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Erythema Multiforme, SLE Vasculitis - 2/6/2013

posted Feb 6, 2013, 7:28 AM by Rohit Das   [ updated Feb 6, 2013, 10:19 AM by Purnema Madahar ]

Whenever I hear the word “rash” in a chief complaint, a stabbing feeling of uncertainty throws me into intracranial chaos. This was the case yet again for a woman with a history of recurrent, refractory cutaneous SLE who presented with lower extremity, ecchymotic plaques that seemed like purpuric, vasculitic lesions. On biopsy, though, it turned out to be Erythema Multiforme (EM). After reading about some stuff, I feel a little less clueless…so…

·         SLE and vasculitis – what’s the epidemiology? What types of vasculitides occur and how do they present?

·         What is the pathophysiology behind EM, and what in particular is it associated with?

·         What are the manifestations of EM and what else is on the differential?

·         How is EM diagnosed and what’s the prognosis?

SLE and vasculitis – what’s the epidemiology? What types of vasculitis occur and how do they present?

·         Before going into this, it’s important to first understand that vasculitis (presence of inflammatory leuckocytes within vascular walls, consequently leading to vessel wall damage and integrity) is generally classified into large, medium or small-vessel categories. Some examples:

o   Large Vessel – Takayasu Arteritis, Giant Cell (Temporal) Arteritis

o   Medium Vessel – Polyarteritis Nodosa (PAN) is most classic

o   Small Vessel – Wegener’s, Cryoglobulinemia, Microscopic Polyarteritis are some of many examples.

Vasculitis has long been known to be one of the many systemic manifestations of SLE, and based on the appearance of this patient’s rash along with her previous history, SLE associated vasculitis was the initial impression.

·         So, some numbers. In the attached study (which is definitely victim to some referral bias), within a cohort of around 700 patients with SLE, 11% had vasculitis (60% biopsy proven, 40% by clinical ACR critera). Of that population, 90% had cutaneous symptoms as the presenting manifestation, with the most frequent being erythematous punctuate lesions on the fingertips/palms (40%, see Figure 2) and palpable purpuric lesions (25%, see Figure 1). The most common locations of cutaneous lesions were the lower limbs and the hands, both around 40%.

·         Nearly 90% of these patients were classified as small-vessel vasculitis (SVV) and the remaining 10% as medium-vessel vasculitis (MVV). SLE is not associated with large vessel disease. SVV was largely due to associated SLE, but there was also a good proportion of cryoglobulinemic vasculitis and urticarial vasculitis. MVV, which often presented as mononeuritis multiplex, was due to SLE or PAN.

So, the bottom line after all that? Given our patient’s presentation and the above numbers, we felt that the odds were good that she had a cutaneous, small vessel vasculitis due to SLE, in the context of a very recurrent, refractory natural history…well, we were wrong.

What is EM, and what in particular is it associated with?

·         EM is an immune mediated, usually acute, mucocutaneous syndrome with characteristic “target” like lesions on the skin. It may or may not be associated with mucosal (oral, genital, ocular, or a combination of the above) ulceration. If purely just cutaneous, EM is termed erythema multiforme minor. The incidence of EM is not clear, but it’s definitely very rare…like <1% rare. One may then ask why I’m even writing about it – the answer is, I don’t really know, but doesn’t “erythema multiforme” just roll of your tongue so perfectly??

·         Over 90% of cases of EM are due to infection, with HSV and Mycoplasma pneumoniae being most commonly reported (former more than the latter).  Drugs account for the remaining 10%, with the most common agents being NSAIDs, sulfonamides, antibiotics and antiepeleptics. The pathophysiology of EM has best been described in the context of HSV infection, in which case CD4 T-cells release inflammatory cytokines in reaction to HSV antigens contained in keratinocytes…why are they in keratinocytes? It has to do with antigen presenting cells localizing to the dermis…but the article does a better job explaining it than I possibly could…

What are the manifestations of EM and what else is on the differential?

·         The classic “target-like,” papular lesion is characterized by a central area of epidermal necrosis (often appearing like a blister) that is contained with a red, edematous, inflammatory zone. This is surrounded a lighter, pale edematous zone with another erythematous “ring” on the extreme periphery…best to look at some pictures, refer to page 892 of the attached review. Classically, EM has a symmetric, acral distribution along the extensor surfaces. The rash usually spreads centripetally, but the trunk is much less affected than the extremities.

·         Generally, the rash appears over the course of 3-5 days. Prodromal symptoms are unusual, unless cutaneous symptoms are accompanied by significant mucosal involvement (25-60% of cases). Oral ulcers are most common (70%).

·         The problem with EM is that it can present atypically, and “typical” lesions can evolve into atypical lesions in the same patient over the course of the illness. There are several other diagnoses that closely mimic EM, including Stevens-Johnson’s Syndrome, Small Vessel Vasculitis, urticaria, drug eruptions, Sweet’s Syndrome, and Rowell’s Syndrome…that last diagnosis was termed in 1963 as a SLE-cutaneous syndrome characterized by concurrent chronic discoid lupus and EM type lesions. However, based on some recent literature, whether this diagnosis should even exist is controversial.

How is EM diagnosed and what’s the prognosis?

·         Definitive diagnosis is made on biopsy, which usually needs to be done given all the other competing diagnoses. However, in the setting of an acute, self-limited episode with associated infectious signs consistent with HSV or Mycoplasma, the diagnosis can be made clinically.

·         The treatment of acute EM is mainly symptomatic with topical steroids and/or oral antihistamines and discontinuation of any potential offending agents. Since acute EM is most commonly herpetic in etiology, studies have looked at the efficacy of anti-HSV drugs, but have not shown benefit, reinforcing the self-limited nature of this phenomenon. Mucosal symptoms can also be treated supportively, but if disabling, may warrant systemic glucocorticoid therapy.

·         As alluded to, EM is generally an isolated, self-limited episode that resolves over the course of 1-2 weeks (though may be longer depending on the extent of involvement). In some instances, however, EM can be recurrent. Studies have shown, for the most part, that recurrent disease is associated with subclinical (asymptomatic patients with HSV detected by PCR) or clinically apparent HSV infection. Recurrent disease, whether clearly associated with HSV or not (i.e., idiopathic), is treated with at least a 1-2 year course of anti-HSV therapy. Immunosuppressants, particularly azathioprine, have also been studied. As always, difficult to assess the efficacy of treatments for uncommon complications of an uncommon disease…

Special shout-out to Dan Morris for providing the literature for this very interesting topic.  Along with the literature aforementioned, I’ve also attached a very thorough, pictorial review of the various dermatologic manifestations of SLE, enjoy.

Vasculitis in Systemic Lupus Erythematous
Ramos-Casals et. al., Medicine (Baltimore) 2006, Volume 85 (2): 95-104

Sokumbi et. al., Int J of Derm 2012, Volume 51: 889-902

Walling et. al., Am J Dermatol 2009, Volume 10 (6): 365-81