Upadacitinib in active ankylosing spondylitis: results of the 2-year, double-blind, placebo-controlled SELECT-AXIS 1 study and open-label extension.

INTRODUCTION: Long-term safety and efficacy of upadacitinib in patients with active ankylosing spondylitis (AS) has not been previously reported. METHODS: In SELECT-AXIS 1, patients receiving placebo were switched to upadacitinib 15 mg once daily at week 14 while patients initially randomised to upadacitinib continued their regimen through week 104. Efficacy was assessed using as-observed (AO) and non-responder imputation (NRI). RESULTS: Of 187 patients randomised, 144 patients (77%) completed week 104. Among patients receiving continuous upadacitinib, 85.9% (AO) and 65.6% (NRI) achieved Assessment of SpondyloArthritis international Society 40 response (ASAS40) at week 104. Similar magnitude of ASAS40 responses were observed among patients who switched from placebo to upadacitinib (88.7% and 63.8%, respectively). The mean change from baseline to week 104 in Spondyloarthritis Research Consortium of Canada MRI spine and sacroiliac joint inflammation scores were -7.3 and -5.3, respectively, in the continuous upadacitinib group and -7.9 and -4.9 in the placebo-to-upadacitinib switch group. The mean (95% CI) change from baseline to week 104 in the modified Stoke Ankylosing Spondylitis Spine Score was 0.7 (0.3, 1.1) in the total group. Adverse event rate was 242.7/100 patient-years. No serious infections, adjudicated major adverse cardiovascular events, lymphoma, non-melanoma skin cancer, or gastrointestinal perforations were observed. CONCLUSIONS: Upadacitinib 15 mg once daily showed sustained and consistent efficacy over 2 years for ASAS40 and other clinically relevant endpoints. A low rate of radiographic progression was observed and no new safety findings were observed.

Efficacy of Rho kinase inhibitor fasudil in secondary Raynaud's phenomenon.

OBJECTIVE: The RhoA/Rho kinase pathway plays a pivotal role in cold-induced vasoconstriction, vascular smooth muscle cells function, and vascular homeostasis. This study evaluates the efficacy of fasudil, a RhoA/Rho kinase inhibitor, to reverse cold-induced vasospasm in patients with Raynaud's phenomenon (RP) secondary to systemic sclerosis (SSc; scleroderma). METHODS: This is a single-center, double-blind, placebo-controlled, randomized, 3-period crossover study of oral fasudil (40 mg or 80 mg) or placebo administered 2 hours before a standardized cold challenge. The fall in skin temperature after the cold challenge and time to recover 50% and 70% of prechallenge digital skin temperature were used as primary outcomes. Digital blood flow assessed by laser Doppler, time to minimum skin temperature, and rate of skin cooling were also measured. RESULTS: A total of 17 patients with SSc and RP completed the study. After the cold challenge, skin temperatures and the average time (minutes) to recover 50% (7.9 minutes for placebo, 7.5 minutes for fasudil 40 mg, and 8.2 minutes for fasudil 80 mg; P = 0.791) and 70% (18.2 minutes for placebo, 15.0 minutes for fasudil 40 mg, and 17.1 minutes for fasudil 80 mg; P = 0.654) of prechallenge skin temperature were not significantly different across the 3 groups. The digital blood flow measurements were higher in fasudil-treated groups than placebo, but differences were not significant (P = 0.693). CONCLUSION: Fasudil administered at a single oral dose of 40 mg or 80 mg was not associated with significant benefit in terms of the skin temperature recovery time and the digital blood flow after the cold challenge.

Effects of glucocorticoids on weight change during the treatment of Wegener's granulomatosis.

OBJECTIVE: Weight gain is a side effect of glucocorticoid (GC) use, but the natural history and health implications of changes in weight that occur during the treatment of inflammatory disease are not understood. METHODS: We evaluated data from the Wegener's Granulomatosis Etanercept Trial. Patients were categorized according to clinical outcome at 1 year: remission (no disease flares), single flare, or multiple flares. Risk factors for gaining > or =10 kg were examined in multivariate models. RESULTS: Weights at baseline and 1 year were available for 157 (93%) of the 168 patients analyzed. During year 1, the mean cumulative prednisone dosage in the multiple flares subgroup was 7.9 gm, compared with 6.0 gm and 3.9 gm in the single flare and remission subgroups, respectively (P < 0.001). Patients in these subgroups gained an average of 2.6 kg, 4.1 kg, and 5.8 kg, respectively (P = 0.005). Weight gain did not correlate with cumulative GC dose (R = 0.10, P = 0.25). Thirty-five patients (22.3%) gained and maintained > or =10 kg in the first year. New diagnosis of Wegener's granulomatosis at baseline was an independent predictor of gaining > or =10 kg at 1 year (odds ratio 19.7, 95% confidence interval 2.4-162.6, P = 0.006). Among the 78 patients in the remission subgroup, 40 sustained remissions through the 2-year time point. For these 40 patients, the mean weight gained at year 1 did not regress by the end of year 2, despite the absence of continued GC use. CONCLUSION: Disease control was associated with lower cumulative GC doses but greater weight gain. More than one-fifth of patients gained >10 kg in the first year of treatment. The quantity of weight gained by patients during treatment has potential future health implications.

Therapeutics of Wegener's granulomatosis.

The treatment of Wegener's granulomatosis, one of the most common forms of systemic vasculitis, has changed substantially over the past two decades. The principal aims of therapy are to control the disease swiftly, to limit the extent and severity of permanent organ damage, and to minimize the short-term and long-term morbidities that often result from therapy. This review provides an overview of the treatment regimens that are currently available for inducing and maintaining remission in patients with Wegener's granulomatosis, and also discusses newer agents that might have a role in the management of this disease in the future. Severe toxicity associated with the available agents and, therefore, there is keen interest in the development of alternative treatment strategies for this disease.

Herpes zoster in immunocompromised patients: incidence, timing, and risk factors.

PURPOSE: To evaluate the risk factors for herpes zoster as well as the incidence and timing of this complication in patients who were treated with immunosuppression because of active Wegener's granulomatosis. SUBJECTS AND METHODS: We studied the 180 Wegener's granulomatosis patients in the Wegener's Granulomatosis Etanercept Trial (WGET). Herpes zoster events during WGET were documented prospectively. Follow-up questionnaires were employed to describe the location, treatment, and complication(s) of herpes zoster and its therapy. Univariate and multivariate analyses were performed to evaluate risk factors, including history of herpes zoster, for the occurrence of herpes zoster during the trial. All analyses were based on the time to first occurrence of herpes zoster. RESULTS: Eighteen patients (10% of the WGET cohort) suffered a total of 19 herpes zoster episodes over a mean follow-up period of 27 months. The annual incidence of herpes zoster in the WGET cohort was 45 cases/1000 patient-years (95% confidence interval [CI]: 27, 70). The median time from enrollment to the occurrence of herpes zoster in the subgroup of patients with that complication was 16.5 months (+/- 9.4). Fifteen of the 19 herpes zoster events (79%) occurred between months 6 and 36, many months after the period of most intensive immunosuppression. In univariate analyses, history of serum creatinine > or =1.5 mg/dL before enrollment was associated with a relative risk (RR) of 3.0 (95% CI: 1.1, 7.8) for herpes zoster during WGET (P=.03). In multivariate analyses, serum creatinine > or =1.5 mg/dL was associated with an RR of 6.3 (95% CI: 2.0, 19.8; P=.002), and female sex with an RR of 4.6 (95% CI: 1.6, 13.2; P=.004). CONCLUSION: Renal dysfunction and female sex were consistently strong risk factors for herpes zoster events in this population. Contrary to expectation, most herpes zoster events did not occur during periods of most intensive immunosuppression. These data may inform studies of interventions designed to prevent herpes zoster in patients on treatment for immune-mediated diseases.