Scleromyxedema in a 47-year-old female treated with colchicine and topical steroids

Eunice Kaye M. Rayos-Lopez, MDa; Mary Catherine T. Galang, MD, DPDSb;

Ricky H. Hipolito, MD, DPDSc; Ma. Teresita G. Gabriel, MD, FPDSc

Introduction: Scleromyxedema is a rare skin disorder characterized by fibroblast proliferation and mucin deposition in the dermis, in the absence of thyroid disease. The precise mechanisms whereby increased fibroblast activity results in mucin deposition remain to be defined, but the etiology of the disorder still remains to be unknown.

Case Summary: We report a rare case of a 47-year-old female with a three-year history of multiple erythematous to light brown, firm, waxy, slightly pruritic papules and plaques on the earlobes, nose, buttocks and extremities. Dermatologic examination showed multiple 2-3mm firm, waxy, closely-spaced papules and plaques symmetrically distributed on the earlobes, nose, arms, buttocks, extending into thighs and knees. Routine laboratory tests and thyroid function test results were within the normal range. Skin punch biopsy was done on the right arm and histopathologic results were consistent with diagnosis of papular mucinosis. Patient was treated with topical steroids and colchicine with significant improvement of the lesions.

Conclusion: Scleromyxedema is a rare, chronic and unpredictable disease with no specific definitive treatment. Most commonly used therapies are intravenous and immunogloblulin (IVIg) and systemic steroids. Few data are available on more cost-effective treatment options. Colchicine should be further explored as cost-effective and safer alternative treatment in the management of this disease.

Keywords: Scleromyxedema, Papular mucinosis, Lichen myxedematosus, Colchicine

INTRODUCTION

Scleromyxedema is an idiopathic, rare disease characterized by lichenoid papules, plaques and nodules due to mucin dermal deposition, and a variable degree of fibrosis

without thyroid dysfunction.1 A spectrum of the disease is recognized, with the more localized, less severe forms and the more sclerotic, diffuse forms.1-2

The terms papular mucinosis, lichen myxedematosus and scleromyxedema are used interchangeably in literature.1 Some published reports use the terms papular mucinosis or lichen myxedematosus to describe the localized, relatively non-lethal form while its generalized form or scleromyxedema is associated most frequently with monoclonal gammopathy and many systemic disorders.2

The etiology of the disorder remains unknown. The precise mechanisms whereby increased fibroblast activity results in mucin deposition remain to be defined. Published reports show no evidence to support a specific treatment for scleromyxedema.1-3 Before, the therapy of choice would be monthly courses of melphalan, targeting plasma cell dyscrasia which is most commonly associated with the disease. However, this alkylating agent has also been implicated in 30% of the deaths secondary to induction of hematologic malignancies and septic complications. The most commonly used therapies

are intravenous immunoglobulin (IVIG) and systemic steroids. IVIG proved to be effective as first-line therapy both alone and in conjunction with other treatment modalities.3

Only few data are available on more cost-effective treatment options for scleromyxedema. We report a unique case responding favorably to colchicine owing to its anti-inflammatory mechanism of action, in combination with topical steroids.

CASE REPORT

A 47-year-old female presented to us with a three-year history of multiple erythematous to light brown, firm, waxy, slightly pruritic papules and plaques on the earlobes, nose, buttocks and extremities. Prior consult was done with a physician and an assessment of Hansen’s Disease was considered. Patient was biopsied, revealing moderate lymphocytic vasculitis and was negative for acid-fast bacilli. Patient was prescribed with halobetasol ointment used interchangeably with clobetasol propionate ointment, cetirizine tablet as needed for six months and an unrecalled dose of prednisone for 3 months with no improvement noted. Persistence of lesions, prompted referral to our institution. Past medical, family and personal social history were unremarkable.

Dermatological examination showed multiple, 2-3mm, firm, waxy, closely-spaced papules and plaques symmetrically distributed on the earlobes, nose, arms, buttocks, extending into thighs and knees (Fig. 1-2)

Routine laboratory tests including a complete blood count, liver and renal function tests, urinalysis and chest radiography were normal. Thyroid function tests including T3, T4 and thyroid stimulating hormone levels were all within

Department of Dermatology, Research Institute of Tropical Medicine, Muntinlupa Citya Resident physician b Resident graduate c Consultant

Source of funding: noneConflict of interest: none Corresponding author: Eunice Kaye M. Rayos-Lopez, MDEmail: ekmrlopez@gmail.com

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Figure 2. Closer view showing coalescing 2-3mm, erythematous to light brown, waxy, closely-spaced papules in the (A) ears, (B) buttocks and (C) right arm.

Figure 3. Histopathology shows proliferation of fibroblasts and increased collagen deposition in the dermis (black arrows, H&E, 400x). Alcian blue revealed increased interstitial mucin (red arrows, 400x)

Figure 1. Multiple, 2-3mm, erythematous to light brown, waxy, closely-spaced papules and plaques symmetrically distributed on the (A) face, (B) arms, and (C) legs .

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normal range. A serum protein electrophoresis done revealed a positive monoclonal gammopathy with a monoclonal peak concentration of 6.7% at the gamma region. Further serum immunotyping was recommended to identify the specific immunoglobulin involved.

A 4-mm skin punch biopsy was taken from the right arm which showed on histopathology a basket-woven stratum corneum, acanthosis of the epidermis and hyperpigmentation of basal cell layer. The dermis revealed loosely arranged collagen bundles in the papillary dermis, a sparse interstitial inflammatory infiltrate of lymphocytes and some fibroblasts. The clinical and histopathologic features were consistent with the diagnosis of papular mucinosis (Figure 3A). An Alcian blue stain revealed an increased amount of interstitial mucin (Figure 3B).

The patient was treated with halobetasol ointment twice a day for two weeks and colchicine 500mcg/tab, 1 tab twice daily for two weeks. Patient was seen after a month with minimal decrease in erythema and flattening of some lesions, with no new lesions noted. Patient was then shifted to clobetasol ointment twice a day for two weeks and maintained the dosage of colchicine at 500 mcg/tab twice daily. Patient followed-up on the second month with significant decrease in erythema and flattening of most lesions. Only colchicine was continued thereafter and follow up on the 4th month showed marked improvement and flattening of lesions on the earlobes and of the nasal area (Figure 4).

DISCUSSION

In literature, the terms papular mucinosis, lichen myxedematosus, and scleromyxedema are often used indiscriminately. Most patients reported to have papular

mucinosis without indication of the subtype, appear in fact to have scleromyxedema with monoclonal gammopathy.1

Because of its rarity, information about this group of disorders have been retrieved from anecdotal or single case reports. Based on the anatomical and clinical manifestations of the published cases, it is important to distinguish clearly between a generalized form with systemic, even lethal manifestations and a localized form, which does not run a disabling course.1-2

Diagnosis of scleromyxedema should fulfill the following criteria: 1) generalized papular and sclerodermoid eruption, 2) mucin deposition, fibroblast proliferation and fibrosis confirmed by histopathology, 3) the absence of thyroid disease and 4) monoclonal gammopathy.2 Our patient fulfills this criteria for scleromyxedema.

The largest case series to date,3 confirms previously described features of the classic scleromyxedema patient profile, including a 70% chance of comorbidities. Extracutaneous manifestations are mainly neurologic (30%), rheumatologic (25%) and cardiac (22%). Another case series from John Hopkins, differ in the results, wherein gastrointestinal and pulmonary involvements were more common. This therefore reflects, that this disease entity is extremely unpredictable and close monitoring is warranted.4

The pathogenesis of scleromyxedema is unknown.1-4 The main hypothesis is that circulating cytokines, such as interleukin-1, tumor necrosis factor, and transforming growth factor-B, known to stimulate glycosaminoglycan synthesis and fibroblast proliferation in the skin, could play a role.4

In scleromyxedema, numerous 2-3mm, firm, waxy, closely spaced skin lesions develop in a widespread symmetrical distribution pattern. The most common sites of involvement are the head and neck region, upper trunk, hands, forearms, and thighs.1 Papules are often arranged in a strikingly linear array as evidenced by our patient. The surrounding skin is shiny and indurated, i.e. sclerodermoid in appearance, and the glabella is typically involved with deep longitudinal furrowing, representing later progression. Severe involvement of the face can result in a leonine facies, and in addition to earlobe nodules, is often mistaken for Hansen’s Disease. As the condition progresses, erythematous and infiltrated plaques may appear with skin stiffening, sclerodactyly and decreased motility of the mouth and joints.4

Scleromyxedema is almost always associated with paraproteinemia. Most studies report that the monoclonal gammopathy is usually IgG and the light chains are more commonly lambda. Although mild plasmacytosis may be observed in bone marrow biopsies, less than 10% of patients with scleromyxedema progress to multiple myeloma.1,4 Patients who test positive, as in our case, can have a number of internal manifestations. Dysphagia, proximal muscle weakness due to myositis, disturbances of the central nervous system leading to unexplained coma, peripheral neuropathy, arthopathies, carpal tunnel syndrome, restrictive or obstructive lung disease, and a scleroderma-like renal disease may accompany or follow the cutaneous manifestations. A “dermato-neuro syndrome”, a potentially

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Figure 4. Comparison of patient’s photos at baseline (A-C), and response to colchicine and topical steroids at 16 weeks (D-F)

BASELINE

16 WEEKS

REFERENCES

1. Rongioletti, F, Rebora A. Updated classification of papular mucinosis, lichen myxedematosus, and scleromyxedema. J Am Acad Dermatol 2001; 44:273-81.

2. Rongioletti, F, Rebora, A. The new cutaneous mucinoses: A review with an up-to-date classification of cutaneous mucinoses. J Am Acad Dermatol 1991; 24:265-70.

3. Rongioletti F, Merlo G, Cinotti E, et. al. Scleromyxedema: A multicenter study

of characteristics, comorbidities, course, and therapy in 30 patients. J Am Acad Dermatol 2013; 69:66-72.

4. Bolognia, J, Jorizzo, J, Schaffer, J. Dermatology. 3rd edition, 2012.

5. Vanderschueren, S, Mylle, M, Dierickx, D, et.al. Monoclonal Gammopathy of Undetermined Significance: Significant beyond hematology. Mayo Clinic Proceedings 2009; 84:842-845.

6. Samuelsson A, Towers, TL, Ravetch JV. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 2001; 291:484-6.

7. Desai AD, James WD. Lichen myxedematosus. In: Lebwohl MG, Heymann WR, Berth-Jones J, Coulson IC, editors. Treatment of skin disease: comprehensive therapeutic strategies. 2nd ed. London (UK): Elsevier, 2006. pp.343-4.

8. Cunningham, B, Kirchmann, T, Woodley, D. Colchicine for Epidermolysis Bullosa Acquisita. J Am Acad Dermatol 1996; 34:781-4.

life-threatening encephalopathy, has also been described.4 This syndrome begins abruptly with a worsening of skin lesions, a flu-like syndrome, fever and seizures, and can lead to unexplained coma. An example of this has been mentioned in one case series,5 of a histopathologically-proven case of scleromyxedema with a positive M protein IgG which presented with four episodes of confusion during a 2-year period, each predated by a flu-like illness and culminating in status epilepticus with prolonged postictal coma. Neuroimaging and cerebrospinal fluid analysis were unrevealing. Moreover, the M protein value increased in a month’s time, and the patient developed systemic symptoms such as anemia and bony plasmacytoma with subsequent diagnosis of Multiple myeloma. This further highlights the importance of screening for monoclonal gammopathies in all patients presenting with skin lesions of scleromyxedema. It is also recommended that routine testing and follow-up titers should be done in every patient, as it is theoretically believed to predict sequelae. Subsequent referral to immunologists and hematologists is recommended to improve disease outcomes.

The histopathology of scleromyxedema is characterized by a triad of a diffuse deposit of mucin in the upper and mid reticular dermis, an increase in collagen deposition, and a marked proliferation of irregularly arranged fibroblasts.4

There are limited data regarding the course and prognosis of scleromyxedema. No consensus on the optimal therapy of this potentially fatal disease exists, because of the limited number of cases, the lack of randomized, controlled trials, and poorly understood pathogenesis.1-4 Melphalan, systemic corticosteroids, and plasmapheresis are considered as first-line treatments in recent discussions. Second-line therapeutic options include isotretinoin, acitretin and intralesional corticosteroids. Third-line strategies include the use of 2-chlorodeoxyadenosine, cyclophosphamide, cyclosporine, methotrexate, thalidomide, autologous stem cell transplantation, extracorporeal photophoresis, intravenous immunoglobulin, interferon alfa-2b, psoralens plus ultraviolet radiation (PUVA), and radiation.3-4,6-7

The largest scleromyxedema case series to date,3,7

support the contention that IVIG is a relatively effective and safe treatment compared to other treatment modalities, and still provide the highest success rate and longest clinical remission; although the mechanism of action is unclear. Drawbacks of IVIG are related to their high cost and the time-consuming administration.6

This report explores the possible potential use of colchicine as a more cost-effective systemic treatment option for scleromyxedema. Colchicine has long been used in the treatment of many dermatologic disorders mainly for its anti-inflammatory effect and its use as a steroid-sparing agent. Colchicine inhibits cell division by binding to tubulin dimers and preventing polymerization into microtubules. It also interferes with polymorphonuclear leukocyte chemotaxis. The possible mechanism of action of Colchicine on scleromyxedema may be similar to the treatment of epidermolysis bullosa acquisita. Colchicine decreases collagen and increases collagenase production, resulting in intracellular accumulation of procollagen with a subsequent reduction in procollagen synthesis.8 Our patient illustrates a case which responded favorably with 16 weeks of Colchicine administration, after no further improvement with topical steroids was noted.

CONCLUSION

Scleromyxedema is a rare, chronic and unpredictable disease with no specific definitive treatment, and with varied therapeutic responses. Acknowledgment of the spectrum of disease is therefore important to aid early detection and importance of classification of the disorder whether of the localized or generalized form. It is important also to emphasize the use of laboratory evaluation including thyroid function tests and serum protein electrophoresis, and possibly immunotyping to predict prognosis and direct treatment strategies. Colchicine should be further explored as a cost-effective and safer alternative treatment in the management of this disease.

76 J Phil Dermatol Soc • November 2017 • ISSN: 2094-201X