新人999如何治疗顽固性湿疹配图，仅供参考
5. Available Treatment Possibilities for Atopic DermatitisThe field of AD treatment in dermatology is currently experiencing a renaissance,as regulatory institutions worldwide have already approved new medications for AD patients,and many other drugs are still in the clinical trial phase. The treatment of AD includes typical skincare along with topical and systemic treatment. Aside from preventive measures for AD and topical therapy,there are standard conventional systemic therapies (cyclosporine,methotrexate,azathioprine) and ongoing developments of other systemic medications,including biological agents and JAK inhibitors ).
# 5.1. Preventive Measures and Emollients
Skincare is the basis of treatment for AD patients,and it should be carried out continuously,i.e.,during both the phases of deterioration and the resting stages of the disease. Thus,prevention of exacerbations includes various methods and interventions (e.g.,allergen avoidance,protective cream use,wearing soft clothing,using a humidifier,and others),where education and other measures play crucial roles. The basic treatment for AD includes moisturizers/emollients and baths. Due to sufferers’ deficit in cutaneous corneal lipids (especially ceramide) and “natural moisturizing factor” (a mix of amino acids resulting from filaggrin breakdown),emollients/moisturizers which include those ingredients are helpful for AD patients . Skin hydration is crucial for AD patients,so emollients should be used frequently (≥2 times daily),especially after contact with water (e.g.,immediately after bathing or handwashing). Thick creams or ointments (e.g.,petroleum jelly) without water are preferable because they are more effective. For severe AD manifestations,wet dressings (wet wraps) may be used to help soothe the skin,decrease itch,and stop the itch–scratch cycle .
# 5.2. Topical Steroids,Topical Immunomodulators,and Other Topical Agents
Topical corticosteroids remain the gold standard of AD treatment as the quickest and most effective at calming and controlling skin inflammation. The strength of the corticosteroids used is based on the severity of the disease and patient age. The frequency of their use varies but is usually relatively short to avoid the rebound phenomenon. Other adverse effects of prolonged use include skin atrophy (thinning),telangiectasias,folliculitis,striae,purpura,and contact dermatitis. In addition,long-term topical corticosteroid use (especially high- or super-high-potency preparations) on large areas can lead to adrenal suppression . Thus,“corticophobia” is common among patients. Still,a proactive therapy regimen primarily using topical corticosteroids is important. It is very useful in the maintenance and prevention of relapses.
When topical corticosteroids cannot be applied over a longer time due to thin skin (e.g.,eyelids) or the occlusive effect in skin folds (skin folds including axillae and groins,anogenital area),the topical immunomodulators tacrolimus and pimecrolimus are recommended. They exert an anti-inflammatory effect by inhibiting calcineurin in skin cells and,unlike corticosteroids,do not cause side effects (e.g.,skin atrophy). They are indicated for ameliorative phases and as proactive therapy.
Therapy sometimes depends on the localization of AD lesions. For lesions on the trunk and limbs,thicker emollients and moderate-potency topical corticosteroid fatty preparations are useful,with potent topical steroids for flare-ups. Sometimes pulse therapy is possible,when the potent preparation is prophylactically used two consecutive days per week. For facial lesions,light emollients are recommended,while topical corticosteroids such as hydrocortisone cream are effective on active lesions. For maintenance therapy,pimecrolimus is used,and for severe facial manifestations,moderate-potency topical corticosteroids are approved for short-term use. For lesions on the hands and feet and for very thick stratum corneum (palmoplantar sites),ultrapotent topical corticosteroids may be given. For axillary and groin lesions,hydrocortisone or pimecrolimus is usually adequate (flexures generally do not require emollients,and potent topical steroids may only sometimes be used for a short period of time).
AD patients are at increased risk for associated cutaneous infections,predominantly bacterial,but also viral and fungal infections . Staphylococcus aureus (S. aureus) is a frequent skin colonizer in AD patients (as recorded in 70% of AD lesions and 39% of nonlesional skin of AD patients),although this bacterium’s role in driving AD severity is still unclear. In addition,there is a large body of evidence supporting a relationship between heavy S. aureus colonization and eczema severity,as the pooled colonization rate is higher in patients with severe AD than in those with mild AD (83%:43%) . Concerning therapy,topical mupirocin cream is useful for patients with localized bacterial infections; however,prolonged topical antibiotic use can lead to therapy-resistant strains and should be avoided. In more extensive infections,a two-week treatment with oral antibiotics such as cephalosporins or penicillinase-resistant penicillins is recommended. Since sodium hypochlorite has anti-staphylococcal properties (6% solution) and also has an effect on methicillin-resistant Staphylococcus aureus (MRSA),diluted bleach baths are an adjunct to topical therapy between episodes of infection . For viral infections,lesions with herpes simplex are treated with oral antiviral therapy,and intravenous antiviral therapy can sometimes be used in severe cases. Concerning fungal infections,dermatophyte infections are the most frequent in AD patients and can be treated with standard antifungal therapy (in patients with head/neck manifestations of AD,commensal Malassezia furfur yeast may trigger flare-ups).
Other topical preparations mentioned in the literature are crisaborole,a topical phosphodiesterase 4 (PDE4) inhibitor (a topical selective JAK inhibitor ruxolitinib 1.5% cream,approved by the FDA),as well as topical doxepin,a tricyclic antidepressant with potent H1- and H2-blocking properties.
In the future,it is expected that new topical drugs will become available,but currently,no drug has proven superior in effect to topical corticosteroids.
# 5.3. Phototherapy and Conventional Systemic Therapy
Phototherapy for AD is predominantly narrow-spectrum UVB phototherapy; thus,the UVB rays penetrate the epidermis and up to the upper/top dermal layer,where they are absorbed by the cells. It has the effect of altering DNA expression and the release of anti-inflammatory cytokines,which has an immunosuppressive effect on the skin’s immune system. Phototherapy usually requires 3–5 patient visits per week to facilitate where phototherapy is used until a certain number of irradiations have been completed (usually around 20),which requires time and discipline.
Systemic AD therapy includes systemic corticosteroids,phototherapy,conventional systemic treatment (cyclosporine,methotrexate,azathioprine),and recently,new,specific drugs,interleukin inhibitors and JAK inhibitors . Systemic corticosteroids are only used for a short time in the acute stages,and it is necessary to avoid using them over a longer period of time.
# Table 1
Prominent systemic drugs for atopic dermatitis and their characteristics.
Systemic Drugs for Atopic Dermatitis
Mechanisms (in Atopic Dermatitis)
Adverse Reactions
Systemic corticosteroids
Glucocorticoids act by binding to and activating intracellular glucocorticoid receptors. When activated,glucocorticoid receptors bind to regions of DNA responsible for the promotion and activation of transcription factors,which then results in the inactivation of genes. Methylprednisolone is a powerful medication with anti-inflammatory properties and the ability to inhibit the immune system.
Congestive heart failure in susceptible patients,hypertension,fluid retention,muscle weakness,loss of muscle mass,steroid myopathy,osteoporosis,tendon rupture,vertebral compression fractures,aseptic necrosis of femoral and humeral heads,pathologic fracture of long bones,peptic ulcer with possible perforation and hemorrhage,pancreatitis,abdominal distention,ulcerative esophagitis,impaired wound healing,petechiae and ecchymoses,may suppress reactions to skin tests,thin and fragile skin,facial erythema,increased sweating,increased intracranial pressure with papilledema (pseudo-tumor cerebri),convulsions,vertigo,headache. Cushingoid state,growth suppression in children,secondary adrenocortical and pituitary unresponsiveness,menstrual irregularities,decreased carbohydrate tolerance,latent diabetes mellitus,increased requirements of insulin or oral hypoglycemic agents in diabetics. Posterior subcapsular cataracts,increased intraocular pressure,glaucoma,exophthalmos.
Laboratory values: sodium retention,potassium loss,hypokalemic alkalosis,increases in ALT,AST,and ALP,negative nitrogen balance.
Cyclosporine
Cyclosporine has potent immunosuppressive properties. Cyclosporine inhibits cell-mediated reactions and T-cell-dependent antibody production. Cyclosporine inhibits the production and release of lymphokines including I- 2 at the cellular level.
Anorexia,tremor,headache,convulsions,paraesthesia,hypertension,flushing,nausea,vomiting,abdominal discomfort/pain,diarrhea,gingival hyperplasia,peptic ulcer,hirsutism,acne,hypertrichosis,myalgia,muscle cramps,pyrexia,fatigue.
Laboratory values: leucopenia,hyperlipidemia,hyperglycemia,hyperuricemia,hyperkalemia,hypomagnesemia,hepatic function abnormal,renal dysfunction.
Methotrexate
Methotrexate has the capacity to decrease inflammation and suppress an overactive immune system. Methotrexate is a folic acid antagonist,with antimetabolite properties. It inhibits DNA synthesis by the competitive inhibition of the enzyme dihydrofolate reductase.
Headache,tiredness,drowsiness,pneumonia,interstitial alveolitis/pneumonitis often associated with eosinophilia,stomatitis,dyspepsia,nausea,loss of appetite,abdominal pain,oral ulcers,diarrhea,exanthema,erythema,pruritus.
Laboratory values: leukopenia,anemia,thrombopenia,abnormal liver function tests (increased ALT,AST,ALP,and bilirubin).
Azathioprine
Azathioprine is an imidazole derivative of 6-mercaptopurine (6-MP). Azathioprine is broken down into 6-MP and a methylnitroimidazole. The 6-MP is converted in the cell into several purine thioanalogs.
Viral,fungal,and bacterial infections in transplant patients receiving azathioprine in combination with other immunosuppressants,bone marrow depression,nausea.
Laboratory values: leukopenia,thrombocytopenia.
Mycophenolic acid
Mycophenolate mofetil has immunosuppressive properties. It is converted into mycophenolic acid which blocks an enzyme called “inosine monophosphate dehydrogenase”. The enzyme inosine monophosphate dehydrogenase is important for the formation of DNA in cells,especially in lymphocytes. Consequently,it reduces the rate of lymphocyte multiplication.
Bacterial infections,fungal infections,viral infections,benign neoplasm of skin,neoplasm,skin cancer,ecchymosis,pseudolymphoma,gout,weight loss,confusion,depression,insomnia,agitation,anxiety,cognitive impairment,dizziness,headache,hypertonia,paresthesia,somnolence,tremor,convulsion,dysgeusia,tachycardia,hypertension,hypotension,lymphocele,venous thrombosis,vasodilatation,cough,dyspnea,pleural effusion,abdominal distension,abdominal pain,colitis,constipation,decreased appetite,diarrhea,dyspepsia,esophagitis,eructation,flatulence,gastritis,gastrointestinal hemorrhage,gastrointestinal ulcer,gingival hyperplasia,ileus,mouth ulceration,nausea,pancreatitis,stomatitis,vomiting,hypersensitivity,hepatitis,jaundice,acne,alopecia,common rash,skin hypertrophy,arthralgia,muscular weakness,asthenia,chills,edema,hernia,malaise,pain,pyrexia,hematuria,renal impairment.
Laboratory values: anemia,leukocytosis,leukopenia,pancytopenia,thrombocytopenia,acidosis,hypercholesterolemia,hyperglycemia,hyperkalemia,hyperlipidemia,hypocalcemia,hypokalemia,hypomagnesemia,hypophosphatemia,hyperuricemia,hyperbilirubinemia,increased alkaline phosphatase,lactate dehydrogenase,hepatic enzyme,creatinine,blood urea.
Dupilumab
Dupilumab is a monoclonal antibody. It is designed to block receptors for IL-4 and IL-13. It relieves symptoms by blocking receptors and preventing IL-4 and IL-13 from working. Patients suffering from AD have high levels of IL-4 and IL-13,which can cause inflammation of the skin leading to symptoms.
Conjunctivitis,oral herpes,conjunctivitis allergic,arthralgia,injection site reactions (includes erythema,edema,pruritus,pain,and swelling).
Laboratory values: eosinophilia.
Abrocitnib
Abrocitinib blocks the action of Janus kinase enzymes which have an important role in inflammation that occurs in AD. Abrocitinib reduces inflammation and itching of the skin.
Herpes simplex,herpes zoster,headache,dizziness,nausea,vomiting,upper abdominal pain,acne.
Laboratory values: increased CPK.
Baricitinib
Baricitinib is an immunosuppressant medication and works by disabling the Janus kinase enzymes which have an important role in the processes of inflammation and damage that occur in patients with AD. Baricitinib reduces skin inflammation and symptoms of AD.
Upper respiratory tract infections,herpes zoster,herpes simplex,gastroenteritis,urinary tract infections,pneumonia,folliculitis,headache,nausea,abdominal pain,rash,acne.
Laboratory values: thrombocytosis,hypercholesterolemia,increased ALT,CPK.
Upadacinib
Upadacitinib has immunosuppressant properties and acts by blocking the Janus kinase enzymes which are involved in the processes that lead to inflammation,and blocking them controls symptoms.
Upper respiratory tract infections,bronchitis,herpes zoster,herpes simplex,folliculitis,influenza,urinary tract infection,cough,abdominal pain,nausea,acne,urticaria,rash,fatigue,pyrexia,weight increased,headache.
Laboratory values: anemia,neutropenia,lymphopenia,hypercholesterolemia,hyperlipidemia,increased CPK,ALT,AST.
[Open in a separate window](https://ncbi.nlm.nih.gov/pmc/articles/PMC10305021/table/life-13-01419-t001/?report=objectonly)
Abbreviations: CPK—creatine phosphokinase; ALP—alkaline phosphatase; ALT—alanine transaminase; AST—aspartate transaminase; 6-MP—6-mercaptopurine.
Conventional systemic medications for AD include immunosuppressive and immunomodulatory drugs that do not act specifically on AD but suppress the patient’s immune system and calm inflammation. Cyclosporine has been approved for treatment,while methotrexate,azathioprine,and mycophenolate mofetil are used off-label. Cyclosporine is an immunosuppressant that blocks numerous immune cells and inhibits the activation of T cells and NK cells and antigen presentation by APCs through a calcineurin-dependent pathway,as well as the production of IL-2 and GM-CSF. It is nephrotoxic and may cause hypertension,changes in differential blood counts,gingival hyperplasia,hypertrichosis,and headaches. Methotrexate is an immunomodulatory drug that comes in oral and subcutaneous forms and is taken with folic acid. It is an antifolate metabolite that blocks the synthesis of DNA,RNA,and purines,inhibiting T cells. The main side effects of methotrexate include hepatotoxicity and a reduction in the number of leukocytes and platelets in the blood. Azathioprine is a purine analog that inhibits DNA production in T and B cells. The drug is hepatotoxic and can cause leukopenia and gastrointestinal symptoms. Therefore,when using all three drugs,intensive monitoring of laboratory parameters and other clinical signs and symptoms is required.
# 5.4. Biologic Therapies and JAK Inhibitors
Recently,several specific drugs have been approved,or are about to be approved (country-specific),for treating moderate to severe clinical AD. These therapy options primarily include biological drugs that inhibit IL-4,IL-13,and IL-33 and JAK inhibitors (baricitinib,abrocitinib,upadacitinib,etc.) ).
Among biological drugs,a breakthrough came when dupilumab,which is directed against IL-4 and IL-13 receptors,was designed and introduced . Dupilumab is designed to block receptors for IL-4 and IL-13,and it is used as a modifying drug for patients suffering from moderate to severe AD for whom topical therapies are insufficient and other systemic treatments are not recommended. In March 2017,dupilumab was approved in the U.S. as first-line therapy for moderate and severe AD in adults,after which it was also approved for children and adolescents (12–18 years). In November 2020,it was also approved for severe AD in younger children (6 to 11 years). The recommended dose for adults and adolescents (>60 kg) is 600 mg subcutaneously,followed by 300 mg every second week. These patients should also use daily emollients and may use topical anti-inflammatory drugs as necessary . The most common side effects include conjunctivitis (usually temporary),ocular complications,and skin reactions at the site of application .
There are also three Janus kinase (JAK) inhibitors approved for the treatment of moderate to severe AD: baricitinib,upadacitinib,and abrocitinib. They specifically and simultaneously inhibit inflammatory pathways,thus improving the patient’s condition. Janus kinase inhibitors are intracellular enzymes that transduce signals (which result from interactions between cytokines or growth factors and cell receptors) to influence hematopoiesis and immune cell functioning. Janus kinase inhibitors phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) that modulate intracellular activity,including genetic expression. When taking into consideration contraindications,necessary laboratory controls,and side effects,JAK inhibitors represent a highly effective and safe treatment option for patients with severe AD . According to clinical trials and the first real-life data results,JAK inhibitors offer rapid and effective itch reduction and condition improvement,leading to a better quality of life. The safety profile is favorable,although data on long-term safety,especially for the treatment of AD patients,are still lacking . Other JAK inhibitors are tofacitinib,ruxolitinib,and deucravacitinib,but limited data on their use and effectiveness are available.
In October 2020,the European Medicines Agency (EMA) approved baricitinib for moderate and severe AD in adults. Baricitinib was the first approved oral selective inhibitor of JAK-1 and JAK-2. Baricitinib is a selective and reversible inhibitor of JAK1 and JAK2,which inhibits inflammatory processes via intracellular actions . The recommended dose of baricitinib is 4 mg peroral once daily (or less as needed). Adverse reactions are respiratory infections,hypercholesterolemia,herpes infections,uroinfections,gastroenteritis,and thromboembolism,among others . Previous study results (BREEZE-AD1,BREEZE-AD2,BREEZE-AD7) have shown significant improvements in AD patients’ clinical pictures . Upadacitinib is also an oral selective JAK1 inhibitor,and the EMA approved it in August 2021 for the treatment of moderate to severe AD,for children older than 12,adolescents,and adults . The generally recommended dose for AD is 30 mg daily,which quickly and significantly improves the patient’s condition,even within the first week . Upadacitinib has been shown to be safe and efficacious in several clinical trials. Common adverse events are respiratory infections,herpes zoster infections,blood test abnormalities (increase in blood creatine phosphokinase (CPK)) papulopustular acne,and others . In addition,abrocitinib inhibits JAK1,which modulates multiple cytokines involved in AD pathogenesis and manifestations (IL-4,IL-13,IL-31,IL-22,and stromal timus lymphopoietin). It is used for moderate and severe AD in those older than 12. Abrocitinib was approved in December 2021 in Europe as a peroral drug (100 mg and 200 mg daily). Common adverse reactions are nausea and respiratory infections.
In addition,the biological drug tralokinumab has recently been approved for AD. Tralokinumab is the first fully human monoclonal antibody that binds specifically to IL-13 and which has been shown to be safe and effective in clinical trials. In combination with topical corticosteroids,tralokinumab provides quick and persistent AD improvement,as exhibited in patients’ clinical pictures. The most frequent adverse events are AD flare-ups,skin reactions at the injection site,respiratory infections,and conjunctivitis . Other biological agents mentioned in the literature are nemolizumab and mepolizumab,but only limited study results are available.
Despite these therapy options,the high cost of newer drugs is often a barrier to treatment access,which is why some countries are not able to purchase biological agents such as dupilumab. Since healthcare costs and spending are generally high and increase over time,data on affordability and access to new treatments,as well as the economic consequences of treatment costs,needs to be systematically documented and analyzed. In addition,AD is clinical condition that significantly affects patients’ quality of life and requires continuous care . Various measures (indices) (EASI,DLQI,NRS) can be used to determine disease severity and the positive influence post-treatment improvement has on quality of life. These measures have shown a positive correlation between annual therapy results and clinical variables . So,although these therapies are expensive,their efficacy can make them well worth the cost.
On the other hand,the use of traditional biologics (rituximab,omalizumab,or ustekinumab) as a treatment for AD cannot be recommended. In certain cases where standard therapy is ineffective,mepolizumab may be considered as a treatment option.
# Figure 2
[](https://ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click on image to zoom&p=PMC3&id=10305021_life-13-01419-g002.jpg)
[Open in a separate window](https://ncbi.nlm.nih.gov/pmc/articles/PMC10305021/figure/life-13-01419-f002/?report=objectonly)
Roles/activities of biologic therapies and JAK inhibitors in the pathogenetic network in atopic dermatitis—modified based on the article by Eichenfield et al. . Adapted with permission from Ref. . Copyright 2023,copyright Eichenfield et al.","department":"
