Non-sedating antihistamines that block the histamine H1 receptors are the first line of therapy. First generation antihistamines such as diphenhydramine or hydroxyzine block both central and peripheral H1 receptors and can be sedating. Second generation antihistamines such as loratadine, cetirizine, or desloratadine selectively antagonize the peripheral H1 receptors and are less sedating, less anticholinergic, and generally preferred over the first generation antihistamines.

People who don’t respond to the maximum dose of H1 antihistamines may benefit from increasing the dose, then to switching to another non-sedating antihistamine, then to adding a leukotriene antagonist, then to using an older antihistamine, then to using systemic steroids and finally to using ciclosporin or omalizumab.

Other options for refractory symptoms of chronic hives include anti-inflammatory medications, omalizumab, and immunosuppressants.

Potential anti-inflammatory agents include dapsone, sulfasalazine, and hydroxychloroquine. Dapsone is a sulfone antimicrobial agent and is thought to suppress prostaglandin and leukotriene activity. It is helpful in therapy-refractory cases and is contraindicated in patients with G6PD deficiency. Sulfasalazine, a 5-ASA derivative, is thought to alter adenosine release and inhibit IgE mediated mast cell degranulation, Sulfasalazine is a good option for people with anemia who cannot take dapsone. Hydroxychloroquine is an antimalarial agent that suppresses T lymphocytes. It has a low cost however it takes longer than dapsone or sulfasalazine to work.

Omalizumab was approved by the FDA in 2014 for patients 12 years old and above with chronic hives. It is a monoclonal antibody directed against IgE. Significant improvement in pruritus and quality of life was observed in a phase III, multicenter, randomized control trial.

Immunosuppressants used for CU include cyclosporine, tacrolimus, sirolimus, and mycophenolate. Calcineurin inhibitors, such as cyclosporine and tacrolimus, inhibit cell responsiveness to mast cell products and inhibit T cell activity. They are preferred by some experts to treat severe symptoms. Sirolimus and mycophenolate have less evidence for their use in the treatment of chronic hives but reports have shown them to be efficacious. Immunosuppressants are generally reserved as the last line of therapy for severe cases due to their potential for serious adverse effects.

Some patients and researchers have successfully treated solar urticaria with Omalizumab (trade name Xolair) which is commonly used to treat Idiopathic Urticaria. Omalizumab is a recombinant humanized monoclonal antibody against IgE. It acts by binding free IgE at the same site that IgE would bind to its high-affinity receptor (FcεRI) on mast cells, thereby reducing free IgE in the serum

This form of treatment is meant to reduce the intensity or altogether eliminate the allergic reactions people have by gradually increasing exposure to the form of radiation that brings about the reaction. In the case of solar urticaria, phototherapy and photochemotherapy are the two major desensitization treatments.

Phototherapy can be used for prevention. Exposure to a certain form of light or UV radiation enables the patient to build up a tolerance and outbreaks can be reduced. This type of treatment is generally conducted in the spring. However, the benefits of this therapy only last for two to three days.

Photochemotherapy, or PUVA, is considered superior to phototherapy because it produces a longer-lasting tolerance of the radiation that initiates the outbreak. When treatment first begins, the main goal is to build up the patient's tolerance to UVA radiation enough so that they can be outdoors without suffering an episode of solar urticaria. Therefore, treatments are regulated at three per week while constantly increasing the exposure to UVA radiation. Once the patient has reached an adequate level of desensitization, treatments are reduced to once or twice per week.

There are no permanent cures for urticaria pigmentosa. However, treatments are possible. Most treatments for mastocytosis can be used to treat urticaria pigmentosa. Many common anti-allergy medications are useful because they reduce the mast cell's ability to react to histamine.

At least one clinical study suggested that nifedipine, a calcium channel blocker used to treat high blood pressure, may reduce mast cell degranulation in patients with urticaria pigmentosa. A 1984 study by Fairly et al. included a patient with symptomatic urticaria pigmentosa who responded to nifedipine at dose of 10 mg po tid. However, nifedipine has never been approved by the FDA for treatment of urticaria pigmentosa.

Another mast cell stabilizer Gastrocrom, a form of cromoglicic acid has also been used to reduce mast cell degranulation.

The first-line therapy in ColdU, as recommended by EAACI/GA2 LEN/EDF/WAO guidelines, is symptomatic relief with second-generation H1- antihistamines. if standard doses are ineffective increasing up to 4-fold is recommended to control symptoms.

The second-generation H1-antihistamine, rupatadine, was found to significantly reduce the development of chronic cold urticaria symptom without an increase in adverse effects using 20 and 40 mg.

Allergy medications containing antihistamines such as diphenhydramine (Benadryl), cetirizine (Zyrtec), loratidine (Claritin), cyproheptadine (Periactin), and fexofenadine (Allegra) may be taken orally to prevent and relieve some of the hives (depending on the severity of the allergy). For those who have severe anaphylactic reactions, a prescribed medicine such as doxepin, which is taken daily, should help to prevent and/or lessen the likelihood of a reaction and thus, anaphylaxis. There are also topical antihistamine creams which are used to help relieve hives in other conditions, but there is not any documentation stating it will relieve hives induced by cold temperature.

Cold hives can result in a potentially serious, or even fatal, systemic reaction (anaphylactic shock). People with cold hives may have to carry an injectable form of epinephrine (like Epi-pen or Twinject) for use in the event of a serious reaction.

The best treatment for this allergy is avoiding exposure to cold temperature.

Studies have found that Omalizumab (Xolair) may be an effective and safe treatment to cold urticaria for patient who do not sufficiently respond to standard treatments.

Ebastine has been proposed as an approach to prevent acquired cold urticaria.

There is no treatment that will rid the patient of symptoms of aquagenic urticaria. Most treatments are used to lessen the effects of the disease to promote more comfort when the body must come in contact with water.

- Oral antihistamine: Antihistamines such as hydrochloride, hydroxyzine, terfenadine and cyproheptadine have frequently been used to reverse or minimize the effects of aquagenic urticaria. The therapeutic response to these medications will vary from patient to patient and the benefits of applying a histamine antagonist to the skin has not been found to create a direct link to the minimization of water based urticaria effects.

- Topical corticosteroids: Parenteral corticosteroids have been used to help treat aquagenic uricaria in the past. The actual effect of this medication and its benefits are not clear at this time.

- Epinephrine: Patients with severe bouts of urticarial that appear to be acute will frequently use this medication to help decrease the appearance of cutaneous vasodilation. This can also help inhibit mast cell degranulation which may contribute to the presence of aquagenic urticaria.

- PUVA therapy: In one test a 21-year-old woman was given PUVA therapy four times a week in increased doses to help manage the symptoms of aquagenic urticaria. As the dosage was increased the lesions and itching caused by the disease disappeared.

- Ultraviolet radiation: Radiation is commonly used alongside antihistamines to help rid the patient of lesions and outbreaks caused by aquagenic urticaria. This therapy will cause thickening of the epidermis which can prevent water from penetrating this layer and interacting with the cells underneath. Ultraviolet therapy may also cause mast cells to limit their response to stimuli and immunosuppression which can help prevent these reactions.

- Stanazolol: Treatments for the human immunodeficiency virus or HIV have been found to help with the symptoms of aqugenic urticaria as well.

- Capsaicin: This medication is often used for producing Zostrix, a cream applied to lessen pain caused by aquagenic urticaria.

- Barrier methods: In some circumstances an oil in water solution or emulsion cream can be applied to the skin to protect it from water exposure while washing or performing aquatic activities. There does not appear to be a side effect to this method and the application is easier than many other options. Doctors will also recommend that these patients use physical barriers such as an umbrella or protective clothing to avoid contact with water to protect patients from potential outbreaks. Activities such as swimming or visiting a water park will also need to be avoided to minimize the risk of an outbreak.

Antihistamine agents are the typically prescribed drug for the treatment of physical urticaria. They block the effect of histamine, a compound produced by the body which forms a part of the local immune response consequently causing inflammation. Some research has suggested that the use antihistamines and antagonist in synergy are better for the treatment of physical urticarias.

The cascade of events that link the autoantibody-antigen reaction with the production and release of histamine is not well characterized. Therefore, the focus of treatment for physical urticaria has been on characterizing the effectiveness of antihistamines rather than analysis of receptor binding or the pathomechanisms.

The more poignant part of this disorder is the lack of desensitization for water and aqua intile injection as allergen even on repeated exposure. Avoidance of allergen as a general principle in any allergic disorder necessitates the evasion of water exposure. Topical application of antihistamines like 1% diphenhydramine before water exposure is reported to reduce the hives. Oil in water emulsion creams, petrolatum as barrier agents for water can be used prior to shower or bath with good control of symptoms. Therapeutic effectiveness of various classes of drugs differs from case to case.

Dermographism can be treated by substances (i.e. an antihistamine) which prevent histamine from causing the reaction. These may need to be given as a combination of H antagonists, or possibly with an H-receptor antagonist such as cimetidine.

OTC Vitamin C, 1000 mg daily, increases histamine degradation and removal.

Not taking hot baths or showers may help if it is generalized (all over) and possibly for localized cases (in a specific area). If taking hot showers helps, it may be a condition called shower eczema. If it affects mainly the head, it may be psoriasis. In rare cases, allergy tests may uncover substances the patient is allergic to.

While cromoglycate, which prevents histamine from being released from mast cells, is used topically in rhinitis and asthma, it is not effective orally for treating chronic urticaria.

There is currently no cure for mastocytosis, but there are a number of medicines to help treat the symptoms:

- Antihistamines block receptors targeted by histamine released from mast cells. Both H and H blockers may be helpful.

- Leukotriene antagonists block receptors targeted by leukotrienes released from mast cells.

- Mast cell stabilizers help prevent mast cells from releasing their chemical contents. Cromoglicic acid is the only medicine specifically approved by the FDA for the treatment of mastocytosis. Ketotifen is available in Canada and Europe, but is only available in the U.S. as eyedrops (Zaditor).

- Proton pump inhibitors help reduce production of gastric acid, which is often increased in patients with mastocytosis. Excess gastric acid can harm the stomach, esophagus, and small intestine.

- Epinephrine constricts blood vessels and opens airways to maintain adequate circulation and ventilation when excessive mast cell degranulation has caused anaphylaxis.

- Salbutamol and other beta-2 agonists open airways that can constrict in the presence of histamine.

- Corticosteroids can be used topically, inhaled, or systemically to reduce inflammation associated with mastocytosis.

Antidepressants are an important and often overlooked tool in the treatment of mastocytosis. Depression and other neurological symptoms have been noted in mastocytosis. Some antidepressants, such as doxepin, are themselves potent antihistamines and can help relieve physical as well as cognitive symptoms.

Calcium channel blockers of the dihydropyridine type are sometimes used to treat high blood pressure. At least one clinical study suggested nifedipine, one of the dihydropyridines, may reduce mast cell degranulation in patients who exhibit "urticaria pigmentosa". A 1984 study by Fairly et al. included a patient with symptomatic "urticaria pigmentosa" who responded to nifedipine. However, nifedipine has not been approved by the FDA for treatment of mastocytosis.

In rare cases in which mastocytosis is cancerous or associated with a blood disorder, the patient may have to use steroids and/or chemotherapy. The agent imatinib (Glivec or Gleevec) has been found to be effective in certain types of mastocytosis.

The laboratory AB Science filed a new drug application for its molecule masitinib at the EMA, as its clinical trials are progressing. In spite of the refusal of the EMA, AB Science decided to restart its clinical trial.

There are clinical trials currently underway testing stem cell transplants as a form of treatment.

Acne treatment may require oral tetracycline antibiotics or isotretinoin. Treatments directed at tumor necrosis factor (TNF) (infliximab, etanercept) and interleukin-1 (anakinra) have shown a good response in resistant arthritis and pyoderma gangrenosum. Other traditional immunosuppressant treatments for arthritis or pyoderma gangrenosum may also be used.

In hereditary angioedema, specific stimuli that have previously led to attacks may need to be avoided in the future. It does not respond to antihistamines, corticosteroids, or epinephrine. Acute treatment consists of C1-INH (C1-esterase inhibitor) concentrate from donor blood, which must be administered intravenously. In an emergency, fresh frozen blood plasma, which also contains C1-INH, can also be used. However, in most European countries, C1-INH concentrate is only available to patients who are participating in special programmes. The medications ecallantide and icatibant may be used to treat attacks. In 2017 these medications cost between 5,700 and 14,000 per dose in the United States, prices that tripled in two years.

Future attacks of hereditary angioedema can be prevented by the use of androgens such as danazol, oxandrolone or methyltestosterone. These agents increase the level of aminopeptidase P, an enzyme that inactivates kinins; kinins (especially bradykinin) are responsible for the manifestations of angioedema.

It was noted that although antihistamines and anti-inflammatory drugs such as, colchicine, sulphasalazine, dapsone, and topical steroid are advocated for in the treatment of DPU, most if not all are unsatisfactory in relieving symptoms. Even a second generation antihistamine, ketotifen, was unable to efficiently and satisfactorily relieve symptoms of DPU

In allergic angioedema, avoidance of the allergen and use of antihistamines may prevent future attacks. Cetirizine is a commonly prescribed antihistamine for angioedema. Some patients have reported success with the combination of a nightly low dose of cetirizine to moderate the frequency and severity of attacks, followed by a much higher dose when an attack does appear. Severe angioedema cases may require desensitization to the putative allergen, as mortality can occur. Chronic cases require steroid therapy, which generally leads to a good response. In cases where allergic attack is progressing towards airway obstruction, epinephrine may be life-saving.

Since interleukin 1β plays a central role in the pathogenesis of the disease, therapy typically targets this cytokine in the form of monoclonal antibodies (such as canakinumab), binding proteins/traps (such as rilonacept), or interleukin 1 receptor antagonists (such as anakinra). These therapies are generally effective in alleviating symptoms and substantially reducing levels of inflammatory indices. Case reports suggest that thalidomide and the anti-IL-6 receptor antibody tocilizumab may also be effective.

There have been attempts to control the inflammation using drugs that work in other conditions where inflammation is a problem. The most successful of these are steroids, but they have side effects when used long term. Other medications, including methotrexate, colchicine and canakinumab, have been tried with some success. Otherwise, the treatment is supportive, or aimed solely at controlling symptoms and maximizing function.

The aim of acute treatment is to halt progression of the edema as quickly as possible, which can be life-saving, particularly if the swelling is in the larynx. In Germany, most acute treatment consists of C1 inhibitor concentrate from donor blood, which must be administered intravenously; however, in most European countries, C1 inhibitor concentrate is only available to patients who are participating in special programs. In emergency situations where C1 inhibitor concentrate is not available, fresh frozen plasma (FFP) can be used as an alternative, as it also contains C1 inhibitor.

Other treatment modalities can stimulate the synthesis of C1 inhibitor, or reduce C1 inhibitor consumption. Purified C1 inhibitor, derived from human blood, has been used in Europe since 1979. Several C1 inhibitor treatments are now available in the U.S. Food and Drug Administration and two C1 inhibitor products are now available in Canada. Berinert P (CSL Behring), which is pasteurized, was approved by the F.D.A. in 2009 for acute attacks. Cinryze (ViroPharma), which is nanofiltered, was approved by the F.D.A. in 2008 for prophylaxis. Ruconest (Pharming) is a recombinant C1 inhibitor approved in the US and Europe that does not carry the risk of infectious disease transmission due to human blood-borne pathogens.

The medication ecallantide inhibits plasma kallikrein, and was approved by the F.D.A. (but not in Europe) for acute attacks in 2009. Icatibant inhibits the bradykinin B2 receptor, and was approved in Europe and the USA.

In hereditary angioedema, specific stimuli that have previously led to attacks may need to be avoided in the future. It does not respond to antihistamines, corticosteroids, or epinephrine.

Short-term prevention is normally administered before surgery or dental treatment. In Germany, C1-INH concentrate is used for this and given 1–1.5 hours before the procedure. In countries where C1-inhibitor concentrate is not available or only available in an emergency (laryngeal edema), high-dose androgen treatment is administered for 5–7 days.

Most patients with hyper IgE syndrome are treated with long-term antibiotic therapy to prevent staphylococcal infections. Good skin care is also important in patients with hyper IgE syndrome. High-dose intravenous gamma-globulin has also been suggested for the treatment of severe eczema in patients with HIES and atopic dermatitis.

In general, there is no treatment available for CMTC, although associated abnormalities can be treated. In the case of limb asymmetry, when no functional problems are noted, treatment is not warranted, except for an elevation device for the shorter leg.

Laser therapy has not been successful in the treatment of CMTC, possibly due to the presence of many large and deep capillaries and dilated veins. Pulsed-dye laser and long-pulsed-dye laser have not yet been evaluated in CMTC, but neither argon laser therapy nor YAG laser therapy has been helpful.

When ulcers develop secondary to the congenital disease, antibiotic treatment such as oxacillin and gentamicin administered for 10 days has been prescribed. In one study, the wound grew Escherichia coli while blood cultures were negative.

Usually, a common form of treatment for the condition is a type of hand cream which moisturises the hard skin. However, currently the condition is incurable.

Treatment is most commonly directed at autoimmune disease and may be needed to treat bulky lymphoproliferation. First line therapies include corticosteroids (very active but toxic with chronic use), and IVIgG, which are not as effective as in other immune cytopenia syndromes.

Second line therapies include: mycophenolate mofetil (cellcept) which inactivates inosine monophosphate, most studied in clinical trials with responses varying (relapse, resolution, partial response). It does not affect lymphoproliferation or reduce DNTs, with no drug-drug interactions. This treatment is commonly used agent in patients who require chronic treatment based on tolerance and efficacy. It may cause hypogammaglobulinemia (transient) requiring IVIgG replacement.

Sirolimus (rapamycin, rapamune) which is a mTOR (mammalian target of rapamycin) inhibitor can be active in most patients and can in some cases lead to complete or near-complete resolution of autoimmune disease (>90%) With this treatment most patients have complete resolution of lymphoproliferation, including lymphadenopathy and splenomegaly (>90%) and have elimination of peripheral blood DNTs. Sirolimus may not be as immune suppressive in normal lymphocytes as other agents. Some patients have had improvement in immune function with transition from cellcept to rapamycin and it has not been reported to cause hypogammaglobulinemia. Hypothetically, Sirolimus may have lower risk of secondary cancers as opposed to other immune suppressants and requires therapeutic drug monitoring. It is the second most commonly used agent in patients that require chronic therapy. It is mostly well tolerated (though side effects include mucositis, diarrhea, hyperlipidemia, delayed wound healing) with drug-drug interactions. It has better activity against autoimmune disease and lymphoproliferation than mycophenolate mofetil and other drugs; however, sirolimus requires therapeutic drug monitoring and can cause mucositis. A risk with any agent in pre-cancerous syndrome as immune suppression can decreased tumor immunosurvellence. Its mTOR inhibitors active against lymphomas, especially EBV+ lymphomas. The Goal serum trough is 5-15 ng/ml and can consider PCP prophylaxis but usually not needed.

Other treatments may include drugs like Fansidar, mercaptopurine: More commonly used in Europe. Another is rituximab but this can cause lifelong hypogammaglobulinemia and a splenectomy but there is a >30% risk of pneumococcal sepsis even with vaccination and antibiotic prophylaxis

National Institute of Allergy and Infectious Diseases scientists have been studying and treating patients with mastocytosis for several years at the National Institutes of Health (NIH) Clinical Center.

Some of the most important research advances for this rare disorder include improved diagnosis of mast cell disease and identification of growth factors and genetic mechanisms responsible for increased mast cell production. Researchers are currently evaluating approaches to improve ways to treat mastocytosis.

Scientists also are focusing on identifying disease-associated mutations (changes in genes). NIH scientists have identified some mutations, which may help researchers understand the causes of mastocytosis, improve diagnosis, and develop better treatments.

Overall, the prognosis for patients with NOMID is not good, though many (80%) live into adulthood, and a few appear to do relatively well. They are at risk for leukemia, infections, and some develop deposits of protein aggregated called amyloid, which can lead to kidney failure and other problems. The neurologic problems are most troubling. The finding that other diseases are related and a better understanding of where the disease comes from may lead to more effective treatments.