Management of coccidioidomycosis in patients receiving biologic response modifiers or disease‐modifying antirheumatic drugs

Objective

Coccidioidomycosis (valley fever) is an endemic fungal infection of the American Southwest, an area with a large population of patients with rheumatic diseases. There are currently no guidelines for management of patients who develop coccidioidomycosis while under treatment with biologic response modifiers (BRMs) or disease‐modifying antirheumatic drugs (DMARDs). We conducted a retrospective study of how both concurrent diseases were managed and the patient outcomes at 2 centers in Tucson, Arizona.

Methods

A retrospective chart review identified patients who developed coccidioidomycosis during treatment with DMARDs or BRMs. Patients were seen at least once in a university‐affiliated or Veterans Affairs outpatient rheumatology clinic in Tucson, Arizona, between 2007 and 2009.

Results

Forty‐four patients were identified. Rheumatologic treatment included a BRM alone (n = 11), a DMARD alone (n = 8), or combination therapy (n = 25). Manifestations of coccidioidomycosis included pulmonary infection (n = 29), disseminated disease (n = 9), and asymptomatic positive coccidioidal serologies (n = 6). After the diagnosis of coccidioidomycosis, 26 patients had BRMs and DMARDs stopped, 8 patients had BRMs stopped but DMARD therapy continued, and 10 patients had no change in their immunosuppressive therapy. Forty‐one patients had antifungal therapy initiated for 1 month or longer. Followup data were available for 38 patients. BRM and/or DMARD therapy was continued or resumed in 33 patients, only 16 of whom continued concurrent antifungal therapy. None of the patients have had subsequent dissemination or complications of coccidioidomycosis.

Conclusion

Re‐treating rheumatic disease patients with a BRM and/or a DMARD after coccidioidomycosis appears to be safe in some patients. We propose a management strategy based on coccidioidomycosis disease activity.     

HIV virological suppression influences response to the AS03‐adjuvanted monovalent pandemic influenza A H1N1 vaccine in HIV‐infected children

Design

Children with HIV are especially susceptible to complications from influenza infection, and effective vaccines are central to reducing disease burden in this population. We undertook a prospective, observational study to investigate the safety and immunogenicity of the inactivated split-virion AS03-adjuvanted pandemic H1N1(2009) vaccine in children with HIV.

Setting

National referral centre for Paediatric HIV in Ireland.

Sample

Twenty four children with HIV were recruited consecutively and received two doses of the vaccine. The serological response was measured before each vaccine dose (Day 0 and Day 28) and 2 months after the booster dose. Antibody titres were measured using a haemagglutination inhibition (HAI) assay. Seroprotection was defined as a HAI titre ≥ 1:40; seroconversion was defined as a ≥ fourfold increase in antibody titre and a postvaccination titre ≥ 1:40.

Main outcome measures

The seroconversion rates after prime and booster doses were 75% and 71%, respectively. HIV virological suppression at the time of immunization was associated with a significantly increased seroconversion rate (P = 0·009), magnitude of serological response (P = 0·02) and presence of seroprotective HAI titres (P = 0·017) two months after the booster dose. No other factor was significantly associated with the seroconversion/seroprotection rate. No serious adverse effects were reported. Vaccination had no impact on HIV disease progression. The AS03-adjuvanted pandemic H1N1 vaccine appears to be safe and immunogenic among HIV-infected children. A robust serological response appears to be optimized by adherence to a HAART regimen delivering virological suppression.     

Brief Report: Effect of ambrisentan treatment on exercise‐induced pulmonary hypertension in systemic sclerosis: A prospective single‐center,open‐label pilot study

Objective

Exercise‐induced pulmonary hypertension (ePH) may represent an early, clinically relevant phase in the spectrum of pulmonary vascular disease. The purpose of this pilot study was to describe the changes in hemodynamics and exercise capacity in patients with systemic sclerosis (SSc) spectrum–associated ePH treated with open‐label daily ambrisentan.

Methods

Patients were treated with ambrisentan, 5 mg or 10 mg once daily, for 24 weeks. At baseline and 24 weeks, patients with SSc spectrum disorders exercised in a supine position, on a lower extremity cycle ergometer. All patients had normal hemodynamics at rest. We defined baseline ePH as a mean pulmonary artery pressure of >30 mm Hg with maximum exercise and a transpulmonary gradient (TPG) of >15 mm Hg. The primary end point was change in pulmonary vascular resistance (PVR) with exercise. Secondary end points included an improvement from baseline in 6‐minute walking distance, health‐related quality of life assessments, and cardiopulmonary hemodynamics.

Results

Of the 12 enrolled patients, 11 completed the study. At 24 weeks there were improvements in mean exercise PVR (85.8 dynes × second/cm⁵; P = 0.003) and mean distance covered during 6‐minute walk (44.5 meters; P = 0.0007). Improvements were also observed in mean exercise cardiac output (1.4 liters/minute; P = 0.006), mean pulmonary artery pressure (−4.1 mm Hg; P = 0.02), and total pulmonary resistance (−93.0 dynes × seconds/cm⁵; P = 0.0008). Three patients developed resting pulmonary arterial hypertension during the 24 weeks.

Conclusion

Exercise hemodynamics and exercise capacity in patients with SSc spectrum–associated ePH improved over 24 weeks with exposure to ambrisentan. Placebo‐controlled studies are needed to confirm whether this is a drug‐related effect and to determine optimal therapeutic regimens for patients with ePH.

     

Comparison of zinc acetate hydrate and polaprezinc for zinc deficiency in patients on maintenance hemodialysis: A single‐center,open‐label,prospective randomized study

The efficacy and safety of zinc acetate hydrate (ZAH) for zinc supplementation in patients on maintenance hemodialysis (MHD) remains unknown. In this prospective, single‐center, open‐label, parallel‐group trial for MHD patients with serum zinc level <70 μg/dL, we compared ZAH (zinc; 50 mg/day) and polaprezinc (PPZ; zinc; 34 mg/day) beyond 6‐month administration in a 1:1 randomization manner. The ZAH and PPZ groups had 44 and 47 patients, respectively. At 3 months, the change rate of serum zinc levels in the ZAH group was significantly higher than that in the PPZ group. Three months after the study, serum copper levels significantly decreased in the ZAH group, but not in the PPZ group. No significant differences were noted in anemia management in either group. ZAH was superior to PPZ in increasing serum zinc levels. Clinicians should note the stronger decline in serum copper levels when using ZAH for MHD patients.     

Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease‐modifying antirheumatic drugs: A one‐year randomized,placebo‐controlled study

Objective

To assess the safety of abatacept, a selective costimulation modulator, in patients with active rheumatoid arthritis (RA) who had been receiving ≥1 traditional nonbiologic and/or biologic disease‐modifying antirheumatic drugs (DMARDs) approved for the treatment of RA for at least 3 months prior to entry into the study.

Methods

This was a 1‐year, multicenter, randomized, double‐blind, placebo‐controlled trial. Patients were randomized 2:1 to receive abatacept at a fixed dose approximating 10 mg/kg by weight range, or placebo.

Results

The abatacept and placebo groups exhibited similar frequencies of adverse events (90% and 87%, respectively), serious adverse events (13% and 12%, respectively), and discontinuations due to adverse events (5% and 4%, respectively). Five patients (0.5%) in the abatacept group and 4 patients (0.8%) in the placebo group died during the study. Serious infections were more frequent in the abatacept group than in the placebo group (2.9% versus 1.9%). Fewer than 4% of patients in either group experienced a severe or very severe infection. The incidence of neoplasms was 3.5% in both groups. When evaluated according to background therapy, serious adverse events occurred more frequently in the subgroup receiving abatacept plus a biologic agent (22.3%) than in the other subgroups (11.7–12.5%).

Conclusion

Abatacept in combination with synthetic DMARDs was well tolerated and improved physical function and physician‐ and patient‐reported disease outcomes. However, abatacept in combination with biologic background therapies was associated with an increase in the rate of serious adverse events. Therefore, abatacept is not recommended for use in combination with biologic therapy.

     

Tofacitinib with conventional synthetic disease‐modifying antirheumatic drugs in Chinese patients with rheumatoid arthritis: Patient‐reported outcomes from a Phase 3 randomized controlled trial

Aim

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We assess the effect of tofacitinib + conventional synthetic disease‐modifying anti rheumatic drugs (csDMARDs) on patient‐reported outcomes in Chinese patients with RA and inadequate response to DMARDs.

Methods

This analysis of data from the Phase 3 study ORAL Sync included Chinese patients randomized 4 : 4 : 1 : 1 to receive tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, placebo→tofacitinib 5 mg twice daily, or placebo→tofacitinib 10 mg twice daily, with csDMARDs. Placebo non‐responders switched to tofacitinib at 3 months; the remaining placebo patients switched at 6 months. Least squares mean changes from baseline were reported for Health Assessment Questionnaire‐Disability Index (HAQ‐DI), patient assessment of arthritis pain (Pain), patient global assessment of disease activity (PtGA), physician global assessment of disease activity (PGA), Functional Assessment of Chronic Illness Therapy‐Fatigue (FACIT‐F) scores, Short Form 36 (SF‐36), and Work Limitations Questionnaire (WLQ), using a mixed‐effects model for repeated measures.

Results

Overall, 216 patients were included (tofacitinib 5 mg twice daily, n = 86; tofacitinib 10 mg twice daily, n = 86; placebo→tofacitinib 5 mg twice daily, n = 22; placebo→tofacitinib 10 mg twice daily, n = 22). At month 3, tofacitinib elicited significant improvements in HAQ‐DI, Pain, PtGA, PGA and SF‐36 Physical Component Summary scores. Improvements were generally maintained through 12 months.

Conclusion

Tofacitinib 5 and 10 mg twice daily + csDMARDs resulted in improvements in health‐related quality of life, physical function and Pain through 12 months in Chinese patients with RA.     

Similar effects of disease‐modifying antirheumatic drugs,glucocorticoids, and biologic agents on radiographic progression in rheumatoid arthritis: Meta‐analysis of 70 randomized placebo‐controlled or drug‐controlled studies,including 112 comparisons

Objective

To define the differences in effects on joint destruction in rheumatoid arthritis (RA) patients between therapy with single and combination disease‐modifying antirheumatic drugs (DMARDs), glucocorticoids, and biologic agents.

Methods

Randomized controlled trials in RA patients, investigating the effects of drug treatment on the percentage of the annual radiographic progression rate (PARPR) were included in a meta‐analysis performed with the use of Review Manager 5.0 software according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) Statement protocol.

Results

Data from 70 trials (112 comparisons, 16 interventions) were summarized in 21 meta‐analyses. Compared with placebo, the PARPR was 0.65% smaller in the single‐DMARD group (P < 0.002) and 0.54% smaller in the glucocorticoid group (P < 0.00001). Compared with single‐DMARD treatment, the PARPR was 0.62% smaller in the combination‐DMARD group (P < 0.001) and 0.61% smaller in the biologic agent plus methotrexate (MTX) group (P < 0.00001). The effect of a combination of 2 DMARDs plus step‐down glucocorticoids did not differ from the effect of a biologic agent plus MTX (percentage mean difference –0.07% [95% confidence interval –0.25, 0.11]) (P = 0.44).

Conclusion

Treatment with DMARDs, glucocorticoids, biologic agents, and combination agents significantly reduced radiographic progression at 1 year, with a relative effect of 48–84%. A direct comparison between the combination of a biologic agent plus MTX and the combination of 2 DMARDs plus initial glucocorticoids revealed no difference. Consequently, biologic agents should still be reserved for patients whose RA is resistant to DMARD therapy. Future trials of the effects of biologic agents on RA should compare such agents with combination treatments involving DMARDs and glucocorticoids.