Lecture 14 – Inpatient Dermatology PDF

Lecture 14 – Inpatient Dermatology Cutaneous Drug Reactions: Drug reactions are divided into limited cutaneous reactions, systemic reactions with cutaneous findings, and serious cutaneous reactions. Each is discussed below. Drug Rash/Limited cutaneous reaction Typical drug rashes are very common...

Lecture 14 – Inpatient Dermatology Cutaneous Drug Reactions: Drug reactions are divided into limited cutaneous reactions, systemic reactions with cutaneous findings, and serious cutaneous reactions. Each is discussed below. Drug Rash/Limited cutaneous reaction Typical drug rashes are very common in hospitalized patients. They become more common with increasing age and increasing numbers of medications. They are also more common in females. The typical drug rash is fairly easily recognized. It consists of pink-to-red macules, papules and plaques without scale (Figure 14.1) (Figure 14.2) (Figure 14.3) (Figure 14.4). It is usually itchy. It is frequently called “exanthematous” or “maculopapular”, but specific descriptions are preferred, such as: 1-3 cm, pink plaques without scale, covering 60% of the body, accentuated in warm areas (inner thighs (Figure 14.5) and axillae). The most common causative drugs are β-lactam antibiotics, sulfa drugs, and anti-convulsants. The rash can start anywhere from 1-14 days after the first dose of the medication and can persist for up to 14 days after the medication is stopped. Typical drug rashes are T-cell-mediated processes. The drug, or a metabolite of the drug, binds to a protein. The drug-protein complex is internalized by an antigen presenting cell and then presented in the context of MHC II, driving an immune reaction. The typical drug reaction is treated symptomatically with oral antihistamines and topical steroids. Based on when various medications were started and when the rash started, a list of likely causative drugs is generated. Any drug started within the two weeks prior to the rash starting should be suspected, even if the patient stopped the medication before the rash started. Any drugs on this list should be stopped, if safe to do so. If available, a medication from a different class should be substituted (e.g., if a cephalosporin is suspected, a non-β-lactam antibiotic covering the relevant bacteria can be substituted). If a substitute is not available and the suspected medication is necessary (e.g., a cephalosporin is suspected and the bacteria is not susceptible to any other medications), then the medication can be continued while carefully monitoring the patient for signs a systemic hypersensitivity reaction (“treating through”). When evaluating a patient with a drug rash, always ask the following: Are they having fevers? Do they have a sore throat? Are they short of breath? Is their urine a dark color? A yes answer to any of these questions should raise suspicion of systemic drug hypersensitivity. In addition, on physical examination, it is important to check for lymphadenopathy, purpura, mucous membrane abnormalities (oral, ocular, genital), blisters, and target lesions. Any of these findings should raise suspicion for a systemic drug reaction or a serious cutaneous drug reaction. A few laboratory studies should also be ordered in almost all patients with drug reactions: CBC with differential, liver function studies, and urinalysis. If any abnormalities are detected that cannot be explained by the patient’s underlying medical condition, it should raise the suspicion of a systemic drug reaction. Systemic Drug Hypersensitivity with Cutaneous Features 1) Acute Generalized Exanthematous Pustulosis (AGEP) 2) Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) AGEP AGEP is much less common than typical cutaneous drug reactions. AGEP typically presents with erythema in the groin, axillae, or inner thighs (Figure 14.6). On close inspection, tiny (1 mm) pustules can be noted in the erythema (Figure 14.7), but these can be easily overlooked. Over several hours to several days, the erythema and pustules can spread over much of the body. In addition to the rash, patients often have spiking fevers and elevated neutrophil counts on CBC. The most common causative medications are β-lactam antibiotics, macrolide antibiotics, and calcium-channel blockers. The rash and fevers usually start within 1-2 days after the causative drug is started. AGEP is also thought to be a T-cell-mediated reaction. T-cells in this disease probably release cytokines that activate neutrophils. The reason for this particular profile of cytokine release is unknown. AGEP is treated by stopping the causative medication, which was started within 3 days of rash onset, making it much easier to identify than in a typical drug reaction. Treating through AGEP should not be done unless the causative drug absolutely cannot be stopped without putting the patient’s life in danger. First, AGEP closely resembles a systemic infection, and as long as the drug is continued and the AGEP persists, it can mask an underlying infection. Second, if allowed to progress, AGEP can cause fluid management problems and potential avenues for infection, as the skin ceases to be an effective barrier against water loss or microbial entry. Finally, AGEP can progress to vasculitis if the medication is continued. DRESS DRESS is about as common as AGEP. However, both are far less common than regular drug rashes. DRESS starts later than other drug eruptions, usually at least 2-6 weeks after the drug was started. It typically starts with a fever and rash. The most classic presentation is to start off looking like a typical “drug rash”, but relatively quickly, the rash develops into widespread, confluent erythema with skin swelling. The face and neck are usually the most prominently and earliest involved areas. In fact, facial edema with erythema is a very suggestive finding for DRESS, in addition two sore throat and significant lymphadenopathy. Laboratory findings are generally a reflection of organ system involvement. The major exception is eosinophilia, which is seen in almost all cases. The other significantly common laboratory finding is elevated LFTs (AST/ALT), indicative of hepatotoxicity. Other organs at risk include the kidneys (nephritis), muscles (myositis), joints (arthritis), heart (myocarditis), lungs (pneumonitis), thyroid (thyroiditis), and CNS (encephalitis/meningitis). CBC and LFTs are the most important labs to check, and should always be checked if DRESS is suspected. The most common causative drugs are the aromatic anticonvulsants (phenytoin, carbamazepine, phenobarbital). It is important to note that patients who react to one of these medications have at least a 70% chance of reacting to the other two. Sulfonamides are the other class of drugs that are reported to cause DRESS. DRESS syndrome is probably related to accumulation of toxic drug metabolites in patients who have deficiencies in the normal metabolic pathways for certain drugs. For example, patients with DRESS secondary to aromatic anticonvulsants often have a deficiency in the enzyme epoxide hydrolase. As a result, toxic metabolites (arene oxides), accumulate, and are thought to be responsible for DRESS. This probably explains the long period between starting the drug and getting the eruption; a sufficient amount of the metabolite must accumulate to cause DRESS. Patients with DRESS secondary to sulfonamides are often “slow acetylators”. Acetylation is a key pathway of metabolism to detoxify sulfonamides. Patients who perform this step slowly accumulate toxic metabolites, leading to DRESS. The most important aspect of treating DRESS is diagnosing it quickly and stopping the relevant medication. The syndrome may take 2-6 weeks to resolve, as it generally takes as long to clear the toxic metabolites as it took for them to accumulate. If the disease is limited to skin involvement and peripheral eosinophilia, then stopping the drug and using topical steroids are probably sufficient. If other organs are involved (liver, kidney, lungs, heart, or muscles), then systemic steroids should be considered to reduce inflammation. It is very important to counsel patients and physicians that in patients who get DRESS from an aromatic anticonvulsant, all aromatic anticonvulsants are strictly prohibited for the rest of the patient’s life due to the high probability of recurrence of DRESS. Finally, for some reason, patients with DRESS are at very high risk for developing hypo- thyroidism several months after the episode of DRESS. Therefore, thyroid function studies should be checked 3 months and 6 months after the acute eruption. Toxic Epidermal Necrolysis (TEN) and Stevens-Johnson Syndrome (SJS) TEN and SJS are rare, both having incidences of about 1 case per million people per year. They are more common in the immunosuppressed, in patients with HIV, and in patients undergoing radiation therapy for brain tumors. TEN and SJS are closely related diseases, almost exclusively caused by adverse reactions to medications, that differ by the amount of skin involvement. The epidermis dies in both diseases, leading to blister formation and sloughing of the skin and mucous membranes. Both diseases typically manifest anywhere from 1-3 weeks after starting the causative medication. Sometimes the rash is preceded by fever or pain of the eyes and mouth. The rash typically begins as painful erythematous macules on the trunk and/or palms and soles (Figure 14.8) (Figure 14.9) (Figure 14.10) (Figure 14.11). The erythema spreads, typically involving the trunk, proximal extremities, face, neck, and palms and soles. Involved areas go from a bright erythema to dusky. Soon after the duskiness appears, the epidermis begins to slough off (Figure 14.12) (Figure 14.13), either in sheets or as blisters that quickly rupture. As the skin findings are developing, the patient experiences pain and sloughing of the mucous membranes, including the ocular, nasal, oral, and genital mucosae (Figure 14.14) (Figure 14.15). At least two mucous membranes are always involved; however, some patients have involvement of all mucous membranes. Some patients with TEN or SJS will go through a stage during which the erythematous macules will have a targetoid appearance similar to that seen in erythema multiforme (Figure 14.16). SJS is typically defined as sloughing of ≤10% of the skin, with painful erosions on at least two mucous membranes. TEN is defined as sloughing of ≥30% of the skin. If the amount of skin sloughed is between 10% and 30%, it is called SJS/TEN overlap. In severe cases of TEN, there can be sloughing of the esophageal lining, trachea lining, intestinal lining, and bladder wall. The most common medications to cause TEN/SJS are non-steroidal anti-inflammatories, aromatic anticonvulsants (especially phenytoin), and sulfa drugs. In erythema multiforme, much less than 10% of the body surface area involved with involvement of ≤1 mucous membrane. Erythema multiforme also differs in that it is usually caused by a reaction to herpes simplex or mycoplasma and only very rarely caused by a medication. Similar to DRESS, TEN and SJS are thought to be related to an accumulation of toxic drug metabolites that lead to immune activation. Interestingly, a dramatic overexpression of Fas- FasLigand has been shown during TEN/SJS, and it is hypothesized (and somewhat supported by clinical observations) that blocking the activity of FasLigand can significantly ameliorate disease duration and severity. It is suspected that toxic metabolite accumulation leads to FasLigand expression on the immune cells. FasLigand binds Fas on keratinocytes, initiating apoptosis. Treatment of TEN/SJS is difficult. All possible causative agents must be stopped immediately. The focus of treatment is good supportive care (wound care, hydration, nutrition, ophthalmologic care, etc.). Whenever possible, these patients should be treated in a burn unit. There is controversy surrounding the use of systemic steroids and intravenous immunoglobulin (IVIG) for TEN. IVIG consists of immunoglobulin harvested from donated blood. Several small studies have been conducted on the effectiveness of IVIG, with contradictory results. At the very least, we know that IVIG only works if it is given at high doses early in the disease (probably within 96 hours of onset). IVIG is thought to work by providing antibodies (found in most people’s blood) to FasLigand, blocking the interaction between Fas and FasLigand. IVIG is extracted from pooled blood, so that enough of these antibodies are combined to provide a clinically relevant block of the Fas/FasLigand interaction thought to cause TEN. Coumadin Necrosis Coumadin necrosis is uncommon. Overweight women are at greatest risk. Coumadin necrosis typically begins within the first week of initiating coumadin therapy in patients who are not concurrently on heparin. It affects skin over-lying significant subcutaneous fat (breasts, thighs, buttocks, pannus). It starts with pain in the skin, proceeds to erythema, and progresses to purpura and necrosis (Figure 14.17). Coumadin necrosis is a result of thrombosis of small vessels in the subcutaneous fat. When coumadin therapy is initiated, it produces a transient hypercoaguable state, because protein C has the shortest half life of the proteins whose synthesis is inhibited by coumadin. As a result, after initiating coumadin, protein C, an anticoagulant, is depleted before the procoagulant factors, II, VII, IX, and X, resulting in the transient hypercoaguable state and causing thrombosis. Once the procoagulant proteins become depleted, the hypercoagulable state resolves and there is no longer a risk of coumadin necrosis. A particular group of patients at particular risk are those with an inherited partial deficiency of protein C, in whom the hypercoagulable state develops more quickly and is more severe. Coumadin necrosis is prevented by putting patients on heparin while coumadin therapy is started. They should be kept on heparin until the coumadin becomes therapeutic (i.e., until depletion of the procoagulant proteins occurs and outweighs the depletion of the anticoagulant protein C).