shown, considerable damage to the joints occurs early in the disease: thus DMARD therapy is being initiated earlier. Clinical trials with DMARD monotherapy in early RA are reviewed with consideration given to efficacy, onset of therapeutic effect, and the toxicity profile of currently available drugs.

Intranasal administration of recombinant human cartilage glycoprotein-39. A phase I escalating cohort study in patients with rheumatoid arthritis.

OBJECTIVE: To investigate safety and tolerability and pilot efficacy of repeated single doses of Org39141 in patients with active rheumatoid arthritis (RA). Org 39141 is recombinant human cartilage glycoprotein-39, intended to induce mucosal tolerance upon intranasal administration. METHODS: RA patients with moderate disease activity were treated for 4 weeks and followed for another 8 weeks. The trial had a sequential cohort design: RA patients in the first cohort received 4 intranasal doses (one per week) of either 25 microg Org 39141 or placebo; in subsequent cohorts, treatment with 125microg, 625 microg, or 3125 microg Org39141 was compared to placebo. Safety was evaluated by means of reporting adverse events, standard laboratory testing, and nose examination. The primary efficacy endpoint was RA disease activity as measured by the Disease Activity Score 28 (DAS28). RESULTS: A total of 36 patients were randomized. Org39141 was well tolerated, and no severe or serious adverse events (AE) were reported. In the pooled placebo group, a decrease in DAS28 was observed, but to a lesser extent than in the Org 39141 treatment groups. After 4 weeks of treatment, the mean decrease in DAS in the 625 microg Org 39141 treatment group (-24%) was statistically (p = 0.02) and clinically (EULAR criteria) significantly larger than in the pooled placebo group (-3%). Once-weekly intranasal treatment with Org39141 was well tolerated, and no serious or severe AE were reported. A trend towards efficacy was observed. Our results are encouraging for further clinical development of Org39141.

Reshaping the shared epitope hypothesis: HLA-associated risk for rheumatoid arthritis is encoded by amino acid substitutions at positions 67-74 of the HLA-DRB1 molecule.

OBJECTIVE: To further analyze the association of HLA-DRB1 alleles with disease susceptibility in recent-onset rheumatoid arthritis (RA). METHODS: One hundred sixty-seven Caucasian RA patients and 166 healthy controls were typed for HLA-DRB1. RESULTS: The association of susceptibility to RA with the group of alleles encoding the shared epitope susceptibility sequences (SESSs) was confirmed in recent-onset RA. Among non-SESS alleles, DRB1*07, *1201, *1301, and *1501 showed significant protective effects. Even after correction for the influence of SESS alleles, significant independent protective effects of DRB1 alleles were observed. Protective alleles shared a third hypervariable region motif. Independent homozygosity effects were observed both for susceptibility and for protective alleles. CONCLUSION: Nonsusceptibility alleles differ significantly with regard to RA risk. Protective alleles show clear homology at positions 67-74, often encoding isoleucine at position 67 or aspartic acid at position 70. Susceptibility and protective alleles both show homozygosity effects. Based on these results and on data reported in the literature, in order to incorporate the finding of differential risks among nonsusceptibility alleles, we propose to reshape the shared epitope hypothesis as follows: HLA-associated risk for RA is encoded by amino acid substitutions at positions 67-74 of the HLA-DRB1 molecule.

Research in complex diseases.

Many diseases that have a substantial effect on health have a complex pathogenesis. Examples are atherosclerosis, diabetes mellitus, and rheumatoid arthritis. Here, we discuss a hierarchy of goals of research in complex diseases, and introduce a stepwise approach for the development of disease models, paying specific attention to the position of genetic factors and stochastic variables in these models.

Role of Fcgamma receptors IIA, IIIA, and IIIB in susceptibility to rheumatoid arthritis.

OBJECTIVE: To investigate the role of Fcg receptor (FcgR) genes in susceptibility to rheumatoid arthritis (RA) using family based studies, to examine possible interactions between FcgR genotypes and the shared epitope (SE), and to assess linkage disequilibrium between FcgR loci. METHODS: Association studies were performed in 95 Caucasian, single-case, nuclear Caucasian families with both parents alive using haplotype based haplotype relative risk (HHRR) and transmission disequilibrium test (TDT) statistics. Three FcgR polymorphisms (FcgRIIA-131H/R, FcgRIIIA-158V/F, and FcgRIIIB-NA1/NA2) were genotyped using polymerase chain reaction methods. Linkage analysis was performed using 3 microsatellite markers (D1S498, D1S2844, D1S2762) flanking the FcgR region in an independent set of 90 Caucasian, multiple-case families. Potential effects of disease heterogeneity, including sex and the presence of rheumatoid factor, SE, and erosive or nodular disease, were taken into account in the analysis. Logistic regression analysis was performed to determine whether FcgR alleles are independent risk factors for the susceptibility to and/or severity of RA. Linkage disequilibrium was calculated using pairwise linkage disequilibrium statistics. RESULTS: HHRR and TDT analysis showed no evidence of preferential transmission of any FcgR alleles studied, and there were no important associations with any given disease phenotype. Moreover, neither linkage to microsatellite markers close to the FcgR genes on chromosome 1 nor linkage disequilibrium between FcgR loci was present in our population. The distribution of inherited genotypes provided evidence for an interaction between the SE and the FcgRIIIA-158V allele and between the SE and the FcgRIIIA-158V-FcgRIIA-131H 2-locus haplotype since the combined presence of these factors increased the susceptibility to RA (OR 4.13, 95% CI 1.6-10.62 and OR 2.83, 95% CI 1.25-6.38, respectively). However, regression analysis showed that neither the 158V allele nor the 158V-131H haplotype contributed as independent factors to susceptibility or severity of RA. CONCLUSION: Isolated FcgR genes do not play a major independent role in susceptibility to RA. To a limited extent, the presence of high-binding alleles at the FcgRIIIA locus or at the FcgRIIIA-FcgRIIA haplotype might predispose to RA in SE positive individuals.