Chronic Spontaneous Urticaria (CSU)

[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]