John J. Condemi

Omalizumab in Severe Allergic Asthma Inadequately Controlled With Standard Therapy: A Randomized Trial

BACKGROUND Inhaled corticosteroids (ICS) and long-acting β(2)-agonists (LABAs) are recommended in patients with asthma that is not well-controlled; however, many patients continue to have inadequately controlled asthma despite this therapy. OBJECTIVE To evaluate the efficacy and safety of omalizumab in patients with inadequately controlled severe asthma who are receiving high-dose ICS and LABAs, with or without additional controller therapy. DESIGN Prospective, multicenter, randomized, parallel-group, double-blind, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00314575). SETTING 193 investigational sites in the United States and 4 sites in Canada. PATIENTS 850 patients aged 12 to 75 years who had inadequately controlled asthma despite treatment with high-dose ICS plus LABAs, with or without other controllers. INTERVENTION Omalizumab (n = 427) or placebo (n = 423) was added to existing medication regimens for 48 weeks. MEASUREMENTS The primary end point was the rate of protocol-defined exacerbations over the study period. Secondary efficacy end points included the change from baseline to week 48 in mean daily number of puffs of albuterol, mean total asthma symptom score, and mean overall score on the standardized version of the Asthma Quality of Life Questionnaire (AQLQ[S]). Safety end points included the frequency and severity of treatment-emergent adverse events. RESULTS During 48 weeks, the rate of protocol-defined asthma exacerbations was significantly reduced for omalizumab compared with placebo (0.66 vs. 0.88 per patient; P = 0.006), representing a 25% relative reduction (incidence rate ratio, 0.75 [95% CI, 0.61 to 0.92]). Omalizumab improved mean AQLQ(S) scores (0.29 point [CI, 0.15 to 0.43]), reduced mean daily albuterol puffs (-0.27 puff/d [CI, -0.49 to -0.04 puff/d]), and decreased mean asthma symptom score (-0.26 [CI, -0.42 to -0.10]) compared with placebo during the 48-week study period. The incidence of adverse events (80.4% vs. 79.5%) and serious adverse events (9.3% vs. 10.5%) were similar in the omalizumab and placebo groups, respectively. LIMITATIONS The results are limited by early patient discontinuation (20.8%). The study was not powered to detect rare safety events or the treatment effect in the oral corticosteroid subgroup. CONCLUSION In this study, omalizumab provided additional clinical benefit for patients with severe allergic asthma that is inadequately controlled with high-dose ICS and LABA therapy. PRIMARY FUNDING SOURCE Genentech and Novartis Pharmaceuticals.

Procainamide-induced lupus erythematosus: Clinical and laboratory observations☆

Abstract Procainamide hydrochloride in conventional doses can elicit a syndrome closely resembling systemic lupus erythematosus (SLE). The most frequent symptoms are polyarthralgia, myalgia, fever and pleurisy. Renal disease is notably absent. Conventional serologic tests give results similar to those in SLE except that serum complement is not decreased. A photodynamically induced complex between deoxyribonucleic acid (DNA) and procainamide is described which may be useful as a pathogenetic model. By a globulin precipitation method, patients with procainamide-induced lupus appear to have anti-body to denatured DNA and nucleohistone, but in contrast to idiopathic SLE, have little or no antibody to native DNA.

The addition of salmeterol to fluticasone propionate versus increasing the dose of fluticasone propionate in patients with persistent asthma

BACKGROUND Current treatment guidelines define inhaled corticosteroids such as fluticasone propionate (FP) as the cornerstone of anti-inflammatory therapy for asthma. OBJECTIVE The objective was to evaluate the efficacy and safety of adding salmeterol therapy to patients who remain symptomatic while receiving FP as compared with increasing the dose of FP. METHODS In a multicenter, double-blind study conducted over 24-weeks, 437 patients aged 12 years and older and receiving FP 88 microg twice daily for 2 to 4 weeks were randomly assigned to receive either salmeterol (42 microg twice daily) or FP 220 microg twice daily. The primary efficacy endpoint was morning peak expiratory flow. Secondary measures included FEV1, symptom scores, nighttime awakenings, and supplemental albuterol use. Safety was assessed by reported adverse events and asthma exacerbations. RESULTS The addition of salmeterol resulted in significantly greater improvements in lung function and symptom control as compared with increasing the dose of FP. Over weeks 1 to 24, morning peak expiratory flow was increased by 47 L/min from baseline with salmeterol treatment as compared with 24 L/min with FP 220 microg twice daily (P < .001) while the percent of symptom-free days increased from baseline by 26% of days as compared with 10% of days (P < .001). The adverse event profiles were similar between groups and fewer exacerbations were reported with salmeterol treatment. CONCLUSIONS The addition of salmeterol therapy to patients who remain symptomatic while using a low dose of FP was clinically and statistically superior to increasing the dose of FP.

Abetimus sodium for renal flare in systemic lupus erythematosus: Results of a randomized, controlled phase III trial†

OBJECTIVE To investigate whether treatment with abetimus delays renal flare in patients with lupus nephritis. Secondary objectives included evaluation of the effect of abetimus on C3 levels, anti-double-stranded DNA (anti-dsDNA) antibody levels, use of high-dose corticosteroids and/or cyclophosphamide, and major systemic lupus erythematosus (SLE) flare. METHODS We conducted a randomized, placebo-controlled study of treatment with abetimus at 100 mg/week for up to 22 months in SLE patients. Three hundred seventeen patients with a history of renal flare and anti-dsDNA levels >15 IU/ml were randomized to a treatment group (158 abetimus, 159 placebo); 298 (94%) were enrolled in the intent-to-treat (ITT) population (145 abetimus, 153 placebo), based on the presence of high-affinity antibodies for the oligonucleotide epitope of abetimus at baseline screening. RESULTS Abetimus did not significantly prolong time to renal flare, time to initiation of high-dose corticosteroid and/or cyclophosphamide treatment, or time to major SLE flare. However, there were 25% fewer renal flares in the abetimus group compared with the placebo group (17 of 145 abetimus-treated patients [12%] versus 24 of 153 placebo-treated patients [16%]). Abetimus treatment decreased anti-dsDNA antibody levels (P < 0.0001), and reductions in anti-dsDNA levels were associated with increases in C3 levels (P < 0.0001). More patients in the abetimus group experienced > or =50% reductions in proteinuria at 1 year, compared with the placebo group (nominal P = 0.047). Trends toward reduced rates of renal flare and major SLE flare were noted in patients treated with abetimus who had impaired renal function at baseline. Treatment with abetimus for up to 22 months was well tolerated. CONCLUSION Abetimus at 100 mg/week significantly reduced anti-dsDNA antibody levels but did not significantly prolong time to renal flare when compared with placebo. Multiple positive trends in renal end points were observed in the abetimus treatment group.

Antinuclear antibody induced by procainamide. A prospective study.

Abstract Sixteen patients were followed prospectively for the possible development of the lupus syndrome while being treated for cardiac arrhythmias with conventional doses of procainamide hydrochloride. In eight antinuclear antibody developed. Two of the eight had positive slide reactions with nucleoprotein-coated latex particles. In one of these two rheumatoid factor (anti-IgG) activity in low titer also developed. Another two of the eight showed symptoms consistent with the lupus syndrome. The high percentage of patients in this study in whom antinuclear antibody developed suggests that the lupus response appearing in patients treated with procainamide is not restricted to the small proportion of the population that may have a genetic predisposition to idiopathic lupus erythematosus.

Penicillin resensitization among hospitalized patients

The purpose of this study was to determine the frequency of resensitization to penicillin after oral or intravenous treatment with beta-lactam antibiotics in hospitalized patients with histories of penicillin allergy. Seventeen adults (aged 24 to 76 years) and one child (aged 10 years) were treated intravenously and/or orally with beta-lactam antibiotics after negative skin tests were obtained with benzylpenicilloyl polylysine, potassium penicillin G, and alkaline hydrolysis products of penicillin G as minor determinant mixture. Repeat skin testing was performed 1 to 12 months after the therapy. Three patients (16%) became skin test positive after the treatment. Two patients reacted to potassium penicillin G alone, and the other patient reacted to benzylpenicilloyl polylysine and minor determinant mixture. These three patients were among the 15 patients who were treated with intravenous antibiotics. This study reveals a high percentage of skin test conversion after intravenously administered penicillin therapy and confirms the present practice of advising patients with a history of penicillin allergy who have successfully completed penicillin treatment to have a repeat skin test before future exposure to beta-lactam antibiotics.

Long‐term safety profile of belimumab plus standard therapy in patients with systemic lupus erythematosus

OBJECTIVE To evaluate the safety profile of long-term belimumab therapy combined with standard therapy for systemic lupus erythematosus (SLE) in patients with active disease. METHODS Patients who were randomized to receive intravenous placebo or belimumab 1, 4, or 10 mg/kg, plus standard therapy, and completed the initial 52-week double-blind treatment period were then allowed to enter a 24-week open-label extension phase. During the extension period, patients in the belimumab group either received the same dose or were switched to 10 mg/kg and patients in the placebo group were switched to belimumab 10 mg/kg. Patients who achieved a satisfactory response during the 24-week extension period were allowed to participate in the long-term continuation study of monthly belimumab 10 mg/kg. Adverse events (AEs) and abnormal laboratory results were analyzed per 100 patient-years in 1-year intervals. RESULTS Of the 364 patients who completed the 52-week double-blind treatment period, 345 entered the 24-week extension, and 296 continued treatment with belimumab in the long-term continuation study. Safety data through 4 years of belimumab exposure (1,165 cumulative patient-years) are reported. Incidence rates of AEs, severe/serious AEs, infusion reactions, infections, malignancies, grades 3/4 laboratory abnormalities, and discontinuations due to AEs were stable or declined during 4-year belimumab exposure. The most common AEs included arthralgia, upper respiratory tract infection, headache, fatigue, and nausea. Serious infusion reactions were rare: only 1 occurred during the 4-year followup period. Rates of serious infection decreased from 5.9/100 patient-years to 3.4/100 patient-years, and no specific type of infection predominated. CONCLUSION Belimumab added to standard therapy was generally well-tolerated over the 4-year treatment period in patients with SLE, which suggests that belimumab can be administered long term with an acceptable safety profile.

Raynaud's phenomenon of the lung☆

To determine if pulmonary vessels develop vasospasm during Raynauds phenomenon, digital vasospasm was induced by hand immersion in 15 degrees C water (cold pressor test) in 17 subjects, and pulmonary function was measured during the subsequent 120 minutes. Five healthy persons were control subjects, seven subjects had well documented systemic disorders associated with Raynauds phenomenon (secondary Raynauds), and five subjects had a history of Raynauds phenomenon but no evidence of an associated disorder (primary Raynauds). The only measure of pulmonary function that changed significantly following cold pressor testing was carbon monoxide diffusing capacity. Subjects with primary Raynauds phenomenon had normal baseline carbon monoxide diffusing capacity (23.7 +/- 4.6 ml/minute/mm Hg) but demonstrated significant decreases (p less than 0.05) at 15 minutes (21.2 +/- 3.5 ml/minute/mm Hg), 45 minutes (19.5 +/- 3.7 ml/minute/mm Hg), and 120 minutes (17.1 +/- 2.1 ml/minute/mm Hg) after cold pressor testing. Subjects with secondary Raynauds phenomenon had low baseline carbon monoxide diffusing capacity (71 percent predicted) and showed no significant change following cold pressor testing. These findings indicate that digital vasospasm in patients with primary Raynauds phenomenon is part of a systemic vascular response that includes a decrease in the size of the pulmonary capillary bed.

Immunologic Reactions of Bronchial Tissues in Asthma

Abstract Bronchial tissues obtained from 18 patients with bronchial asthma showed thickened basement membranes that stained positively for immunoglobulins in five of 11 biopsy specimens and six of seven autopsy specimens. Complement (C3) was identified in the deposit in three cases. IgM was the immunoglobulin most frequently seen. Similar studies in controls demonstrated no basement-membrane thickening, but fluorescence with antiserum to IgG was found in 10 per cent and to IgM in 3 per cent. These deposits beneath the bronchial basement membrane may represent precipitation of antibody from serum with respiratory antigens from the bronchial lumen, a process that appears to occur frequently in asthma and less frequently in other forms of pulmonary disease.

Vascular disease in the antiphospholipid syndrome: A comparison with the patient population with atherosclerosis

The antiphospholipid syndrome was diagnosed in 19 of 1078 patients treated between 1987 and 1991. All patients with antiphospholipid syndrome had either anticardiolipin antibody (16/19) or lupus anticoagulant (10/19); three patients had thrombocytopenia, eight patients had a prolonged partial thromboplastin time, and 10 patients had an elevated erythrocyte sedimentation rate. The most common site of involvement was the cerebral circulation (nine patients), manifested by transient ischemic attacks or stroke. Eight patients had upper extremity disease, characterized by symptoms of Raynauds phenomenon, with angiographic lesions involving the brachial, radial, ulnar, and/or digital arteries. Lower extremity disease occurred in seven patients, with clinical presentations similar to those of atherosclerosis and varying angiographic patterns. In comparison with the population having atherosclerosis, patients with arterial manifestations of antiphospholipid syndrome were more likely to be women (13 of 19 versus 411 of 1078, p less than 0.02), were significantly younger (46.2 years versus 63.6 years, p less than 0.0001), did not smoke (1 of 19 patients versus 700 of 1078, p less than 0.0001), had a higher percentage of upper extremity involvement (8 of 18 versus 13 of 1078, p less than 0.0001), and had a higher incidence of early graft failure (9 of 12 grafts versus 13 of 371 grafts, p less than 0.0001). The syndrome is associated with the repetitive failure of vascular reconstructions and occlusion of native vessels. Antiphospholipid syndrome should therefore be suspected in young, female, nonsmokers with vascular disease, especially those with involvement of the upper extremity, cerebrovascular disease with normal findings on extracranial carotid angiography, and premature graft failure.