Subcutaneous abatacept versus intravenous abatacept: a phase IIIb noninferiority study in patients with an inadequate response to methotrexate.

OBJECTIVE: To compare the efficacy and safety of subcutaneous (SC) and intravenous (IV) abatacept. METHODS: In this phase IIIb double-blind, double-dummy, 6-month study, patients with rheumatoid arthritis (RA) and inadequate responses to methotrexate were randomized to receive 125 mg SC abatacept on days 1 and 8 and weekly thereafter (plus an IV loading dose [∼10 mg/kg] on day 1) or IV abatacept (∼10 mg/kg) on days 1, 15, and 29 and every 4 weeks thereafter. The primary end point for determining the noninferiority of SC abatacept to IV abatacept was the proportion of patients in each group meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at month 6. Other efficacy end points, immunogenicity, and safety were also assessed. RESULTS: Of 1,457 patients, 693 of 736 (94.2%) treated with SC abatacept and 676 of 721 (93.8%) treated with IV abatacept completed 6 months. At month 6, 76.0% (95% confidence interval 72.9, 79.2) of SC abatacept-treated patients versus 75.8% (95% confidence interval 72.6, 79.0) of IV abatacept-treated patients achieved an ACR20 response (estimated difference between groups 0.3% [95% confidence interval -4.2, 4.8]), confirming noninferiority of SC abatacept to IV abatacept. Onset and magnitude of ACR responses and disease activity and physical function improvements were comparable between the SC and IV abatacept-treated groups. The proportions of adverse events (AEs) and serious AEs over 6 months were 67.0% and 4.2%, respectively, in the SC abatacept-treated group and 65.2% and 4.9%, respectively, in the IV abatacept-treated group, with comparable frequencies of serious infections, malignancies, and autoimmune events between groups. SC injection site reactions (mostly mild) occurred in 19 SC abatacept (IV placebo)-treated patients (2.6%) and 18 IV abatacept (SC placebo)-treated patients (2.5%). Abatacept-induced antibodies occurred in 1.1% of SC abatacept-treated patients and 2.3% of IV abatacept-treated patients. CONCLUSION: SC abatacept provides efficacy and safety comparable with that of IV abatacept, with low immunogenicity and high retention rates, consistent with the established IV abatacept profile. Rates of injection site reactions were low. SC abatacept will provide additional treatment options, such as an alternative route of administration, for patients with RA.

[An unusual case of Kartagener's syndrome associated with rheumatoid arthritis]. / Rzadki przypadek wspólistnienia zespolu kartagenera z reumatoidalnym zapaleniem stawów.

We observed a 56-year-old woman with Kartagener's syndrome and severe seropositive rheumatoid arthritis. This is the third case of such association in the world literature and a second one being diagnosed in our Department. The patient was also as the previous one a carrier of HLA DR1 and B27 antigens. An electromicroscopic study showed normal bronchial cilia in contrast to classical course of the disease. A number of immunological disturbances were observed, especially defective granulocyte function. We suggest that the severe course of rheumatoid arthritis may be related to the chronic stimulation of immune system by microbes continuously present in the patients airways.

Changes in agalactosyl IgG levels correlate with radiological progression in early rheumatoid arthritis.

Immunoglobulin G-lacking galactose (Gal[0]) appears to be helpful in differential diagnosis of early synovitis, and correlates with disease activity in rheumatoid arthritis (RA). Its utility for RA monitoring and prognosis has been evaluated in the present study. Forty-eight patients with early RA were observed for 3 years. Hand radiographs were assessed according to Larsen and results were expressed as damage score (DS) and progression of damage score (PDS). Gal[0], DS, and PDS were evaluated at the onset of the study and after 1 and 3 years. The average values of Gal[0] in RA patients at the onset of the observation were significantly higher as compared to healthy controls (0.43 +/- 0.22 vs. -0.03 +/- 0.09, P < 0.05). The findings of Gal[0] after a 3-year follow-up were also higher as compared to healthy controls (0.37 +/- 0.21 vs. -0.03 +/- 0.09, P < 0.05). Radiological progression (PDS > 15) was observed in 16 patients. This group was characterized by a constantly high level of Gal[0]. The level of Gal[0] in patients without or with moderate radiological progression (PDS < 15) was significantly lower at the onset of the study and remained low during the observation. The relationship between Gal[0] and radiological progression was shown. The data thus far obtained suggest that Gal[0] may serve as an indicator for the disease course in patients with RA. Secondly, we cannot exclude the possibility that the constantly elevated level of Gal[0] causes erosions.

[Overdose of methotrexate with a fatal outcome in a patient with rheumatoid arthritis]. / Przedawkowanie metotreksatu przyczyna zgonu chorej na reumatoidalne zapalenie stawów.

A 52-year old female patient with rheumatoid arthritis (RA) had mistakenly taken 112.5 mg methotrexate (MTX) over a period of five days. As a result, extensive erosions along with necrotic changes occurred in the oral cavity, the groins and vulva mucous membrane. Haemorrhages in the gastrointestinal tract, dermal xanthochromia, interstitial pneumonia and progressive renal insufficiency, as well as hair loss, also followed. Laboratory examination showed peripheral blood agranulocytosis, a decrease in the overall number of blood platelets, anaemia, an increase in the level of transaminases and bilirubin, along with megakaryocyte deficiency. Cultivated dermal specimens initially developed bacteria, then Candida albicans. The patient died on the 22nd day after the overdose from pneumonia and extensive mycosis.

Interleukin 10 inhibits interleukin 6 production and acute phase response in rheumatoid arthritis.

To evaluate the effect of interleukin 10 (IL-10) on acute phase response, we determined serum levels of IL-10, interleukin 6 (IL-6), C-reactive protein (CRP), alpha-1-acid glycoprotein (AGP), alpha-1-anti-chymotrypsin (ACT) in 34 rheumatoid arthritis (RA) patients. IL-10 and IL-6 levels were evaluated using an enzyme-linked immunoassay (ELISA). CRP, AGP and ACT levels were measured using rocket immunoelectrophoresis. The results showed that IL-10 serum level was increased in RA patients as compared to controls (60.0 +/- 17.5 pg/ml vs. 7.2 +/- 1.9 pg/ml). IL-6 level was significantly elevated (87.3 +/- 32.7 pg/ml vs. 45 +/- 19 pg/ml, p < 0.05). CRP was significantly increased as compared to healthy controls (34 +/- 19 mg/1 vs. 3 +/- 2 mg/1, p < 0.05). AGP and ACT serum levels were increased in RA patients, but we did not find these changes to be statistically significant. A good negative correlation between IL-10 and IL-6 serum level was found (r = -0.73, p < 0.05). A positive significant correlation between IL-6 serum level and CRP (r = 0.62, p < 0.05), AGP (r = 0.74, p < 0.05) and ACT (r = 0.45, p < 0.05) was established. Moreover, a negative correlation between IL-10 and serum level of CRP (r = -0.76, p < 0.05), AGP (r = -0.60, p < 0.05) and ACT (r = -0.37, p < 0.05) was also shown. According to the data thus far obtained it seems that IL-10 decreases IL-6 production, and by that indirectly affects acute phase response, decreasing CRP, AGP and ACT synthesis.

Acute-phase response in early refractory rheumatoid arthritis: long-term follow-up study.

In order to investigate the role of the acute-phase response in early rheumatoid arthritis (RA), we followed the changes of alpha 1-acid glycoprotein (AGP), alpha 1-antitrypsin (AT) and alpha 1-antichymotrypsin (ACT) in the sera of 25 patients with refractory rheumatoid arthritis (RA) during the first 3 years of the disease. Serum levels of AGP, ACT and AT were measured using rocket immunoelectrophoresis, and AGP, ACT and AT microheterogeneities were performed using two-dimensional immunoelectrophoresis with concanavalin A (Con A) as ligand. On average, serum levels of AGP, ACT and AT proteins were higher at the onset of the disease as compared with healthy controls. After 3 years, a significant decrease in serum levels of all three acute-phase proteins (APPs) was observed, but only in patients without anatomical progression was this decrease statistically significant. At the beginning of the study, only the AT reactivity coefficient (RC) was decreased in comparison with healthy subjects. However, after 3 years of disease, AGP, ACT and AT RCs all decreased. This investigation provided two new observations. The first is that only AT RC is significantly lower in comparison with normal values at the beginning of RA, whereas AGP RC and ACT RC remain within the normal range of values; a decrease in AGP RC and ACT RC appeared later. The second observation is that the highly elevated levels of APPs at the onset of RA decrease during the course of the disease. Moreover, this decrease does not depend on the disease activity, but a relationship with radiological progression was shown.