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Are You Confident of the Diagnosis?
Chilblain lupus is a rare type of chronic cutaneous lupus erythematosus (CLE). It is characterized by red or violaceous papules and plaques located on acral areas (Figure 1). Cold temperatures, particularly moist cold climates, precipitate the lesion. Mild pain, pruritus and/or hyperhidrosis may be associated with chilblains. The lesions typically evolve into atrophic scarring and dyspigmentation, resembling discoid lesions both clinically and microscopically.
Figure 1.
Chilblain lupus: red/violaceous patches and papules on the toes. (Courtesy of Bryan Anderson, MD)
Characteristic findings on physical examination
Most patients present with discoid lupus erythematosus (DLE) lesions elsewhere, especially the face and head, making the condition easier to diagnose. DLE typically precedes the development of chilblains. However, isolated lesions make the diagnosis difficult unless the index of suspicion is high.
Specifically, the majority of chilblain lesions develop on the knee, calves, toes, fingers and elbows and have some hyperkeratosis and/or fissuring associated with the lesions (Figure 1). Nasal lesions are rare. When finger or toe pulp lesions develop, fissuring is common. However, atrophic papules and ulceration is typically absent.
Chilblain lupus or lupus pernio (Hutchinson) differs from lupus pernio (Besnier), which is caused by sarcoidosis. The latter can be seen in a “pernio” distribution, mostly nose, ear and cheeks, but is not specifically precipitated by cold. These lesions are violaceous papules and under dermoscopy show an “apple jelly” color. On the nose, they usually present as beaded violaceous papules around the nasal ala. Histopathology is most helpful with lupus pernio (Besnier) by showing sarcoidosis.
Pernio or “frostnip” is an inflammatory disorder provoked by cold, wet, non-freezing conditions and seen during the time when central heating was not present. Typically the distal fingers and toes are affected and associated with a burning and stinging sensation. Clinically, deep blue or violet macules and/or papules are seen.
Diagnosis confirmation
Histopathology is nonspecific and shows superficial and deep lymphohistiocytic inflammation with prominent perieccrine involvement. Dermal edema is also prominent. (Figure 2, Figure 3).
Figure 2.
Chilblain lupus, low power.
Figure 3.
Chilblain lupus, high power.
The differential diagnosis for acral violaceous plaques precipitated by cold include cold-induced syndromes, such as cryoglobulinemic vasculitis, cold agglutinin disease, cryofibrinogenemia and hematologic disorders. The following laboratory tests can be performed:
– Complete blood count (CBC) to rule out hemolytic anemia and myelomonocytic leukemia.
– Cryoglobulin, direct Coombs test (done at 35 to 37 degrees Celsius) and cold agglutinin titers (done at 30 degrees Celsius) and cryofibrinogen to evaluate for a cold-sensitive dysproteinemia. Of note, the sample for cryoglobulins must be kept warm before the test is run to avoid loss of cryoglobulins and a false negative result.
– Serum and urine protein electrophoresis, and immunofixation to rule out monoclonal gammopathy.
To further delineate between cold sensitive syndromes and chilblain lupus, most cold-sensitive conditions predominantly affect the ears and nose, areas of involvement not often seen with chilblain lupus.
Raynaud’s phenomenon should not be be confused with chilblain lupus, as both are precipitated by the cold. Specifically, Raynaud’s phenomenon causes a well defined area of white, blue, and red color change pattern to fingers and toes when exposed to the cold. This is a result of episodic vasospasms of digital arteries, rather than occlusion of digital vessels. These symptoms resolve after warming. However, if chronic, atropic scarring and ulcerations can occur at the digit pulps. This is seem more often with Raynaud’s phenomenon caused by underlying medical conditions, or secondary Raynaud’s phenomenon, such as scleroderma.
Several other conditions can cause acral purpura, but they do not require cold to precipitate the lesions. These include hypercoagulable states (eg, antiphospholipid syndrome), thromboemobolic events, heparin-induced thrombocytopenia thrombotic syndrome, and systemic vasculitis. Many of these conditions must be considered but can be ruled out based on clinical, serologic and histopathology. To help establish a proper diagnosis of chilblain lupus, diagnostic criteria from the Mayo Clinic were proposed. Both major and minor criteria need to be present to diagnose chilblain lupus.
Two major criteria:
1. Skin lesions of acral sites induced by exposure to cold or a drop in temperature
2. Evidence of lupus erythematosus in the skin lesions, as determined by histopathologic examination or direct immunofluorescence
Three minor criteria:
1. Coexistence of systemic lupus erythematosus (SLE) or other skin lesion of discoid lupus erythematosus
2. Response to anti-lupus therapy
3. Negative cryoglobulin and cold agglutinin studies
Histopathologic findings in chilblain lupus are consistent with discoid lupus and most show hyperkeratosis, vacuolated basement membrane, and predominantly lymphocytic perivascular and periadnexal infiltrate (Figure 2, Figure 3). Depending on the age of the lesion biopsied, an atrophic epidermis and thickened basement membrane may be noted. Direct immunofluorescence will show granular basement membrane deposition of IgM, C3 and/or IgG.
Who is at Risk for Developing this Disease?
Similar to other forms of CLE, chilblain lupus is more common in females. The vast majority of cases discussed in the literature have been of women. Age of onset can range from 20 to 70 years.
What is the Cause of the Disease?
Pathophysiology
The pathophysiology of chilblain lupus is not entirely known. Hyperviscosity due to immunologic abnormalities together with vasoconstriction or microvascular injury due to cold temperatures is thought to play a role. Patients with chilblain lupus commonly have a positive rheumatoid factor and speckled antinuclear antibody (ANA) pattern, supporting an immune-mediated etiology. Cryoglobulins and cryoprecipitates are negative in chilblain lupus.
Systemic Implications and Complications
Screening for underlying SLE with clinical history, physical examination and laboratory evaluation to assess for involvement of the central nervous, renal, hematologic, pulmonary and cardiovascular systems is warranted in all patients newly presenting with CLE.
An initial ANA, CBC, and urinalysis are 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 SLE, further testing is warranted. These may include anti-dsDNA, anti-Smith, CBC with differential, creatinine, albumin, total protein, erythrocyte sedimentation rate, and complements (C3, C4). If significant systemic symptoms of SLE are suspected, a rheumatologist should be involved in the case.
Less than 20% of patients with chilblain lupus go on to develop SLE. Of note, those that develop DLE and chilblain lesions simultaneously were at greatest risk of SLE development.
Treatment Options
Trearment options are outlined in Table I.
Table I.
| TopicalCold avoidance and physical protectionTopical steroids, class I or IIMupirocin 2% ointment for wound infectionsSystemicNifedipine ER 30mg/day, or diltiazem ER 30mg/dayPentoxifylline 400mg 3 times/dayHydroxychloroquine 6.0 to 6.5mg/kg IBWHydroxychloroquine + quinacrine 100mg dailyChloroquine <3.5mg/kg IBW +/- quinacrine 100mg dailyDapsone 50mg/dayPrednisone 0.5 to 0.75mg/kg/dayMethotrexate 5 to 25mg/weekMycophenolate mofetil 2 to 3g/day |
ER = extended release
IBW = ideal body weight
The reason topical steroids (which are vasoconstrictors) work is that the vasoconstriction that occurs with chilblain LE is due to deeper vessel vasoconstriction +/- hyperviscosity, not superficial dermal papillary vessels as occurs with topical steroid use.
Optimal Therapeutic Approach for this Disease
The treatment goal of chilblain LE is to prevent development of new lesions and expedite the healing of current lesions hopefully to avoid discomfort and scarring. Assessment of treatment response should focus on improvement in erythema and active coexistent DLE lesions. Established dyspigmentation and scarring will not resolve with the above treatments, but may slowly improve over time. Cosmetics such as Covermark and Dermablend may be used for dyspigmentation in cosmetically sensitive areas, such as the face.
Cold and moist environments should be avoided, and the use of physical protection is paramount to lesion prevention and treatment. Overall, treatment is difficult in chilblain lupus and no one agent is deemed superior. Furthermore, lesions tend to be persistent and take longer to respond to CLE therapies.
Cigarette smokers are more likely to develop CLE and SLE and suffer from more severe disease. Antimalarials may be less effective in smokers, and smokers are more likely to have skin disease that is refractory to all therapies. This is particularly true for chilblain LE given the effects of smoking on vessel wall injury. As a result, all patients with CLE and SLE should be counseled on smoking cessation.
Topical Therapy
To start, topical steroids can be initiated as first-line therapy, with or without calcineurin inhibitors. Class I or II topical steroids should be tried in patients with mild skin disease prior to starting systemic therapies. Lower steroid strengths can be used on the face. Topical calcineurin inhibitors may also be effective and offer a decreased risk of telangiectasia development compared with topical steroids. Combining topical steroids and calcineurin inhibitors may provide an added benefit.
Open fissures are common in chilblain lupus and are prone to infection. Use of topical antibiotics, such as mupirocin 2% ointment, may be used.
Calcium Channel Blockers
For systemic treatments, calcium channel blockers, such as nifedipine XL 30mg a day, can be used to minimize vasoconstriction. This dose can be increaed to 60mg a day in 4 to 6 weeks if effects are unsatisfactory. Although these are small doses of calcium channel blockers, monitoring blood pressure is still necessary to avoid symptomatic hypotension. A baseline blood pressure should be measured prior to initiating therapy and repeated in 2 to 4 weeks. When discontinuing this medication, the dose should be tapered gradually.
Other side effects include peripheral edema, headache, dizziness and flushing; all are a result of the vasodilatory effect of calcium channel blockers. Less commonly, gingival hyperplasia, photosensitivity reactions and telangiectasia development can occur. Many of these side effects can be treated by lowering the dose.
Pentoxifylline
Pentoxifylline lowers blood viscosity and improves erythrocyte flexibility. It has been effective in the treatment of local chilblain lupus alone or in combination with nifedipine. A dose of 400mg 3 to 4 times a day is well tolerated, but typically takes 2 to 4 months for a maximal therapeutic benefit to be noted. Common side effects include nausea, gastrointestinal (GI) upset and headaches. It should be avoided in patients with severe cardiac disease and renal dysfunction.
Antimalarials
For refractory or extensive lesions, other systemic therapies are warranted. Antimalarials take longer to take effect in chilblain lupus compared with other CLE lesions, but given the safety profile and frequent concomitant DLE skin lesions, it should be tried together with calcium channel blockers, with or without pentoxifylline, as first-line therapy. Antimalarials inhibit platelet aggregation and thrombus formation, which is thought to contribute to their mechanism of action in chilblain lupus.
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 (IBW) 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). Although CLE such as DLE typically resolves within 3 months of initiation of antimalarial therapy, chilblain lupus may persist. This should not be taken as treatment failure for chilblain lupus.
Antimalarials should be used for at least 4 to 5 months in the treatment of chilblain lupus before deeming them ineffective. However, if improvement is not satisfactory after 10 to 12 weeks, quinacrine 100mg daily may be added. Quinacrine can only be obtained at a compounding pharmacy. It may cuase yellow discoloration of the skin. If the combination of hydroxychloroquine and quinacrine are ineffective, two options are (1) switch to chloroquine and quinacrine or (2) start dapsone 50mg daily.
Chloroquine is typically started at a dose of 250mg 5 to 7 days a week and should not exceed 3.5mg/kg IBW per day. The lowest possible effective dose should be used for maintenance therapy. Antimalarials may be used safely for long periods of time.
Dapsone
Dapsone has been shown in a few cases to be effective in chilblain lupus. A starting dose of 50mg a day 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 of 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 and LFTs (every 1 week while the dose is being increased, then monthly for 3 months, then every 3 months).
If CLE does not respond to first-line therapy, use of steroid-sparing immunosuppressant may be required. However, little to no data exist for their use in chilblain lupus. For severe disease and those cases that have other forms of CLE and/or SLE, these agents may be warranted.
The use of prednisone for severe cases can assist with rapid improvement, but long-term use should be avoided. Addition of a steroid-sparing agent to allow steroid tapering is imperative. No data exists as to which immunosuppressive modality is superior. All take approximately 6 to 1 weeks to take effect in chilblain lupus. Of note, antimalarials and calcium channel blockers may be continued, in combination with these other agents.
Prednisone
Given the chronic and recurrent nature of most CLE subsets, use of steriods is only recommended for severe or refractory disease. Prednisone has been used in severe chilblain lupus at dosages 0.5mg/kg/day to 0.75mg/kg/day with rapid improvement in lesions. However, lesions recurred once prednisone was stopped. Use of a steroid-sparing agent is warranted to allow taper of prednisone. This may take 3 to 4 weeks to achieve. 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 with even short courses of prednisone.
Methotrexate
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. However, chilblain lupus may take a bit longer. 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. Dosage as low as 5mg a week has been successfully used to maintain clinical remission in CLE.
A potential for hepatotoxicity, with long-term use, and pulmonary toxicity are important considerations. Patients who drink alcohol should not receive MTX, 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 laboratory tests should be done in 1 week. If laboratory tests 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 GI intolerance due to oral MTX.
Mycophenolate Mofetil
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 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. Laboratory tests should 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 doses of 1.5 to 3g a day can be used safely.
Patient Management
The diagnosis of chilblain lupus can be difficult. It is important to rule out other cold induced syndromes prior to initiating therapy. Chilblain lupus is persistent, thus once lesions have developed they may take 4 to 6 months to resolve. Allowing a longer time for observation before switching therapeutic modalities is warranted. Also, the cessation of new lesion development can be used as an indicator of disease stabilization.
All patients 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, particularly chronic CLE (CCLE) and systemic CLE (SCLE), have disease that primarly affects the skin. These patients should be reassured that their diease progression is relatively benign.
The next step is to provide patients with therapeutic modalities that minimize disease progression and improve treatment response. All patients must be counseled on cold avoidance and protection. 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 begin a smoking cessation program.
The goal of any therapy for chilblain lupus is to minimize new lesion development and expedite healing of older lesions. Mainstay therapies for the majority of CLE subsets include topical therapies and antimalarials. Both of these therapies have limited severe adverse reactions. However, patients with refractory or widespread disease may need 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 chilblain lupus lesions. Thus, when ascending the therapeutic ladder, individualizing therapy for each patient based on their co-morbidities is necessary. Furthermore, after clearance of active chilblain lupus lesions, therapies should be reduced to the lowest effective dose, or discontinued.
Unusual Clinical Scenarios to Consider in Patient Management
Autosomal dominant variants of chilblain lupus have been associated with mutations in TREX1. Chilblains is a broad term used for a cold-related tissue injury and can be idiopathic or seen in anorexia (BMI <5% of the normal population), myelodysplasia and sepsis. In anorexia they may be more likely to develop chilblains, but not chilblains lupus.
What is the Evidence?
Doutre, MS, Beylot, C, Beylot, J, Pompougnac, E, Royer, P. “Chilblain lupus erythematosus: Report of 15 cases”. Dermatology. vol. 184. 1992. pp. 26-8. (A retrospective study that describes the clinical, histologic and laboratory features of 15 cases of chilblain lupus. Effective treatment options are briefly discussed.)
Millard, LG, Rowell, NR. “Chilblain lupus erythematosus (Hutchinson)”. Br J Dermatol. vol. 98. 1978. pp. 497(Chilblain LE lesions are described in a table format of 17 cases, including lesion location, laboratory and histologic findings. Of particular note is the progression of perniotic lesions despite the resolution of concomitant DLE lesions.)
Su, WPD, Perniciaro, C, Rogers, RS, White, JW. “Chilblain lupus erythematosus (lupus pernio): clinical review of the Mayo clinical experience and proposal of diagnostic criteria”. Cutis. vol. 54. 1994. pp. 395(Based on five cases and a review of the literature, the authors propose a diagnostic criteria for chilblain lupus erythematosus.)
Boehm, I, Bieber, T. “Chilblain lupus erythematosus Hutchinson: successful treatment with mycophenolate mofetil”. Arch Dermatol. vol. 137. 2001. pp. 235-6. (The article discusses the treatments used for chilblain lupus and the first case of mycophenolate mofetil use to treat a refractory case of chilblain lupus erythematosus.)
Kalia, S, Dutz, JP. “New concepts in antimalarial use and mode of action in dermatology”. Dermatologic Therapy. vol. 20. 2007. pp. 160-74. (A comprehensive discussion of the mechanism of action of antimalarials, including inhibition of platelet aggregation and thrombus formation.)
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