Chronic Spontaneous Urticaria (CSU)
Treatment
[1-3, 29-31]
- Goal: Control disease, optimize quality of life, treat until resolution [1]
o UCT < 12 ~ uncontrolled; step up therapy
o UCT 12-15 ~ well-controlled; continue therapy
o UCT 16 ~ completely controlled; step down therapy
- Since course is variable without adequate predictors for resolution, evaluate every 3-6 months in those who are well-controlled
- Minimize polypharmacy: discontinue medications that are not beneficial
- Tapering: decrease dose and/or lengthen interval between dosing
o Usually want a minimum of 3 months of adequate control prior to tapering
o Longer period of control, slower taper in those with long-standing, severe and/or
difficult to control symptoms and/or comorbid physical urticarias
- Autoimmune CSU may be more difficult to treat [2, 13]
- Epinephrine autoinjector only if symptoms concerning for systemic reaction [25]
- No known cure [3]
- First Line: Regular (daily) administration of standard-dose second generation H1 anti
histamine – cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine
o Proven efficacy in pediatrics – weight-adjusted dosing, consider syrup/dissolvable tablet formulations [1]
o Loratadine and cetirizine preferred in pregnant/lactating women ([1, 32]); if high
dosing needed, loratadine preferred as this has the most safety data
o No other recommendations on specific anti-histamines as well-designed efficacy
trials are lacking [1]
- Second Line: Increase dose (up to quadruple, 4x) of second generation H1 anti-histamine
o Updosing preferred over mixing different anti-histamines [1]
o Either 1 tab QID or 2 tabs BID
o May consider sedating first generation anti-histamine (ex. hydroxyzine,
diphenhydramine) if bothersome symptoms at night – caution regarding side
effects, drug interactions
o May consider addition of H2 antagonists (ex. famotidine) or anti-leukotrienes (ex.
montelukast) – efficacy unclear
o Systemic corticosteroids: brief courses (< 10 days) if rapid control is needed [2, 3]
- Third Line: Omalizumab 300mg every 4 weeks (approved for ≥ 12 y/o)
o If needed, increase (dose and/or frequency, up to 600 mg Q2wks) [1, 3, 11, 33-49]
o Give 16 weeks to demonstrate response [33, 47]; most respond first couple of
weeks, smaller group with more delayed response
o Safe during pregnancy [50]
- Fourth Line: Cyclosporine – start 2-3 mg/kg, max dose 5 mg/kg (divided BID) [1, 2, 29,
51]
o Monitor BP, renal function
o Side effects are common: hirsutism, gingival hyperplasia, paresthesias, headache,
nausea, abdominal pain, hypertension [29]
o May induce remission [2]
- Alternative therapy [2, 3, 29, 52]: For recalcitrant disease
o Immunosuppressants: may induce remission, high risk of side effects
▪ Anti-TNF: potential for significant side effects [53]
▪ Mycophenolate mofetil: start 1000 mg BID, may increase by 500 mg BID
every month (up to 2000 mg BID) [29]
• Response time 1 to 9 weeks
• GI side effects common
• Monitor for leukopenia, infections
• Teratogenic [29])
▪ Methotrexate: variable response time – 3 weeks to > 6 months; monitor
for gastrointestinal, pulmonary and hematologic abnormalities
▪ Tacrolimus: alternative to cyclosporine; similar adverse effects but less
hirsutism and gingival hyperplasia [29]
▪ Cyclophosphamide: relatively high risk for serious side effects (delayed
malignancy, hemorrhagic cystitis) [54]
• Need for lab monitoring
o Colchicine: limited data, main side effect is diarrhea [55]
o Theophylline: start 200 mg BID
▪ Not FDA-approved for urticaria, data on efficacy not robust [56]
o Anti-coagulants: antifibrinolytics, warfarin, heparin – risks generally outweigh
benefits [14, 57]
o Anti-leukotrienes: montelukast, zafirlukast, zileuton [2]o Corticosteroids, for short duration only per above (caution re: rebound worsening)
o H2 antagonists: famotidine [2]
▪ Cimetidine may be considered, but issues regarding drug-drug interactions
o Doxepin
o Nifedipine: if concomitant hypertension – small studies on efficacy [58]
o Dapsone: start at 100 mg QD; dose-related hemolysis (stop if H/H drops > 25%)
▪ Side effects include methemolglobinemia and peripheral neuropathy
▪ Need baseline G6PD levels and monitoring for anemia and hepatotoxicity [29]
o Sulfasalazine: start 500 mg QD-BID x 1 week, gradual increase to 1 g BID
gradually
▪ Response typically within 1 month, doses > 2 g QD not beneficial
▪ GI side effects can be seen (nausea, emesis, decreased appetite, dyspepsia)
▪ Need monitoring for hematologic abnormalities, proteinuria, hepatotoxicity [29]
o Hydroxychloroquine: start 200 mg BID, response slow (allow 3 months).
▪ Side effects include nausea, skin lesions, headache and ophthalmologic
issues (corneal deposits, retinopathy) [29]
▪ Need baseline ophthalmologic exam
o High dose vitamin D: 4000 IU/day; extent of benefit unclear in general
population, relatively low-risk [59])
o UV A, UVB, narrowband UVB and psoralen + UV A (PUV A) [3]
o Thyroid management if hyper-/hypothyroidism identified
▪ Treatment of euthyroid patients is controversial
o Other therapies can be considered under special circumstances: IVIg,
plasmapheresis, rituximab
o Therapies in development [3]:
▪ Anti-IgE mAb (greater affinity for IgE vs omalizumab) Ligelizumab: two
phase III trials demonstrated two doses of ligelizumab was superior for
urticaria activity at 12 weeks compared to placebo, but not compared to
omalizumab
• Injection site reactions more common with ligelizumab (9.4% 72
mg, 11.1% 120 mg) versus omalizumab (3.8%) and placebo
(1.8%) [60]
▪ BTK inhibitor:
• Fenebrutinib: phase II study terminated, on partial hold from FDA
due to transaminitis in multiple sclerosis trials [61, 62]
• Remibrutinib: improvement in urticaria activity starting at week 1
and continuing to week 52 in a phase III study, with similar
adverse event profile to placebo [63, 64]
• Rilzaburtinib: in phase II clinical trial
▪ Anti-KIT Barzolvolimab: phase II study in anti-histamine-refractory CSU
demonstrated significant improvement in urticaria activity scores
compared to placebo at 12 weeks; was well-tolerated [65]
▪ Anti-IL5 Benralizumab: phase IIb study terminated due to failure to meetits primary endpoint – no change in urticaria activity or itch severity
despite depletion of blood eosinophils [66, 67]
▪ Anti-IL4/-13 Dupilumab: two phase III trials in subjects with symptomatic
CSU despite anti-histamines demonstrated improvement in urticaria activity
(UAS7 -8.5) and itch severity compared to placebo [68]
• Subset of subjects with omalizumab intolerance or incomplete
response, improvement in urticaria activity with a non-statistically
significant trend toward decreased itch with dupilumab was noted
• Safety data were consistent with the known side effect profile of
dupilumab
• Case series noted improvement in disease control and decreased
anti-histamine use when utilized as add-on therapy in CSU [69]
▪ Anti-Siglec 8 Lirentelimab: an open-label phase IIa study demonstrated
improved urticaria control in subjects with anti-histamine resistant CSU
and inducible urticaria [70]
• Decrease in urticaria activity was noted in omalizumab-naïve and
omalizumab-refractory (77% and 45%, respectively) subjects
• No treatment-related serious adverse events were reported
▪ Anti-IL17 Secukinumab:
• Case report on a subject with psoriasis and CSU noted
improvement in urticaria with combination of secukinumab and
omalizumab [71]
• Another case series noted increased IL-17A positive CD4+ T cells
and mast cells in individuals with CSU, with improvement in
urticaria activity in those treated with secukinumab (UAS7
decrease 55% at 30 days, 82% at 90 days) [72]
▪ Wild type c-KIT inhibitor BLU-808
• Phase I study showing potent and selective investigational WT
KIT inhibitor that is CNS sparing and orally bioavailable with
wide therapeutic window for modulating mast cell activity [73]
▪ c-KIT inhibitor Briquilimab
• Phase 1b/2a study with a targeted aglycosylated monoclonal
antibody that blocks stem cell factor from binding to the
cell-surface receptor c-Kit, thereby inhibiting signaling through
the receptor. This inhibition disrupts the critical survival signal,
leading to the depletion of the mast cells via apoptosis which
removes the underlying source of the inflammatory response in
mast cell driven diseases such as chronic urticaria [74]