Because of its requirement for signaling by multiple cytokines, Janus kinase 3 (JAK3) is an excellent target for clinical immunosuppression. We report the development of a specific, orally active inhibitor of JAK3, CP-690,550, that significantly prolonged survival in a murine model of heart transplantation and in cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associated with hypertension, hyperlipidemia, or lymphoproliferative disease. On the basis of these preclinical results, we believe JAK3 blockade by CP-690,550 has potential for therapeutically desirable immunosuppression in human organ transplantation and in other clinical settings.

ObjectivePatients with rheumatoid arthritis (RA) are at increased risk for herpes zoster (HZ) (i.e., shingles). The aim of this study was to determine whether treatment with tofacitinib increases the risk of HZ in patients with RA.MethodsHZ cases were identified as those reported by trial investigators from the databases of the phase II, phase III, and long-term extension (LTE) clinical trials in the Tofacitinib RA Development Program. Crude incidence rates (IRs) of HZ per 100 patient-years (with 95% confidence intervals [95% CIs]) were calculated by exposure group. Logistic regression analyses were performed to evaluate potential risk factors for HZ (e.g., age, prednisone use).ResultsAmong 4,789 participants, 239 were identified as having tofacitinib-associated HZ during the phase II, phase III, and LTE trials, of whom 208 (87%) were female and whose median age was 57 years (range 21–75 years). One HZ case (0.4%) was multidermatomal; none of the cases involved visceral dissemination or death. Twenty-four patients with HZ (10%) permanently discontinued treatment with tofacitinib, and 16 (7%) were either hospitalized or received intravenous antiviral drugs. The crude HZ IR across the development program was 4.4 per 100 patient-years (95% CI 3.8–4.9), but the IR was substantially higher within Asia (7.7 per 100 patient-years, 95% CI 6.4–9.3). Older age was associated with HZ (odds ratio 1.9, 95% CI 1.5–2.6), and IRs for HZ were similar between patients receiving 5 mg tofacitinib twice daily (4.4 per 100 patient-years, 95% CI 3.2–6.0) and those receiving 10 mg twice daily (4.2 per 100 patient-years, 95% CI 3.1–5.8). In the phase III trials among placebo recipients, the incidence of HZ was 1.5 per 100 patient-years (95% CI 0.5–4.6).ConclusionIn the Tofacitinib RA Development Program, increased rates of HZ were observed in patients treated with tofacitinib compared with those receiving placebo, particularly among patients within Asia. Complicated HZ among tofacitinib-treated patients was rare.

Regardless of purity and origin, therapeutic insulins continue to be immunogenic in humans. However, severe immunological complications occur rarely, and less severe events affect a small minority of patients. Insulin autoantibodies (IAAs) may be detectable in insulin-naive individuals who have a high likelihood of developing type 1 diabetes or in patients who have had viral disorders, have been treated with various drugs, or have autoimmune disorders or paraneoplastic syndromes. This suggests that under certain circumstances, immune tolerance to insulin can be overcome. Factors that can lead to more or less susceptibility to humoral responses to exogenous insulin include the recipient's immune response genes, age, the presence of sufficient circulating autologous insulin, and the site of insulin delivery. Little proof exists, however, that the development of insulin antibodies (IAs) to exogenous insulin therapy affects integrated glucose control, insulin dose requirements, and incidence of hypoglycemia, or contributes to beta-cell failure or to long-term complications of diabetes. Studies in which pregnant women with diabetes were monitored for glycemic control argue against a connection between IAs and fetal risk. Although studies have shown increased levels of immune complexes in patients with diabetic microangiopathic complications, these immune complexes often do not contain insulin or IAs, and insulin administration does not contribute to their formation. The majority of studies have shown no relationship between IAs and diabetic angiopathic complications, including nephropathy, retinopathy, and neuropathy. With the advent of novel insulin formulations and delivery systems, such as insulin pumps and inhaled insulin, examination of these issues is increasingly relevant.

No abstract