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Incidence of HSV and HPV with azathioprine
No full textIBd
Incidence of HSV and HPV
with azathioprine
Mario Cottone and Sara Renna
severe infections are an established risk of immunosuppressive therapy;
however, the risk of opportunistic infections in patients with IBd who
receive immunosuppressive therapy has so far only been studied
retrospectively. the increased incidence of herpes flares and development
or worsening of viral warts in patients with IBd who receive azathioprine
has now been demonstrated for the first time in a prospective study.
the rate of opportunistic infections
in patients with iBD is dependent on the
patient’s nutritional status, degree of innate
immune system activity, whether the
patient has undergone surgery and their
use of immunosuppressive drugs or biological
therapy.1 severe infections are a
welldocumented
risk in patients who are
treated with immunosuppressive therapy;2
however, use of immunosuppressants
as maintenance therapy in patients with
iBD is becoming increasingly common.
in a 2004–2005 crosssectional
study of
20,000 patients with iBD, conducted in
France, >50% of patients with Crohn’s
disease and approximately 25% of patients
with ulcerative disease had received the
immuno suppressant azathioprine.3
infections with varicellazoster
virus and
herpes simplex virus (Hsv) are common,
nonfatal conditions characterized by a unilateral,
painful, vesicular rash in a dermatomal
distribution. Patients with iBD are
hypothesized to be at increased risk of
these viral infections because of diseaserelated
alterations in immune function
and frequent use of immunosuppressive
medications. Data on infection with human
papillomavirus (HPv) species in patients
with iBD are scarce but seem to show
an increased incidence of this infection
in such patients.4 Different studies have
used various metho dological approaches
to evaluate the risk of these three viral
infections in patients with iBD but no
studies have evaluated the incidence of all
three viruses.
Korelitz et al.5 reported the incidence of
varicellazoster
infection in patients with
iBD who were treated with 6mercaptopurine
to be 2.2%. However, the researchers
did not provide a comparison with the
incidence of this infection in a control
population, which limits the conclusions
that can be drawn.
a case–control study by toruner et al.1
sought to identify the factors associated
with iBD and infection by comparing 100
consecutive patients with iBD who had
opportunistic infections to patients with
iBD who did not have a history of opportunistic
infection. although the relative
risk of infection was greatest in patients
>50 years of age (compared with those
≤24 years of age) and was independent
of immuno suppressant treatment, use of
cortico steroids, azathioprine and infliximab
was also associated with a significantly
increased risk of opportunistic infection.
the researchers reported a higher incidence
of varicellazoster,
Candida albicans and
Hsv infections in patients who received
immunosuppressant treatment than in
those who did not receive this therapy, but
did not provide values for the risk of any
single infection.
Gupta et al.6 carried out a similar but
larger study, in which the incidence of
varicellazoster
infections in 7,823 patients
with Crohn’s disease and 1,930 patients with
ulcerative colitis was compared with its
Practice points
■ The incidence of opportunistic infections,
for example with varicella-zoster virus
and human papillomavirus species,
are increased in patients with iBD who
receive immunosuppressant therapy
■ Concomitant treatment of the
opportunistic infection or suspension of
immunosuppressive medication are two
possible therapeutic strategies
■ vaccination for human papillomavirus
species is recommended for women
with iBD
© 2009 Macmillan Publishers Limited. All rights reserved
nature reviews | gastroenterology & hepatology volume 6 | auGust 2009 | 445
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incidence in 79,563 individuals without
iBD. Patients with Crohn’s disease or
ulcerative colitis had a higher risk of
varicellazoster
infection than indivi duals
in the control group. in a nested, case–
control study, 185 patients with Crohn’s
disease and varicellazoster
infections
and 266 patients with ulcerative colitis and
varicellazoster
infections were compared
with 1,787 patients with iBD but without
varicellazoster
infection. Patients who
received immuno suppressant medications
had a greater risk of varicellazoster
infection than those who did not receive
such therapy. the unadjusted and adjusted
odds ratios for receipt of a prescription
for azathioprine or 6mercapto
purine and
varicellazoster
infection were both 3.1.
unfortunately, this study did not investigate
the incidence of other opportunistic
infections, such as Hsv.
the studies described above are all
retrospec tive and are, therefore, constrained
by the usual limitations of this study type.
retrospective analyses of safety data cannot
accurately assess the true incidence of
benign infections because they are transient
conditions. such analyses, therefore,
rely on accurate recall of information by the
patient and can result in an underestimation
of incidence of infection. thus, the information
available from case–control studies
is of limited value; no direct way exists to
estimate the incidence or prevalence of
disease, nor the attributable or excess risk
of particular groups of patients.
the study by seksik et al.7 is the first
prospec tive study to investigate the
incidence of opportunistic infection in
patients with iBD who receive azathioprine
therapy. in this study, 230 patients with
iBD received either azathioprine (n = 169)
or nonimmuno suppressive therapy (n = 61).
the patients underwent a comprehensive
skin examination and completed a questionnaire
every 3–6 months, and the number
of opportunistic infections, including ear,
nose, and throat infections, bronchitis and
oral or genital Hsv flares was recorded.
the incidence of Hsv flares was significantly
greater in the group of patients who
received azathioprine than in patients
who did not do so (1.0 ± 2.6 versus 0.2 ± 0.8
per year, P = 0.04). similarly, significantly
more patients who received azathioprine
treatment experienced newonset
or
worsening viral warts (17.2% versus 3.3%
P = 0.004). these findings are in line with
those from other studies that have reported
an increased incidence of warts in immunosuppressed
patients—an observation that
was initially reported in renal transplant
recipients.8 Contrary to other studies in
the literature,1,5,6,9 however, seksik et al. did
not show an increase in the incidence of
varicellazoster
or cytomegalovirus infection
in patients with iBD who received
immunosuppressant therapy.
what are the implications of seksik et al.’s
findings? a detailed history of herpes infection
should be collected before immunosuppressive
treatment is initiated in
patients with iBD. However, no agreement
exists on what to do when an Hsv or other
infection is diagnosed during immunosuppressive
therapy. viget et al.10 suggest
that immunosuppressant therapy should
be withdrawn as soon as possible after the
identification of an opportunistic infection,
but seksik et al. suggest azathio prine
treatment should be maintained and concomitant
treatment with antiHsv
drugs
should be initiated. no data on the risk
of anogenital cancer related to persistent
HPv infection exist; therefore, in the case
of warts, suspension of immuno suppressive
treatment is advisable.
importantly, the findings from this
study suggest that gynecological examination
and cervical cancer screening should
be planned for women with iBD before
and after immuno suppressant treatment.
HPv vaccination is safe, immunogenic
and highly effective against infection with
specific species of HPv. Predictive data
also indicate that implementation of HPv
vaccination within a national screening
program is likely to be more costeffective
than current clinical practice methods.
the increasing incidence of HPv infection
in young women with iBD also indicates
that, in the future, emphasis may be placed
on the new generation of recombinant
HPv vaccines.
Dipartimento di Medicina, Pneumologia e
Fisiologia della Nutrizione, Università di
Palermo, Palermo, Italy (M. Cottone, S. Renna).
Correspondence: M. Cottone, Dipartimento di
Medicina, Pneumologia e Fisiologia della
Nutrizione, Università di Palermo. Ospedale V.
Cervello, Via Trabucco 180, 90146 Palermo,
Italy
[email protected]
doi:10.1038/nrgastro.2009.110
competing interests
The authors declare no competing interests.
1. Toruner, M. et al. Risk factors for opportunistic
infections in patients with inflammatory bowel
disease. Gastroenterology 134, 929–936
(2008).
2. Lichtenstein, G. R. et al. serious infections and
mortality in association with therapies for
Crohn’s disease: TReAT registry. Clin.
Gastroenterol. Hepatol. 4, 621–630 (2006).
3. Beaugerie, L. et al. The use of
immunomodulators and biologics in
inflammatory bowel diseases (iBD): a crosssectional
French nationwide cohort 2004–
2005 [Abstract]. Gastroenterology
130 (4 suppl. 2), A2 (2006).
4. Kane, s., Khatibi, B. & Reddy, D. Higher
incidence of abnormal Pap smears in women
with inflammatory bowel disease. Am. J.
Gastroenterol. 103, 631–636 (2008).
5. Korelitz, B. i., Fuller, s. R., warman, J. i. &
Goldberg, M. D. shingles during the course of
treatment with 6-mercaptopurine for
inflammatory bowel disease. Am. J.
Gastroenterol. 94, 424–426 (1999).
6. Gupta, G., Lautenbach, e. & Lewis, J. D.
incidence and risk factors for herpes zoster
among patients with inflammatory bowel
disease. Clin. Gastroenterol. Hepatol. 4,
1483–1490 (2006).
7. seksik, P. et al. incidence of benign upper
respiratory tract infections, Hsv and HPv
cutaneous infections in inflammatory bowel
disease patients treated with azathioprine.
Aliment. Pharmacol. Ther. 29, 1106–1113
(2009).
8. spencer, e. s. & Andersen, H. K. viral
infections in renal allograft recipients treated
with long-term immunosuppression. Br. Med. J.
2, 829–830 (1979).
9. warman, J. i., Korelitz, B. i., Fleisher, M. R. &
Janardhanam, R. Cumulative experience with
short- and long-term toxicity to
6-mercaptopurine in the treatment of Crohn’s
disease and ulcerative colitis. J. Clin.
Gastroenterol. 37, 220–225 (2003).
10. viget, n., vernier-Massouille, G., salmon-
Ceron, D., Yazdanpanah, Y. & Colombel, J. F.
Opportunistic infections in patients with
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Credit: CDC images
© 2009 Macmillan Publishers Limited. All rights reserve
Investigational agents for Crohn's disease.
No full textIMPORTANCE OF THE FIELD: Increased understanding of the biological mechanisms of Crohn's disease has opened the door to a large number of new molecules; some of these are approved for clinical use, while others remain under evaluation. In this review, we examine the clinical efficacy of all the new drugs that have been evaluated in controlled trials in the last 12 years.
AREAS COVERED IN THIS REVIEW: Anti-TNF therapy has been reviewed briefly, given the many comprehensive reviews on this topic; attention is focused mainly on the other biological therapies. In assessing the clinical efficacy of these molecules, we consider only the remission rate, as this is considered the most meaningful end point in clinical practice.
WHAT THE READER WILL GAIN: We analyzed the main biological mechanisms of Crohn's disease and the new drugs whose use is based on insights into these mechanisms. We reviewed the following new drugs: probiotics, GM-CSF, IL-10, IL-11, anti-IL-6, anti-IL-12/-23, everolimus, anti-IFN-γ, IFN-β-I, co-stimulators, anti-integrins, anti-intercellular adhesion molecule 1, small molecules and mitogen-activated protein kinase inhibitors.
TAKE HOME MESSAGE: Anti-TNF therapies remain the best options, followed by anti-integrin drugs. The most promising new therapies are anti-IL-23, but further data are necessary. The disappointing results with other molecules may depend on the quality of trials and possibly on inadequate dosage of the drug
Prurigo nodularis of Hyde treated with low-dose thalidomide.
Full text linkPrurigo nodularis of Hyde is a skin disorder characterized by pruritic excoriated nodules. Improvement in pruritus and decrease in nodules was demonstrated in patients treated with oral thalidomide 200-400 mg daily. We report a case of a 52 year old woman with a history of widespread, persistent, and intensely pruritic lesions on all extremities and a histological diagnosis of “prurigo nodularis”. The patient was treated with topical agents without significant improvement. Cyclosporine was administered with partial improvement but it had to be discontinued because of side effects. Treatment with corticosteroids and antibiotics resulted in significant improvement, but at reduction of steroid dosage the skin lesions reappeared. Thalidomide was started at a dose of 100 mg once a day and after one month it was reduced to 50 mg and 100 mg orally on alternate days. Six months after starting thalidomide treatment the patient was in remission with a few residual scars and sporadic asymptomatic lesions. No significant side effects occurred.
In this clinical case, a woman with prurigo nodularis was successfully treated with low-dose of thalidomide. We consider that in the treatment of prurigo nodularis is better to test a low dose of thalidomide before starting higher dosages because low dose of this drug can be efficacy without clinical development of side effects
Meta-analysis of the placebo rates of clinical relapse and severe endoscopic recurrence in post-operative Crohn's disease
No full textMeta-analysis of the placebo rates of clinical relapse and severe endoscopic
recurrence in postoperative Crohn's disease.
Renna S, Cammà C, Modesto I, Cabibbo G, Scimeca D, Civitavecchia G, Mocciaro F,
Orlando A, Enea M, Cottone M.
Dipartimento di Medicina, Pneumologia e Fisiologia della Nutrizione Umana,
Università di Palermo, Palermo, Italy.
BACKGROUNDS & AIMS: The benefit of therapy for prevention of postoperative
recurrence of Crohn's disease (CD) is limited. Clinical relapse and severe
endoscopic recurrence are the main outcomes in the evaluation of trials on
prevention of recurrence. The aim of this meta-analysis was to focus on knowledge
of the placebo rates of relapse and recurrence in postoperative CD and to
identify factors influencing these rates.
METHODS: We performed a meta-analysis of placebo-controlled, randomized clinical
trials, evaluating therapies for postoperative maintenance of CD identified on
MEDLINE from 1990 to 2006. Primary outcomes were clinical relapse and severe
endoscopic recurrence.
RESULTS: The pooled estimate of the placebo relapse rate was 23.7% (95%
confidence interval [CI], 13-35; range 0-78). There was a statistically
significant heterogeneity among studies (P < .0001). Heterogeneity in clinical
relapse was present even if the trials were stratified according to the time of
outcome. The pooled estimate of the severe endoscopic recurrence rate was 50.2%
(95% CI, 28-73; range, 30-79). There was significant heterogeneity among the
studies (P = .00038). This heterogeneity was less apparent in studies carried out
within 12 months. The logistic analysis identified only duration of follow-up as
a variable associated with different placebo relapse rates. No variable was
identified as a predictor of a placebo endoscopic recurrence rate.
CONCLUSIONS: There is significant heterogeneity among placebo rates in
postoperative CD. No single design variable was identified that explained the
heterogeneity in placebo outcomes for clinical or endoscopic recurrence
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Nd:YAG laser welding of fine sheet metal butt joints in AZ31 magnesium alloy
No full textMagnesium alloys have been used increasingly in various areas of industry, such as the automotive sector, electronic components. A reliable method for joining components produced with these materials will definitely allow for a wider use of these alloys. In this article, the laser welding process with an Nd:YAG laser using a maximum power of 2 kW was studied and reported. The effect of welding parameters, such as laser and welding, was analysed. Metal sheets of 1mm thickness in AZ31B magnesium alloy were butt-welded with helium and argon as shielding gas in the absence of filler material. The mechanical characteristics were measured during tensile tests, using digital image correlation (DIC) as a deformation measurement technique. After a preliminary experimental plan aimed at exploring the range of process parameters, the welding process was optimized using an approach based on the design of experiments (DoE). Consecutive experimental plans led to optimized butt joints, which, following a tensile test, showed a sound weld bead with fracturing in the base material. Local strain analysis by DIC highlighted different tensile behaviours, in terms of deformation of the weld bead, in the optimized butt joints with respect to those that were not optimized
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