Are You Confident of the Diagnosis?
What you should be alert for in the history
A history of photosensitivity is commonly elicited; patients may complain of the induction of new lesions, exacerbation of the pre-existing eruption, a burning or stinging sensation, or intensification of the pruritus following sun exposure.
Characteristic findings on physical examination
Reticular erythematous mucinosis (REM) is characterized by persistent, mildly pruritic, reticulated erythematous macules, papules or urticarial plaques that most often occur on the upper back and chest (Figure 1).
Rarely, REM may occur on the extremities, head, neck, or groin, and there has been a single report of gingival involvement in a patient with typical lesions on the chest.
Expected results of diagnostic studies
Despite the frequency of photosensitivity by history, results of photo-provocative testing are often negative. Positive photo-testing has been demonstrated in some patients following exposure to UVB, UVC, and/or solar simulator light sources but has been negative in many others.
Rare patients even report improvement following sun exposure, or treatment with UVB or UVA-1 phototherapy. A delay of up to 4 weeks following phototesting may occurs before erythema presents at the test site. Hormonal flares occurring during pregnancy, menstruation, and with the use of oral contraceptive pills have been reported. The eruption is chronic, often lasting for decades, but it may spontaneously regress.
The histologic features of REM include a superficial and deep perivascular and periadnexal lymphocytic infiltrate and abundant ’mucin’ (glycosaminoglycan) deposition throughout the dermis. Mucin deposition can usually be appreciated with routine hematoxylin and eosin staining, but immunostains such as alcian blue or colloidal iron may be useful to confirm this finding. Direct immunofluorescence studies are typically negative.
REM shares clinical and histopathologic features with lupus erythematosus tumidus (tumid lupus erythematosus) and Jessner’s lymphocytic infiltrate. These entities may not, in fact, be distinct. Some authors suggest that patients with lupus erythematosus tumidus are more likely to have positive photo-provocative testing (demonstrated in 70-80% of patients), and a more dense lymphocytic infiltrate than patients with REM.
ANA testing is positive in fewer than half of patients with REM or lupus erythematosus tumidus, and progression to or co-occurrence with systemic lupus erythematosus is rare in patients diagnosed with either dermatosis.
Other entities in the differential diagnosis of REM include:
Polymorphous light eruption: Differentiated by a clear history of photosensitivity, transient/less persistent than REM, often more widespread, dermal edema rather than dermal mucin
Confluent and reticulated papillomatosis: Differentiated by surface change – verrucous/papillomatous surfaced reticulated papules in contrast to smooth papules/plaques or macules in REM and distinct histology
Seborrheic dermatitis: Differentiated by presence of scale, facial involvement in classic distribution, and distinct histology, though biopsy is rarely needed
Lichen myxedematosus/papular mucinosis: Differentiated by multiple coalescing dome-shaped waxy papules often on face and extremities, may be associated with paraproteinemia, minimal inflammatory infiltrate histologically
Who is at Risk for Developing this Disease?
REM is most common in women (2:1 female:male) in the third and fourth decades of life, although its onset has been reported in children and in adults as late as the eight decade of life. Family history is usually negative for other affected members; however, there is one report of REM occurring in siblings.
What is the Cause of the Disease?
The etiology of REM remains unknown. The photosensitivity and photodistribution observed in many patients suggests that solar irradiation may play a role in the pathogenesis of REM.
Ultrastructural studies of REM skin biopsies have demonstrated features that can be seen in virally infected cells raising the possibility of viral infection as a possible trigger. These ultrastructural findings (specifically, interwoven tubular aggregates in the expanded cisternae of rough endoplasmic reticulum and in endothelial cells of dermal vessels), however, are not specific to an individual virus and have also been described in skin biopsies from patients with dermatomyositis, and systemic lupus erythematosus.
The photosensitivity and typical prompt improvement following therapy with antimalarials in REM has led to the suspicion that immunologic alterations similar to those occurring in lupus erythematosus may be important in the pathogenesis of REM.
Systemic Implications and Complications
The majority of patients with REM are otherwise healthy; however, case reports suggesting an association of REM with a number of immunologic, endocrine, and neoplastic conditions exist. These include systemic lupus erythematosus, diabetes mellitus, Hashimoto’s thyroiditis, idiopathic thrombocyopenic purpura, hyperthyroidism, uveitis, breast carcinoma, and colon adenocarcinoma.
Despite the anecdotal nature of these reports, REM is a rare dermatosis, and it therefore is reasonable for patients with the diagnosis to undergo a thorough history and physical examination followed up with further testing if indicated by any unusual findings as well as age-appropriate malignancy screening.
Because REM and lupus erythematosus tumidus one and the same, and both have been reported to occur in patients with systemic lupus erythematosus, it is reasonable to perform basic screening for lupus erythematosus with a thorough review of systems, physical examination and laboratory testing including CBC with differential, renal function testing, urinalysis and antinuclear antibody (ANA) testing.
Antimalarial agents (hydroxychloroquine, chloroquine)
Topical calcineurin inhibitors
Pulsed-dye laser therapy
Phototherapy with UVB or UVA-1
Optimal Therapeutic Approach for this Disease
Patients should be reassured that REM is not a life-threatening condition and that most patients with it do not have associated medical problems. Nonetheless, given the overlapping features of REM and lupus erythematosus tumidus, patients should be screened for lupus erythematosus via thorough review of systems, physical examination and laboratory studies (CBC with differential, renal function testing, urinalysis and ANA). Patients with evidence of systemic lupus erythematosus (rare), should be referred to a rheumatologist.
Patients should be educated about the chronic nature of REM. Although spontaneous improvement has been reported, most patients have disease that persists for years.
Photoprotection should be recommended. Patients should be advised to use broad spectrum sunscreens, clothing, shade, and avoidance of tanning beds and sunbathing.
The most successful therapy reported for REM is antimalarial therapy. The mechanism is not well known, but these agents are photoprotective and have a number of immunologic effects that appear to reduce autoimmune phenomena.
Hydroxychloroquine is the safest of this group of drugs. Dosages should not exceed 6.5mg/kg daily, and most patients respond to doses of 200mg daily to 200mg twice daily. Responses are typically prompt, occurring 1-2 months after initiation of antimalarial treatment.
Relapses are typically prompt after discontinuation of antimalarials. Patients must undergo ophthalmologic monitoring for ocular toxicity (baseline and annually for hydroxychloroquine), and should have periodic blood tests to monitor for hematologic, hepatic, and renal toxicity (all very rare at recommended dosages).
A few reports have suggested that topical calcineurin inhibitors (tacrolimus 0.1% ointment and pimecrolimus 1% cream) may be beneficial. Patients noted improvement within 6 months of initiating therapy. Topical calcineurin inhibitors should be considered in patients unable to tolerate antimalarials or for whom antimalarials are contraindicated.
Calcineurin inhibitors are safe for long-term use and may be used safely with antimalarial therapy. It seems reasonable to consider these agents as maintenance therapy although this has not been formally studied in patients with REM.
Topical corticosteroids are often ineffective, but not in all cases. Due to the chronic nature of REM, the lowest possible strength corticosteroid that provides benefit should be chosen, and patients should be warned of and monitored for evidence of cutaneous atrophy.
Successful treatment of REM with pulsed dye laser therapy (585nm) has been reported in several patients. In the few reported patients, 2-5 treatment sessions utilizing energy densities of 4.8-6.9J/cm2 and pulse durations of 450 microseconds resulted in long-term clearance of REM lesions.
Individual case reports document the successful clearance of REM following phototherapy with UVA-1 (340-400nm), UVB excimer lamp (308nm), and broadband UVB plus steroid impregnated tape. Given the scant data on these treatment modalities and the photosensitivity reported by the majority of patients with REM, phototherapy is not presently recommended. If utilized, it should be considered with extreme caution, and patients should be phototested before proceeding with treatment.
Patients should be educated about the chronic nature of REM, and reassured that it is not a dangerous skin condition.
Photoprotection is very important and should be re-emphasized regularly throughout the patients’ visits. For patients not bothered by pruritus or the appearance of the eruption, photoprotection alone is reasonable.
Because of the chronic nature of this disease, long-term treatment is usually necessary for those patients wishing to pursue it. Antimalarials are the most effective agents, but relapses are common once these drugs are stopped, and long-term antimalarial therapy (more than 3 months) requires regular ophthalmologic and laboratory screening.
A trial of topical calcineurin inhibitors either prior to starting antimalarials and/or as maintenance therapy is worthwhile. Pulsed dye laser treatment may offer the possibility of long-term improvement or cure; however, this has not been evaluated in well-powered or controlled trials, and given the rarity of REM, likely never will be.
Unusual Clinical Scenarios to Consider in Patient Management
REM is usually not associated with serious systemic disease. It shares many features with lupus erythematosus tumidus, and some authors believe that these are not distinct entities.
Lupus erythematosus tumidus is very rarely associated with systemic manifestations of lupus erythematosus, and some have even questioned whether it should be considered a form of lupus. Patients with REM should be screened for systemic lupus erythematosus, but reassured that they are unlikely to develop it.
Due to the few reports of REM occurring in association with malignancies, endocrine abnormalities, and other autoimmune problems, it is reasonable to refer patients to their primary care physicians for a thorough history and physical examination followed by targeted laboratory/radiologic evaluation or other as indicated, as well as age-appropriate malignancy screening.
What is the Evidence?
Perry, HO, Kierland, RR, Montgomery, H. “Plaque-like form of cutaneous mucinosis”. Arch Dermatol. vol. 82. 1960. pp. 980-985. (This is the first description of the entity now known as REM. The authors describe three patients and suggest that the eruption might be a form of lichen myxedematosus.)
Steigleder, GK, Gartmann, H, Linker, U. “REM syndrome: reticular erythematous mucinosis (round-cell mucinosis), a new entitity”. Br J Dermatol. vol. 91. 1974. pp. 191-199. (The authors coin the term REM syndrome in their description of three patients, and note the similarities between their patients and those reported by Perry et al in 1960 as plaque-like mucinosis.)
Quimby, SR, Perry, HO. “Plaquelike cutaneous mucinosis: Its relationship to reticular erythematous mucinosis”. J Am Acad Dermatol. vol. 6. 1982. pp. 865-861. (This review follows up on the original three patients described in 1960 by Perry et al, and reviews the published literature on the clinical and histologic feature of REM through 1982. The authors conclude that plaque-like mucinosis and REM are the same entity and provide their rationale.)
Braddock, SW, Davis, CS, Davis, RB. “Reticular erythematous mucinosis and thrombocytopenic purpura: Report of a case and review of the world literature, including plaque-like cutaneous mucinosis”. J Am Acad Dermatol. vol. 19. 1988. pp. 859-868. (This is an excellent and thorough review of REM including all cases reported through 1988. Clinical, histologic, and ultrastructural features as well as diseases or systemic findings reported in association with REM and treatment are thoroughly reviewed.)
Tomasini, D, Mentzel, T, Hantschke, M, Cerri, A, Paredes, B, Rutten, A. “Plasmacytoid dendritic cells: an overview of their presence and distribution in different inflammatory skin diseases, with special emphasis on Jessner's lymphocytic infiltrate of the skin and cutaneous lupus erythematosus”. J Cutan Pathol. vol. 37. 2010. pp. 1132-1139. (In this study, 353 skin biopsies of various types of cutaneous lupus erythematosus, Jessner's lymphocytic infiltrates, and other inflammatory dermatoses were compared immunohistochemically for the presence and distribution of plasmacytoid dendritic cells. The findings demonstrate similarities among REM, Jessner's lymphocytic infiltrate and lupus erythematosus tumidus and add to the growing evidence that these entities are closely related, if not one and the same.)
Morison, WL, Shea, CR, Parrish, JA. “Reticular erythematous mucinosis syndrome: Report of 2 cases”. Arch Dermatol. vol. 115. 1979. pp. 1340-1342. (The case reports describe two patients with REM and the extensive phototesting performed to characterize their photosensitivity. The conflicting results of phototesting in patients with REM is discussed.)
Sidwell, RU, Francis, N, Bunker, CB. “Hormonal influence on reticular erythematous mucinosis”. Br J Dermatol. vol. 144. 2001. pp. 628-650. (This case report describes a patient with REM whose disease was convincingly related to hormonal fluctuations, and reviews similar cases reported previously.)
Mansouri, P, Farshi, S, Nahavandi, A, Safaie-Naraghi, Z. “Pimecrolimus 1% cream and pulsed dye laser in treatment of a patient with reticular erythematous mucinosis syndrome”. Dermatology Online Journal. vol. 13. 2007. pp. 22(This case and review describes REM and its treatment, highlighting the use of laser and topical calcineurin inhibitors for this disease.)
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