Adalimumab for long-term treatment of psoriatic arthritis: 2-year data from the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT).

OBJECTIVE: To evaluate the long-term effectiveness and tolerability of adalimumab in the treatment of psoriatic arthritis (PsA). METHODS: Patients with PsA who completed a 24-week, double-blind study of adalimumab versus placebo were eligible to enroll in an open-label extension study and receive adalimumab 40 mg subcutaneously every other week for up to an additional 120 weeks. At the time of this analysis, available efficacy evaluations throughout 2 years of treatment (n = 245) included American College of Rheumatology (ACR) 20%, 50% and 70% improvement scores, measures of joint disease and skin disease, disability and quality of life; modified total Sharp scores (mTSS) were available for 2.75 years of treatment for patients who received adalimumab in the 24-week study. RESULTS: After 24 weeks of double-blind treatment, the mean change in mTSS was -0.2 for the adalimumab group (N = 144) and 1.0 for the placebo group (N = 152; p<0.001), and outcomes for all individual ACR component variables were significantly improved in adalimumab compared with placebo-treated patients. Compared with 24-week responses, inhibition of radiographic progression and improvements in joint disease were maintained in most patients during long-term, open-label adalimumab treatment. Also, improvements in skin disease were maintained, with >20% of patients achieving the strict criterion of psoriasis area and severity index 100. The nature and frequency of adverse events during long-term adalimumab treatment were consistent with the safety profile during short-term treatment. CONCLUSIONS: The clinical and radiographic efficacy of adalimumab demonstrated during short-term treatment was sustained during long-term treatment. Adalimumab has a favourable risk-benefit profile in patients with PsA. TRIAL REGISTRATION NUMBER: NCT00195689.

The cytotoxicity of leukocytes and lymphocytes from patients with rheumatoid arthritis for synovial cells.

Unseparated peripheral blood leukocytes obtained from patients with rheumatoid arthritis (RA) were cytotoxic for synovial cells. The cytotoxic reactions produced by RA leukocytes were more frequent and of greater magnitude than cytotoxicity induced by leukocytes from normal persons and patients with other diseases, primarily connective tissue diseases. Furthermore, the cytotoxic activity of RA leukocytes was greater for RA synovial cells than for nonrheumatoid synovial cells, in contrast to the cytotoxicity of other leukocytes, which did not discriminate between synovial cells according to their origin. Tests with purified lymphocytes showed that the cytotoxicity of unseparated leukocytes directed against RA synovial cells was due to lymphocyte cytotoxicity. These data are consistent with the possibility that sensitized lymphocytes from patients with RA recognize a distinctive antigen present on rheumatoid synovial cells.

Antiglobulins and glomerulonephritis. Classification of patients by the reactivity of their sera and renal tissue with aggregated and native human IgG.

Renal biopsies and sera from 41 consecutive patients were studied to determine if antiglobulins were found more frequently in patients with severely diseased glomeruli. Patients were classified into three groups: A, 12 patients with normal renal function and minimal histological evidence of glomerular disease; B, 18 patients with normal renal function but distinctly abnormal biopsies (16 cases) or proteinuria greater than 16 g/24 h (2 cases); and C, 11 patients with both decreased function and abnormal histology. Positive latex fixation tests for rheumatoid factor were found in none of group A, four (22%) of group B, and five (45%) of group C patients. Sera heated 56 degrees C for 30 min contained precipitins reactive with heat-aggregated IgG in none of seven group A, five of ten (50%) group B, and four of ten (40%) group C patients. The quantity of 135I-labeled patient globulin which bound to immunoadsorbents coated with Cohn fraction II in competition with an equal quantity of 131I-labeled globulin from pooled plasma of normal donors was also measured. Patient globulins bound in significantly greater quantity (greater than or equal 2 SD) than the control in none of the group A, 7 of 18 (39%) group B, and 7 of 11 (64%) group C patients. Renal biopsies from 18 patients were also studied for the ability to fix fluorescein-conjugated heat-aggregated and native human IgG. None of nine tissue specimens from group A or B patients fixed either fluorescein-conjugated protein whereas tissue from eight of nine group C patients showed glomerular localization of one or both reagents. Severity of disease as judged by renal function and glomerular histology correlated with the presence of tissue-fixed and serum antiglobulins. Thus, detection of antiglobulins in glomeruli and sera of patients with glomerulonephritis may indicate a relatively poor prognosis and raises the possibility that antiglobulins may be implicated in some way in the pathophysiology of human glomerulonephritis.

Infectious arthritis.

One hundred thirteen patients with 120 episodes of septic arthritis were seen during a 14-year period. The most common bacteria cultured from joint fluid or blood during the acute episodes were gonococci, staphylococci, and streptococci. Seventeen other bacteria were the infecting organisms in one or more cases each. Other infections and medical conditions frequently were present. In some instances the septic arthritis was a complication of another infection. In other patients septic arthritis appeared to occur because of diminished resistance to infection. The majority of patients responded well to medical treatment, but eight died and 26 had persistence of articular pain at follow-up examination.

Ranitidine protects against gastroduodenal mucosal damage associated with chronic aspirin therapy.

A randomized, double-blind, placebo-controlled study examined whether concomitant administration of ranitidine could protect against the gastroduodenal mucosal damage associated with long-term aspirin therapy in healthy men. Twenty-four subjects received ranitidine (150 mg twice daily) plus aspirin (650 mg four times daily), and 19 received placebo twice daily plus aspirin (650 mg four times daily) for four weeks. Gastric injury and duodenal injury were assessed separately according to a numerical rating scale for incidence and severity of lesions observed during endoscopic examinations at baseline and after four weeks of treatment. The ranitidine/aspirin group had significantly less mucosal damage in the stomach and duodenum than the placebo/aspirin group. Mean serum salicylate levels were similar between treatment groups after two and four weeks of aspirin therapy. Therefore, the protective effect of ranitidine was achieved with no compromise in salicylate absorption.

Multicenter comparison of naproxen and indomethacin in rheumatoid arthritis.

In a double-blind, crossover study, naproxen, 250 mg twice a day, naproxen, 500 mg taken at bedtime, and indomethacin, 25 mg four times a day, were compared in 132 patients with rheumatoid arthritis; six centers participated in the study. Objective indices of arthritis activity, such as number of clinically active joints, walking time, and duration of morning stiffness, were nearly identical for the three treatment regimens. Of particular interest was the observation that efficacy of a single daily dose of naproxen was comparable to that of the twice-daily dosage. Naproxen was better tolerated than indomethacin, as shown by a statistically significant difference in the incidence of CNS complaints.

Polyarthritis, polyarteritis and hepatitis B.

An association between viral hepatitis and two rheumatic disease syndromes has been observed. Twenty-nine patients manifested a transient polyarthritis, sometimes associated with a rash (Group I). Ten patients were seen with a multisystem disease (Group II). Histologic evidence of arteritis or glomerulonephritis was present in seven of ten patients with multisystem disease. Liver tissue from 18 patients showed morphologic evidence of hepatitis with viral features in 9 of 10 patients in Group I and in 6 of 8 patients in Group II. Hepatitis B surface antigen (HBsAg) and/or antibody to HBsAg were detected in sera of all 39 patients. Abnormal liver functions were present in 36. Twelve Group I patients and 2 Group II patients became jaundiced. Rheumatoid factor was present in sera of seven patients in each group. The third component of complement (C3) was depressed in 13 patients in Group I and 7 patients in Group II. The fourth component of complement (C4) was decreased in 8 of 21 Group I and 3 of 7 Group II patients. Synovial fluid C3 was decreased in 2 of 11 Group I and 1 of 4 Group II patient's fluids. Articular inflammation in patients with transient polyarthritis responded in three to seven days to aspirin, acetominophen and/or bedrest alone and rashes disappeared spontaneously. Patients with multisystem disease generally had a prolonged illness and responded somewhat unpredictably to prednisone or a combination of prednisone and cyclophosphamide.

Effect of plasma exchange on circulating immune complexes and antibody formation in patients treated with cyclophosphamide and prednisone.

A patient with systemic lupus erythematosus (SLE) and a patient with an immune complex disease resembling Goodpasture's syndrome were treated with cyclophosphamide, prednisone and repeated plasma exchanges. Circulating immune complexes decreased, and symptoms of central nervous system disease remitted for up to 15 to 20 days after plasma exchange in the patient with SLE. In vitro lymphocyte blastogenic responses to antigens were also transiently increased on two occasions following treatment. In the second patient, decreases in circulating immune complexes and clinical improvement were ascribed chiefly to immunosuppressive drug treatment. Serum antibody to keyhole limpet hemocyanin was relatively unaffected by plasma exchange in both patients. These results suggest that plasma exchange may help to deplete circulating immune complexes or alter the equilibrium between soluble antigen and antibody which causes complexes to form and circulate. It may be less effective in reducing circulating antibody levels in patients who continue to produce new antibody.

Therapeutic considerations in respiratory muscle function.

Inspiratory muscle function is impaired in many patients with severe COPD. This functional impairment often leads to hypercapnic respiratory failure via inspiratory muscle fatigue. Factors responsible for this functional impairment are: (1) an excessive mechanical load (high resistance and low compliance) for the inspiratory muscles to overcome; (2) the low, flat configuration of the diaphragm owing to lung hyperinflation; (3) reduced inspiratory muscle blood flow relative to the increased respiratory work requirement; and (4) tachypnea which increases the duty cycle (TI/Ttot) for inspiratory muscles, increases hyperinflation, wastes ventilation, and otherwise causes deterioration of gas exchange. Therapy is directed toward improving inspiratory muscle function and has three strategic goals: (1) to reduce the load imposed on the inspiratory muscles and reduce their mechanical disadvantage; (2) to improve the contractile characteristics of the inspiratory muscles; and (3) if goals 1 and 2 cannot be attained otherwise, to rest the inspiratory muscles using mechanical ventilation. Inspiratory muscle training offers promise as a means of preventing hypercapnic respiratory failure. Available data suggest that some COPD patients benefit from it. To be determined are which patients will benefit from it and which will not, as well as which training regimens are most effective.

Dirhythmic breathing.

Four patients with severe chronic obstructive lung disease and recent respiratory failure are described in whom two distinct simultaneous respiratory rhythms were identified, one at 8 to 13 breaths per minute and the other at 39 to 65 per minute. Magnetometer measurements of thoracoabdominal motion together with simultaneous electromyograms of multiple inspiratory muscles suggested that both rhythms were the result of coordinated action of several inspiratory muscles. We suggest that this phenomenon, which we have called dirhythmic breathing, results from the conflicting influence upon respiratory centers and motoneurons of two or more stimuli, some favoring rapid shallow breaths and others slow deep breaths.

Effect of metabolic acidosis upon sleep apnea.

The effects of metabolic acidosis upon the pattern of apnea during sleep were assessed in ten sleep apnea patients. Four had pure obstructive apnea, two pure central apnea, and four had mixed apnea. Acidosis was induced with acetazolamide. Acid-base shifts had little effect in pure obstructive and pure central apnea, but had a significant effect in mixed apnea. In two of the mixed apneic patients, metabolic acidosis converted predominantly central apnea into nearly pure obstructive apnea, prolonging apneic periods and worsening hypoxemia. A suggested explanation for this is the greater stimulating effect of acidosis upon the lower bellows muscles than upon the muscles which act to maintain patency of the upper airways. The observation that some patients with mixed sleep apnea appear to have central apnea while relatively alkalotic and obstructive apnea while acidotic emphasizes the need for more careful and detailed characterization of apneic disorders with respect to their responses to body states and therapeutic agents.

Respiratory failure due to Strongyloides stercoralis in a patient with a renal transplant.

We report a case of respiratory failure caused by Strongyloides stercoralis in a patient with a renal transplant; the respiratory failure showed dramatic response to therapy with thiabendazole. The clinical aspects of infestation with S stercoralis in the immunocompromised host are discussed, and features are demonstrated which may have significant implications concerning primary treatment and prophylaxis.

Respiratory muscle strength in congestive heart failure.

In experimental animals, conditions which drastically decrease cardiac output may reduce the strength and endurance of respiratory muscles leading to hypercapnic respiratory failure. Because patients with chronic CHF have reduced cardiac output and vital capacity (FVC), we measured PImax and PEmax and maximal handgrip force in 16 patients with CHF and 18 AMNs. The patients with CHF had a mean left ventricular ejection fraction of 26 +/- 7 percent. Maximal respiratory pressures were significantly reduced; group mean values (+/- SD) for PImax at FRC were 41.4 +/- 5.6 cm H2O (CHF) and 102.1 +/- 27.4 cm H2O (AMN) (p less than 0.001), with PImax values in five patients with CHF as low as 20 to 30 cm H2O. In most patients, PEmax was comparably reduced. Handgrip force was less dramatically reduced, suggesting selective respiratory muscle weakness. Possible explanations include reduction in respiratory muscle blood flow or generalized muscular atrophy and weakness related to cardiac cachexia.

Dynamic imaging of the respiratory cycle with 81mKr.

To define the regional ventilation of the human lung, subjects were monitored with a gamma camera, while breathing air labeled with radioactive 81mKr which is being continuously eluted from a generator. The information observed is displayed as a reiterated multiframe moving picture. This is accomplished by storing the information from multiple breaths, selecting acceptable cycles (determined by the duration of inspiration and expiration and the amplitude to extremes of the cycles), and normalizing the usable information and converting the summed data into sequential frames, which are repeatedly shown on a video screen from computer memory.

Use of the respiratory magnetometer in diagnosis and classification of sleep apnea.

Seventeen patients with sleep apnea were studied with reference to the frequency and duration of apneic episodies, the mechanism of the apnea and the extent to which oxygen saturation was depressed by the apnea. In all patients, esophageal pressure was recorded simultaneously with respiratory magnetometer records of rib cage and abdominal motion. Thermistor records from the nose and mouth indicated the presence of apnea. Nine patients had purely obstructive apnea and eight a mixture of central and obstructive apnea. In all instances the magnetometer records alone permitted distinction between obstructive and central apnea. Inspiratory efforts against an occluded airway produced a very different pattern of motion when compared to unobstructed breathing or to central apnea. We propose that magnetometer monitoring of thoracoabdominal motion indicates upper airway obstruction reliably and provides a noninvasive and thus more acceptable alternative to esophageal pressure recording for detecting upper airway obstructive apnea.

The immunology of arthritis: interpretation of serologic studies. (Summary of presentation).

Results of serologic tests in rheumatic disease require good judgment in interpretation, based upon familiarity with the present knowledge of immunologic mechanisms, including the action of antibodies, auto-antibodies, T-cells and B-cells.

Effect of muscle length on electromyogram in a canine diaphragm strip preparation.

The relationship between diaphragm electromyogram (EMG), isometric force, and length was studied in the canine diaphragm strip with intact blood supply and innervation under three conditions: supramaximal tetanic (100 Hz) phrenic nerve stimulation (STPS; n = 12), supramaximal phrenic stimulation at 25 Hz (n = 15), and submaximal phrenic stimulation at 25 Hz (n = 5). In the same preparation, the EMG-length relationship was also examined with direct muscle stimulation when the neuromuscular junction was blocked. EMG from three different sites and via two types of electrodes (direct or sewn-in and surface) were recorded during isometric contraction at different lengths. Direct EMGs were recorded from two bipolar electrodes sutured into the strip, one near its central end and the other near its costal end. A third EMG electrode configuration summed potentials from the whole strip by recording potentials between central and costal sites. Surface EMGs were recorded by a bipolar spring clip electrode that made contact with upper and lower surfaces of the muscle strip with light pressure. In all conditions of stimulation with different types of electrodes, all EMGs decreased significantly (P less than 0.05) when muscle length was changed from 50 to 120% of resting length (L0). Minimal and maximal force outputs were observed at 50 and 120% of L0, respectively, in all experiments. The results of this study indicated that the muscle length is a significant variable that affects the EMG recording and that the diaphragmatic EMG may not be an accurate reflection of phrenic nerve activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Structural change of the thorax in chronic obstructive pulmonary disease.

This study examines structural changes of the thorax in hyperinflated subjects with chronic obstructive pulmonary disease (COPD). Age-matched normal subjects were used for comparison. Thoracic dimensions were determined using anteroposterior and lateral chest radiographs performed at total lung capacity, functional residual capacity, and residual volume. Rib cage dimensions (lateral diameter, rib angle, anteroposterior diameter) and diaphragm position were determined at each lung volume. There were no significant differences in rib cage dimension between the COPD and normal subjects for all lung volumes. In contrast, the diaphragm was significantly lower in the COPD subjects. The change of rib cage dimensions in the COPD subjects (for a similar volume change) was not different from that in normal subjects, whereas the change of diaphragm position in the COPD subjects (for a similar volume change) was reduced. In conclusion, the primary structural change of the thorax in COPD with chronic hyperinflation is confined to the diaphragm, with no appreciable structural change in the rib cage.

The rib cage in normal and emphysematous subjects: a roentgenographic approach.

The configuration and motion of the bony rib cage were studied from lateral chest roentgenograms in 10 young normal subjects (YN), 12 elderly normal subjects, and 12 hyperinflated emphysematous patients [chronic obstructive pulmonary disease subjects (COPD), mean total lung capacity (TLC) 133% of predicted]. The acute angles formed by the fourth through seventh ribs with an axial reference plane were measured at residual volume, functional residual capacity, and TLC in both supine and standing positions and correlated with corresponding lung volumes. both rib angles (RA) and changes in RA with lung volume were greatest with the fourth rib and decreased progressively going down (caudad) the chest. At TLC the RA of upper ribs was significantly less in EN and significantly greater in COPD than in YN. RA's were greater supine than standing. When RA information was used together with autopsy data on the angles formed by intercostal muscles with adjacent ribs, intercostal muscle lengths in hyperinflation could be calculated. Computed intercostal muscle length data suggested that hyperinflation should not be associated with degrees of intercostal muscle shortening or overstretching, that would interfere seriously with tension generation.

Use and acceptance of ventolin Rotacaps and the Rotahaler in 1235 asthmatic patients.

This open-label study was performed to characterize the acceptance, reliability, and adverse event profile of a dry powder delivery system for albuterol. A total of 1235 asthmatic outpatients, aged 11 to 84 years, were studied for 1 month. Each patient enrolled was documented as having a specific complaint concerning the use of a standard metered-dose inhaler. At the end of 4 weeks of treatment, the patients completed a questionnaire to record their opinions and preferences. The results were as follows: 93% stated that Rotacaps were easy to use; 92% that they could use Rotacaps during an asthma attack; 99% that they had no problems with breakage of the device; 94% that the drug tasted pleasant or had no taste; 70% that they could inhale a full dose with one breath; and 79% that Rotacaps were at least as effective as the metered-dose inhaler they had used previously. Drug-related adverse events were reported by 6% of the patients; no single event was reported by more than 1% of the patients. The results indicate that Rotacaps are a safe, effective, and well-accepted alternative to metered-dose inhalers in asthmatic patients.