Arthur Bookman

The bimodal mortality pattern of systemic lupus erythematosus

The changing pattern of mortality in systemic lupus erythematosus (SLE) led to an examination of the deaths in a long-term systematic analysis of 81 patients followed for five years at the University of Toronto Rheumatic Disease Unit. During the follow-up 11 patients died; six patients died within the first year after diagnosis (group I) and five patients died an average of 8.6 years (from 2.5 to 19.5 years) after diagnosis (group II). In those who died early, the SLE was active clinically and serologically, and nephritis was present in four. Their mean prednisone dose was 53.3 mg/day. In four patients a major septic episode contributed to their death. In those who died late in the course of the disease, only one patient had active lupus and none had active lupus nephritis. Their mean prednisone dose was 10.1 mg/day taken for a mean of 7.2 years. In none was sepsis a contributing factor to their death. All five of these patients had had a recent myocardial infarction at the time of death; in four, ti was the primary cause of death. Mortality in SLE follows a bimodal pattern. Patients who die early in the course of their disease, die with active lupus, receive large doses of steroids and have a remarkable incidence of infection. In those who die late in the course of the disease, death is associated with inactive lupus, long duration of steroid therapy and a striking incidence of myocardial infarction due to atherosclerotic heart disease.

Effect of a topical diclofenac solution for relieving symptoms of primary osteoarthritis of the knee: a randomized controlled trial

Background: Treatment of osteoarthritis with oral NSAID therapy provides pain relief but carries a substantial risk of adverse effects. Topical NSAID therapy offers an alternative to oral treatment, with the potential for a reduced risk of side effects. The objective of this trial was to assess the safety and efficacy of a topical diclofenac solution in relieving the symptoms of primary osteoarthritis of the knee. Methods: We identified 248 men and women from southern Ontario with primary osteoarthritis of the knee and at least moderate pain. The patients were randomly assigned to apply 1 of 3 solutions to their painful knee for 4 weeks: a topical diclofenac solution (1.5% wt/wt diclofenac sodium in a carrier containing dimethyl sulfoxide [DMSO]); a vehicle-control solution (the carrier containing DMSO but no diclofenac); and a placebo solution (a modified carrier with a token amount of DMSO for blinding purposes but no diclofenac). The primary efficacy end point was pain relief, measured by the Western Ontario and McMaster Universities (WOMAC) LK3.0 Osteoarthritis Index pain subscale. Secondary end points were improved physical function and reduced stiffness (measured by the WOMAC subscales), reduced pain on walking and patient global assessment (PGA). Safety was evaluated with clinical and laboratory assessments. Results: In the intent-to-treat group the mean change (and 95% confidence interval [CI]) in pain score from baseline to final assessment was significantly greater for the patients who applied the topical diclofenac solution (–3.9 [– 4.8 to –2.9]) than for those who applied the vehicle-control solution (–2.5 [– 3.3 to –1.7]; p = 0.023) or the placebo solution (–2.5 [–3.3 to –1.7]; p = 0.016). For the secondary variables the topical diclofenac solution also revealed superiority to the vehicle-control and placebo solutions, leading to mean changes (and 95% CIs) of –11.6 (–14.7 to –8.4; p = 0.002 and 0.014, respectively) in physical function, –1.5 (–1.9 to –1.1; p = 0.015 and 0.002, respectively) in stiffness and –0.8 (–1.1 to –0.6; p = 0.003 and 0.015, respectively) in pain on walking. The PGA scores were significantly better for the patients who applied the topical diclofenac solution than for those who applied the other 2 solutions (p = 0.039 and 0.025, respectively). The topical diclofenac solution caused some skin irritation, mostly minor local skin dryness, in 30 (36%) of the 84 patients, but this led to discontinuation of treatment in only 5 (6%) of the cases. The incidence of gastrointestinal events did not differ between the treatment groups. No serious gastrointestinal or renal adverse events were reported or detected by means of laboratory testing. Interpretation: This topical diclofenac solution can provide safe, site-specific treatment for osteoarthritic pain, with only minor local skin irritation and minimal systemic side effects.

Efficacy and safety of topical diclofenac containing dimethyl sulfoxide (DMSO) compared with those of topical placebo, DMSO vehicle and oral diclofenac for knee osteoarthritis

ABSTRACT While topical non‐steroidal anti‐inflammatory drugs are considered safe, their long‐term efficacy for osteoarthritis has been suspect. We conducted a 12‐week, double‐blind, double‐dummy, randomized controlled trial of topical diclofenac (TDiclo) in a vehicle solution containing dimethyl sulfoxide (DMSO) in 775 subjects with radiologically confirmed, symptomatic primary osteoarthritis of the knee. This 5‐arm study compared TDiclo with a placebo solution, the DMSO vehicle, oral diclofenac (ODiclo) and the combination of TDiclo + ODiclo for relieving the signs and symptoms of knee osteoarthritis. Subjects applied study solution, 40 drops four times daily, and took one study tablet daily for 12 weeks. Co‐primary efficacy variables were WOMAC pain and physical function and a patient overall health assessment. Secondary variables were WOMAC stiffness and patient global assessment (PGA) of the knee osteoarthritis. TDiclo was superior to placebo for pain (−6.0 vs. −4.7, P = 0.015), physical function (−15.8 vs. −12.3, P = 0.034), overall health (−0.95 vs. −0.37, P < 0.0001), and PGA (−1.36 vs. −1.01, P = 0.016), and was superior to DMSO vehicle for all efficacy variables. No significant difference was observed between DMSO vehicle and placebo or between TDiclo and ODiclo. The commonest adverse event associated with TDiclo was dry skin (18.2%). Fewer digestive system and laboratory abnormalities were observed with TDiclo than with ODiclo. Addition of TDiclo to ODiclo did not increase the incidence of systemic adverse events. TDiclo in DMSO vehicle is an effective treatment option for knee osteoarthritis with efficacy similar to, but tolerability better than ODiclo. DMSO vehicle was no more efficacious than placebo.

Local delivery of a recombinant adenoassociated vector containing a tumour necrosis factor α antagonist gene in inflammatory arthritis: a phase 1 dose-escalation safety and tolerability study

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 α (TNFα) 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 1×1010 (n = 5) or 1×1011 (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 TNFα 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.

Office capillaroscopy in systemic sclerosis

The aims of this study are to assess the reliability of two office techniques, the ophthalmoscope and the Dermlite® dermatoscope, and to detect nailfold capillaroscopy abnormalities in systemic sclerosis (SSc). Two separate studies were performed. In the first, the nailfolds of two fingers on one hand of 13 SSc patients and two normals were examined by four rheumatologists using an ophthalmoscope. In the second, the nailfolds of the two fingers of each hand of six SSc patients and two normals were examined by six rheumatologists with a Dermlite® dermatoscope. Widefield capillary microscopy was performed by one observer in the ophthalmoscope study to assess validity. The examiners determined the presence or absence of dilated loops, giant capillary loops, and/or avascular areas on each digit. The kappa coefficient was calculated to demonstrate agreement. With the ophtalmoscope, the inter-observer kappa coefficients were 0.43, 0.54, and 0.19; the average intra-observer agreements were 0.61, 0.56, and 0.31; and the ophthalmoscope–microscope agreement were 0.63, 0.52, and <0.1 for dilated capillaries, giant capillaries, and avascular areas, respectively. With the dermatoscope, the kappa values for inter-observer reliability were 0.63, 0.40, and 0.20; and intra-observer reliability was 0.71, 0.55, and 0.40 for dilated capillaries, giant capillaries, and avascular areas, respectively. The ophthalmoscope and the dermatoscope provide moderate to substantial reliability to detect the presence of giant and dilated capillaries but poor inter-observer agreement for avascular areas. The ophthalmoscope is valid when compared to the microscope for detecting giant or dilated capillaries. We conclude that these techniques are useful office tools to detect capillary abnormalities in SSc.

Primary Biliary Cirrhosis, Sicca Complex, and Dysphagia

Abstract. We investigated symptoms suggestive of swallowing problems in patients with primary biliary cirrhosis, some of whom displayed features of sicca complex. A prospective study of 95 consecutive patients with primary biliary cirrhosis was conducted at a single teaching hospital using a questionnaire administered over the telephone. Some symptoms of sicca complex (dry mouth and/or dry eyes) were found in 65 patients (68.4%). Subjective xerostomia alone was present in 45 patients (47.4%). The questionnaire revealed an increase in incidence of dysphagia in xerostomia subjects, affecting 21 of 45 patients, compared with 6 of 50 non-xerostomia patients. Multivariate logistic regression analysis showed that confounding factors such as age, obesity, cigarette smoking, and medications associated with a dry mouth could not explain these findings. Twenty-eight patients complained of hoarseness, 23 of coughing, and 14 of wheezing, all of which were significantly more frequent than in the 50 patients without xerostomia. Heartburn affected 17 xerostomia patients and 15 non-xerostomia patients, indicating no difference in frequency between these two groups, even after age, obesity, cigarette smoking, and medications associated with heartburn were considered in the multivariate analysis. Acid regurgitation, nausea, and vomiting were also similar in frequency between patients with and without xerostomia. Swallowing problems, manifested primarily as dysphagia, are common in primary biliary cirrhosis patients who have subjective xerostomia.

Significance of anticentromere antibody in idiopathic Raynaud's syndrome

Fifty-eight patients with Raynauds syndrome who had no evidence of definite underlying connective tissue disease had serum analyzed for the presence of anticentromere antibody using indirect immunofluorescence techniques on HEp-2 cell lines. Eighteen patients (31 percent) were anticentromere antibody-positive. The anticentromere antibody-positive group demonstrated significantly more frequent digital telangiectases, digital edema, elevated levels of immunoglobulins, and low C4 values. Photoplethysmography revealed significantly diminished blood flow in the anticentromere antibody-positive group. Capillary microscopy revealed significantly increased avascularity and number of dilated loops in the anticentromere antibody-positive group. Giant loops were seen exclusively in the anticentromere antibody-positive group. The clinical findings in the anticentromere antibody-positive group are suggestive of a transition to a connective tissue disease with features of the CREST syndrome.

Time to Disease-modifying Antirheumatic Drug Treatment in Rheumatoid Arthritis and Its Predictors: A National, Multicenter, Retrospective Cohort

Objective. To determine the proportion of patients with rheumatoid arthritis (RA) under rheumatologic care treated with disease-modifying antirheumatic drugs (DMARD) within 6 months from symptom onset and the components of time to treatment and its predictors. Methods. A historical inception cohort of 339 patients with RA randomly selected from 18 rheumatology practices was audited. The proportion that initiated DMARD treatment within 6 months from symptom onset was estimated using Kaplan-Meier analysis. Time to each component of the care pathway was estimated. Multivariable modeling was used to determine predictors of early treatment using 12 preselected variables available in the clinical charts. Bootstrapping was used to validate the model. Results. Within 6 months from symptom onset, 41% (95% CI 36%−46%) of patients were treated with DMARD. The median time to treatment was 8.4 (interquartile range 3.8−24) months. Events preceding rheumatology referral accounted for 78.1% of the time to treatment. The most prominent predictor of increased time to treatment was a concomitant musculoskeletal condition, such as osteoarthritis or fibromyalgia. The significance of other variables was less consistent across the models investigated. Included variables accounted for 0.69 ± 0.03 of the variability in the model. Conclusion. Fewer than 50% of patients with RA are treated with DMARD within 6 months from symptom onset. Time to referral to rheumatology represents the greatest component delay to treatment. Concomitant musculoskeletal condition was the most prominent predictor of delayed initiation of DMARD. Implications of these and other findings warrant further investigation.

Whole stimulated salivary flow: Correlation with the pathology of inflammation and damage in minor salivary gland biopsy specimens from patients with primary Sjögren's syndrome but not patients with sicca

OBJECTIVE To determine which measure of the salivary flow rate, stimulated or unstimulated, is most strongly associated with pathologic changes in minor salivary gland (MSG) biopsy specimens, and to explore the correlation of salivary flow with oral surface damage, disease duration, and symptom severity in patients with primary Sjögrens syndrome (SS). METHODS In all patients (n = 32), a biopsy of the MSG was performed, and stimulated salivary flow was assessed. Beginning in 2002, unstimulated salivary flow was also assessed. Scores for the severity of symptoms, according to the decayed/missing/filled teeth (DMF) index, were recorded. Associations between measures of salivary flow and covariates characterizing pathology were examined. RESULTS A definite association between stimulated salivary flow and the MSG focus score, the grade of MSG fibrosis, the duration of dry mouth symptoms, and the DMF score was observed. In contrast, unstimulated salivary flow was not associated with fibrosis, atrophy, the DMF score, or the duration of dry mouth symptoms. In patients with primary SS, the DMF score was associated with pathologic changes in the MSG. Among patients with sicca, 57.9% had an abnormal unstimulated salivary flow rate (versus 82.4% of patients with primary SS), and 15.2% had an abnormal stimulated salivary flow rate (versus 61.8% of patients with primary SS). Among patients with sicca, neither stimulated salivary flow nor unstimulated salivary flow was associated with the degree of fibrosis or atrophy or with the DMF score. CONCLUSION Compared with unstimulated salivary flow, stimulated salivary flow appeared to be a better measure of inflammation (according to the focus score) and fibrosis. In patients with sicca, the unstimulated salivary flow rate appeared to be abnormal more commonly compared with the stimulated salivary flow rate. In the future, stimulated salivary flow may serve as a noninvasive surrogate biomarker of inflammation and fibrosis as well as a measure of response to treatment in patients with primary SS.

Rose Bengal Staining of the Temporal Conjunctiva Differentiates Sjögren's Syndrome from Keratoconjunctivitis Sicca

PURPOSE To compare the clinical presentation of 231 patients with primary Sjögrens syndrome (pSS) with 89 patients with aqueous-deficient dry eye (keratoconjunctivitis sicca; KCS), to determine those procedures that best differentiate these groups in the eye care clinic. METHODS The records of all patients seen at the University Health Network Sjögrens Syndrome Clinic from October 1992 to July 2006 were reviewed and documented. The diagnosis of pSS was based on the AECC (American European Consensus Criteria) of 2002. KCS control subjects were non-SS patients with symptoms of dry eye and Schirmer scores of <or=10 mm in 5 minutes in at least one eye. There were 90 variables used in the analysis of the total database. Recursive partitioning was used to generate tree diagrams that demonstrated which characteristics best distinguished pSS from KCS. RESULTS Recursive partitioning of the full database demonstrated that the serum immunoglobulin Ro and the status of the salivary gland biopsy were most important in distinguishing pSS and KCS. The presence of rose bengal staining of the temporal conjunctiva was the most important noninvasive ocular variable that separated the groups. Total rose bengal staining also improved sensitivity. When only noninvasive techniques were used, staining of the temporal conjunctiva and severity of dry mouth symptoms were the major factors in distinguishing pSS from KCS. CONCLUSIONS Rose bengal staining of the ocular surface is an important observation in the detection of SS and the differentiation of pSS and KCS.