Are You Confident of the Diagnosis?
Characteristic findings on physical examination
Lupus erythematosus panniculitis (LEP) is characterized by chronic and recurrent subcutaneous inflammatory lesions and is considered a form of chronic cutaneous lupus erythematosus (CLE). Clinically, LEP appears as erythematous, deeply indurated, tender plaques and nodules. The overlying epidermis is typically normal, but over time it attaches to the deeper component and can appear bound down with associated deep depressions (Figure 1). In such cases, LEP can be confused with morphea or lipoatrophy.
Occasionally, lesions drain and ulcerate, leading to scarring. The proximal extremities, trunk, face, and scalp are most commonly involved.
Features of discoid lupus erythematosus (DLE) can overlie the indurated plaque or nodule. In such cases, erythema, scale, and follicular plugging are seen in association with tender, indurated plaques or nodules. Overall, the atrophy and scarring produced by lupus panniculitis or lupus profundus can cause significant cosmetic disfigurement. A large majority of patients with LEP have coexisting, independent DLE lesions.
Expected results of diagnostic studies
The differential diagnosis includes other forms of panniculitis: factitial panniculitis, traumatic panniculitis, morphea profundus, dermatomyositis and subcutaneous panniculitis-like T cell lymphoma. To confirm a diagnosis of LEP, a deep punch biopsy or incisional biopsy is indicated to assure ample subcutaneous tissue is obtained.
Histopathologic findings include a lobular lymphocytic panniculitis with hyaline degeneration of fat and lymphoid nodular structures in the deep dermis and subcutaneous fat. Lupus profundus/panniculitis can demonstrate overlying DLE histopathologic findings of hyperkeratosis, hydropic degeneration of the basal layer, perivascular and periappendageal lymphocytic infiltrate and increased mucin deposition (Figure 2).
The most important differential diagnosis to rule out is subcutaneous panniculitis-like T cell lymphoma. In this case, atypical lymphocytes may be seen rimming adipocytes and erythrophagocytosis may be present. The infiltrate is predominantly CD8 positive, CD5 and CD7 negative, or may label strongly for CD56 or CD30. Unfortunately, many of these features may be seen in LEP and thus close clinical follow-up and repeat biopsy may be necessary in patients that develop constitutional symptoms or are not responding to typical LEP treatments.
Histopathology of traumatic and factitial panniculitides often demonstrates foreign material with polarization. Morphea and dermatomyositis histopathology can closely resemble LEP; thus clinical and laboratory data must be used to help differentiate between these entities.
A positive antinuclear antibody (ANA) test is commonly seen in patients with LEP. Leukopenia, hypocomplementemia, positive rheumatoid factor and elevated erythrocyte sedimentation rate (ESR) can be seen, particularly in those with concomitant systemic lupus erythematosus (SLE).
Who is at Risk for Developing this Disease?
LEP is more common in women and has a female to male ratio of 4.5:1. The age of onset ranges from 20 to 60 years, and the mean age is 36 years. The frequency of occurrence of lupus erythematosus panniculitis in SLE is approximately 1% to 3%.
What is the Cause of the Disease?
CLE, including lupus panniculitis, is an autoimmune disease felt to be due to the interplay of genetics, hormones and environment. Given that lupus is more common in women of childbearing age, estrogen is felt to be a cause. In terms of genetics, genes encoding cytokines, cytokine receptors, adhesion molecules and apoptosis genes are felt to contribute to the development of lupus erythematosus.
Inherited deficiencies of complement also play a role in the risk of CLE development. Specifically, C4 deficiencies are seen in patients with LE profundus. The most well known environmental trigger of SLE and most CLE lesions is ultraviolet (UV) light. UV light induces pro-inflammatory cytokines, chemokines and adhesion molecules that eventually lead to tissue injury. Both UVB and/or UVA can contribute to induction of skin lesions. Trauma or koebnerization can also play a role in CLE development through pro-inflammatory factors. LEP may be precipitated or aggravated by trauma, but the role of UV light in the pathogenesis is unclear.
ANA titers tend to be low or nonexistent in patients with LEP. Skin direct immunofluorescence testing can detect deposition of immunoglobulins and complement at the dermal-epidermal junction in patients with LEP who have overlying DLE. The role of these antibodies in the local induction of clinical lesions is unknown.
Overall, this complex inflammatory cascade between necrosis, apoptosis, autoantibodies, T and B cells, and vascular changes leads to the development of CLE. However, a complete understanding of the pathophysiology of CLE and LEP is unknown.
Systemic Implications and Complications
Screening for underlying SLE with clinical history, physical examination and laboratory evaluation to assess for central nervous system, renal, hematologic, pulmonary and cardiovascular system involvement is warranted in all patients newly presenting with CLE, including LEP.
An initial ANA, complete blood count (CBC) and urinalysis is sufficient for those patients without other symptoms. Given that an ANA assay has a 99% negative predictive value, it is rare for a patient with SLE to have a negative ANA. This is also a more cost-effective way to use specific autoantibody tests. If the ANA is elevated (> 1:160) or a patient has symptoms suggestive of systemic lupus, further testing is warranted. These may include anti-dsDNA, anti-Smith, CBC with differential, creatinine, albumin, total protein, ESR, urinalysis, and complement (C3, C4).
Approximately 10% to 50% of patients with LEP will eventually develop SLE; however, the systemic disease tends to be mild. For instance, severe lupus nephritis is uncommon in this subset of patients. Follow-up visits should be used to evaluate for new signs or symptoms that suggest progression to SLE.
Table I. Medical treatment options
|Sun protection and avoidance Broad spectrum, UVA and UVB, sunscreen protectionSmoking cessation Topical (for overlying DLE)Topical steroid, class I or II (may use lower strength on face)Topical calcineurin inhibitors with or without topical steroid Tacrolimus 0.1% ointment Pimecrolimus 1% cream SystemicAntimalarials: Hydroxychloroquine 6.0 to 6.5mg/kg/day ideal body weight (IBW) Hydroxychloroquine + quinacrine 100mg daily Chloroquine < 3.5mg/kg/day IBW +/- quinacrine 100mg dailyThalidomide 50 to 100mg/dayDapsone 50 to150mg/dayPrednisone 0.5 to 0.75mg/kg/dayMethotrexate 5 to 25mg/weekMycophenolate mofetil 2 to 3g/dayAzathioprine 1 to 2.5 mg/kg/dayCyclosporine 2 to 5mg/kg/dayIVIG 0.4g/kg/day x 5 days monthly|
Optimal Therapeutic Approach for this Disease
The treatment goal of LEP is to decrease inflammation to avoid scarring and disfigurement. Treatment response should be based on improvement in active inflammation, as atrophy, depressions and scarring will not be affected by therapy. Treatment options are summarized in the Table I.
Sun avoidance and protection with the use of broad spectrum sunscreen that covers both the UVA and UVB ranges should be discussed with all patients with lupus panniculitis. Although the exact role of UV in the pathogenesis of lupus panniculitis is not clear, we do know that UV light does play a role in other CLE lesions and SLE. The use of broad spectrum sunscreens to cover the UVB and UVA spectrum is necessary and ideally includes sunscreens with helioplex, mexoryl or physical blockers (titanium dioxide, zinc oxide). An SPF of at least 30 is necessary for daily use.
Cigarette smokers are found to have more severe CLE disease. Antimalarials may be less effective in those patients who smoke. As a result, all patients with CLE should begin a smoking cessation program.
Topical therapy is reserved for patients with overlying DLE. Given the deep inflammatory nature of LEP, topical therapy is not effective in this condition. As with DLE, topical steroids can be initiated first with or without calcineurin inhibitors. The effectiveness of topical calcineurin inhibitors alone has been shown to be as effective as class I topical steroids with a decreased risk of telangiectasia development.
Thus, in areas such as the face, the use of topical calcineurin inhibitors is an effective and safe choice. Combining topical steroids and calcineurin inhibitors may provide an added benefit. Of note, intralesional triamcinolone is not recommended given the concern that the trauma of the needle may induce lesion break down and ulceration within existing lesions.
Antimalarials are recommended as first-line systemic therapy for CLE and SLE, given their effectiveness in preventing and treating symptoms such as photosensitivity, acute malar rash, DLE, oral ulcers, alopecia, arthritis, pleuritis, and pericarditis. Lupus panniculitis can be effectively treated with antimalarials.
Hydroxychloroquine is the treatment of choice over chloroquine given its lower ocular toxicity risk. Typically, hydroxychloroquine is started at 200mg to 400mg a day. To avoid ocular toxicity, the daily dose should not exceed 6.5mg/kg ideal body weight per day.
Ideal body weight is calculated as follows: 45.5kg (use 50kg for males) + 2.3 kg for each inch over 5 feet; or 45.5kg + 2.3kg * (height [inches]-60).
Antimalarials take 2 to 3 months for improvement to be noticed and up to 6 months for a intravenous immunoglobulin (IVIG) response. After 8 to 12 weeks, if improvement is not satisfactory, 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 have not provided complete response after 2 to 3 months, changing to chloroquine and quinacrine is an option. Chloroquine is typically started at a dose of 250mg 5 to 7 days a week, with a dose that does 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 are based on the maximal safe dose from an ocular safety perspective. The retinopathy associated with chloroquine is often irreversible. The blurred vision and corneal deposition that may occur is reversible. The use of hydroxychloroquine necessitates eye examinations every 6 months and with chloroquine every 4 months. The eye examination should include visual acuity, visual fields, and fundoscopic examination. 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 examination, a CBC and liver function test is recommended at baseline and after 1 month of use.
Severe or progressive lupus panniculitis that does not respond to combination antimalarials or concomitant SLE symptoms may benefit from steroid-sparing immunosuppressants. However, limited or no data exist for their use in lupus panniculitis.
If antimalarials are ineffective, thalidomide can be used as a second-line agent together with antimalarials. Thalidomide is also an option for patients who are unable to tolerate antimalarials. Thalidomide produces relatively rapid improvement, as soon as 2 to 3 weeks, and clinical remission is typically achieved within 8 weeks. Up to 90% of patients respond to thalidomide therapy. A starting dose of 50mg nightly of thalidomide is recommended and may be increased to normally 100mg at night over 6 to 8 weeks for peak effect, assuming tolerable side effects.
Thalidomide dose can often be decreased once CLE lesions are improved. The dose of thalidomide can be decreased to 50mg per day and then 50mg every 2 or 3 days as maintenance if continued therapy is needed. Thalidomide can also be used in short courses for disease flare in patients on maintenance antimalarials. Of note, thalidomide is effective for CLE and associated arthralgias, but has little effect on the visceral symptoms associated with SLE.
Thalidomide is known to be efficacious in CLE, but its utility in clinical practice is limited by its toxicities. The most common side effects of thalidomide are dose-related sedation, headaches, and amenorrhea. Severe side effects include teratogenicity, reversible sensory neuropathy and venous thromboembolic events. Sensory neuropathy can present with tingling or numbness in the distal extremities but can also be clinically asymptomatic but have abnormal sensory nerve action potentials. The dose can be decreased or discontinued if symptoms are severe.
To prevent birth defects, physicians are required to enroll in the System for Thalidomide Education and Prescribing Safety (STEPS) program. Only a month’s supply may be given at a time. To decrease the risk of deep vein thrombosis, the use of an antimalarial or aspirin is recommended.
In cases refractory to antimalarials, dapsone may be an adjunctive treatment in CLE at dosages of 25 to 150 mg daily. Bullous SLE, SCLE and oral ulcerations have been shown to benefit the most from dapsone therapy. A starting dose of 50mg can be increased by 25mg weekly to 150mg a day if laboratory tests permit. Maintenance doses as low as 50mg may be used once disease is stable.
Severe adverse effects are related to hematotoxicity and can be seen as hemolytic anemia and/or methemoglobinemia. Both are dose dependent and occur, to some degree, in all patients that take dapsone. A glucose-6-phosphate dehydrogenase (G6PD) level should be tested in all patients being considered for dapsone, as the risk of hemolytic anemia is significantly increased if there is a deficiency. Peripheral motor neuropathy can be observed and typically resolves completely after dose reduction or drug discontinuation.
Agranulocytosis is a serious, idiosyncratic adverse effect of dapsone. Patients normally will experience a 2g/dL drop in hemoglobin, but greater drops, or drops below 10g/dL necessitate an adjustment of dose. Patients may experience a clinically unimportant drop in their 02 saturation, which is not routinely monitored.
Baseline laboratory tests include CBC with differential, complete metabolic panel (liver function tests and renal function), urinalysis and G6PD level. During each visit assess peripheral motor neuropathy, CBC with differential (every 1 week while the dose is being increased, then monthly for 3 months, then every 3 months), and complete metabolic panel (every 3 months).
Given the chronic and recurrent nature of CLE, including LEP, use of steroids should be avoided. Use in cases of severe widespread disease, while awaiting antimalarials or other less toxic therapies to take effect, is reasonable.
Typically, prednisone has been used in severe LEP at dosages of 0.5mg/kg/day to 0.75mg/kg/day in combination with antimalarials, or with other anti-inflammatory or immunosuppressive agents discussed above. Prednisone should not be used alone, as lesions recur once prednisone is stopped. Tapering prednisone as tolerated once the CLE lesions are stable is recommended.
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, osteonecrosis can occur during short courses of therapy.
Methotrexate (MTX) in lupus erythematosus can be used in doses of 5 to 25mg weekly. MTX typically takes 3 to 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. A dose as low as 5mg a week has been successfully used to maintain clinical remission.
A potential for hepatotoxicity with long-term use and pulmonary toxicity are important considerations. 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 MTX, a CBC and liver function laboratories should be done in 1 week. If laboratories 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 MTX.
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 agent is GI side effects, 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 to 4 weeks to goal dose of 2 to 3g/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. Laboratories would 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, are recommended. Maintenance doses of 1.5 to 3g 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 to 3mg/kg/day. In CLE, azathioprine doses of 100 to 150mg are commonly needed to achieve desired effects. Clinical effects are typically seen in 4 to 8 weeks. The maintenance dose can range from 50 to 150mg daily and may be continued for years.
Side effects include GI symptoms of nausea, vomiting and abdominal cramping. Pancreatitis and hepatotoxicity have also been reported. Hypersensitivity reactions, 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 performed, 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.
Cyclosporine has been used successfully in refractory cases of LEP and has the advantage of a fast onset of action. It also can be used during pregnancy. Starting doses of 3mg/kg/day are recommended and may be increased to 5mg/kg/day to achieve clinical remission. Cyclosporine is used to induce remission and is not intended as a long-term therapy. Given the severe cosmetic disfigurement that can result from widespread LEP, cyclosporine offers the advantage of rapid improvement in inflammation, allowing for a decrease in subsequent scarring and atrophy, especially in cosmetically sensitive areas.
Thus, a potential role for cyclosporine is to induce remission in widespread, severe LEP. Improvement in disease activity has been reported within 2 to 3 weeks, and disease remission may be achieved within 4 to 8 weeks of drug initiation. At this time, transitioning to another, less toxic, steroid-sparing agent is warranted. Ideally, short-term use of cyclosporine is for 3 to 6 months.
Cyclosporine has several severe adverse reactions including nephrotoxicity, hypertension, and neurotoxicity. Other side effects include hypertrichosis, paresthesias, GI symptoms, and gingival hyperplasia.
Baseline laboratory tests include renal function, CBC, liver function, fasting lipid profile, magnesium and potassium. Renal function, CBC and liver function tests should be assessed every 2 weeks for the first month, then monthly therafter. A blood pressure measurement should be taken at each visit.
IVIG has been shown in a few case reports to provide rapid improvement (within 2 to 3 weeks) in lupus panniculitis in patients with underlying SLE. Doses of 1g/kg/day for 2 days and 0.4g/kg/day for 5 days have been reported. IVIG can be administered monthly or every 3 months depending on disease activity. Given the high cost, close monitoring during infusions, and adverse reactions, IVIG has been used in those patients with concomitant severe SLE on high doses of corticosteroids, combined with other cytotoxic agents.
Common adverse effects include headache, low-grade fever, and chills. Severe side effects include acute renal failure and thrombotic events. Individuals with IgA deficiency are at increased risk of developing an anaphylactic reaction; thus serum IgA levels should be assessed before administration of IVIG.
Any patient newly diagnosed with CLE should be counseled on the specific disease course, including any potential risk for scarring and disfigurement. The vast majority of patients with CLE, including LEP, have disease that primarily affects the skin. Patients with LEP should be aware that there is a risk of progression to SLE ranging from 10% to 50%, but that the disease is mild.
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 artificial 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.
The goal of any therapy for CLE, including LEP, is to improve the patient’s appearance and prevent deforming scars, atrophy or dyspigmentation. Mainstay therapies for the majority of LEP subsets include topical therapies and antimalarials. Both of these therapies have limited severe adverse reactions. However, patients with refractory or widespread disease must begin therapies that carry higher risks for severe side effects. 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 CLE lesions. Thus, when ascending the therapeutic ladder, individualizing therapy for each patient based on their co-morbidities and disease severity is necessary. Furthermore, after clearance of CLE lesions, therapies should be reduced to the lowest effective dose, or discontinued.
Unusual Clinical Scenarios to Consider in Patient Management
Subcutaneous panniculitic T-cell lymphoma may mimic lupus panniculitis both clinically and histologically. If patients diagnosed with lupus panniculitis are not responding to therapeutic measures, consideration for repeated biopsies of the lesions, with appropriate immunohistochemistry and molecular studies, would be warranted to be certain the subcutaneous panniculitic T-cell lymphoma is ruled out.
What is the Evidence?
Wenzel, J, Zahn, S, Tuting, T. “Pathogenesis of cutaneous lupus erythematosus: common and different features in distinct subsets”. Lupus. vol. 19. 2010. pp. 1020-8. (A review of the main pathologic mechanisms involved in CLE with a particular focus on the differences in the subsets of CLE lesions. The genetics and inflammatory pathways that have been implicated to contribute to CLE are also discussed.)
Ujiie, H, Shimizu, T, Ito, M, Arita, K, Shimizu, H. “Lupus erythematosus profundus successfully treated with dapsone: review of the literature”. Arch Dermatol. vol. 142. 2006. pp. 399-401. (One case of LEP responding to dapsone therapy at an initial dose of 75mg. The interesting aspect of the case was the rapid improvement in pain within several days.)
Hansen, CB, Callen, JP. “Connective tissue panniculitis: lupus panniculitis, dermatomyositis, morphea/scleroderma”. Derm Ther. vol. 23. 2010. pp. 341-9. (A comprehensive description of the various types of panniculitides that allows for a better understanding of how to clinically differentiate them. Treatment options are also briefly discussed.)
Arai, S, Katsuoka, K. “Clinical entity of lupus erythematosus panniculitis/lupus erythematosus profundus”. Autoimmunity Rev. vol. 8. 2009. pp. 449-52. (A description of 44 cases of LEP encountered by the authors, including the patient characteristics, serologic results, and histologic findings.)
Espírito Santo, J, Gomes, MF, Gomes, MJ, Peixoto, L, C Pereira, S, Acabado, A. “Intravenous immunoglobulin in lupus panniculitis”. Clinic Rev Allerg Immunol. vol. 38. 2010. pp. 307-318. (The article discusses the various treatment options for lupus panniculitis, including IVIG. Details about composition, dose, mechanism of action and side effects are offered.)
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