Module 10C – Hypersensitivity Syndromes and Vasculitis
Here concentrate on Erythema multiform following herpes simplex. Know about Stevens Johnson syndrome and the severe Toxic Epidermal Necrolysis. Erythema nodosum is important and know about Sweet's syndrome and it's relationship to underlying diseases. Henoch Schonlien purpora is the archetypical vasculitis so know it's features. The ANCA positive vasculitides are rare. Just remember Churg Straus involves the lungs and Wegeners hits the kidneys! Don't read a lot in Habif on these . There is too much detail. Just use the Modules.
Hypersensitivity Syndromes
These conditions are all diagnosed via the CUL DVA EVIE algorithim as they are red nonscaly diseases. They are usually Type2 cell mediated or Type 3 immune complex mediated disorders to an antigen that might be a virus or bacterium or to a drug the patient is taking.( The potential list of causes for each condition can be found from the following infection, drug, chemical, flavouring or preservative, Autoimmune or collagen diseases, immune protein disorders such as myeloma or even rarely to an underlying malignancy!) These potential causes also apply to urticara which we discussed in Module 10B.)
Now view this discussion of the images in this section of the Module before reading through the text itself.When I discuss the first image I say it is Erythema nodosum when I meant to say erythema multiforme!
This group of diseases are amongst the most interesting in dermatology and often some of the most distinctive in their clinical features. They include conditions such as erythema multiforme, the Stevens Johnson Syndrome, toxic epidermal necrolysis, erythema nodosum and Sweet’s Syndrome. Milder versions of hypersensitivity disorders include both urticaria and erythema annulare centrifugum but these have been discussed in previous chapters.
Erythema multiforme has characteristic target lesions. These are usually in the acral areas of the hands and feet, sometimes even on the palms and soles. The rash is characteristically seen following a herpes simplex virus infection, usually seven to ten days afterwards. It can be seen with a variety of other precipitating conditions including chest infections due to Mycoplasma and as a drug reaction.
Most cases are self limiting once the original infection is controlled and settled but if there is a chronic recurrent erythema multiforme then drugs such as Prednisolone or Thalidomide can be used.
Oral involvement on the lips and buccal mucosae in erythema multiforme
The Stevens Johnson Syndrome – toxic epidermal necrolysis spectrum of disease is typically seen as a drug reaction, particularly to the Sulphonamide antibiotics. In Stevens Johnson Syndrome there is characteristic involvement of mucosal surfaces such as the lips and the conjunctivae. In toxic epidermal necrolysis the severity of the condition is much increased and there is often full thickness involvement of large sheets of epidermis with blistering and peeling. There is also much greater risk of permanent sequale from oral and ocular involvement.
On page 720 Habif goes into toxic epidermal necrolysis in some detail and also lists some of the common drugs that may cause it. The patient will present with red tender skin that may tear and the epidermis slough off with lateral pressure. You will think the patient has the staph scalded skin syndrome but the skin is much too tender for that. This is a condition that can cause blindness because of severe conjunctival involvement so it is important to get on top of it quickly although once the condition takes a hold, it is dubious that even oral steroids make any difference. Recently intravenous immunoglobulin has been used with some success provided it is used early enough..
Update on the medical management of toxic epidermal necrolysis.
Speaker: Ricotti C Jr Summary: The medical management of toxic epidermal necrolysis (TEN) as followed by the University of Miami hospital, a TEN referral centre, begins with withdrawal of offending medication and pain control to achieve comfort and reduce movement during recovery. Early administration of intravenous immunoglobulin (IVIG) therapy plays an essential role, as do higher IVIG doses; patient survival increases significantly with each 1-g/kg increase in IVIG dose (odds ratio 4.2). In a typical IVIG protocol at this hospital, patients receive 1-g/kg per day for 4 days..
The comprehensive medical management addresses fluid loss, possible infection, impaired thermal regulation, altered immunity, and increased energy expenditure. The disparities between patients with TEN and burns patients were emphasised; TEN typically features less oedema, minimal vascular damage, and less damage to regenerative tissue, leading to more rapid tissue re-epithelialisation. A high caloric intake is stipulated by the treatment protocol, as is strict fluid monitoring, in order to decrease fluid overload and thereby minimise pulmonary involvement and improve outcomes. Routine heparin anticoagulation is given to prevent deep vein thrombosis, proton pump inhibitors for gastrointestinal prophylaxis, and tobramycin and dexamethasone for eye infections. Comment: This presentation underlines the importance of supportive care in TEN, and of early use of IVIG..
The higher the dose of IVIG, the better the survival rate. The differences of these patients to burn patients are important and highlighted. The days of treating these patients with parenteral steroids are well and truly over, as this can increase the risk of infection and impair survival. This presentation also underlines the fact that, although the condition traditionally has a high mortality rate, survival can be significantly enhanced with proper modern supportive care techniques and treatment..
From a Colleague with experience of managing this condition.
Nothing else really new. Jury still out as when you did your BJD review as per the best way to go. Balance of it probably favours IVIg, and that's what we use at the Alfred. I've just reviewed the literature recently, as I'm talking to the Registrars about Derm Emergencies in May. .
IVIg should stop the progression of keratinocyte apoptosis, so one could argue in this lady that it's palliative as well as therapeutic. The less excruciatingly painful denuded skin she has to contend with (in her last days, or not), the better. 1g/kg for at least 3 days if you can get it. We have had to fight to get the 3rd dose at the Alfred in recent times, but can usually make a case for it. IVIg not immunosuppressive and may be protective to an extent against infection, so a good option from that point-of-view in your lady..
The Acute Pain team here often use morphine-ketamine infusions with good effect in these patients. I know your patient is going to Pall Care, but this is quite different to the type of pain management they usually deal with. It may be worth asking the Acute Pain team to see her. Just some thoughts. Good luck!.
Recent Development Use of a single dose of Etanercept 50 mgs subcutaneously, a TNF alpha inhibitor, showed excellent results in an Italian uncontrolled trial. J Am Acad Dermatol 2014 Jun 10;[EPub Ahead of Print], A Paradisi, D Abeni, F Bergamo, F Ricci, D Didona, B Didona.
The image below is of Toxic Epidermal necrolysis with sloughing skin.
Toxic epidermal necrolysis note severe lip and eye involvement
Generalised red tender peeling skin in toxic epidermal necrolysis
A composite image of the features of toxic epidermal necrolysis
The lesions of erythema nodosum are quite characteristic with tender red nodules on the lower legs particularly on the shins that evolve with bruising and gradually soften. The condition often follows streptococcal throat infections but again it can be seen with Mycoplasma chest infections and some fungal infections particularly the deep fungi such as coccidioidomycosis. The condition is also seen as a sensitivity reaction in sarcoidosis and in some women on the contraceptive pill. Erythema nodosum should also make you think of a patient with underlying lymphoma such as Hodgkin’s Disease.
The image below is of Erythema nodosum on the legs
Tender nodules on the anterior shins in erythema nodosum
This shows a septal panniculitis of erythema nodosum where the inflammation is involving the septae between the fat lobules rather than the lobules themselves.
Consider - Biopsy timing, Cell type seen, vessel plexus involved. Site of vascular damage and clinical presentation.
Vasculitis is a difficult subject. The recognition of it is not,(palpable purpura) but the investigation to find a cause often is difficult. I would advise you to learn about Henoch Schonlein purpura and build up your knowledge of vasculitis around it. Consider the various causes including infection, drugs and collagen diseases and then tack on the rarer vasculitides such as polyarteritis nodosa(large vessel), and then Wegeners and Churg Straus. Vasculitis plus levido on the lower legs = Polyarteritis nodosa. Vasculitis plus lung disease (asthma) = Churg Straus. Vasculitis plus oral ulcers and renal disease = Wegeners.
For these diseases check the ANCA levels. cANCA is raised in Wegeners. Both cANCA and pANCA can be raised in Churg Straus and ANCA is usually negative in Polyarteritis nodosa but these are just generalisations! It is probably best to divide it into small vessel, medium vessel and large vessel disease and whether it is leukocytoclastic or lymphocytic. Clinical presentation is with palpable purpura although if there is a large vessel involvement as in polyarteritis nodosa, skin necrosis and eschar formation may occur.
Anti neutrophil cytoplasmic antibodies ANCA are serological markers for many forms of necrotizing vasculitis. The presence or absence of these antibodies coupled with histopathology gives a much greater diagnostic significance than biopsy alone. There are two types of immunofluorescence and neutrophils seen in this, either the diffuse granular staining of the cytoplasm or C ANCA or concentration of fluorescence around the nucleus called peri nuclear or P ANCA.
The conditions characterised as ANCA positive small vessel vasculitis include Wegener’s granulomatosis. In this condition there is often necrosis of the nasal septum with perforation or sudden onset of facial nerve injury. Churg-Strauss Syndrome has allergic rhinitis, asthma, and eosinophilic infiltrates.
Microscopic polyangiitis is a necrotizing small vessel vasculitis without granulomatous inflammation which typically affects the kidneys and the lungs but does have palpable purpura. ANCA negative small vessel vasculitis includes such things as cryoglobulinemia.
The following is a useful summary of the interpretation of some of these tests. Palpable purpura tends to indicate involvement of small vessel vasculitis in the upper dermis. Livedo racemosa, nodular lesions and skin ulceration are indicative of involvement of small to medium-sized vessel vasculitis in the lower dermis to subcutaneous fat.
The first step is to measure serum antineutrophil cytoplasmic antibodies (ANCA) levels. If the patient is positive for myeloperoxidase - pANCA, Churg–Strauss syndrome or microscopic polyangiitis or drug induced vasculitis can be suspected, and if proteinase 3 c-ANCA is positive, Wegener's granulomatosis is most likely. If both patterns are found consider drugs as the likeliest cause. Next, if cryoglobulin is positive, cryoglobulinemic vasculitis should be suspected. Third, if direct immunofluorescence of the skin biopsy specimen reveals immunoglobulin A deposition within the affected vessels, Henoch–Schönlein purpura is indicated. Finally, the presence of anti-phosphatidylserine–prothrombin complex antibodies and/or lupus anticoagulant and histopathological necrotizing vasculitis in the upper to middle dermis (leukocytoclastic vasculitis) indicates cutaneous leukocytoclastic angiitis, whereas if necrotizing vasculitis exists in the lower dermis and/or is associated with the subcutaneous fat, cutaneous polyarteritis nodosa is indicated.
In cutaneous polyarteritis nodosa, warfarin or clopidogrel therapies should be administrated, and in cases that have associated active inflammatory lesions, corticosteroids or mizoribine (mycophenolate mofetil) therapy should be added. Also watch out for the renal complications in patients with Henoch–Schönlein purpura.
It is important to know how to investigate these cases. The first thing is to establish if there is any systemic involvement and this can be simply done by examining for joint involvement and examining the urine to see if there is any blood. Thereafter there are a variety of tests including the ANCA’s that should be done. These are covered by Habif in box 18.11. Note the Hepatitis B and Hepatitis C virus antibody studies. These are becoming an increasing cause of vasculitis in the Western world.
Henoch-Schoenlein purpura is a very characteristic vasculitis occurring in children, with lesions particularly concentrated on the lower legs and buttocks and with associated joint and gastrointestinal symptoms. There is a characteristic IgA antibody deposited at the basement membrane and the same antibody can be deposited in the kidneys giving rise to renal involvement that is often found in this condition. However the unusual things that may occur in this disorder are acute scrotal swelling, occurring in up to 15% of boys with Henoch-Schonlein purpura. Watch these patients for a delayed onset of features of renal failure. Always check the urine for blood both in the acute situation and after a couple of weeks of the illness.
The vasculitis below is typical of Henoch Schonlein Purpura
Colchicine use in Leukocytoclasstic vasculitis Colchicine can be used rather than steroids in some types of recurrent vasculitis. It does however interact with the Cytochrome P450 drug breakdown system in the liver and hence potentiates the effects of other drugs metabolised by Cytochrome P 450 such as Cyclosporin, Macrolide antibiotics (erythromycin) and azole drugs eg (Itraconazole, Ketoconazole). Strategies to minimise this include using azithromycin, drink orange juice and use Fluconazole as it is the least risky azole drug.If instead the Colchicine level rises you get fever, diarrhoea, abdominal pain, myopathy, paraesthesia and death! Start with 1 tab daily.
Henoch Schonlein IgA purpura involving the lower legs. The purpura is palpable. Look for renal involvement and blood in the urine.
Another case of acral vasculitis. Non blanching purpura
Henoch Schonlein purpura involving the thighs and buttocks
The neutrophilic dermatoses have very characteristic presentations particularly Sweet’s Syndrome. Often these are infiltrated plaques with a raised papular edge, sometimes studded with pustules but it is again a hypersensitivity reaction to a variety of different antigens including drugs and infection. They respond rapidly to oral steroids. There may be underlying myelodysplastic syndrome or even leukaemias in some cases particularly those presenting with blistering bullous eruptions on the doral surfaces of the hands.
This is a gross Bullous Sweet's reaction.Orf looks very similar
Typical pseudoblister appearance of bullous Sweets syndrome
Sweets in a patient with underlying Ulcerative collitis. If using the pustules algorithim it is I for inflammatory (drugs, psoriasis and now a neutrophilic infiltrating disorder!
Again typical colour and mammilated surface of a case of Sweets syndrome. If using the red non scaly algorithm it is I for infiltrates but cross diagnosing via Pustules might help.
Erythema elevatum diutinum is a rare skin disease typically presenting with infiltrated plaques particularly around joints on the dorsum of the hands. They tend to last for quite some time. The cause is unknown. Histology is characteristic with a leukocytoclastic vasculitis in a large dermal infiltrate of neutrophils, histocytes and macrophages.
In this case the perijoint nodules were on the palmar surface maximally.
Lipodermatosclerosis Worth knowing this condition. Usually seen in obese individuals with thick legs and stasis from varicose veins or previous DVT. This is a small vessel vasculitis involving the medial aspect of the lower legs where the skin is tight and the underlying tissues are sclerotic. The damage extends down into the fat layer with excess collagen laid down. Biopsies here take ages to heal. Many cases are associated with significant venous disease. Best treatment is a short course of oral steroids followed by some strong topical steroids and compression stockings. Vasodilators such as Trental (Pentoxipheline) can also be tried.
Yellowish nodules of erythema elevatum diutinum but on the palmar surface of the hand.
This is nodular vasculitis sometimes also known as erythema induratum secondary to TB
These are a localised immune complex vasculitis called Janeway lesions seen in bacterial endocarditis.View the case here
Pyoderma gangrenosum is a very important disease to know in dermatology. It can occur at sites of injury. It is rapidly progressive and painful with an infiltrating, undermined ulcer edge and is often associated with underlying disorders such as rheumatoid arthritis, blood diseases and gastrointestinal disorders such as ulcerative colitis and Crohn’s disease.
This condition should always be sought for in a patient who presents with this condition. On page 742 Habif describes the investigations in a patient with pyoderma gangrenosum and the differential diagnosis of other ulcers that may resemble it. It is always important to exclude infection before treating this condition with oral steroids to which it does respond, but it needs high doses.
Pyoderma Gangrenosum has occurred in the surgical scar of this patient
Pyoderma gangrenosum commencing in a surgical scar on the abdominal wall in a patient with ulcerative collitis.
Pyoderma gangrenosum at the ankle in a patient with ulcerative collitis. She previously also had Sweets syndrome lesions.
Massive painfull ulceration in pyoderma gangrenosum. These ulcers have a rapid onset and are always painful.
Habif ends this section with Schamberg’s Disease or localised capillaritis, particularly on the lower legs. This is a very mild vasculitic reaction with release of small amounts of red blood cells which are reabsorbed, giving hemosiderin staining. It has a variety of causes but is otherwise asymptomatic and will slowly resolve. It is often seen on the lower legs of individuals who have some degree of venous insufficiency. It can perhaps be a sensitivity reaction to colourants and foods in children. It is often described as a Pigmented Purpuric Dermatosis.
The image below is typical of Schamberg's or Capillaritis
Golden colour of older capillaritis from iron staining in the skin from the breakdown of extravasated red blood cells.
Further example of the pinpoint hemorrhage of capillaritis
A degree of stasis dermatitis may be associated with capillaritis
Important points
You should now go to the Image Diagnosis Section and filter for the Image Diagnosis cases for Module 10. There is additional information regarding some of the conditions mentioned in this module.
View the Module 10 Webinar below
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