Treatment pathways in an inception lupus cohort over the first three years.

Objective The treatment algorithm for new onset systemic lupus erythematosus (SLE) is less well defined than for other rheumatic diseases. We examined the treatment patterns in an inception cohort of SLE patients over the first three years of disease between 2000 and 2010. Methods Patients fulfilled the American College of Rheumatology classification criteria for SLE within 12 months of enrollment and completed three subsequent annual visits. Data collection included patient demographics, SLE manifestations, medications, SLE disease activity index-2K (SLEDAI-2K) and Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index. Analysis included descriptive statistics and repeated measures mixed models. Results Seventy-nine patients, 83.5% female and 91.1% Caucasian were studied. At baseline the mean (SD) age was 40.6 (16.4) years, disease duration was 0.36 (0.28) years and SLEDAI-2K was 5.7 (4.6). Over three years, cumulative use of corticosteroids, antimalarials and immunosuppressants was 53.2%, 77.2% and 40.5% respectively. Corticosteroids were usually used in combination with antimalarials and/or immunosuppressants. Between baseline and final assessments the use of corticosteroids fell (44.3% vs 15.2%) in contrast to antimalarials (55.7% vs 70.9%) and immunosuppressants (26.6% vs 34.2%). Of 44/79 (55.7%) patients not receiving corticosteroids at baseline 84.1% remained off corticosteroids for the study duration. Thirty-seven of 79 (46.8%) patients never received corticosteroids and only 5/79 (6.3%) at all four assessments. Patients taking corticosteroids at baseline had higher mean (SD) daily dose and cumulative dose over three years compared with patients not on corticosteroids at baseline (9.0 (0.8) vs 0.3 (1.3) mg; 10.8 (8.5) vs 0.3 (1.2) g). As a group, SLE patients who used corticosteroids either at baseline, at any time in the three year study or in high cumulative doses had the highest average disease activity scores over the same time frame and had a significant fall in SLEDAI-2K scores ( p < 0.05) compared with patients not exposed to corticosteroids. Conclusion Use of corticosteroids occurred in approximately half of new onset SLE, usually in combination with antimalarials and/or immunosuppressants. It was associated with both higher disease activity at baseline and improvement over time. Patients who did not receive corticosteroids at presentation were unlikely to do so over the next three years.

Systemic delivery of peptides and proteins across absorptive mucosae.

As therapeutic peptides and proteins become readily available through rapid advances in recombinant technology, and because rapid presystemic elimination renders them ineffective when administered orally, pharmaceutical scientists are faced with the challenge of delivering these macromolecules systemically; therefore, alternative routes of delivery need to be investigated. Transmucosal delivery through absorptive mucosae represents one of these alternatives. This route has the advantage of being noninvasive and of bypassing hepatogastrointestinal clearance. The absorptive mucosae that have been investigated for delivery of peptides and proteins include buccal, nasal, pulmonary, rectal, and vaginal. Nasal delivery has been studied extensively and has been the most successful--nasal sprays for buserelin, desmopressin, oxytocin, and calcitonin are already available commercially. In general, enzyme inhibitors and permeation enhancers need to be coadministered for successful delivery of these biopharmaceuticals. Classes of enhancers used for transmucosal delivery include bile salts, dihydrofusidates, cyclodextrins, surfactants, and chelating agents. Each of these agents exerts its enhancing effects by a different mechanism, and each has been associated with adverse effects. This article discusses the physiology of each of the mucosae used, the fundamentals of transmucosal delivery, and recent progress in systemic delivery of therapeutic peptides and proteins across each of the mucosae; in an effort to highlight principles of transmucosal delivery, it also discusses the transmucosal delivery of enkephalin, calcitonin, and insulin as case studies.

Transmucosal delivery of leucine enkephalin: stabilization in rabbit enzyme extracts and enhancement of permeation through mucosae.

Leucine enkephalin (Tyr-Gly-Gly-Phe-Leu; Leu-Enk) is a naturally occurring peptide that has been shown to have pain modulating properties. To evaluate the feasibility of using various absorptive mucosae as a route of systemic delivery, the stability of Leu-Enk and the effect of enzyme inhibitors (e.g., amastatin, EDTA, and thimerosal) on stabilization and permeation of Leu-Enk through rabbit mucosae in the presence of dihydrofusidates were investigated. Enzymes in the nasal, rectal, and vaginal mucosae were extracted and Leu-Enk (50 micrograms/mL) was added to each of the enzyme extracts and incubated to determine the kinetics and mechanism of degradation. The rate of degradation in the extracts in the absence of inhibitors followed the order: rectal > vaginal > nasal. Whereas EDTA had the best stabilizing effect on Leu-Enk, thimerosal was the best stabilizer for the degradation intermediates. A combination of amastatin (50 microM), EDTA (5 mM), and thimerosal (50 microM) had the greatest stabilizing effect on Leu-Enk and its degradation intermediates. For permeation studies, each mucosa was mounted onto a Valia-Chien permeation cell with Leu-Enk (200 micrograms/mL) in isotonic phosphate buffer (as donor solution). The enhancers used for the study were sodium tauro-dihydrofusidate (STDHF), sodium glycodihydrofusidate (SGDHF), and phosphato-dihydrofusidate (PHDHF). The greatest effect was achieved by PHDHF for all the mucosae. STDHF had a significant effect only on the rectal permeation, whereas SGDHF had significant effects on rectal and vaginal mucosae. Mechanisms by which the dihydrofusidates enhance permeating may involve micelle formation.(ABSTRACT TRUNCATED AT 250 WORDS)