Rheumatoid Arthritis: Bookman A

Bell M, Askari A, Bookman A, Frydrych S, Lamont J, McComb J, Muscoplat C, Slomovic A. · Sunnybrook and Women's College Health Sciences Centre, Toronto, Canada. · J Rheumatol. · Pubmed #10493692 No free full text.

Abstract: Sjögren's syndrome (SS) is greatly under recognized in clinical practice, primarily for 2 reasons: its presentations are variable and often nonspecific and there are still no clear, uniform diagnostic criteria for this clinical entity. The prevalence, natural history, pathogenesis, and clinical taxonomy of SS are still not well understood. Potential criteria include both subjective symptoms and objective criteria such as measurements of salivary and tear flow, minor salivary gland biopsy, and an increasing variety of serological markers. Physicians often fail to appreciate the profound impact of SS on quality of life. Therefore, screening for SS should include questions exploring symptoms in terms of their effect on the patient's daily life. At present, there is no curative treatment for SS. For symptom relief, local treatments (such as artificial tears or oral topical sprays) are limited in their effects, whereas systemic treatment offers the advantage of addressing a wider range of symptoms. Controlled studies show that oral pilocarpine significantly improves sicca symptoms in the eyes, mouth, and other sites. Clinical experience to date suggests it is safe and well tolerated, with no serious adverse effects, tachyphylaxis, or drug to drug interactions of concern. The most frequent adverse effects are sweating, urinary frequency, diarrhea, and other parasympathomimetic effects, but these do not lead to substantial drug withdrawal rates. Patients should be forewarned that subjective improvement may lag behind improvement in objective measures. Because management often spans several specialties, coordination among them is essential. Dental, gynecological, and ophthalmological perspectives on diagnosis and management are discussed; the primary practitioner has the opportunity to play both a coordinating role and a direct role in early diagnosis and treatment.

Keesal N, Wasserman MJ, Bookman A, Lapp V, Weber DA, Keystone EC. · Department of Medicine, University of Toronto, Centre for Advanced Therapeutics in Arthritis, Mount Sinai Hospital, Ontario, Canada. · J Rheumatol. · Pubmed #10555888 No free full text.

Abstract: OBJECTIVE: To review outcomes in 10 patients with rheumatoid arthritis (RA) treated with thalidomide. METHODS: We reviewed our experience with 10 patients treated with thalidomide using a standard therapeutic protocol and standard outcome measures. RESULTS: We observed no significant improvement in any outcome measure, likely as a consequence of the limited duration of therapy related to thalidomide toxicity. CONCLUSION: Formal studies of the efficacy of thalidomide in RA are required with alternative doses of the compound used by us, or with compounds derived from other sources.

Mease PJ, Hobbs K, Chalmers A, El-Gabalawy H, Bookman A, Keystone E, Furst DE, Anklesaria P, Heald AE. · Seattle Rheumatology Associates/Swedish Medical Center Research, Seattle, Washington, USA. · Ann Rheum Dis. · Pubmed #18678578 No free full text.

Abstract: OBJECTIVE: To examine the safety and tolerability of a single intra-articular injection of rAAV2-TNFR:Fc, an adenoassociated virus serotype 2 vector containing the cDNA for the human tumour necrosis factor-immunoglobulin Fc fusion gene (tgAAC94), in subjects with inflammatory arthritis. METHODS: In a double-blind, placebo-controlled, phase 1, dose-escalation study, 15 subjects with inflammatory arthritis (14 with rheumatoid arthritis and 1 with ankylosing spondylitis) not receiving tumour necrosis factor alpha (TNFalpha) inhibitors with persistent moderate (grade 2) or severe (grade 3) swelling in a target joint due to inflammatory arthritis received a single intra-articular injection of rAAV2-TNFR:Fc at 1 x 10(10) (n = 5) or 1 x 10(11) (n = 6) DNase resistant particles per ml joint volume or placebo (n = 4) into a knee (n = 14) or ankle (n = 1). Safety was assessed through adverse event monitoring. As a secondary objective, changes in injected joint tenderness and swelling scores, each measured on a four-point scale, were evaluated. RESULTS: Intra-articular injections of rAAV2-TNFR:Fc were well tolerated with no major safety issues. One event, mild knee pruritis, was considered probably related. Synovial fluid TNFR:Fc protein was not detected (nor expected) at the doses used. At 12 weeks after injection, a two-point decrease in swelling was noted in 2/11 and 2/4 subjects injected with rAAV2-TNFR:Fc and placebo, respectively. CONCLUSION: A single dose of intra-articular rAAV2-TNFR:Fc appears to be safe and well tolerated in subjects without concurrent systemic TNFalpha antagonist use. It is thus feasible to proceed with larger trials to further test the safety and efficacy of local TNFR:Fc gene transfer as a therapeutic modality for patients with inflammatory arthritis.

Adatia FA, Michaeli-Cohen A, Naor J, Caffery B, Bookman A, Slomovic A. · Department of Ophthalmology, University of Toronto, Toronto, Ont. · Can J Ophthalmol. · Pubmed #15696767 No free full text.

Abstract: BACKGROUND: Previous studies have shown a poor correlation between dry eye symptoms and objective clinical signs in patients with Sjögren's syndrome.We examined the hypothesis that reduced corneal sensitivity is associated with increased ocular surface disease and reduced symptoms in patients with Sjögren's syndrome. METHODS: Eighteen subjects with a diagnosis of Sjögren's syndrome attending a Sjögren's clinic participated in the study. All participants completed the Ocular Surface Disease Index (OSDI) and the Symptom Severity of Discomfort (SSD) scale and answered a question regarding overall severity of dry eye symptoms.The subjects underwent measurement of best-corrected Snellen visual acuity, corneal sensitivity testing with the Cochet-Bonnet esthesiometer, fluorescein and lissamine green staining of the cornea, Schirmer's test I and determination of the tear film break-up time.The results were analysed using Pearson correlational analysis. RESULTS: Both fluorescein and lissamine green staining of the cornea correlated negatively with central corneal sensation (r = -0.3542, p = 0.034, and r = -0.3748, p = 0.029 respectively), indicating that corneal sensation was reduced with increased ocular surface disease. The overall symptom severity correlated negatively with lissamine green staining of the cornea (r = -0.4310, p = 0.011), suggesting reduced symptoms with increased corneal disease. INTERPRETATION: Reduced corneal sensation correlated with increased ocular surface disease. Ocular surface disease similarly demonstrated a reciprocal relation with patients' dry eye symptoms. Consequently, we found that patients with Sjogren's syndrome with advanced corneal staining tended to have fewer dry eye symptoms than patients with less corneal staining.

Winer S, Astsaturov I, Cheung R, Tsui H, Song A, Gaedigk R, Winer D, Sampson A, McKerlie C, Bookman A, Dosch HM. · Hospital for Sick Children, Research Institute, ON, Toronto, Canada. · Lancet. · Pubmed #12383988 No free full text.

Abstract: BACKGROUND: Sjögren's syndrome is a common (about 1% of the population) autoimmune disease of salivary and lacrimal glands. Its cause and pathogenesis are poorly understood, and treatments are mostly for symptoms of the disease. ICA69 is a self-antigen expressed in brain, pancreas, salivary, and lacrimal glands. NOD-strain mice are an animal model of spontaneous Sjögren's syndrome. We aimed to assess the role of ICA69 in autoimmunity against Sjögren's syndrome. METHODS: We inactivated the genomic ICA69 locus, generated NOD congenic mice that were deficient in ICA69, and assessed development of Sjögren's syndrome. ICA69 autoimmunity was investigated in controls and in patients with primary Sjögren's syndrome or systemic lupus erythematosus, and in various NOD mice, some of which were given an ICA69-directed prototype peptide vaccine. FINDINGS: Disruption of the ICA69 locus prevented lacrimal gland disease and greatly reduced salivary gland disease in NOD mice. In healthy NOD mice, ICA69-specific T cells accumulated in lymph nodes that drain salivary tissue. T-cell and B-cell autoreactivity against ICA69 was much the same in patients with primary Sjögren's syndrome, but not in those with systemic lupus erythematosus or in healthy controls. Immunotherapy with a high-affinity mimicry peptide targeting ICA69-specific T-cells reduced established Sjögren's syndrome in wild-type NOD mice in the long term. INTERPRETATION: ICA69 is a new autoantigen in primary Sjögren's syndrome that has an important role in progression of disease and could be of diagnostic value. Immunotherapy of primary Sjögren's syndrome is promising, since autoimmunity in NOD mice with Sjögren's syndrome seems to be uniquely susceptible to such treatment even late in disease.