Tofacitinib is the first Janus kinase (JAK) inhibitor commercially approved for the treatment of rheumatoid arthritis. This compound and a number of other JAK inhibitors are currently being tested in ...phase II and III trials for the treatment of a variety of autoimmune inflammatory diseases. Whereas a characteristic safety profile is emerging for some JAK inhibitors, differences between individual agents might emerge on the basis of distinct potency against their molecular targets. Similarly to biological therapy, JAK inhibition can lead to serious and opportunistic infections, and viral infections seem to be particularly frequent. Although no malignancy signals have been identified to date, long-term follow-up and further research are needed to understand the risk of malignancy associated with these compounds. As is the case for biologic agents, vaccination is important to mitigate the risks of these emerging therapies.
Diseases and therapies that reduce cell-mediated immunity increase the risk of nontuberculous mycobacterial (NTM) disease. Extrapulmonary NTM disease, including disseminated, skin, and ...catheter-related disease, is more common in immunosuppressed than immunocompetent patients. Mycobacterium avium complex remains the most common cause of NTM infection, but rapid growers including Mycobacterium abscessus, Mycobacterium chelonae, and Mycobacterium fortuitum play an important role in skin and catheter-related infections. With the exception of antibiotic prophylaxis for AIDS patients, the prevention of NTM remains difficult. Management is complicated, involving restoration of immune function and removal of catheters in addition to treatment with species-specific antibiotics per current guidelines.
Treatment of Mycobacterium abscessus Complex Strnad, Luke; Winthrop, Kevin L
Seminars in respiratory and critical care medicine,
06/2018, Letnik:
39, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Of the nontuberculous mycobacteria (NTMs) causing lung disease, members of the
complex (MABc) present a formidable obstacle to successful management. This challenge starts from a poorly understood ...pathogenesis, continues with complicated subspecies variation in treatment response, and extends to the multidrug-resistant nature of these organisms. The disease often necessitates the use of intravenous therapy, toxic drug combinations, and, in some cases, lung resection. Like many NTMs, MABc treatment requires prolonged therapy with multiple medications, and pulmonary disease in some subspecies can be impossible to eradicate or cure. This disease also represents a frequent and unique problem in certain populations, including cystic fibrosis and lung transplant recipients, and providers who manage such patients should be familiar with how MABc disease influences management. Because of the rising prevalence of the MABc, especially in patients with complicated underlying pulmonary disease, it is increasingly necessary for infectious diseases and pulmonary medicine clinicians to understand the unique aspects of MABc management and understand when to obtain expert consultation in the care of these patients.
Infection Risk and Safety of Corticosteroid Use Youssef, Jameel; Novosad, Shannon A; Winthrop, Kevin L
Rheumatic diseases clinics of North America,
02/2016, Letnik:
42, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Corticosteroids are frequently used to treat rheumatic diseases. Their use comes with several well-established risks, including osteoporosis, avascular necrosis, glaucoma, and diabetes. The risk of ...infection is of utmost concern and is well documented, although randomized controlled trials of short-term and lower-dose steroids have generally shown little or no increased risk. Observational studies from the real world, however, have consistently shown dose-dependent increases in risk for serious infections as well as certain opportunistic infections. In patients who begin chronic steroid therapy, vaccination and screening strategies should be used in an attempt to mitigate this risk.
For decades, the incidence of pulmonary nontuberculous mycobacteria (NTM) has been reported to be increasing, yet formal epidemiological evaluation of this notion has been lacking until recently. ...Defining the epidemiology of NTM has been more challenging than with Mycobacterium tuberculosis (MTB). Unlike MTB, NTM are soil and water organisms, and infection is thought to be acquired from the environment rather than transmitted from person-to-person, with very rare exceptions. Due to their nearly ubiquitous presence in municipal water supplies, exposure to NTM is common. Further, NTM can colonize the respiratory tract without causing disease. NTM disease is not reportable to public health authorities; therefore, epidemiological and surveillance data are not readily available. Nonetheless, the prevalence of pulmonary NTM disease has increased dramatically in the United States and globally over the past 3 decades. Mycobacterium avium complex (MAC) accounts for the majority of NTM infections worldwide, but there is significant regional variability of various species. Additionally, novel species have been implicated in several countries in NTM pulmonary disease.
The published results of the post-marketing ORAL Surveillance study, which compared the Janus kinase (JAK) inhibitor tofacitinib with anti-TNF therapy in older patients with rheumatoid arthritis who ...have cardiovascular risk factors, have led to changes in the recommendations for the use of JAK inhibitors. Although new safety signals have emerged for tofacitinib, namely malignancy and cardiovascular disease, it should be noted that these signals are relative to those seen with TNF blockers. The new data further raise our intrigue that venous thromboembolism might be a true risk related to JAK inhibition. Reassuringly, the totality of the findings from this newly published study and the other data collected to date suggest that JAK inhibitors can be used safely at approved doses by many patients with rheumatoid arthritis.
The COVID-19 vaccination will be the largest vaccination programme in the history of the NHS. Patients on immunosuppressive therapy will be amongst the earliest to be vaccinated. Some evidence ...indicates immunosuppressive therapy inhibits humoral response to the influenza, pneumococcal and hepatitis B vaccines. The degree to which this will translate to impaired COVID-19 vaccine responses is unclear. Other evidence suggests withholding methotrexate for two weeks post vaccination may improve responses. Rituximab has been shown to impair humoral responses for 6 months or longer post administration. Decisions on withholding or interrupting immunosuppressive therapy around COVID-19 vaccination will need to be made prior to the availability of data on specific COVID-19 vaccine response in these patients. With this in mind, this article outlines the existing data on the effect of antirheumatic therapy on vaccine responses in patients with inflammatory arthritis and formulates a possible pragmatic management strategy for COVID-19 vaccination.
Estimating the annual incidence and prevalence of nontuberculous mycobacterial (NTM) lung disease may assist in improving understanding of the public health and economic impacts of this disease and ...its treatment.
To estimate the yearly incidence and prevalence of administrative claims-based NTM lung disease between 2008 and 2015 in a U.S. managed care claims database.
We used a national managed care claims database (Optum Clinformatics Data Mart) representing a geographically diverse population of approximately 27 million members annually. All medical claims from January 1, 2007, to June 30, 2016, were scanned for diagnosis codes for NTM lung disease (
ICD-9-CM code 031.0 or ICD-10-CM code A31.0). We defined a case of NTM lung disease as having at least two medical claims with a code of 031.0 or A31.0 that were dated at least 30 days apart. Annual incidence and prevalence were estimated for each calendar year from 2008 to 2015.
From 2008 to 2015, the annual incidence of NTM lung disease increased from 3.13 (95% confidence interval CI, 2.88-3.40) to 4.73 (95% CI, 4.43-5.05) per 100,000 person-years, and the annual prevalence increased from 6.78 (95% CI, 6.45-7.14) to 11.70 (95% CI, 11.26-12.16) per 100,000 persons. The average annual changes in incidence and prevalence were +5.2% (95% CI, 4.0-6.4%;
< 0.01) and +7.5% (95% CI, 6.7-8.2%;
< 0.01), respectively. For women, the annual incidence increased from 4.16 (95% CI, 3.76-4.60) to 6.69 (95% CI, 6.19-7.22) per 100,000 person-years, and the annual prevalence increased from 9.63 (95% CI, 9.08-10.22) to 16.78 (95% CI, 16.04-17.55) per 100,000 persons. For individuals aged 65 years or older, the annual incidence increased from 12.70 (95% CI, 11.46-14.07) to 18.37 (95% CI, 16.98-19.87) per 100,000 person-years, and the annual prevalence increased from 30.27 (95% CI, 28.41-32.24) to 47.48 (95% CI, 45.37-49.67) per 100,000 persons. The incidence and prevalence of NTM lung disease increased in most U.S. states and overall at the national level.
The incidence and prevalence of NTM lung disease appears to be increasing in the United States, particularly among women and older age groups.
To evaluate the risks of herpes zoster (HZ) and herpes simplex virus (HSV) infection associated with tofacitinib compared with biologic agents among patients with rheumatoid arthritis (RA).
Using ...health plan data from 2010 to 2014, patients with RA initiating tofacitinib or biologics with no history of HZ or HSV were identified, as were incident cases of HZ or HSV. Crude incidence rates were calculated by drug exposure. Cox proportional hazards models evaluated the adjusted association between tofacitinib and HZ, and a composite outcome of HZ or HSV.
A total of 2526 patients initiating tofacitinib were compared with initiations of other biologics: anti-tumour necrosis factor (TNF) (n=42 850), abatacept (n=12 305), rituximab (n=5078) and tocilizumab (n=6967). Patients receiving tofacitinib were somewhat younger (mean age 55 years) versus those on other biologics, and somewhat less likely to use concomitant methotrexate (MTX) (39% vs 43%-56%, depending on drug). Crude incidence of HZ associated with tofacitinib was 3.87/100 patient-years (py). After multivariable adjustment, HZ risk was significantly elevated, HR 2.01 (95% CI 1.40 to 2.88) compared with abatacept. Rates and adjusted HRs for all other RA biologics were comparable with each other and abatacept. Older age, female sex, prednisone >7.5 mg/day, prior outpatient infection and greater number of hospitalisations were also associated with increased HZ risk. Incidence rates for the combined outcome were greatest for tofacitinib (7.61/100 py) and also significantly elevated after adjustment (HR=1.40, 95% CI 1.09 to 1.81).
The rate of zoster associated with tofacitinib was approximately double that observed in patients using biologics.
Abstract
Objectives
To evaluate the risk of serious infection (SI) and herpes zoster (HZ) in rheumatoid arthritis patients receiving JAK inhibitors.
Methods
We conducted a systematic literature ...review and meta-analysis of phase II and III randomized controlled trials of tofacitinib (5 mg bid), baricitinib (4 mg od) and upadacitinib (15 mg od). Patient-exposure years were calculated. A per-protocol analysis was applied, incorporating follow-up time from patients randomized to placebo who cross into the treatment arm. Pooled incidence rates per 100 person-years of SI and HZ were calculated. Incidence rate ratios (IRRs) of drug vs placebo were compared using a meta-synthesis approach.
Results
Twenty-one studies were included in the meta-analysis; 11 tofacitinib (5888 patients), six baricitinib (3520 patients) and four upadacitinib studies (1736 patients). For SI, the incidence rates were 1.97 (95% CI: 1.41, 2.68), 3.16 (95% CI: 2.07, 4.63) and 3.02 (95% CI: 0.98, 7.04), respectively. The IRRs comparing treatment arm to placebo were statistically non-significant: 1.22 (95% CI: 0.60, 2.45), 0.80 (95% CI: 0.46, 1.38) and 1.14 (95% CI: 0.24, 5.43), respectively. For HZ, the incidence rates were 2.51 (95% CI: 1.87, 3.30), 3.16 (95% CI: 2.07, 4.63) and 2.41 (95% CI: 0.66, 6.18), respectively. The IRR of HZ comparing baricitinib with placebo was 2.86 (95% CI: 1.26, 6.50). Non-significant IRRs were seen with tofacitinib and upadacitinib: 1.38 (95% CI: 0.66, 2.88) and 0.78 (95% CI: 0.19, 3.22), respectively. Indicator opportunistic infections excluding HZ were too rare to provide meaningful incidence rates.
Conclusion
The absolute SI rates were low. However across the JAK inhibitors, the incidence of HZ is higher than expected for the population (3.23 per 100 patient-years). While the risk was numerically greatest with baricitinib, indirect comparisons between the drugs did not demonstrate any significant difference in risk.
Systematic review registration number
Prospero 2017 CRD4201707879.
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