​Kembara Xtra - Medicine - Erythema Multiforme

​Kembara Xtra - Medicine - Erythema Multiforme 
Introduction 

erythema multiforme (EM) is a rare, immune-mediated, self-limiting, mucocutaneous disease that affects the mucous membranes.
– Roughly nine in ten cases are brought on by infectious agents (up to fifty percent of cases are caused by the herpes simplex virus types 1 or 2), or, less frequently, by medications or immunizations.
– Lesions on the skin are characterized by being acrally dispersed, discrete, targetoid papules with concentric color variation (three zones). Oral, vaginal, or ocular mucosal involvement may also be seen at times.
– It is necessary to differentiate EM from Steven-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), both of which are characterized by truncal, flat lesions with or without blisters and can result in considerable mortality. EM is characterized by the absence of these characteristics.
The clinical history, physical examination, skin biopsy, laboratory testing, and specific attention of persistent EM are all helpful in obtaining a diagnosis, but there are no universal diagnostic criteria.

In addition to addressing the underlying etiology of the condition and removing the agents that are contributing to it, the treatment focuses on providing palliative care.
Erythema multiforme is classified into two subtypes: erythema multiforme minor (EMm), which affects fewer than one mucosal site, and erythema multiforme major (EMM), which affects more than two mucosal sites.
 Beginning today, EMM will operate independently of SJS and TEN. Lesions on the skin that are mostly truncal, flat (macular, nonpalpable), and atypical (less strongly defined with just two concentric zones) with or without blisters are more suggestive of SJS or TEN. This is because SJS and TEN are both caused by the same virus.

 Recurrent EM is classified as having fewer than three episodes, however the average number of episodes each year is six, and the average duration is between six and ten years.

Epidemiology Incidence
The estimated annual incidence in the United States is less than one percent.
Prevalence
Most common in young adults between the ages of 20 and 40; extremely uncommon in those younger than 3 years old or older than 50 years old.

There seems to be a little leaning toward male participation.

There does not appear to be any preference based on race.


Causes and effects: etiology and pathophysiology 
● Etiology— Infections caused by viruses, including herpes simplex virus types 1 and 2 (the most prevalent cause), Epstein-Barr virus, hepatitis C virus, coxsackievirus, echovirus, varicella, mumps, poliovirus, cytomegalovirus, HIV, and molluscum contagiosum.
— Infections caused by bacteria, including Mycoplasma pneumoniae (the second most prevalent cause), Treponema pallidum, Mycobacterium TB, and Gardnerella vaginalis
– Drugs including nonsteroidal anti-inflammatory drugs (NSAIDs), antiepileptic medications, antibiotics (penicillin, sulfonamides, erythromycin, nitrofurantoin, and tetracyclines), statins, and TNF- inhibitors, as well as barbiturates
– Vaccines: greater association with HPV, MMR, and small pox vaccines; nevertheless, also associated with hepatitis B vaccine, meningococcal vaccine, pneumococcal vaccine, varicella vaccine, influenza vaccine, diphtheria-pertussis-tetanus vaccine, and Haemophilus influenzae vaccine.
- Herbicides (both alachlor and butachlor), iodoacetonitrile, and heavy metals can be found in occupational exposures.
- Alterations in premenstrual hormone levels due to radiation therapy
– Cancers, such as lymphoma. – IBD, also known as inflammatory bowel disease.
EM can be caused by herpes simplex virus (HSV), and this type of EM is caused by peripheral mononuclear cells that phagocytose HSV and then transfer fragmented HSV DNA to keratinocytes. A TH-1-mediated immune response is caused by the HSV DNA polymerase gene (pol), which is located within the keratinocytes. The activation of HSV-specific CD4+ TH-1 cells subsequently releases cytokines such as interferon (IFN)- and sets off a chain reaction of inflammation, which ultimately results in the mucocutaneous findings.
– However, it appears that the route involves tumor necrosis factor (TNF)-, perforin, and granzyme B rather than IFN-. The development of EM from other inciting factors such as medications and immunizations is not totally understood, but it is known that these proteins are involved.

Genetics It is possible that a genetic predisposition to the condition may play a part in some patients who have EM.
Patients who have EM caused by herpes virus have a significant connection with the HLA-DQB1*0301 allele, according to research.

It has been found that the HLA-B35, -B62, and -DR53 alleles are associated with repeated episodes of EM.


Risk Factors Previous history of EM; age between 20 and 40; being male; using causative agents or being infected with causative pathogens Using causative agents or being infected with causative pathogens

Prevention 
It is best to steer clear of known etiologic agents as well as those that have the potential for cross-reactivity.
Acyclovir or valacyclovir taken orally has the potential to help prevent recurrent EM that is caused by herpes.

The diagnosis is made based on the patient's history and the clinical manifestations, and additional testing is not necessary for the majority of patients. However, histopathologic analysis, immunofluorescence microscopy, and other laboratory techniques can be helpful in reaching a diagnosis in cases when it is ambiguous.


Presenting History Acute, self-limiting episodic course Cutaneous rash with probable mucosal involvement, most commonly in mouth Prodromal symptoms are typically missing, but prevalent in instances with mucosal involvement Prodromal symptoms are typically absent, but common in cases with mucosal involvement

 Signs and symptoms of infections associated with EM, such as an HSV eruption (10 to 15 days prior to the onset of EM lesions) or respiratory symptoms suggestive of M. pneumoniae History of new medication use or vaccination Exposure to other potentially causative agents, such as radiation, herbicides, heavy metals, etc.

The Patient's Clinical Examination 
It is important to perform a full examination of the skin, including the mucous membranes.
– Acral lesions with symmetric distribution and a propensity for extensor surfaces – Typical cutaneous lesions with an erythematous, papular, and targetoid look that has three concentric zones of varying color
– Mucosal involvement ● Mucosal involvement – Oral involvement can be recognized by the presence of erythema, erosions, bullae, and ulcerations on keratinized and nonkeratinized mucosal surfaces, as well as on the vermilion of the lips.
– At least two mucosal sites are involved in EMM, including the eyes (conjunctivitis, keratitis); the mouth (stomatitis, cheilitis, characteristic blood-stained crusted erosions on lips); and possibly the trachea, bronchi, gastrointestinal tract, or genital tract (balanitis and vulvitis). If EMM is present, the mouth is most commonly affected.

Differential Diagnosis SJS - Medication use is the most common trigger for this complication.
- Lesions are scattered all over the body, with the majority located on the trunk
Targetoid lesions are characterized by a lack of clear borders and an unusual appearance.
 The term "atypical" refers to a macular (non-palpable and flat) structure with only two concentric zones.
- Skin tears and blisters covering less than ten percent of the entire body surface area
- A positive Nikolsky sign may be present; applying light pressure to what seems to be unbroken skin will cause the epidermis to shed for a longer period of time.
- Ninety percent of patients have mucosal involvement, most frequently at more than two sites.
- The presence of constitutional symptoms in conjunction with a high temperature (more than 38.5 degrees Celsius)
– May be linked to the presence of hepatic dysfunction, anemia, lymphadenopathy, and elevated C-reactive protein levels (more than 10 mg/dL) (1)
- A mortality rate of fewer than 10%
TEN is quite similar to SJS, but it causes necrosis of the complete skin thickness and skin detachment across more than 30 percent of the total body surface area. It has a fatality rate of up to 50 percent.
Urticaria is characterized by pruritic wheal-and-flare skin lesions; however, unlike EM, these lesions are only temporary, typically lasting less than 24 hours.
Fixed drug eruption; bullous pemphigoid; paraneoplastic pemphigoid; Sweet syndrome; Rowell syndrome; polymorphous light eruption; cutaneous small-vessel vasculitis; mucocutaneous lymph; erythema annulare centrifugum; acute hemorrhagic edema of infancy; subacute cutaneous lupus erythematosus; contact dermatitis; pityria

Herpetic gingivostomatitis Lichen planus Behcet syndrome recurrent aphthous ulcers Herpetic gingivostomatitis


Results From the Laboratory 

It is not necessary to perform laboratory tests or skin biopsies in order to make a diagnosis. However, they can be helpful in understanding the factors that triggered the EM, excluding the possibility of other diseases, and confirming a diagnosis of EM.

Initial Tests (lab, imaging)
Every patient should have a thorough evaluation for an underlying infection (1), as HSV is the most common cause of EM.
– Evaluation may include direct immunofluorescence (DIF), direct fluorescent antibody (DFA), polymerase chain reaction (PCR), viral culture, or Tzanck smear to check for HSV infection in skin biopsy samples; no imaging studies are indicated unless there is a suspicion for Mycoplasma pneumoniae, in which case work-up should include a chest x-ray, PCR testing of a throat swab, and serologic tests.


Additional Assessments, as well as Other Important Factors

Antinuclear antibodies, rheumatoid factor, as well as anti-Ro and anti-La antibodies, might be ordered as diagnostic tests in the event that Rowell syndrome is suspected.

Confirming the diagnosis requires either the presence of IgM antibodies or a rise in IgG antibodies that is higher than twofold.

 Antibody staining to IFN- and TNF- to distinguish between drug-associated EM and HSV.

When a patient has persistent EM, their complement levels in their serum should be tested because they are likely to be low.
In severe cases with mucosal involvement, the erythrocyte sedimentation rate, the white blood cell count, and the liver function enzymes should all be tested because they are likely to be increased in these cases.

Diagnostic Methods and Other Procedures
Histopathologic analysis of lesional and perilesional tissue can aid with diagnosis in equivocal cases. DIF and indirect immunofluorescence (IIF) can be utilized to identify EM from other vesiculobullous disorders. Skin biopsy: Histopathologic analysis of lesional and perilesional tissue can help with diagnosis. IIF is performed on a blood sample, while DIF is performed on a biopsy of perilesional tissue taken from the lesion.
The Interpretation of Tests
EM lesions' histopathology might show any of the following, depending on the case:
Spongiosis, also known as intercellular edema, is characterized by the death of keratinocytes, which in turn leads to the creation of dermal interface bullae.
— An inflammatory infiltration, including lymphocytes, in the junction of the dermis and epidermis, with accentuation around the blood vessels
The results of DIF and IIF tests are typically either negative or nonspecific when applied to EM. There is a possibility that lichenoid inflammatory infiltration and epidermal necrosis will be present, along with circulating immune complexes, deposition of C3, IgM, and fibrin around the dermal blood vessels.


Management 

The treatment will be determined by the severity of the condition, the underlying cause, as well as the progression of the disease.
Figure out whether the patient will receive outpatient or inpatient care.
Identify the root of the EM problem.
– Drug-induced EM: Discontinue the inciting factor and avoid reexposure to the same drug as well as exposure to any other drugs that have the possibility of causing cross-reactivity.
– If infectious, the underlying ailment should be treated as directed. Close monitoring of some instances may be necessary.

Acute EM treatment involves discontinuing the conditions that triggered the condition and treating the underlying ailment.
 Endometritis associated with M. pneumoniae: treatment with antibiotics may be necessary
 HSV-induced EM: The majority of contemporary sources claim that the use of antivirals does not have a proven effect on the progression of EM in patients with acute mild EM.
- A minimal amount of skin involvement
Medium-strength topical steroids for the treatment of lesions on the trunk and the extremities (2) [C]
 Low potency topical steroid preparations for the treatment of lesions on the face and the intertriginous skin (2) [C]
Antihistamines taken orally to treat pruritic lesions
● Mucous membrane EM – Ocular involvement
 Consultation with an ophthalmologist as soon as possible
Ophthalmic medicines such as nonpreserved dexamethasone 0.1% and lubricants such as nonpreserved hyaluronate should only be used under the supervision of an ophthalmologist. 
- Oral involvement
○ Nondisabling
■ High-potency topical corticosteroid gel (e.g., fluocinonide 0.05% gel administered 2 to 3 times per day)
Mouthwashes that contain a combination of lidocaine 2%, antacids, and diphenhydramine 12.5 mg/5 mL (for example, Maalox; swish and spit as needed up to four times a day); Mouthwashes that contain a combination of lidocaine 2%, antacids, and diphenhydramine 12.5 mg/5 mL; Mouthwashes that○ Disabling
If there is not enough food or water being taken in orally, hospitalization may be necessary for pain management as well as to guarantee proper hydration and nutrition.
Systemic corticosteroids may be utilized for severe symptoms; however, controlled trials have not been undertaken to support the efficacy of this method (for example, prednisone may be taken in doses ranging from 40 to 60 milligrams per day and gradually reduced over the course of two to four weeks).

Antiviral prophylaxis for at least six months is the recommended first-line treatment for recurrent EM in patients with HSV-associated or idiopathic recurrent EM (1)[B]. Among the choices are:
 Acyclovir 400 mg, every 12 hours
○ Valacyclovir 500 mg BID
○ Famciclovir 250 mg BID
If the patient is not responding to one antiviral treatment, you have the option of increasing the dose or switching to a different antiviral regimen.
Second-line therapies consist of the following:
○ Dapsone (100 to 150 mg/day)
 Azathioprine, between 100 and 150 milligrams per day
 Mycophenolate mofetil, between 1,000 and 1,500 milligrams taken twice day.
○ Thalidomide (100 to 200 mg/day)
○ Tacrolimus (0.1% ointment daily) ○ Hydroxychloroquine (400 mg/day)
○ Levamisole (75 to 200 mg/week)

Caution 

Even though the risk is quite modest (1–2%), levamisole has been linked to cases of agranulocytosis. Since the agranulocytosis is dosage-dependent, it is recommended that treatment be started with a lower dose, and patients should be monitored often while they are receiving treatment.
– Once the patient is confirmed to be in remission, treatment should be maintained for another 6 to 12 months, after which a dose reduction should be carried out over the next 2 to 4 months to the lowest effective level, or treatment should be stopped altogether.

Referral 

When you are worried about etiologies such as autoimmune illnesses, recurring HSV infections, or the possibility of cancer, you should consider getting the right referrals.

Admissions 

Patients need to be hospitalized for IV hydration, electrolyte repletion, nutrition, and pain control if lesions involve the oral mucosa, which prevents sufficient oral intake. Wound care may also be indicated for cases with epidermal detachment. The majority of cases can be managed as outpatients. Lesions that involve the oral mucosa prevent sufficient oral intake.

Continued Patient Observation and Monitoring

 The condition is self-limiting. Complications are uncommon, and there is no mortality associated with them.
Avoid contact with any etiologic agents that have been identified.

The rash will develop over the course of one to two weeks, and then it will go away within two to six weeks, typically without leaving any scarring or other sequelae.
After the inflammation has subsided, there is a possibility that there will be some postinflammatory hyper- or hypopigmentation.

Secondary infections, scarring, and damage to the eye are complications.

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