Reticular erythematous mucinosis: a review of patients' characteristics, associated conditions, therapy and outcome in 25 cases

Authors


  • Funding sources None.
  • Conflicts of interest None declared.

Summary

Background

Reticular erythematous mucinosis (REM) is an uncommon disease, the nosology and specific characteristics of which are controversial because most reports deal with single cases or small series.

Objectives

To describe the characteristics of patients with REM regarding demographics, clinical and pathological features, comorbidities, treatment and course.

Methods

A retrospective and prospective study was conducted on 25 patients diagnosed with REM in the setting of university-affiliated dermatology departments and dermatopathology centres.

Results

Of the 25 patients with REM, 16 were women (sex ratio 2 : 1) and the mean age was 46 years. The roles of sun exposure and oral contraceptives were ambiguous. Associated diseases included hypertension (= 4), malignancies (= 3), autoimmune diseases (= 3) and Borrelia infection (= 1). Immunological studies (including serology and direct immunofluorescence) were noncontributory. The response to antimalarial treatment was good in > 80% of cases. Worsening or recurrence of the lesion after treatment discontinuation, or in the course of the disease, occurred in 31% of patients.

Conclusions

We present the largest REM case series to date. The reticular pattern with involvement of the midline of the chest and back, the predilection for middle-aged women, the controversial relationship with photosensitivity and the possible association with other conditions such as malignancies and thyroid dysfunctions are the main characteristics that makes REM a recognizable disease.

Reticular erythematous mucinosis (REM) is a rare condition first described in 1974 by Steigleder et al.[1] and classified into the group of primary cutaneous mucinoses. However, its nosology, and in particular its relationship with cutaneous lupus erythematosus (CLE), has been the subject of controversies.[2] This is particularly because of its rarity and, by consequence, because it has been studied almost anecdotally – the two largest series of patients published so far included merely nine[3] and 11 patients.[4] We conducted a retrospective and prospective study on 25 patients with REM, including their clinical characteristics, histopathological and laboratory findings, association with other diseases, response to treatment and course.

Patients and methods

In total 25 patients diagnosed with REM were enrolled in the study. Seventeen were seen at the Dermatology Section, University of Genoa, Italy, and eight were seen at the Department of Dermatology, University of Lyon, France. Data from 19 of the patients were obtained from medical records (January 1990 to December 2007); six additional patients were followed prospectively from January 2007 to October 2012 at the Dermatology Section, University of Genoa. The inclusion criterion was a clinical and histopathological diagnosis of REM.[5] The clinical criteria were erythematous macules and indurated papules with a reticular configuration, or plaque-like lesions that remained isolated and coalesced into reticulated patterns in the midline of the back or chest (Fig. 1a,b). The histopathological criteria included a perivascular and perifollicular, predominantly lymphocytic infiltrate with vascular dilatation and interstitial mucin deposition in the dermis with absent or minimal epidermal changes (Fig. 2a,b). Periodic acid–Schiff, Alcian blue and colloidal iron stains were performed on all skin biopsy specimens (Fig. 2c). The following features were evaluated: age, sex, morphology and location of the skin lesions, associated disorders, drug intake, relationship with sun exposure, histopathological features, laboratory tests, treatment and course.

Figure 1.

Clinical presentations of reticular erythematous mucinosis. (a) Erythematous macules, papules and plaque-like lesions coalescing into reticulated patterns in the midline of the chest. (b) Erythematous macules and papules coalescing into reticulated patterns in the midline of the back.

Figure 2.

Histopathological findings of reticular erythematous mucinosis. (a) A slight-to-moderate perivascular and perifollicular lymphocytic infiltrate in the superficial dermis with absent or minimal epidermal changes (haematoxylin and eosin, original magnification ×40). (b) A slight-to-moderate superficial perivascular and perifollicular lymphocytic infiltrate with interstitial mucin (haematoxylin and eosin, original magnification ×100). (c) Mucin deposition in the upper dermis (Alcian blue stain, original magnification ×40).

Results

The main clinical characteristics of the patients with REM are summarized in Table 1. The patients included 16 women and nine men. Their average age was 45 years (range 29–83). The mean duration of the disease at the diagnosis was 14·7 months (range 1–120; in two cases this information was unavailable). The lesions were erythematous macules with a reticular pattern (= 7), erythematopapular and reticular (= 7) and erythematopapular and reticular with large plaques (= 11), which remained isolated in some patients and coalesced into reticulated-pattern plaques in others. Scaling, other surface changes or annular morphology were not observed. Symptoms were absent in 21 patients; of the others, two complained of slight burning sensation and two of itch. The lesions were located on the midchest in 15 patients and on the upper midback in 13. The chest was exclusively involved in seven cases, the back in six cases and both areas in three cases. Additional uncommon sites of involvement were the neck (four patients), the face (two patients), the upper abdomen (two patients) and the limbs (two patients).

Table 1. Main characteristics of patients with reticular erythematous mucinosis
  1. a

    Not available for two patients.

Number of patients25
Age (years), mean (range)45 (29–83)
Women/men16/9
Mean delay to diagnosis (months)a14·7
Skin lesions, n (%)
Erythematous macules with reticular pattern7 (28)
Erythematous macules/papules with reticular pattern7 (28)
Erythematous macules/papules/plaques with reticular pattern and isolated plaques11 (44)
Symptoms, n
Absent21
Slight burning sensation2
Pruritus2
Sites involved, n
Chest7
Back6
Chest and back3
Back and neck2
Chest and face1
Chest and neck1
Chest, back and neck1
Chest, back, face and arms1
Chest and upper abdomen2
Lower chest, upper abdomen, hips1
Influence of sun exposure, n
Improvement4
Worsening3
Induction2
Phototesting, n
Patients studied for minimal erythemal dose (diminished/normal)5 (2/3)
Patients studied with repeated provocation testing (positive/negative)3 (1/2)
Influence of contraceptive pill intake, n 
Worsening5
Triggering2
None1
Associated conditions, n
Arterial hypertension4
Malignancies (rectal and breast carcinoma, Hodgkin lymphoma)3
Ulcerative colitis1
Hyperthyroidism1
Borreliosis1
Raynaud phenomenon and hepatitis C virus–chronic hepatitis1
Histopathology on the 25 patients, n (%)
Perivascular and perifollicular lymphocytic infiltrate in superficial and mid-dermis21 (84)
Perivascular and perifollicular lymphocytic infiltrate in superficial and deep dermis4 (16)
Mucin deposition in superficial dermis15 (60)
Mucin deposition throughout reticular dermis10 (40)
Direct immunofluorescence on 11 patients, n (%)
Granular IgM at dermoepidermal junction3 (27)
Granular C3 at dermoepidermal junction and superficial vessels1 (9)

Sun exposure was reportedly responsible for triggering the lesions in two patients, and for worsening them in three; however, four patients reported improvement after sun exposure. Oestrogen–progesterone pills were taken by four patients. A possible correlation between ‘the pill’ and REM could be found only in one patient. She developed skin lesions 8 months after starting the contraceptive pill, improved after stopping the drug and taking antimalarials, and relapsed on resuming the contraceptive pill and, later, during pregnancy. Another patient reported having worsened after taking a ‘contraceptive pill’. Two patients did not report any obvious relationship between the intake of contraceptive pills and the lesions, and one of them had been on the contraceptive pill for a long time.

Four patients had arterial hypertension; three of them were taking angiotensin-converting enzyme inhibitors, beta-blockers and amiloride/hydrochlorothiazide. One patient also had diabetes mellitus (for which he was taking glibenclamide, metformin and gliclazide) and had undergone surgery for rectal carcinoma. One patient had had breast carcinoma, and the skin lesions of REM on the chest occurred on the scar of the previous mastectomy. When she underwent contralateral breast biopsy for fibrocystic breast disease, REM extended also to the contralateral scar. One patient each had hyperthyroidism, ulcerative colitis treated with salazopyrin, and hepatitis C virus–chronic hepatitis.

Antinuclear antibodies (ANA) were tested in nine patients. Only two of them had ANA at low titres (1 : 80, speckled pattern). One of them had also an elevated erythrocyte sedimentation rate, while another one had circulating immune complexes and an elevated titre of carcinoembryonic antibody. One patient had IgG and IgM antibodies to Borrelia burgdorferi on Western blot.

The minimal erythemal dose (MED) to monochromator phototesting to ultraviolet (UV) B, UVA and visible light was evaluated in five patients. A low MED to UVA and UVB was found in one case each. Repeated provocation testing with broadband UVA and UVB and solar-simulated radiation was performed in three patients; only one of them developed some erythemato-oedematous plaques after irradiation with either UVA or UVB.

Ten patients were lost to follow-up. Eleven patients were treated with hydroxychloroquine alone with a maximum daily dose of 5–6 mg kg−1 of body weight (total dose 400 mg per day) for at least 3 months. Six experienced lesion clearance within 1–2 months, three improved markedly and two were lost to follow-up. Three patients (two with complete remission and one with improvement) relapsed; in two of them the lesions recurred some days after the drug was withdrawn. Hydroxychloroquine in association with topical and systemic retinoids achieved partial improvement in two cases. Chloroquine alone with a maximum daily dose of 3–4 mg kg−1 of body weight (total dose 250 mg per day) for at least 3 months was effective in two patients, who achieved complete remission. Antimalarials were effective also in clearing the relapses in four patients. One patient who was given antibiotics (ceftriaxone followed by doxycycline for coexisting IgM-positive Borrelia infection) improved partially but subsequently relapsed (Table 2). Five patients were available for follow-up evaluation. The mean follow-up time was 16·8 months (range 6–29). All patients are alive at the time of writing, four without detectable skin disease and one with occasional relapses.

Table 2. Therapy and response in patients with reticular erythematous mucinosis
TreatmentPatientsPatients remittedPatients improvedPatients relapsedPatients lost to post-therapeutic follow-up
Hydroxychloroquine116332
Hydroxychloroquine + topical steroids11 
Hydroxychloroquine + topical steroids + systemic retinoids111
Chloroquine22
Antibiotics (for borreliosis)111
Total168652

Discussion

REM has been considered by some authors to be an idiopathic, primary form of cutaneous mucinosis and by others as a disorder closely related to or associated with CLE, in particular lupus erythematosus tumidus (LET).[1, 5-7] This controversy is not easy to resolve, as there is also some debate as to whether LET itself is a separate subtype of chronic CLE, or a nonspecific manifestation within the lupus erythematosus classification system.[8, 9]

Our present study includes the largest series of cases of REM ever reported in the literature. We confirmed that REM affects predominantly middle-aged women. Clinically, erythematous macules and/or papules coalescing into a reticulate pattern on the midline of the back and chest were present in all patients. This feature therefore should be considered the sine qua non condition for the diagnosis. Four patients presented also with slightly indurated plaques, and this accounts for the term ‘plaque-like cutaneous mucinosis’, which is currently considered as a synonym of REM. However, in the absence of macules/papules/plaques with a reticulate configuration, the diagnosis of REM should be reconsidered in favour of LET. In the literature, only one woman with reticular lesions clinically and pathologically consistent with REM developed features fulfilling the diagnostic criteria of SLE, 6 years later.[10] Most of our patients were asymptomatic, although pruritus has been previously reported to occur in 20–30% of cases.[11]

The role of sunlight was confirmed to be controversial, as sun exposure worsened or triggered REM in five patients, but also improved the disease in another four. Interestingly, only one of them developed reproducible lesions by UVA and UVB phototests. There are some reports linking REM to hormonal factors such as contraceptive pills, pregnancy and menses.[12] In only two of our patients was the rash triggered or exacerbated by oral contraceptive pills and pregnancy. In line with previous reports, we confirmed the sporadically reported associations with malignancies (breast and rectal carcinoma, Hodgkin disease) and with autoimmune disorders, including thyroid disease, diabetes mellitus and ulcerative colitis. Pathological associations reported in patients with REM include breast, lung and colon carcinoma, essential thrombocytosis, refractory anaemia with excess of blasts, monoclonal gammopathy, myxoedema, hypothyroidism, Hashimoto thyroiditis and HIV infection.[13-15] Remarkably, some patients with colon carcinoma and thyroid dysfunctions experienced regression of their REM lesions after treatment of the associated disorder. The association of REM with lung cancer has been more specifically investigated. Some cytokines (such as transforming growth factor-β, interleukins, tumour necrosis factor, interferon and angiogenic factors) secreted by alveolar macrophages of patients with lung cancer could promote lesions of REM by stimulating skin fibroblasts to produce more mucin, and by inducing vascular hyperplasia manifesting as multiple angiectasias. These cytokines could reach the skin through blood and lymphatic circulation, according to the concept of ‘contiguous inflammation of the skin’.[16]

Laboratory tests were not contributory to the diagnosis of REM. In particular, ANA were positive at low titres in only two patients. In line with results from the literature reporting positive direct immunofluorescence analysis in 20% of cases of REM syndrome,[17] we identified IgM deposits at the dermoepidermal junction in three of 11 cases (27%). However, it should be taken into consideration that a similar percentage of healthy people show positive immunofluorescence findings on healthy sun-exposed skin.[18]

There is no single evidence-based treatment for REM, but a recent study on 11 patients and previous observations suggest that antimalarials should be considered as a first-line therapy. In particular, hydroxychloroquine is considered as the treatment of choice because it generally results in improvement or healing of the lesions within 1–2 months.[3] In line with these observations, antimalarials achieved complete remission in > 50%, and partial remission in 33% of our patients. However, worsening or recurrence of the lesion after treatment discontinuation, or in the course of the disease, occurred in five patients. Novel therapeutic approaches that seem to give promising results, such as topical calcineurin inhibitors, UVA1 radiation and pulsed-dye laser, were not tried in our patients.[11, 19, 20]

Our study confirms that REM shows some overlap with LET, as both diseases share common features. These include the plaque-like clinical aspect of lesions, the lack of significant immune serological abnormalities, histopathological findings of perivascular and perifollicular lymphocytic infiltrates with dermal mucin deposition, and response to antimalarial drugs. However, our data also highlight some differences. Briefly, the main differences that make REM a recognizable disease are (i) the reticular pattern with typical involvement of the midline of the chest and back, (ii) the predilection for middle-aged women, (iii) the controversial relationship with photosensitivity and (iv) the possible association with other conditions such as malignancies and thyroid dysfunctions. Conversely, patients with LET had strong photosensitivity and a higher rate of skin immune deposits, and occasionally presented with other clinical manifestations of LE.[6-9] Jessner lymphocytic infiltration of the skin (LIS) should also be discussed in the differential diagnosis of REM; however, a reliable distinction between LIS and LET has been considered as almost impossible both clinically and histologically, as LIS may also sometimes present with increased dermal mucin.[21]

Further studies on large case series using strict clinical and pathological criteria, and increasing efforts to unravel the unknown aetiopathogenesis, disease associations and prospective treatment modalities, may elucidate whether REM syndrome is a distinct disease or whether it belongs to the broad spectrum of chronic lupus erythematosus-like skin changes.

Acknowledgments

We thank Alfredo Rebora MD for revising the paper and for his valuable suggestions.

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