Our data provide the first evidence that blocking IL-6 receptor by tocilizumab has an acceptable safety profile and suggest a possible immunologic and clinical benefit in SLE. Patients tolerated the infusions well with no infusion reactions. Infections were the most common adverse events with two thirds of the patients having at least one infection during the five month study period. Although the rate of infections was higher than expected, consistent with other studies using tocilizumab (24
), most of these were mild and resolved with or without antibiotics on continued tocilizumab therapy. Larger controlled studies are necessary to obtain a better estimate of the risk of infection associated with tocilizumab compared to other drugs in SLE. Liver enzyme abnormalities and increases in serum lipids have been described with tocilizumab previously (25
). We have not observed any clinically important liver function test abnormalities possibly because patients with significant elevations in liver function tests and those taking potentially hepatotoxic medications were excluded from the study.
The main adverse event in this study was dose-related neutropenia. Absolute neutrophil counts decreased by a median 38% and 56% in the 4 mg/kg and 8 mg/kg dose groups, respectively. Most of the changes occurred after the first dose and remained relatively stable during the treatment. Similar decreases in neutrophil counts were observed in other studies. In the OPTION study, one-third of patients with rheumatoid arthritis treated with 8 mg/kg tocilizumab every 4 weeks in combination with stable MTX had an ANC below the lower limit of normal at least once during the study (24
). This is comparable to what we have observed in lupus patients who received 4 mg/kg/tocilizumab every two weeks. It is very important to note that neutropenia did not temporally correlate with infections in either study. The cause of decline in neutrophil count is not clear and requires further investigation. It may be related to decreased production or, more likely, to changes in neutrophil trafficking or both.
IL-6 has a major role in regulating acute phase responses of inflammation and blocking IL-6 is expected to reverse these effects. Accordingly, elevated markers of inflammation decreased promptly following the first dose and remained stable during the treatment phase. The anti-inflammatory effect of tocilizumab was further supported by an improvement in hemoglobin and serum albumin levels. In this study we did not see a significant improvement in proteinuria, and, therefore, the improvement in albumin levels is reflection of decreased systemic inflammation. The most common form of anemia in lupus is anemia of chronic inflammatory disease. Since red blood cells play a major role in immune complex clearance, correcting anemia may increase the clearance of circulating immune complexes and thus may contribute to a decrease in disease activity (28
), in addition to improving oxygen carrying capacity and tissue oxygenation.
Tocilizumab treatment was associated with hypocomplementemia in previous studies but it was not known if this was explained by decreased production or increased consumption of complement components. Our data showing that complement activation products decrease to a similar or higher degree than C3 and C4 provide the first evidence that the tocilizumab associated hypocomplementemia represents decreased production rather than increased activation. Since hypocomplementemia can also herald active lupus, complement activation products, rather than complements should be used as markers of lupus activity in future studies with tocilizumab.
Fifteen patients were available for evaluation of efficacy. Although the number of patients was too small to carry out a formal comparison among the three dose groups we did not detect any obvious differences in clinical outcomes among them. The four patients in the 2 mg/kg group had similar trends as patients in the other two groups, with more individual variations and delayed onset of response. Overall disease activity, measured by two disease activity indices and both patient and physician global assessments, improved by the end of the treatment period. Although, the improvement was modest it was statistically significant and consistent across all measures. We a priori
defined a decrease of 4 points in mSELENA-SLEDAI score as a clinically important change. This was achieved by more than half (8/15) of the patients. One third of the patients also met the more stringent criteria of a decrease of 7 points, which was recently proposed by a consensus panel (23
). The slightly better response in mSELENA-SLEDAI than in the SLAM scores, reflects differences in how the two indices weigh certain manifestations of lupus, such as complete or partial resolution of arthritis and resolution of (even mild) hematuria or pyuria. Most of the changes occurred during the first six weeks and reached maximum levels by 12 week with an increase in disease activity 4–8 weeks after the last treatment. From the individual manifestations arthritis improved the most, with a complete resolution of arthritis in 4/7 patients. Five patients were enrolled in the study with renal involvement. All had chronic glomerulonephritis characterized mainly by proteinuria which did not change during the study. Proteinuria is multifactorial at this stage with significant contribution of non-inflammatory processes, such as hemodynamic abnormalities and fibrosis which may not be altered by IL-6 receptor blockade or may require more time to respond. Although we have seen some improvement in urine sediments, the number of patients with active sediment at baseline and the short duration of the study prevents any conclusion about the potential efficacy of tocilizumab in lupus nephritis.
One of the major biologic actions of IL-6 is its ability to stimulate B-lymphocyte differentiation into immunoglobulin secreting cells. Notably, we observed a statistically significant decrease in circulating plasma cells during treatment as well as a significant decline in anti-dsDNA antibody levels. This change seems to be specific since levels of other autoantibodies did not change and there was only a small, albeit statistically significant, decrease in total IgG levels. The clinical significance of the decrease in anti-dsDNA is unclear but these results are consistent with previous ex vivo observations that IL-6 blockade may alter the B cell abnormalities found in lupus.
There are limitations to our study. First, the 3-month treatment period is too short to estimate long-term toxicities of tocilizumab in SLE. Second, we excluded patients who are on concomitant immunosuppressive treatments and thus this study may not reflect everyday practice. Third, given the open label design and the lack of control group all efficacy data should be considered preliminary. Fourth, because of the small number of patients we could not make formal comparisons among the three dose groups. However, our data suggest that neutropenia is more severe in the 8 mg/kg dose group, therefore, future studies should consider evaluating doses equivalent to 4 mg/kg given every two weeks.
This pilot study provides the first data that tocilizumab can effectively block IL-6 in patients with SLE. The improvements in inflammatory markers as well as clinical and serologic manifestations of lupus activity are encouraging and should be explored further in controlled studies using tocilizumab.