Double‐blind randomized controlled clinical trial of the interleukin‐6 receptor antagonist,tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate

Objective

To establish the safety and efficacy of repeat infusions of tocilizumab (previously known as MRA), a humanized anti–interleukin‐6 (IL‐6) receptor antibody, alone and in combination with methotrexate (MTX), for the treatment of rheumatoid arthritis (RA).

Methods

The study group comprised 359 patients with active RA in whom the response to MTX was inadequate. During a stabilization period, these patients received their current dose of MTX for at least 4 weeks. Following stabilization, they were randomized to 1 of 7 treatment arms, as follows: tocilizumab at doses of 2 mg/kg, 4 mg/kg, or 8 mg/kg either as monotherapy or in combination with MTX, or MTX plus placebo.

Results

A 20% response (improvement) according to the American College of Rheumatology criteria (ACR20 response) was achieved by 61% and 63% of patients receiving 4 mg/kg and 8 mg/kg of tocilizumab as monotherapy, respectively, and by 63% and 74% of patients receiving those doses of tocilizumab plus MTX, respectively, compared with 41% of patients receiving placebo plus MTX. Statistically significant ACR50 and ACR70 responses were observed in patients receiving combination therapy with either 4 mg/kg or 8 mg/kg of tocilizumab plus MTX (P < 0.05). A dose‐related reduction in the Disease Activity Score in 28 joints was observed from week 4 onward, in all patients except those receiving monotherapy with 2 mg/kg of tocilizumab. In the majority of patients who received 8 mg/kg of tocilizumab, the C‐reactive protein level/erythrocyte sedimentation rate normalized, while placebo plus MTX had little effect on these laboratory parameters. Tocilizumab was mostly well tolerated, with a safety profile similar to that of other biologic and immunosuppressive therapies. Alanine transaminase and aspartate transaminase levels followed a sawtooth pattern (rising and falling between infusions). There were moderate but reversible increases in the nonfasting total cholesterol and triglyceride levels and reversible reductions in the high‐density lipoprotein cholesterol and neutrophil levels. There were 2 cases of sepsis, both of which occurred in patients who were receiving combination therapy with 8 mg/kg of tocilizumab plus MTX.

Conclusion

These results indicate that targeted blockade of IL‐6 signaling is a highly efficacious and promising means of decreasing disease activity in RA.

     

Multiple sclerosis: increased expression of interleukin-2 receptors on lymphocytes

The percentage of interleukin-2-receptor-positive peripheral blood lymphocytes in MS patients was significantly higher in acute relapse than in remission or in controls. After stimulation by phytohemagglutinin, the expression of interleukin-2 receptor on peripheral blood lymphocytes of MS patients was within the range of healthy controls, implying no general impairment of receptor expression. These results confirm other evidence that there is a small population of activated T lymphocytes in acute relapse of MS.     

Purification of antigens and monoclonal antibodies

Clinical Rheumatology -     

Antinuclear antibody determination methods

Summary In twelve rheumatoid arthritis (RA)patients, receiving only nonsteroid antiinflammatory therapy, Superoxide anion (0 ₂ ^– ) generation by polymorphonuclear leucocytes (PMNs) was assessed by Cytochrome C reduction. The 0 ₂ ^– production by nonactivated PMNs in RA patients was significantly higher than in healthy controls. The 0 ₂ ^– production by PMNs activated by zymosan and phorbol myristate acetate was significantly lower than in controls. PMNs from controls preincubated with rheumatoid sera generated higher 0 ₂ ^– levels than the same PMNs incubated in normal sera.     

Clock and induction model for somitogenesis.

After many years of research, somitogenesis is still one of the major unresolved problems in developmental biology. Recent experimental findings show a novel type of pattern formation in which a signal sweeps along the presomitic mesoderm and narrows simultaneously as a new somite is formed. The signal then residues in the posterior half of the new somite, and another wave begins to sweep up from the caudal end. This behaviour is not easily explained by the existing theoretical models. We present a new model for somitogenesis that can account for this behaviour and is consistent with previous experimental observations.     

Correlation of functional parameters derived by equilibrium radionuclide angiocardiography and left ventricular size in patients with old myocardial infarction

A total of 131 patients with old (over 6 months) myocardial infarction (MI) and 18 normal subjects underwent equilibrium radionuclide angiocardiography at rest (rERNA). The following rERNA parameters were assessed: left ventricular ejection fraction (LVEF), peak ejection rate (PER), peak filling rate (PFR), regional wall motion and a left ventricular size index. The patients with old MI were divided into four groups (I to IV) according to increasing left ventricular (LV) size, and the behaviour of the numerical parameters (LVEF, PER, PFR) was evaluated in each group. LVEF proved to be the most sensitive numerical parameter of overall LV performance. PFR decreased significantly from group I to group III but not from group III to group IV, suggesting that for extreme degrees of left ventricular enlargement some compensatory mechanism acts to prevent a too large fall in LV compliance. The effects of the site of the previous MI on LV performance were also evaluated. Both LV size and performance were least affected by postero-inferior MI. The LVEF was, however, a better predictor of LV size than the site of the MI.Supported in part by grant no. 71260 by Ministero della Publica Istruzione     

Unsuccessful burch colposuspension: Analysis of risk factors

Seventy-five patients who underwent a Burch colposuspension were evaluated urodynamically before and after the surgical procedure. The women were divided into two groups, one with a urethral closure pressure of 30 cm H₂O or lower and one with a pressure over 30 cm H₂O. The two groups were comparable for age, parity, and weight. Significant differences were found between the two groups for both functional lengths and urethral closure pressure (P<0.005). The difference in the failure rate between the low urethral closure pressure group (21.2%) and the normal urethral pressure group (9.5%) was not statistically significant. On the other hand, the menopause is a condition which increases the surgical failure rate (26.6% versus 6.6%) (P<0.025).