Are You Confident of the Diagnosis?
Cutaneous lupus mucinosis (CLM), or papulonodular mucinosis, is a rare variant of cutaneous lupus erythematosus (CLE) characterized by an abundance of dermal mucin resulting in papular lesions. It occurs in approximately 1.5% of patients with lupus erythematosus.
Secondary mucin deposition can be seen, usually histologically, in more classic lupus erythematosus skin lesions and other connective tissue diseases, such as dermatomyositis and scleroderma. However, the great quantity of mucin required to produce clinical lesions in CLM is not seen in these other instances. CLM occurs more commonly in patients with established systemic lupus erythematosus, but it can also be a presenting feature of the disease. It is rarely seen in cutaneous lupus erythematosus-limited patients.
Characteristic findings on physical examination
Clinically, patients present with asymptomatic skin colored, dome-shaped papules or nodules, most commonly on the trunk and upper extremities (Figure 1). Plaque-like lesions (Figure 2) have been described, as well as lesions with overlying scale and erythema. These lesions heal without scarring. Ultraviolet light is presumed to play a role in aggravating lesions.
Expected results of diagnostic studies
Histopathology reveals, typically, normal epiderms with splaying of collagen throughout the papillary and mid dermis. With alcian blue or colloidal iron staining, abundant mucin is seen within the dermis (Figure 3). There is also a sparse perivascular lymphocytic infiltrate. Thus, the typical findings of cutaneous lupus erythematosus lesions are usually absent. Direct immunoflourescence of lesional skin shows linear or granular deposition of IgG, IgM and C3 at the dermoepidermal junction.
Confusion with other diffuse or disseminated papulonodular lesions is not uncommon, such as lichen myxedematosus, generalized or pretibial myxedema, reticular erythematosus mucinosis, cutaneous focal mucinosis, papular granuloma annulare, xanthomas, eruptive histiocytomas, and possibly sarcoidosis. Clinical history, examnination, laboratory work and sometimes histopathology will help differentiate between these diagnoses.
Lichen myxedematosus has a similar histopathologic presentation, but clinically the two conditions differ. In lichen myxedematosus, the lesions are smaller, grouped and favor the face and arms.Patients with cutaneous focal mucinosis may also have similar histopathology findings, but do not have laboratory abnormalies (eg, antinuclear antibody [ANA] positivity) or systemic symptoms of disease. In terms of laboratory findings, the majority of patients with CLM have ANA positivity with speckled pattern, leukopenia, hypocomplementemia, and microscopic hematuria and proteinuria.
Who is at Risk for Developing this Disease?
As is the case with most autoimmune diseases, CLM is more common in woman, with an age of onset ranging from 20-60 years old. Most cases occur between the ages of 30 to 40. However, compared to systemic lupus erythematosus (SLE) and CLE, CLM occurs often in men. It has been proposed that as many as 30% of cases are males. Patients with SLE are at risk of developing CLM, particularly those with lupus nephritis and arthritis.
What is the Cause of the Disease?
Cutaneous lupus erythematosus, including CLM, is an autoimmune disease felt to be due to an interplay of genetics, hormones, and environment. Specifically, CLM is due to fibroblasts’ increased production of glycosaminoglycans when compared to normal fibroblasts. However, the trigger for fibroblast production is unknown. Several theories have been proposed. Given the predominance of males affected compared to other CLE lesions, androgens may be related. Additionally, skin lesions were found to flare when antibody titers increased, suggesting serum factors may possibly stimulate fibroblast production. While the serum factors have not been identified, but IL-1 and IL-6 cytokines have been implicated.
In general, genes encoding for cytokines, cytokine receptors, adhesion molecules and apoptosis genes are felt to contribute to the development of lupus erythematosus. In terms of environment, the most well-known environmental trigger of SLE and most CLE lesions is ultraviolet light. However, the role of ultraviolet (UV) light in CLM development is not clear. Nevertheless, UV light induced pro-inflammatory cytokines, chemokines, and adhesion molecules leads to tissue injury. UVB, UVA and visible light can all contribute to induction of CLE skin lesions. Trauma or Koebnerization may also play a role in CLE development through pro-inflammatory factors.
Autoantibodies are a hallmark of autoimmune diseases. There are no associated autoantibodies associated with CLM. However, the majority of patients with CLM has SLE and are ANA positive.
Overall, this complex inflammatory cascade between necrosis, apoptosis, autoantibodies, T and B cells, and vascular changes leads to the development of cutaneous lupus erythematosus. However, a complete understanding of the pathophysiology of CLE is unknown.
Systemic Implications and Complications
Cutaneous lupus mucinosis is closely associated with concomitant SLE. It is important to screen for underlying SLE, using clinical history, physical examination, and laboratory evaluation to assess for central nervous system, renal, hematologic, pulmonary and cardiovascular systemic involvement in all patients newly presenting with CLM.
Laboratory studies to evaluate for SLE are warranted, and may include ANA, anti-dsDNA, anti-Smith, complete blood count (CBC) with differential, platelets, creatinine, albumin, total protein, erythroctye sedimentation rate, urinalysis, and complements (C3,C4). Specifically, lupus nephritis and arthritis is seen in over half of the cases with CLM. A high index of suspicion must be used when evaluating for renal involvement in this patient population. Findings of normal creatinine, but hematuria or proteinuria may warrant renal biopsy.
Treatment options for CLM are summarized iin the Table I.
|Sun avoidance and broad|
|spectrum ,UVA and UVB,|
|Topical (for overlying DLE)|
|Topical steroids, Class I or II (lower strength on face)|
|Topical calcineurin inhibitors with or without topical steroid|
|Tacrolimus 0.1% ointment|
|Pimecrolius 1% cream|
|Intralesional triamcinolone 3-5mg|
|Hydroxychloroquine 6.0-6.5mg/kg ideal body weight (IBW)|
|Hydroxychloroquine + quinacrine 100mg daily|
|Chloroquine <3.5mg/kg IBW +/- quinacrine 100mg daily|
|Mycophenolate Mofetil 2-3gm/day|
|Azathioprine 2 mg/kg/day|
Optimal Therapeutic Approach for this Disease
The treatment goal for CLM is resolution of the papulonodular lesions and to control the underlying SLE disease.
Sun avoidance and protection with the use of broad spectrum sunscreen that covers both UVA and UVB ranges should be discussed with all patients with CLE, including those with CLM. Although the exact role of UV light in the pathogenesis of CLM is not clear, we do know that UV light plays a role in many other CLE conditions and SLE, which may also be present.
Cigarette smokers are found to have more severe CLE disease. Antimalarials may be less effective in those patients that smoke. As a result, all patients with CLE should begin a smoking cessation program.
Topical therapy can be used in combination with systemic therapies. The effectiveness of topical steroids and calcineurin inhibitors in CLM are not known. However, for limited, focal disease, it can be used for 2 months as a trial.Combining topical steroids and calcineurin inhibitors may provide an added benefit. Intralesional kenalog has not been studied, but can be attempted at dosages of 3-5mg/m for plaque-like lesions.
Antimalarials are recommended as first-line systemic therapy for cutaneous and systemic lupus erythematosus given its effectiveness in prevention and treatment of symptoms, such as photosensitivity, acute malar rash, discoid lupus erythematosus (DLE), oral ulcers, alopecia, arthritis, pleuritis, and pericarditis.CLM is somewhat responsive to antimalarials.
Hydroxychloroquine is the treatment of choice over chloroquine given its lower ocular toxicity risk. Typically, hydroxychloroquine is started at 200-400mg a day. To avoid ocular toxicity, the daily dose should not exceed 6.5mg/kg ideal body weight per day. Antimalarials take 2-3 months for improvement to be noticed and up to 6 months for a complete response. After 8-12 weeks, if improvement is not satisfactory, addition of quinacrine 100mg daily may be added. Quinacrine can only be obtained at compounding pharmacies. It may cause yellow discoloration of the skin.
If the combination of hydroxychloroquine and quinacrine has not provided complete response after 6 months, changing to chloroquine plus quinacrine is an option.Chloroquine is typically started at a dose of 250mg 5-7 days a week and should not exceed 3.5mg/kg ideal body weight per day. The lowest possible effective dose should be used for maintenance therapy. Antimalarials may be used safely for long periods of time.
The recommended doses listed in the Table I above are based on the maximal safe dose from an ocular safety perspective. The retinopathy associated with antimalarials (chloroquine) is often irreversible. The blurred vision and corneal deposition that may occur is reversible. The use of hydroxychloroquine necessitates eye exams every 6 months and with chloroquine every 4 months. The eye exam should include visual acuity, visual fields, and fundoscopic exam.
Patients with a history of retinopathy should not get hydroxychloroquine or chloroquine. Patients who get a drug exanthem with hydroxychloroquine may be able to tolerate chloroquine, while an urticarial reaction from hydroxychloroquine would preclude use of chloroquine. Other side effects include nausea, headaches, myopathy, and bluish-gray hyperpigmentation of the skin.
In addition to a baseline eye exam, a complete blood count and liver function test is recommended at baseline and after 1 month of use.
The vast majority of CLM lesions respond to antimalarials together with oral and topical steroids. If antimalarials are not effective, second-line systemic therapy with an oral steroid or an immunosuppressive may be required. Specifically, patients with refractory and widespread CLM lesions, or concomitant SLE symptoms, may benefit from these steroid-sparing immunosuppressants. In some instances these immunosuppressants are initially used in combination with prednisone. Once the medication takes effect, the goal is to taper off the prednisone.
Unlike treatments for the other subsets of CLE, prednisone is commonly used early in the disease presentation of CLM together with hydroxychloroquine. The reason is that these lesions tend not to be as chronic and recurrent as many of the other CLE lesions. Furthermore, given that SLE is often associated with CLM, prednisone plays a more active role in the therapeutic ladder.
CLM lesions tend to resolve completely in 2-3 months with the combination of antimalarials and prednisone. At that time, the corticosteriod should be tapered and the antimalarial(s) may be used as maintenance therapy. Typically, prednisone has been used in CLM at dosages of 0.5mg/kg/day to 0.75 mg/kg/day.
The well-known side effects of prednisone include weight gain, fluid retention, psychiatric disturbances, hypertension, and hyperglycemia. Osteoporosis, myopathy and Cushingoid changes are additional adverse reactions that can be avoided with short therapeutic courses. Of note, avascular necrosis can occur during short courses of prednisone therapy.
The degree and extent of bone loss is most closely related to cumulative corticosteroid dose. The most rapid rate of bone loss is during the first 3 to 6 month of therapy. All patients starting gluocorticoids at any dose with an anticipated duration of at least 3 months or longer should start calcium 1200-1500mg/day and vitamin D 800-1000 International Units/day supplementation. These patients should also be counseled on smoking cessation and weight-bearing activities. Additionally, they should be assessed for fall risk, baseline height, and history of fragility/fractures. A baseline bone mineral density scan, or radiographic imaging of the spine or vertebral fracture assessment may be done, particuarly in postmenopausal woman.
In childbearing age woman, the useof bisphosphonates is only considered for those woman with a history of fragility fractures given the unknown risk of long-term bisphosphonate use and risk to the fetus. However, postmenopausal woman are recommended to begin a bisophosphonate, such as alendronate orrisedronate, if the corticosteroid dose is greater than 5mg and the anticipated length of treatment is at least 3 months.
In severe cases that recur after cessation of prednisone or in those that have concomitant SLE symptoms, a steroid-sparing immunosuppressive agent should be initiated. In most instances, limited or no data exists for their use in cutaneous lupus mucinosis.
Methotrexate (MTX) in lupus erythematosus can be used in doses of 5-25mg weekly. MTX typically takes 3-4 weeks for clinical improvement. A typical test dose is 5mg, and then increase 5mg weekly to the dose needed to control symptoms. The lowest possible maintenance dose needed to control disease should be used. Doses as low as 5mg a week have been successfully used to maintain clinical remission.
A potential for hepatotoxicity with long-term use and pulmonary toxicity is an important consideration. Patients who drink alcohol should not receive methotrexate, and underlying viral hepatitis, obesity and diabetes are associated with an increased risk of hepatotoxicity, including liver fibrosis. Bone marrow suppression is a severe adverse reaction. Risk factors for this side effect include drug interactions (TMP/SMX and NSAIDS), renal insufficiency, older age (>65) and no folate supplementation. Frequent CBCs are important to monitor for this adverse reaction and all patients should be on folate supplementation.
Baseline laboratory tests should include CBC, complete metabolic panel (liver and renal function), hepatitis B and C serologies, and HIV testing. After the first dose of methotrexate, a CBC and liver function labs should be done in 1 week. If labs are normal, repeat testing of CBC and liver function, every week as the dose is increased and then monthly thereafter for 3 months is warranted. After a year of a stable dose with no serious toxicity, blood monitoring can decrease to every 3 months. Renal function can be evaluated once a year, or sooner if renal dysfunction is suspected. Weekly intramuscular injections may improve gastrointestinal (GI) intolerance due to oral methotrexate.
Mycophenolate mofetil (MMF) is well tolerated and has been shown to be effective in CLE and SLE. The most common adverse reaction from this therapeutic is gastrointestinal (GI) side effectes, including nausea, vomiting, diarrhea, and abdominal cramps. These symptoms are typically dose-dependent and may be avoided by starting at a lower dose. In patients with GI side effects, one can start with 500mg once or twice a day and then titrate dose up, per tolerability every 2-4 weeks to goal dose of 2-3gm/day. As with any immunosuppressant, MMF can increase the risk of infections. Less common side effects include myelosuppression and transaminitis. MMF typically takes approximately 4 weeks to take effect.
Baseline laboratory tests include CBC with differential and liver function tests. Labs whould be checked 2 weeks after starting therapy, and 2 weeks after increases in dose. Monthly CBC and liver function tests for the first year, then every 3 months, is recommended. Maintenance dosage of 1.5-3gm a day can be used safely.
Azathioprine is an immunosuppressant that has been extensively studied in lupus erythematosus as a steroid-sparing agent. An initial dose of 50mg a day is suggested to determine acute toxicity/sensitivity. The dose can be increased by 25mg every 2 weeks with a goal of achieving a range between 2-3mg/kg/day. In CLE, azathioprine doses of 100-150mg are commonly needed to achieve desired effects. Clinical effects are typically seen in 4-8 weeks. The maintenance dose can range from 50-150mg daily and may be continued for years.
Side effects include gastrointestinal symptoms of nausea, vomiting and abdominal cramping. Pancreatitis and hepatotoxicity have also been reported. Hypersensitivity reaction, aseptic meningitis and increased cancer risk are also known adverse reactions. Flu-like symptoms may occur within the first 2 weeks of use.
Prior to the use of azathioprine, a thiopurine methyltransferase (TPMT) enzyme level can be done, particularly if doses above 50mg a day are used initially. Low levels increase the risk of myelosuppression and potentially fatal neutropenia. A CBC and liver function tests should be performed every 2 weeks while the dose is being adjusted, then every month for the first year, and then every 3 months.
All patients newly diagnosed with CLE should be counseled on the specific disease course. The risk of scarring and disfigurement is rare with CLM lesions. The vast majority of patients with CLE have disease that primarily affects the skin. However, that is not the case with CLM, as the majority of patient have concomitant SLE. Both the physician and patient should monitor for signs and symptoms, if a diagnosis of SLE has not yet been made.
The next step is to provide patients with therapeutic modalities that minimize disease progression and improve treatment response. All patients must be counseled on sun avoidance and protection, including avoidance of artifical tanning beds and photosensitizing medications. On a similar note, the role of smoking in disease severity must be stressed at the initial visit. All patients should be encouraged to stop smoking and should begin a smoking cessation program.
Mainstay therapies for the majority of patients with CLM include topical therapies and antimalarials. Both of these therapies have limited severe adverse reactions. However, patients with widespread disease or concomitant SLE must begin therapies that carry higher side effect risks. It is important to discuss all side effects and monitoring guidelines prior to initiating therapy.
After antimalarials, there is no one agent that is superior in the treatment of CLM lesions. Thus, when ascending the therapeutic ladder, individualizing therapy for each patient based on their co-morbidities is necessary. Furthermore, after clearance of CLM lesions, therapies should be reduced to the lowest effective dose, or discontinued.
Unusual Clinical Scenarios to Consider in Patient Management
Reticular erythematosus mucinosis (REM), or plaque-like cutaneous mucinosis is a photoaggravated dermatosis that is associated with many autoimmune diseases including lupus erythematosus. Clinically, the central part of the chest and back has pink reticulate erythema. Histopathology typically shows perivascular, and sometimes perifollicular, lymphocytic infiltrate, dilated vessels and increased dermal mucin deposition. Direct immunofluorescence may be normal, or can show IgG and C3 granular deposition.
REM and lupus erythematosus do share many similar features, such as photosensitivity, mucin deposition, perivascular and perifollicular lymphocytic infiltrate and occasionally each has a positive direct immunofluorescence. In patients with a positive ANA and other signs of lupus erythematosus, REM can be considered a presentation of lupus erythematosus. In such cases, it is considered a variant of tumid lupus. However, REM falls within the spectrum of cutaneous mucinoses, thus it is included in this section for discussion.
There is little evidence regarding therapy of cutaneous mucinosis during pregnancy. Typically,patients with active SLE and mild disease are managed during pregnancy with oral corticosteroids. If the disease is more severe, treatment with corticosteroids, azathioprine, cyclosporine and intravenous gammaglobulin may be used. At this time, there is not enough safety information on the use of mycophenolate mofetil in pregnancy. Hydroxychloroquine has evidence for its safety and efficacy during pregnancy; however, it is still considered a class C drug by the Food and Drug Administration.
What is the Evidence?
Shekari, AM, Ghiasi, M, Ghasemi, E, Asadi Kani, Z. “Papulonodular mucinosis indicating systemic lupus erythematosus”. Clin Exper Dermatol. vol. 34. 2009. pp. e558-60. (A case of an 18-year–old female who presented with cutaneous papulonodular mucinosis as her first sign of systemic lupus erythematosus.)
Pandya, AG, Sontheimer, RD, Cockerell, CL. “Papulonodular mucinosis associated with systemic lupus erythematosus. Possible mechanism of increased glycoaminoglycan (GAG) accumulation”. J Am Acad Dermatol. vol. 32. 1995. pp. 199-205. (This study used skin fibroblasts from a patient with LE and papulonodular mucinosis, as well as normal fibroblasts to determine if the production of glycoasminoglycans differed. They found that skin fibroblasts from the patient with LE and papulonodular mucinosis produced more GAG than did normal fibroblasts. Also, when the affected patients serum was used to incubate their own fibroblasts and normal fibroblasts, both produced elevated amounts of GAGs.)
Kanda, N, Tsuchida, T, Watanabe, T. “Cutaneous lupus mucinosis: a review of our cases and possible pathogenesis”. J Cutan Pathol. vol. 24. 1997. pp. 553-8. (Five cases of CLM were reveiwed for clinical and histologic features. Based on these findings the authors proposed that male gender, SLE and vasculopathy may all play a role in the development of CLM.)
Del Pozo, J, Pena, C, Almagro, M. “Systemic lupus erythematosus presenting with a reticular erythematosus mucinosis-like condition”. Lupus. vol. 9. 2000. pp. 144-6. (A case report of a woman presenting with features of reticular erythematosus mucinosis syndrome that eventually developed SLE 6 years later. Thus, SLE may present with an REM-like condition.)
Lowe, L, Rapini, RP, Golitz, LE, Johnson, TM. “Papulonodular dermal mucinosis in lupus erythematosus”. J Am Acad Dermatol. vol. 27. 1992. pp. 312-15. (Two cases of lupus erythematosus in an atypical truncal distribution are discussed.)
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