Download Treatment of refractory chronic urticaria with tumor necrosis factor

RECOMMENDATIONS
In which conditions should acitretin be used?
Acitretin monotherapy is recommended in the treatment of:
1) Severe psoriasis, or psoriasis with severe effects on quality
of life, meriting systemic therapy, which is resistant to
topical therapy, phototherapy or is unsuitable for these
treatments (A,1+).
1.1) Acitretin is recommended as a combination with PUVA
therapy or narrowband phototherapy (A, 1+).
1.2) Acitretin is recommended with hydroxycarbamide (D, 3)
1.3) Acitretin is recommended in combination with calcipotriol
ointment (A, 1+).
1.4)The following combinations are not recommended:
Acitretin with ciclosporin: no evidence of additive efficacy (D,
3).
Acitretin with methotrexate: potential for severe hepatic
toxicity (except in exceptional cases) (D, 3).
4) Severe Darier disease (keratosis follicularis) (A,1+).
5) Severe congenital ichthyosis (D, 3).
6) Keratoderma (D, 3).
There is evidence that the following conditions benefit
from acitretin’s antimitotic and keratolytic actions:
1) Lichen planus (A, 1+)
2) Lichen sclerosus (A, 1+)
3) Discoid lupus erythematosus (A, 1+)
4) Prevention of cutaneous malignancies in organ
transplant patients (A, 1+).
What special precautions should be taken when prescribing
acitretin?
Patients should not donate blood either during or for at least 1 year
following discontinuation of therapy.
Acitretin is not recommended in children, as there have been occasional
reports of bone changes,
the child should be carefully monitored for any abnormalities of growth
parameters and bone development including plotting growth charts.
The effects of UV radiation are enhanced by retinoid therapy, therefore
patients should avoid excessive exposure to sunlight and use of sun
lamps.
Women (and men) should refrain from waxing as a method for hair removal
as retinoids cause skin fragility.
Retinoids are associated with greater insulin sensitivity and could therefore
induce hypoglycaemia in patients on antidiabetic medications. In this
subset of patients, serum glucose levels should be checked more
frequently than usual in the early stages of treatment.
People with diabetes, alcoholism and obesity need to be monitored more
What are the preliminary investigations prior to starting acitretin?
• Teratogenicity:
In women of childbearing age pregnancy must be excluded by negative
pregnancy test within 2 weeks prior to therapy. Acitretin should be
started only on the second or third day of the next menstrual cycle.
Effective contraception must be practised for at least 4 weeks before
and during therapy with acitretin, and for 3 years after treatment with
acitretin has ceased.
• Liver disease:
Enquire regarding past or current history of liver disease, excess alcohol
intake, and hepatotoxic drugs.
Check alanine aminotransferase, aspartate aminotransferase,
γ-glutamyltransferase, alkaline phosphatase, bilirubin.
• Renal disease:
Enquire regarding past or current history of renal disease, nephrotoxic
drugs.
Check urea, electrolytes and creatinine.
• Hyperlipidaemia:
Enquire regarding past or current history of disturbances of lipid
metabolism, DM, obesity, alcoholism. Check fasting cholesterol, TG.
How should acitretin be prescribed?
Therapy should be initiated only under the responsibility of a
supervising dermatologist
The capsules should be taken once daily with meals or with milk.
Effective doses of acitretin as a single agent appear to be in the
range of 25–50 mg daily.
Gradual dose escalation has been shown to be the most
effective approach and allows gradual onset of ‘tolerance’ to
side-effects.
The initial daily dose, 25 mg or 30 mg for 2–4 Ws, may give
satisfactory therapeutic results. The maintenance dose must be
based on clinical efficacy and tolerability. In general, a daily dose of
25–50 mg taken for a further 6–8 Ws achieves optimal
therapeutic results. It may be necessary in some cases to increase
the dose up to a maximum of 75 mg daily.
Response is gradual and typically requires 3–6 Ms to
reach a peak . Therapy can be discontinued in
patients with psoriasis whose lesions have improved
sufficiently. Relapses should be treated as described
above.
In patients with Darier disease a starting dose of
10 mg/d may be appropriate. Patients with severe
congenital ichthyosis and Darier disease are likely to
require long-term treatment with acitretin, as are
some patients with psoriasis.
How should acitretin therapy be monitored?
• Liver enzymes every 2–4 weeks for the first 2 Ms of therapy and then
every 3 months. If abnormal results are obtained, weekly checks should
be instituted and acitretin dose adjusted accordingly.
Acitretin should be discontinued if transaminases are elevated to 3 times .
• Fasting serum cholesterol and TG every 2–4 Ws for the first 2 Ms and
then every 3 Ms. In the presence of a good therapeutic response to
acitretin but persistently elevated lipid levels, dietary measures should be
introduced before considering a lipid-lowering drug.
Patients with TG > 400mg/dl should be referred to a lipidologist and
investigated for other causes of hyperTG (e.g. alcohol, SLE, DM,
hypothyroidism, renal and hepatic problems, hormonal dysfunction etc).
HyperTG>800mg/dl warrants discontinuation of acitretin and urgent
referral to a lipidologist, as it is a risk factor for acute pancreatitis.
• BS levels in diabetic patients on insulin or antiglycaemic agents should
also be monitored at similar intervals.
These patients should check their capillary glucose more frequently than usual
during the first few weeks of treatment.
• Radiological investigation for skeletal changes need not be done routinely
THE CUTANEOUS AND SYSTEMIC
MANIFESTATIONS OF
AZATHIOPRINE
HYPERSENSITIVITY
SYNDROME
INTRODUCTION:
Azathioprine (AZA) (Imuran, Azasan), the
nitroimidazole of 6-mercaptopurine (6-MP), was
first used in 1961 as an immunosuppressant for
kidney transplantation. Since then it has become
an effective corticosteroid-sparing agent in a
variety of autoimmune inflammatory diseases to
include RA, SLE, vasculitis, IBD, BP, pemphigus,
and others.
Dose-dependent toxic side effects
(myelosuppression,
gastrointestinal side effects, hepatotoxicity) have
been well recognized.
Case 1:
A 39-year-old Caucasian woman with CD presented with
vomiting, diarrhea, fever, and arthralgias 4 Ws after
starting AZA therapy. Before she started AZA, her
thiopurine methyltransferase (TPMT) levels were in
the normal range. Her AZA dose at presentation was
100 mg/d. She was also taking prednisone, 30 mg/d.
Her AZA was discontinued, and shewas admitted to
the hospital for work-up and treatment of sepsis and
exacerbation of CD.
Her WBC count on admission was elevated at 14,000
with84% NEUT .3 days later a mildly pruritic,
generalized papulopustular eruption developed,
which was most prominent on her lower legs and
A shave biopsy specimen showed a dermal and
perivascular diffuse infiltrate of NEUT, Lym, and
histiocytes with focal leukocytoclasis.Her systemic
symptoms and eruption resolved 5 days after the
AZA had been discontinued. Her work-up for
sepsis yielded negative findings and other Lab
findings were unremarkable. There was no
evidence of eosinophilia or liver dysfunction.
Several weeks later the patient underwent
rechallenge with a 25mg dose of AZA. Within 24
hours, she
developed arthralgias, malaise, and cutaneous
lesions. The skin lesions again erupted on the
Patient 1. Firm, indurated, erythematous papules and
nodules, 5 to 10mm,with central pustules and vesicles.
Case 2:
A 33-year-old obese Caucasian man with SLE complicated by
a recurrence of proliferative glomerulonephritis was
admitted to the hospital for fever, arthralgias, diarrhea, and
dark urine 2 Ws after starting AZA. His TPMT level was in
the normal range. On admission, he was taking AZA, 300
mg/d, and prednisone,35 mg/d.
The AZA was discontinued and a work-up for sepsis was
initiated. His serum Cr was elevated from a baseline of 1.4
to 2.7 mg/dL. He also had elevated alanine
aminotransferase and aspartate aminotransferase at
89 U/L and 113 U/L,respectively. Although he had
neutrophilia (83%), his WBC and eosinophils were within
normal range. On his second day of hospitalization, he
developed an indurated papulopustular eruption on his face,
neck, elbows, and hands .
Patient 2. Erythematous pustules on right side of face.
Patient 2. Indurated papules on palm of left hand.
A biopsy specimen showed marked papillary dermal
edema with a dense infiltrate of neutrophils but no
evidence of vasculitis.
4 days after admission, the patient’s systemic
symptoms improved and his rash resolved. His workup for sepsis was negative. Other laboratory
findings, including complement levels and dsDNA,
were unchanged compared with baseline.
On hospital discharge, his serum Cr remained elevated
at 2.1 mg/dL. He was not re-challenged with AZA as
the initial presentation was consistent with AZA
hypersensitivity syndrome.
Review of the literature:
Including the present case series of two, 67 cases
of AZA hypersensitivity from 1986 through 2009
were reviewed . Of these cases, 49%(33) had
cutaneous manifestations. Of those presenting with
cutaneous findings, 76% (25) had biopsy or clinical
features consistent with a neut dermatosis, whereas
the other 24% (8) were reported as a non-specific
cutaneous eruption.
Several earlier case reports had more detailed
descriptions of skin findings suggestive of neut
dermatoses, but were not biopsy confirmed.
Of the patients with a biopsy-proven neut dermatosis,
64% (16/25) had IBD (CD,UC). Many of these cases
met the diagnostic criteria for drug-induced Sweet’s
syndrome, as described by Walker and Cohen.
.
Other features of AZA hypersensitivity with respect to
onset, systemic symptoms, TPMT activity, Lab
findings, and concurrent steroid use were similar to
those described in other case reports and reviews
The age and sex of patients did not affect the
presentation or risk for AZA hypersensitivity. The
majority of patients developed AZA hyper sensitivity
within the first 4 Ws of therapy.
There were only 3 patients (4%) in our series who had
dermatologic diagnoses (psoriasis,BP, and
pemphigus). Concurrent use of corticosteroids at
presentation was common, occurring in 39% of
patients (26/67).
DISCUSSION:
AZA is an effective and well-tolerated immunosuppressive agent. While
approved by FDA for severe RA and prevention of rejection in renal
transplantation. AZA continues to be a useful steroid-sparing
medication in the treatment of many systemic autoimmune
conditions such as IBD, SLE, MG, and others.
The most common dermatologic conditions treated with AZA are BP and
pemphigus and, less commonly, AD, psoriasis, and CAD.
AZA is a purine analog that inhibits both RNA and DNA synthesis. It was
originally synthesized from 6-MP by the addition of an imidazole ring.
This imidazole ring improved efficacy and reduced the rapid
catabolism of 6-MP. The initial metabolism of AZA results in two
products: 6-MP and the imidazole derivative (methylnitroimidazole
moiety). The metabolism of 6-MP by hypoxanthine phosphoribosyl
transferase results in 6-thioguanine nucleotides, which are
responsible for drug action and dose-dependent side effects.
Further metabolism of 6-MP by TPMT and xanthine oxidase yields
inactive metabolites.
The overall incidence of side effects from use of AZA
necessitating drug withdrawal ranges from 10%-15%.
Cases of a true hypersensitivity syndrome to AZA have
been reported in approximately 2% of patients taking
the drug.
Dose-dependent side effects of AZA, such as
myelosuppression, infection, nausea, vomiting, and
hepatotoxicity, are well characterized and can occur
at any time during drug-therapy. The incidence of
dose-dependent side effects ranges from 4% -27%.
These side effects are not allergic in nature, but are the
result of direct toxicity from 6-thioguanine
nucleotides and can be related to low TPMT activity
or inhibition of xanthine oxidase.
AZA hypersensitivity reactions may be more common
than is generally accepted. In 2001, Craner and
Zajicek reported AZA hypersensitivity in 14 of 21
patients with MS.
This evidence suggests that Patients with IBD or MS
may be at higher risk for AZA hypersensitivity.
The reasons for this are unclear but possibly involve a
genetic polymorphism that predisposes persons to
AZA hypersensitivity.
This may also be due to the fact that more IBD and MS
patients are treated with AZA, under-recognition of
the disease, or reporting bias by certain specialties.
Hypersensitivity reactions to AZA are dose independent
and tend to occur during the first 4 Ws of therapy.
Unlike dose-dependent side effects, these reactions
occur regardless of TPMT levels.
The systemic symptoms of AZA hypersensitivity most commonly include
fever, malaise, arthralgias, myalgias, nausea, vomiting, diarrhea, and rash.
Occasionally, liver or kidney dysfunction, hypotension, and shock may be
present.
Skin manifestations have historically been described as macular-papular,
vesicular, or pustular.
In addition, there are reports of purpura, urticaria, and erythema nodosum.
More recently, there are several reports of Sweet’s
syndrome (SS) associated with AZA hypersensitivity.
Our first patient similarly displayed SS-like lesions,
while our second patient met the diagnostic criteria
for drug-induced SS.
Despite the wide use of AZA in dermatology, there are
very few case reports of hypersensitivity in patients
treated for dermatologic conditions (eg,
immunobullous disease, atopic dermatitis, psoriasis,
photodermatoses).
More than 50% of the time, hypersensitivity reactions to AZA
occur with systemic symptoms identical to those of SS
(fever, leukocytosis, malaise, arthralgias), but no cutaneous
manifestations or cutaneous findings other than SS are
described. There are cases of cutaneous eruptions that
may resemble SS, as in our case, but are not characteristic
or do not meet the diagnostic criteria outlined by Walker
and Cohen.
Similar to our findings (Table I), Fields et al found that 39% of
patients (19/49) who were diagnosed with AZA
hypersensitivity were taking C.S at presentation.
This is atypical for SS since C.S are the treatment of choice.
Other atypical features include the location of lesions and
preponderance of gastrointestinal symptoms.
In our study, 58% (7/12) of patients presented with
gastrointestinal symptoms (nausea,vomiting, diarrhea),
which is uncommon for SS.
On initial presentation, most cases of AZA h.s are confused with
infection or exacerbation of an underlying condition, as was the
case in our patients. The concern for infection is a priority,
especially with fever and leukocytosis in a patient receiving
immunosuppressive therapy.
However, work-up for infection generally yields negative findings
and screening serologies for disease activity, such as
complement levels or dsDNA ab, in SLE tend to be normal.
Under these circumstances, the diagnosis of AZA h.s is implicated
rather than a flare of the underlying disease.
AZA h.s is often recognized upon resuming or re-challenge with
AZA where symptoms recur within hours of the first dose.
The presence of new skin findings in the absence of infection or
disease flare should alert the clinician to the possibility of AZA
hypersensitivity.
Most cases of AZA h.s resolve within 2-3 days after withdrawal of
the medication and may not necessitate an increase in
corticosteroid dose.
we report two cases of AZA
hypersensitivity with
cutaneous manifestations
of neut dermatoses.
Our review of the literature
indicated that the most
common cutaneous
manifestation of AZA
hypersensitivity is a neut
dermatosis.
Biopsy findings were
consistent with SS, EN,
SVV, and AGEP.
AZA hypersensitivity
syndrome tends to occur
within 4 Ws after initiation
of therapy and is unrelated
to the gender or age of the
patient or TMPT levels.
TREATMENT OF REFRACTORY
CHRONIC URTICARIA
WITH
TUMOR NECROSIS FACTOR-ALFA INHIBITORS
Chronic urticaria
is a physically and emotionally debilitating condition
that often fails to respond adequately to
antihistamines.
Systemic therapy with glucocorticoids,sulfasalazine,
colchicine, intravenous immunoglobulin,dapsone,
or other immunosuppressants including
cyclosporine,cyclophosphamide, and
methotrexate are used in many patients with the
associated risks of renal and hepatic toxicity and
anemia.
Unfortunately, some patients have disease
recalcitrant to these treatments.
The pathogenic mechanisms of chronic urticaria are
not well understood, but the primary effector cell is
likely the mast cell.
Activated mast cells release mediators, including
Tumor necrosis factorealfa(TNF-a), that recruit other
immune cells and play a role in perpetuating an
urticarial response.
Several preclinical investigations have shown an
upregulation of TNF-a in patients with chronic
urticaria.
Magerl et al described a patient with severe psoriasis
and delayed pressure urticaria who became free of
urticarial lesions after 4 days of treatment with
etanercept.
Based on these preclinical investigations and the case
report, we treated six of our most refractory chronic
urticaria patients with TNF-a inhibitors.
we used doses tested for other systemic inflammatory
conditions, such as psoriasis.
In our series of six patients who were recalcitrant to all
other immunosuppressive therapies, we observed
dramatic improvement with TNF-a inhibitors. In most
cases, the improvement was durable,lasting for
several years.
These results suggest that targeted TNF-a therapy may
be useful for disease refractory to conventional or
immunosuppressive therapy. Larger, controlled
studies with longer followeup periods are needed to
further confirm the efficacy and safety of TNF-a
inhibitors in the management of patients with chronic
urticaria.
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