Chronic Urticaria Treatment



ACAAI/AAAAI Practice Parameter (2013)

CU algorithm pp 2013.png

EAACI/WHO Guideline (2013)

EAACI CIU Tx Algo.png
  • Note: the same treatment algorithm is recommended for children with chronic urticaria


Allen Kaplan Algorithm

Kaplan algo.png
  • With at least 4X antihistamine dosing, there is no evidence that addition of an H2-antihistamine or leukotriene antagonist would add anything; therefore, this step can be skipped
  • Steroids
    • Cyclosporine and omalizumab have limited my use of corticosteroid to severe acute exacerbations according to current guidelines
    • When used, no more than 10 mg/d or 20-25 mg QOD with tapering about 1 mg/week (for a total course of 3 months). If higher doses are considered for regular use beyond this range, the drug should not be used at all.
    • Alternate-day chronic steroid therapy
      • Determine the lowest possible effective dosage. The author usually starts with prednisone 40 mg in one morning dose for the first 3 days and then decreasing the dosage by 5 mg/day. When the dosage is down to 20 mg/day, it is decreased 5 mg on alternate days. Thus, the daily dosage becomes 20, 15, 20, 10, 20, 5 and so on until a dosage of 20mg every second day is achieved. This alternate-day regimen is effective in the majority of patients.
      • The steroid should then be slowly withdrawn, decreasing the dosage 2.5–5 mg every 2 to 3 weeks. The decision to keep decreasing the dosage depends on achievement of considerable improvement with the 25-mg alternate-day dosage and no obvious worsening of symptoms as the dosage is decreased.
      • Optimally, close to 3 months would be needed to discontinue the steroid. Antihistamines are continued with the corticosteroid and should probably not be tapered until the patient no longer requires the steroid. Sometimes, the duration of steroid therapy must be extended because the drug cannot be tapered below a certain dosage. This is maintained for a while (usually 1 to 2 months), and then the physician should try again to taper the dosage.
      • Occasional associated angioedema of the face or tongue can be treated with 60 mg of prednisone, with 40 mg given the following day; treatment can then be stopped or the alternate-day dosing schedule can be resumed.
  • Cyclosporine
    • Begin at 100 mg BID for “average-sized adult”. If no response by 3 weeks, increase dose to 125 mg BID. If no response by 3 weeks, increase dose to 150 mg BID. If no response by 3 weeks, then we consider patient a cyclosporine failure and give up. If cyclosporine does help, then continue for 3 months to 1 year, depending on past severity and duration of urticaria and the amount of breakthrough hives that the person has while on cyclosporine.
      • Taper steroid - do not begin to taper cyclosporine until steroid is completely weaned off. Keep going down on steroid and don’t stop the steroid taper because an occasional bad day occurs.
      • Taper cyclosporine - If the patient has done well for 4-8 weeks, with little breakthrough hives, then you need to start the cyclosporine taper. Drop the daily dose by 50 mg every 4 weeks until the patient is down to 100 mg per day. Then, drop daily dose by 25 mg every 4 weeks (will need to use 25 mg tablets to do this).
    • My experience has been occasional adverse effects with increasing blood pressure, BUN, or creatinine level (eg, an increase in creatinine level from 0.91 to as high as 2.2 mg/dL). Use of the drug was discontinued, and all patients’ renal function reverted to normal within 4 to 6 weeks. An increase in blood pressure was less common, but when present use of the drug was discontinued.


David Khan Algorithm


Phase 1
1. 2nd generation H1 antihistamine — cetirizine 10 mg once daily, or levocetirizine 5 mg once daily, fexofenadine 180 mg once daily, loratadine 10 mg once daily, desloratadine 5 mg once daily.
2. Increase the dose of the of antihistamine to twice daily if symptoms not controlled adequately within several days.
  • Alternatively, add a different 2nd gen antihistamine (eg, fexofenadine 180 mg in the morning, and cetirizine 10 mg at night).
  • Dosing up to 4 times standard doses may be considered with some agents, such as desloratadine and levocetirizine (not useful with fexofenadine)
3. Add/substitute a 1st generation H1 antihistamine at bedtime, or add an H2 antihistamine. We prefer to add one of the following potent H1 receptor antagonists:
  • Hydroxyzine 10-25 mg initially at bedtime, and increased in weekly increments up to 50 mg before bedtime
  • Doxepin (in adults), may be started at 10 or 25 mg and increased weekly to up to 100-150 mg given once at bedtime or in divided doses during the day. Doxepin is avoided <12 years of age due to limited clinical experience.
  • Some add an H2 antagonist, eg. ranitidine 150 mg BID
4. Leukotriene modifier — add montelukast 10 mg daily while maintaining the highest tolerated dose of H1 antihistamines. Allow at least 4 weeks, and if there is no improvement, discontinue.

Phase 2
5. Treatment of refractory urticaria with an anti-inflammatory agent
  • We most commonly start with dapsone 100 mg daily. The dose can be reduced once there is a clear clinical response. A 4-6 week trial is usually sufficient to determine effectiveness.
  • We choose sulfasalazine instead in patients with underlying anemia or concomitant delayed pressure urticaria. Start at 500 mg BID for one week then increase to 1 gram BID. 4-6 week trial is usually sufficient to determine effectiveness.
  • We use hydroxychloroquine in patients who have suboptimal control of their CU, but only modest impairment in quality of life, as this agent is slow to work and patients with more severe disease may not be able to tolerate the duration of the trial. Start with 200 mg BID. A three month trial is usually required to determine effectiveness.
    • A strategy to circumvent the long latency time of hydroxychloroquine is the initiation of either dapsone or sulfasalazine at the same time. If the patient responds within a few weeks, the hydroxychloroquine can be discontinued as it was unlikely to have been responsible for the improvement. If no benefit is apparent with dual therapy after 4-6 weeks, the other agent (ie, dapsone or sulfasalazine) may be discontinued and the hydroxychloroquine continued for a total trial of 12 weeks.
  • We usually try two antiinflammatory agents before proceeding to immunosuppressant or immunomodulatory agents.
  • In patients who are steroid-dependent and already suffering from steroid-induced toxicity, we may elect to use an immunosuppressant prior to antiinflammatory therapy, as immunosuppressants seem to be more reliably effective in our clinical experience.

Phase 3
6. Treatment of refractory urticaria with an immunosuppressant or immunomodulatory agent
  • We prefer tacrolimus as an initial immunosuppressant. Although there are more data in support of cyclosporine, we prefer tacrolimus because most of our patients are women, and cyclosporine can cause hirsutism and gingival hyperplasia. Anecdotally, we have observed more frequent problematic side effects with cyclosporine than tacrolimus. We start tacrolimus at a dose of 1 mg BID for 1 week, and increase to 2 mg BID if no therapeutic benefit is seen within 1-2 weeks. In our experience, most patients will respond to doses ≤4 mg daily of tacrolimus. Higher doses up to 6 mg/day can be used in patients who partially respond or have no response to lower doses. Once they are hive free for 3 mos, I will taper by 1 mg/month.
    • Alternative tacrolimus protocol (Kessel): 0.05-0.07 mg/kg/day div PO BID x 4 weeks (may increase to 0.07 mg/kg/day if poor response to 0.05 mg/kg/day), then 0.025-0.035 mg/kg/day div PO BID x 6 weeks, then 1 mg/day x 2 weeks, then stop (12 weeks total course)

  • Cyclosporine may be started at 100 mg BID and increased to 5 mg/kg/d divided BID. Certain patients appear to respond better to either tacrolimus or cyclosporine, although if one of these agents has not helped, we generally try mycophenolate next.
  • Mycophenolate mofetil is typically started at 1000 mg BID and may be increased to 1500 mg BID after several weeks if needed.
  • Omalizumab in patients with concomitant asthma — In patients with CU refractory to antihistamines and leukotriene modifiers who have concomitant asthma, use of omalizumab earlier in the stepwise approach is reasonable. In most studies, omalizumab has been dosed based on established asthma dosing guidelines (ie, according to IgE level and body weight). Responses to omalizumab typically occur within days of the first dose, but we generally recommend 2-3 months of omalizumab to determine efficacy.
  • IVIG considered for patients refractory to the step-wise approach above. It may be an appropriate earlier option in patients in whom an immunodulator would be preferable to an immunosuppressive agent, such as those with a history of malignancy in the past.

Exacerbations
  • Prednisone 20 mg BID for 2-3 (up to 10) days. Occasional patients require higher initial doses. Once symptoms are controlled, the dose should be tapered down to 10 mg daily or less, which can be done in increments of 10 mg. If rebound worsening occurs, return to the last effective dose and then try to taper again more gradually.

Tapering Medications
  • We recommend 3 months of good control prior to tapering therapies, and we extend this longer for patients with one or more of the following characteristics: symptoms that were present for years, were very severe, or were difficult to control, concomitant physical urticarias, which tend to be longer-lasting than simple CU, symptoms that are mostly controlled, but still present at a low level.



Sarbjit Saini Algorithm

1. Non-sedating H1 antihistamine
2. If symptoms persist after 2 weeks: increase dose of non-sedating H1 antihistamine
3. If symptoms persist after 2 weeks: add H2 antihistamine, add LTRA, change type of non-sedating H1 antihistamine, supplement with sedating antihistamine
4. If symptoms persist after 1-4 weeks, consider:
  • Skin biopsy
    • If neutrophil-rich urticaria
      • Dapsone 25-100 mg daily. Start with 25 mg/d for first week then increase by 25 mg each week until a max of 100 mg/day.
      • Colchicine 500 mg daily to 3x/day.
    • If lymphocyte/eosinophil rich urticaria
      • Sulfasalazine 500 mg to 4 grams daily. Start with 500 mg/d for first week then increase by 500 mg each week until a max of 2-4 g/day. Maintain an antihistamine during sulfasalazine tapers.
      • Cyclosporine (2-5 mg/Kg/d)
  • Omalizumab
  • Low dose daily oral corticosteroid with gradual taper
5. Treat exacerbations with oral corticosteroids for 3-7 days

Tom Casale Algorithm

Casale CIU algo.png


Pseudoallergen-free diet



Omalizumab

  • FDA approved for the treatment of chronic idiopathic urticaria in adults and adolescents (12 yo) who remain symptomatic despite H1 antihistamine treatment
  • The potential for a salutary response cannot be predicted based demographic characteristics (eg, age and sex); laboratory data, including findings that reflect autoimmunity (eg, autologous serum skin test, autologous plasma skin test, autoantibodies to IgE or the high-affinity IgE receptor, or antithyroid antibodies); histopathologic findings; biomarkers; or the nature or previous course of the disease
  • Dosing
    • Not dependent on serum IgE level or body weight
    • FDA approved dosing is 150 or 300 mg SC every 4 weeks
      • 300 mg (and to a lesser extent 150 mg) every 4 weeks x 3 doses was effective in controlling symptoms in patients with CIU resistant to low doses of H1-antihistamines, however symptoms trended back to baseline about 3 months after the last dose
      • Standard (asthma) dosing was effective in patients with anti-TPO IgE antibodies and CIU resistant to H1 antihistamines
      • Single 300 or 600 mg dose provided rapid (1-2 weeks) treatment in patients with CIU resistant to H1- antihistamines
    • Proposed algorithm for omalizumab dose adjustment based on urticaria activity score: xolair urticaria algo.png


Ketotifen

  • Inhibitor of the release and/or activity of mast cell and basophil mediators (including histamine, neutrophil, and eosinophil chemotactic factors, arachidonic acid metabolites, prostaglandins, and leukotrienes)
  • Dosing
    • 0.5 mg PO BID for children (6 mo - 3 yo), 1 mg BID for older children/adults
    • Titrate dose to effect, up to 6 mg/day total, with dose increases preferably starting at night due to sedation
  • Available from compounding pharmacies in US or Canadian online pharmacies



Sympathomimetics

  • Anecdotal report of effectiveness of Adderall 10-20 mg PO BID, then tapered to the minimal effective dose
    • Doses 5-40 mg/day are used for adult ADHD


Vitamin D3

  • In one study, addition of vitamin D3 4000 IU PO QD to cetirizine, ranitidine, and montelukast provided a decrease in urticaria severity symptoms over time, regardless of the baseline vitamin D level



Chronic Urticaria Exacerbation Treatment

  • Kaplan: Occasional associated angioedema of the face or tongue can be treated with 60 mg of prednisone, with 40 mg given the following day; treatment can then be stopped or the alternate-day dosing schedule can be resumed.
  • Kahn:
    • Prednisone 20 mg BID for 2-3 (up to 10) days. Occasional patients require higher initial doses. Once symptoms are controlled, the dose should be tapered down to 10 mg daily or less, which can be done in increments of 10 mg.
    • If rebound worsening occurs, return to the last effective dose and then try to taper again more gradually.
  • Saini, EAACI/WHO guideline: Treat exacerbations with oral corticosteroids for 3-7 days
  • Asero:
    • For patients with CIU with no/partial response to initial antihistamines: Prednisone 25 mg PO QD x 3 days then 12.5 mg PO QD x 3 days then 6.25 mg PO QD x 4 days (10 days total); repeat course if rebound with steroid taper or discontinuation.
    • 59% (n=90) were able to maintain control of CIU with antihistamines after 1 or 2 courses of prednisone

Short-term Treatment of Sleep Disturbance due to CIU

  • Zuberbier: combining modern non-sedating antihistamines with drugs like zolpidem (Ambien) is recommended.
    • Initiation of sleep with sedating antihistamines is less beneficial than one can achieve with modern sedatives like zolpidem, because sedating antihistamines impair REM and frequently cause a hangover, resulting in impaired reflexes that could affect daily activities
      • Note that tolerance/dependence may develop if remaining on zolpidem >2 weeks
      • In most cases, as soon as the itchiness is under control, normal sleeping patterns are easily reached again by patients

Monitoring Drug Adverse Effects

Alternative CIU tx table.png
Drug
Adverse Effects
Monitoring
Dapsone

Time to response:
Several days to several weeks

Time to relapse:
Several days
Dose-related anemia, peripheral neuropathy (uncommon but often irreversible), rash, gastrointestinal complaints

Rarely, methemoglobinemia and blood dyscrasias, hepatitis, dapsone hypersensitivity syndrome

Avoid in patients with hemoglobin M or low levels of G6PD or methemoglobin reductase
Review
  • Baseline: G6PD level, BUN/Cr, UA, LFTs, CBC
  • Follow-up: CBC 1–2 weeks after starting, then periodically

Package insert
  • CBC: q wk x 4, q mo x 6, then q6 mo
  • LFTs: baseline and periodically

Khan
  • G6PD at baseline; CBC at baseline, 2 weeks, then q mo x 3-6, then less often, LFTs at baseline and then periodically
  • 10-20% decline in Hgb or HCT is common and therapy is not stopped unless decline >25%

Saini
  • CBC, LFTs, BUN/Cr, UA, G6PD at baseline
  • CBC, LFTs weekly then monthly
Sulfasalazine

Response:
Several days to several weeks

Relapse:
Several days
Headache, gastrointestinal complaints, reversible oligospermia

Rarely, rash, photosensitivity, proteinuria, cytopenias, cyanosis, hepatotoxicity (adverse effects more common above 3–4 g/d)
Review
  • Baseline: G6PD, CBC, LFTs, BUN/Cr, UA
  • Follow-up: CBC monthly for first 3 months then periodically

Package insert
  • CBC: q2-3 wks x 2-3 mo, then q3-6 mo
  • LFTs: q2 wks x 3 mo, q mo x 3, then q3 mo

Khan
  • CBC, LFTs, UA q mo x 3, then less often

Saini
  • CBC, LFTs weekly, monthly, then quarterly
  • Add folic acid if treatment persists >1 mo
Hydroxychloroquine

Response:
1-3 months

Relapse:
Unknown
Gastrointestinal complaints

Rarely, retinopathy (risk factors include >5 years use at which point the risk increases to only 1%, >1000 g cumulative dose, >400 mg/d dosing, elderly, preexisting kidney/liver disease or retinal disease or maculopathy), nonretinal ocular reactions, myopathy; caution: children and patients with porphyria, psoriasis, low levels of G6PD; retinitis may initially be asymptomatic
Review
  • Baseline: G6PD, CBC, BUN/Cr, LFTs, eye exam for planned treatment with higher doses or long duration
  • Follow-up: periodic eye examinations if higher dose or long duration, attention to any ocular complaints
AAO 2011
  • Baseline exam within 1st year of use (typically 6 months), annual screening after 5 years of use, annual screening with initiation if risk factors present
Colchicine

Response:
Several days to 1 month

Relapse:
Several days
Gastrointestinal complaints, stomatitis, marrow depression, rash, peripheral neuropathy, alopecia
Review
  • Baseline: CBC, BUN/Cr, LFTs
  • Follow-up: CBC periodically
Cyclosporine,
Tacrolimus

Response:
2 days to several
weeks;
with CsA 35‐40% fail to respond or have intolerance, 30% long‐term remission, 30% reduction in symptoms

Relapse:
1 day to several
weeks
Gastrointestinal complaints, headache, tremor, renal dysfunction, hypertension, hyperlipoproteinemia, hirsutism, gingival hyperplasia, leukopenia, neuropathy

Rarely dose-dependent immune suppression-related infections and neoplasia. Risk of new-onset diabetes with tacrolimus.

Contraindicated in uncontrolled HTN, renal disease, serious infection, breast feeding, previous history of malignancy
Review
  • Baseline: BP, BUN/Cr, electrolytes, lipid panel, LFTs
  • Follow-up: BP, BUN/Cr, electrolytes at least monthly for first 3 months then periodically
  • Consider drug levels q3 weeks in some patients (cyclosporine <300 ng/mL; tacrolimus <20 mcg/mL)

Package insert (cyclosporine)
  • CBC, K+, Mg2+, lipid panel, uric acid, BUN/Cr, BP (x2) at baseline, q2 wks x 3 mo, then q1 mo
  • LFTs periodically

BJD guidelines 2007 (cyclosporine)
  • BP, BUN/Cr at 2,4,6, 8 weeks and then qmonth
  • CBC, BMP, LFTs, Mg qmonth
  • TB skin test at baseline
  • Dental evaluation at baseline and 6 month intervals to monitor for gingival hyperplasia
  • Vaccinations should be given prior to initiating treatment


Redding (cyclosporin and tacrolimus)
  • Baseline CBC, BMP, LFTs, uric acid, UA, Hgb A1C (for tacrolimus), baseline BP
  • CBC, LFTs, drug level q2 week x 2
  • BMP q2 weeks x 4 then q4 weeks x 4 (or no lab if dose decreasing) then q6 months if dose stable/decreasing
  • Lipid panel at 6 months then yearly
  • BP at each visit/lab
  • Drug level 2 weeks after each dose increase or change in patient drug regimen
  • Dose adjustment for creatinine:
    • If increased 25%, decrease dose by 25-50% and re-check creatinine in 2 weeks.
    • If increased by 50%, stop drug
Mycophenolate

Response:
Several weeks?

Relapse:
Unknown
Gastrointestinal complaints; rarely leukopenia, anemia, dose-dependent immune suppression-related infections; associated with miscarriage and congenital malformations when used in pregnancy
Review
  • Baseline: CBC, LFTs
  • Follow-up: CBC periodically
  • Two methods of birth control advised
Prednisone

Response:
Several days to 1 week

Relapse:
Variable
Mood alteration, adipose and fluid weight gain, hypertension, hyperglycemia, hyperlipoproteinemia, cataracts, raised intraocular pressure, headache, gastrointestinal complaints, dermal atrophy, osteopenia, infections; caution: children, preexisting psychiatric disorders, diabetes
Review
  • Baseline: consider glucose, mental status examination, BP, lipid panel
  • Follow-up: same, periodically
Methotrexate

Response:
Several days to within 2 weeks

Relapse:
Within 2–3 weeks
Gastrointestinal complaints, stomatitis, marrow suppression, rash, hepatotoxicity, alopecia, and infections; caution: ensure dosing is understood to be weekly (not daily) and embryotoxicity
Review
  • Baseline: CBC, BUN/Cr, LFTs
  • Follow-up: CBC monthly and BUN/Cr, LFTs every 1–2 months or more frequently in settings of increasing blood level or suspected toxicity

Package Insert
  • CBC baseline and q mo, LFTs, BUN/Cr baseline and q1-2 mo, albumin baseline and periodically
  • CXR at baseline (risk of pneumonitis, pulmonary fibrosis)
IVIG

Response:
Several days to several weeks after starting

Relapse:
Several days to several
months
Flushing, myalgias, headache, fever, backache, nausea, chest tightness, wheezing, and hemodynamic changes

Rarely, aseptic meningitis and anaphylaxis
Review
  • Baseline: blood cell counts, liver enzymes, renal function, and viral hepatitis studies; consider IgA level in some cases
Adapted from review article Therapeutic Alternative for CU (Khan, Annals 2008)

cyclosporine adv effects table.png
  • Additional CsA usage notes (Saini):
    • Use "cyslosporine (modified)" (Neoral), which has higher bio-availability than regular cyclosporine (Sandimmune); exercise caution when converting regimens from unmodified to modified
    • Document discussion of potential side effects and black box warning (late lymphomas)
    • Two methods of birth control when applicable
    • Those with underlying hypertension are at greatest risk of adverse effects; calcium channel blockers are the anti‐hypertensive agent of choice
    • Limit prescriptions to last until the next appointment, no refills

Tapering Alternative Treatments (Khan)

  • Treat patients who have achieved minimal or no urticaria with an alternative agent for an additional 3 months before tapering the dosage
    • Anti-inflammatory and immunosuppressive agents: decrease by 25% on a monthly basis
    • Omalizumab: reducing the frequency of injections from q4 weeks to every 6 weeks or longer


Prognosis

  • Typically a self-limited chronic disease.
  • Spontaneous remission occurs in 30-50% of patients by one year, although nearly 20% of patients still have symptoms after five years. Those with more severe symptoms may have longer lasting disease. Up to 40% with CIU longer than 6 months still have urticaria 10 years later.
  • Khan:
    • Educate patients with CIU that it may last several years but at some point will go away.
    • For those with physical urticarias, their condition may be better measured in decades, rather than years.
    • Although their condition may last years, it can typically be controlled during that time to minimize the impact on their quality of life.




References



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