Κυριακή 21 Ιουλίου 2019

Cutaneous Mucinoses,
Franco Rongioletti
First published: 09 October 2016 https://doi.org/10.1002/9781118441213.rtd0060 Cited by: 2
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Abstract
The cutaneous mucinoses are a heterogeneous group of disorders whose main characteristic is abnormal mucin deposition in the skin. The aetiopathogenesis of cutaneous mucinoses is unknown, although cytokines such as tumour necrosis factor α and β, interleukin 1, interleukin 6 and transforming growth factor β and/or polyclonal and monoclonal immunoglobulins and other unidentified factors in the serum of affected patients may induce up‐regulation of glycosaminoglycan synthesis. The cutaneous mucinoses are divided into two categories: (i) primary cutaneous mucinoses in which the mucin deposit is the main histological feature resulting in clinically distinctive lesions; and (ii) secondary mucinoses in which the mucin deposition is only an additional histological epiphenomenon. Primary mucinoses can be divided into dermal and follicular mucinoses. The former includes lichen myxoedematosus, reticular erythematous mucinosis, scleroedema, mucinoses in thyroid disease, papular and nodular mucinosis in connective tissue diseases, self‐healing juvenile cutaneous mucinosis, cutaneous focal mucinosis, digital myxoid cyst; the latter include Pinkus follicular mucinosis and urticaria‐like follicular mucinosis. Associated disorders include paraproteinaemia (scleromyxoedema, scleroedema), diabetes mellitus (scleroedema), hyperthyroidism (pretibial myxoedema), hypothyroidism (generalized myxoedema) and lupus erythematosus, dermatomyositis or scleroderma (papular and nodular mucinosis in connective tissue diseases).

    Lichen myxedematosus is an idiopathic, cutaneous mucinosis with 2 clinicopathologic subsets. There is the generalised papular and sclerodermoid form, more properly termed scleromyxedema, and the localised papular form. We report the first case, to our knowledge, of lichen myxedematosus in association with rheumatoid arthritis as well as a case in association with dermatomyositis. An up-to-date literature review on cutaneous mucinoses and connective tissue diseases, excluding the common association of primary and secondary mucinoses with systemic lupus erythematosus, was also performed.
    Lichen myxedematosus (LM) is an idiopathic, cutaneous mucinosis with 2 clinicopathologic subsets.1 There is the generalised papular and sclerodermoid form, more properly termed scleromyxedema, and the localised papular form, which has 4 variants. The 4 main clinical variants of localised LM are (1) a discrete papular form, (2) an acral persistent form, (3) papular mucinosis of infancy, and (4) a nodular form.2 Unlike scleromyxedema, the localised form of LM is not associated with sclerosis, paraproteinemia, thyroid disease, or other systemic involvement.1 It is important to distinguish between the localised and generalised forms as the management and prognosis differ for each. Recently, Nofal et al3 proposed diagnostic criteria and classification of LM. Their classification differentiated LM into a pure cutaneous subtype, which could have localised or limited skin involvement, including the above papular and nodular variants, or have generalised or extensive skin involvement without systemic manifestations, and a systemic subtype representing scleromyxedema.
    LM has been observed in association with human immunodeficiency virus (HIV), hepatitis C viral (HCV) infection, obesity,4 and exposure to toxic oil or L-tryptophan.2 Reports of cutaneous mucinoses in systemic lupus erythematosus (SLE) are well established.5,6 Cases of LM in other connective tissue diseases (CTDs) are rare.7 We report 2 cases of LM in association with CTD, one in a patient with dermatomyositis (DM) and one associated with rheumatoid arthritis (RA). As well, we review the literature on cutaneous mucinoses and CTDs, excluding the common association of primary and secondary mucinoses with SLE.

    Case 1

    A 55-year-old man was diagnosed with RA 8 months prior to his presentation to dermatology. His RA was well controlled on methotrexate, hydroxychloroquine, and etanercept. He stated that 2 years ago, he developed lesions on the upper arms bilaterally. He was slowly developing new papules, but after his diagnosis of RA, they seemed to be spreading more rapidly and more recently started to involve his inner thighs bilaterally. During the time of more rapid development of lesions, he states that his RA symptoms were poorly controlled. The papules were asymptomatic, and they did not wax or wane. He had not had any treatment for the papular lesions in the past. His only other relevant medical history was of gout. Review of systems was unremarkable.
    Physical exam revealed discrete, skin-colored, 2- to 4-mm, monomorphic, firm papules on the upper extensor arms and inner mid thighs (Figure 1).
    
                        figure
    Figure 1. Left lateral arm showing multiple, discrete, waxy, skin-colored papules.
    Laboratory studies were highly positive for rheumatoid factor and anti–cyclic citrullinated peptide (CCP) antibodies. All other autoantibodies were negative. Serum protein electrophoresis and thyroid levels were normal. HIV and HCV were negative.
    Histopathology analysis showed widely spaced papillary dermal collagen with mild fibroblast proliferation and no sclerosis (Figure 2). Colloidal iron stained strongly, confirming the deposition of mucin.
    
                        figure
    Figure 2. Hematoxylin and eosin stain (×10) showing separation of collagen in the papillary dermis with mild fibroblast proliferation and no sclerosis. Colloidal iron staining positive for mucin (inset).
    The patient was being treated with oral hydroxychloroquine 200 mg twice daily for his RA and had not noticed any improvement of his cutaneous lesions over the past 8 months. Topical clobetasol propionate 0.05% cream was prescribed daily, but no benefit was seen.

    Case 2

    A 59-year-old man with an 8-year history of DM currently in remission presented with a 3-month history of a papular eruption on his chest, neck, and shoulders. He had not been on any medications for his DM for 5 years, and previous treatments included prednisone, methotrexate, and azathioprine. The papules were persistent and asymptomatic. His DM continued to be asymptomatic, and overall review of systems was unremarkable.
    Physical exam revealed numerous white- to skin-colored, dome-shaped, waxy 2-mm papules on the posterior neck, upper chest, and shoulders of a Fitzpatrick skin type V male (Figure 3).
    
                        figure
    Figure 3. Numerous, skin-colored, firm papules on the posterior neck.
    Laboratory studies were positive for SS-A/Ro 60 antibodies, antinuclear antibodies (ANAs) and TIF1ϒ antibodies, but a recent complete malignancy workup was negative. Serum protein electrophoresis revealed a gamma globulin level at the upper limit of normal but no paraproteinemia. Thyroid levels were normal, and he was HIV and HCV negative.
    Histopathology showed a superficial and mid-dermal infiltrate of mucin revealed by strong colloidal iron staining (Figure 4). There was no fibroblast proliferation or increase in collagen. There was a mild perivascular lymphocytic infiltrate within the superficial dermis with a well-demarcated grenz zone with absence of mucin in the papillary dermis.
    
                        figure
    Figure 4. Skin biopsy from the posterior neck at ×10 magnification. Hematoxylin and eosin stain showing separation of collagen in the papillary dermis with no fibroblast proliferation or sclerosis. Colloidal iron staining positive for mucin (inset).
    The patient was treated with oral hydroxychloroquine 200 mg twice daily and topical clobetasol propionate 0.05% cream. There was no improvement in the cutaneous lesions after 9 months.
    Localised LM presents with 4 main clinical forms. The discrete papular form appears as skin-colored, firm papules that can affect any body part but typically affects the limbs and trunk in a symmetrical pattern.2 The acral persistent form affects only the dorsal hands and extensor wrists. Papular mucinosis of infancy, also known as cutaneous mucinosis of infancy, appears as firm, opalescent papules on the upper arms and trunk. There have been no reports of spontaneous resolution with this form.1 Nodular LM typically affects the limbs and trunk with a minimal papular component. In contrast to the other forms of localised LM that deposit mucin in the superficial dermis, mucin is found in the deeper dermis in nodular LM.2 In addition to excess mucin deposition in the dermis, skin biopsy for localised LM will reveal variable fibroblast proliferation but no fibrosis.8
    Mucin is a jelly-like material composed of acid glycosaminoglycans (GAGs) produced in small amounts by fibroblasts. The presence of mucin in the skin is a characteristic finding in lupus and dermatomyositis.9 The aetiology of mucin deposition in connective tissue disorders has yet to be fully elucidated. It has been theorised that circulating autoantibodies and elevated cytokines stimulate the skin fibroblasts into synthesising excess GAGs.10
    Mucin deposition in CTD can be primary (metabolic) or secondary (catabolic).11 It is well documented in lupus, where it most commonly takes the form of papulonodular mucinosis (nodular cutaneous lupus mucinosis) and was reported in 1 series to be found in 1.5% of patients with lupus erythematosus (LE).12Papulonodular mucinosis has been reported in SLE, discoid LE, and subacute cutaneous LE. These cutaneous lesions are usually unrelated to typical skin lesions of lupus and would therefore be considered primary, but it has been debated whether they are in fact caused by the underlying LE and would therefore be considered secondary.13 These cutaneous lesions are different from the common subclinical histologic deposition of mucin found in LE.14
    We define a primary mucinosis associated with a CTD as mucin deposits occurring in normal skin producing clinical lesions and not within skin showing the histologic features of the CTD with accompanying mucin deposition. When mucin deposition occurs in skin that also shows histologic features of the CTD, it is usually subclinical and microscopic only. However, rarely a secondary form of mucin deposition in a CTD can produce macroscopic deposits of mucin leading to clinical lesions.15-18 These clinical mucinoses are still secondary and must be differentiated from a primary mucinosis in a CTD.
    In rheumatoid arthritis, primary cutaneous mucinosis is very rare. There have been only 4 reports of patients with rheumatoid arthritis developing a cutaneous mucinosis (Table 1).19-22 All of the reports were associated with the development of mucinous nodules overlying an affected joint, with 2 cases occurring after an intra-articular joint injection.19,20
    Table
    Table 1. Reported Primary Cutaneous Mucinoses in Association With Connective Tissue Disease.
    Table 1. Reported Primary Cutaneous Mucinoses in Association With Connective Tissue Disease.
    Our patient had mucinous papules that were not only localised over affected joints but also showed the typical morphology and distribution (symmetrical trunk and limbs) of the discrete papular form of localised LM.2 In addition, the development of his lesions preceded his diagnosis of RA, a phenomenon that has been reported in SLE.23 To our knowledge, this is the first case of localised LM of the discrete papular form in a patient with RA.
    Scleromyxedema, the generalised form of lichen myxedematosus, can be associated with numerous systemic symptoms, including RA-like manifestations.2,24 Although these patients can develop destructive erosions, these patients are not classified as having rheumatoid arthritis since they are typically seronegative.25
    Localised lichen myxedematosus of the discrete papular form needs to be differentiated from scleromyxedema type of LM. Scleromyxedema also must be differentiated from cases of progressive systemic sclerosis (PSS) with primary localised LM.26
    Similar to LE, mucin can be seen histologically in microscopic amounts in cutaneous lesions of DM.27However, primary cutaneous mucinoses have been rarely reported in DM.
    There have been 11 reported patients with clinically significant primary cutaneous mucinoses associated with DM unrelated to scleromyxedema (Table 1).10,27-34 One report labeled the case as “lichen myxedematosus,” but based on the facial involvement and current classification, it is most likely scleromyxedema.35 Five of the reported patients fit the criteria, based on the clinical description in the publication, for the discrete papular type of localised LM.10,27,28,31,34 Our patient also fits with this subtype of LM and would represent the sixth reported case of localised LM of the discrete papular type.
    Only 3 of the 11 DM patients were considered paraneoplastic,27,28,32 suggesting that the development of a primary cutaneous mucinosis in DM is unlikely related to an underlying malignancy. However, it is interesting that in 1 of the 3 paraneoplastic cases (nasopharyngeal carcinoma), the skin lesions resolved 2 months after treatment of the malignancy.32
    Reports of papular and nodular mucinosis in PSS are very rare.26 There have been 3 cases of PSS with an associated cutaneous mucinosis. All cases were clinically consistent with LM.16,17,26 However, only 1 report26 is a true case of a primary mucinosis (papular and nodular mucinosis) with PSS. The other 2 cases16,17 resembled LM but actually represented macroscopic deposits of mucin within areas of sclerosis. This differentiates these cases from primary LM associated with PSS in which the mucin deposits would occur only in nonsclerodermatous skin. As in LE and DM, microscopic amounts of mucin have been reported in skin lesions of progressive systemic sclerosis.18
    There have been 2 cases of LM associated with mixed connective tissue disease (MCTD).7
    The discrete papular form of LM is limited to the skin and has little or no morbidity.1 The usual recommendation is to treat conservatively by monitoring for changes and advising the patient that spontaneous resolution is unlikely, although it has been reported.1 Treatment can be considered if the lesions are pruritic or in cosmetically sensitive areas. Due to the rarity of this condition, there is no strong evidence regarding treatment options.
    Topical and intralesional steroids have been trialed with variable results.36 Both of our patients did not respond to topical corticosteroids. Topical pimecrolimus relieved the pruritus in 1 patient, but the lesions showed no improvement.36 Topical tacrolimus 0.1% applied twice daily cleared the lesions of 2 patients in 1 and 3 months, respectively.37 Two patients, both with no CTD, have seen improvement with intralesional steroid injections in combination with fluandrenolide-impregnated tape and carbon dioxide laser, respectively.38,39 Improvement with the use of electrocoagulation has also been reported.40 Hyaluronidase injection was successful in decreasing the lesion size in 1 case.41
    Oral corticosteroids for the discrete papular type of LM have been tried alone and in combination with other medications. Two patients with DM improved or cleared with oral corticosteroids alone.10,34 Two other patients with DM received corticosteroids in combination with hydroxychloroquine, methotrexate, and azathioprine of varying doses but did not exhibit any benefit to their cutaneous lesions.27,31 The additional systemic medications in these 2 cases were added for DM control and not the cutaneous lesions.
    In 2 patients with MCTD, there was an improvement in cutaneous lesions with an increase of azathioprine to 2 mg/kg/d in 1 patient and the addition of chloroquine 250 mg/d with an increase in prednisone to 20 mg/d in the other patient.7 Oral isotretinoin was effective in a patient with HIV,42 and oral thyroxine reportedly failed in a patient.36 In patients with SLE, antimalarials have been reported to help, especially in conjunction with systemic corticosteroids.43 The use of extracorporeal photopheresis has been theorised to help suppress mucin production of pathogenic B-cell clones.44
    The development of clinically significant cutaneous mucinosis is known to occur in SLE. Although rare in other CTDs, it can be associated with RA, dermatomyositis, systemic sclerosis, and mixed connective tissue disease. Finding effective treatment of primary cutaneous mucinoses associated with CTDs remains a therapeutic challenge.
    Declaration of Conflicting Interests
    The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
    Funding
    The author(s) received no financial support for the research, authorship, and/or publication of this article.
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