Dermatologic Therapy, Vol. Vol.••, 28,2015, 2015,••–•• 287–290 Printed in the the United United States States · All All rights rightsreserved reserved
C 2015 Wiley Periodicals, Inc. V © 2015 Wiley Periodicals, Inc.
DERMATOLOGIC DERMATOLOGIC THERAPY THERAPY ISSN ISSN1396-0296 1396-0296
THERAPEUTIC HOTLINE: HOTLINE THERAPEUTIC SHORT PAPERS Pulsed intravenous immunoglobulin therapy in refractory ulcerated livedoid vasculopathy: seven cases and a literature review Eun Jee Kim*, So Young Yoon†, Hyun Sun Park*, Hyun-Sun Yoon* & Soyun Cho* *Department of Dermatology, Seoul National University Boramae Hospital and †Clean-up Dermatologic Clinic, Seoul, Korea
ABSTRACT: Livedoid vasculopathy (LV) is a thrombotic vasculopathy of the skin of unknown origin. No treatment has been validated in this indication, but case reports demonstrated successful use of intravenous immunoglobulins (IVIg) in LV. We assessed the efficacy and tolerability of 2 g/kg IVIg therapy every month for 2∼3 cycles in patients with refractory LV. We analyzed the efficacy, side effects and recurrence after long-term follow-up (51.9 ± 14.0 months) in seven patients with LV treated with 2 g/kg of IVIg. Mean clinical score of sum of erythema, ulceration and pain index (each: 0–3) was 5.7 ± 0.9 before the therapy and significantly lower after therapy (1.1 ± 0.5) (p = 0.001). Even after just one cycle of IVIg, the score decreased significantly from 5.7 ± 0.9 to 3.7 ± 0.9 (p = 0.002), especially the pain score. In one patient, LV has not recurred for over 7 years; six patients experienced recurrence after a mean of 12.7 ± 2.8 months. Out of the six patients, two patients were re-administered IVIg whereas the others were well controlled by conventional therapy. We propose that IVIg is a rapid, effective, and safe therapeutic option in LV refractory to other treatment modalities. KEYWORDS: intravenous immunoglobulin, livedoid vasculopathy
Introduction Livedoid vasculopathy (LV) is characterized by purpuric macules and papules of the lower legs and feet, sometimes ulcerated. The skin lesions heal slowly, leaving stellate, atrophic, porcelainwhite scars with surrounding hyperpigmentation Address correspondence and reprint requests to: Soyun Cho, MD, PhD, Department of Dermatology, Seoul National University Boramae Hospital, 20, Boramae Road 5-gil, Dongjak-gu, Seoul, 156-707, Korea, or email: [email protected].
and telangiectasia (atrophie blanche). Intravenous immunoglobulin (IVIg) has been used in LV, and the case reports showed good results. Herein we summarize the results of the retrospective analysis regarding the long-term efficacy and tolerability of IVIg in Korean patients with refractory LV.
Materials and methods The patients with resistant ulcerated LV who visited department of dermatology in Seoul National
287 1
288 2
20 17 6 7
F, female; FANA, fluorescent anti-nuclear antibody; M, male; PD, prednisolone; PGE1, prostaglandin E1; PT INR, prothrombin time international normalized ratio.
1 year 9 months 2 years 9 months 17 19 Yes Yes 2 3
28 5
F M
4 5
Summer Summer
Student Student
FANA 1:40 weakly positive PT INR 1.20 Normal Nurse Summer 3
23 4
F
24 3
F
5
Summer
Student
FANA 1:40 weakly positive Normal Office worker Summer 3
39 43 1 2
F
Oriental medicine Pentoxifylline, danazol, PGE1
2 years 1 months 12 Yes 3
4 years 5 months No 3
2 years 5 Yes 3
19 4 Yes Yes 3 3
Pentoxifylline Aspirin, nifedipine, pentoxifylline Aspirin, pentoxifylline, colchicine Methyl PD, pentoxifylline, hyperbaric oxygen Does not know Normal Normal Tailor Housewife Summer None 1 10
Previous therapy Lab findings Occupation Sex Age Patient
F F
Recurrence
Time till recurrence (months) IVIg cycles Seasonal worsening Disease duration (year)
A total of seven patients with mean age of 27.7 ± 3.7 years were treated by IVIg (Table 1). The LV lesions in all patients were either unresponsive or minimally responsive to conventional oral treatment (Table 1). Six patients underwent three cycles, and one underwent two cycles. In all patients, significant regression of skin lesions was observed after IVIg (Fig. 1). Mean clinical score was 5.7 ± 0.9 before IVIg and 1.1 ± 0.5 after two to three cycles of IVIg (p = 0.001) (Fig. 2). Even after just one cycle, score decreased dramatically (p = 0.002) (Fig. 2). In one patient, LV did not recur for 4 years and 5 months, but six patients experienced recurrence (12.7 ± 2.8 months) (Table 1). Out of the recurred patients, two (patients 1 and 7) retook IVIg whereas
Table 1. Summary of the patients’ clinical course
Results
Total follow-up period
Boramae Hospital between January 2005 and September 2014 were enrolled. All patients underwent biopsy, which revealed segmental hyalinization, endothelial proliferation, thrombosis of dermal vessels without neutrophilia or leukocytoclasia, consistent with LV. We assessed demographic data, occupation, general medical history, disease duration before diagnosis, seasonal worsening, previous and concomitant treatments and total follow-up period through retrospective chart review. Laboratory findings including complete blood cell count, routine blood chemistry testing, urine analysis, thrombophilia screen (prothrombin time, bleeding time, activated partial thromboplastin time, fibrinogen), C-reactive protein, anti-streptolysin O, and vasculitis screen (antinuclear antibody, anti-DNA antibody, antineutrophilic cytoplasmic antibody, rheumatoid factor, lupus anticoagulant, C3, C4, cold agglutinin, cryoglobulin) were reviewed to rule out peripheral vascular diseases and inflammatory vasculitis. The treatment protocol of IVIg was 2 g/kg divided over 3–5 days monthly repeated for 2∼3 cycles. The outcome evaluation was performed according to a semi-quantitative clinical scoring, consisting of the summation of erythema, ulceration, and pain index (0–9). Erythema score was graded as none (0), mild (1), moderate (2) or severe (3), and ulceration score was graded as none (0), epidermis (1), dermis (2), or subcutaneous (3). Finally, pain score was graded as none (0), mild (1), moderate (2), or severe (3). We used paired t-test and Friedman’s test using the Statistical Package for the Social Sciences (SPSS; SPSS, Inc.., Chicago, IL, USA) software to compare scores. A p-value less than 0.05 was considered significant.
9 years 2 months 8 years 1 months
al. Kim et al.
Pulsed PulsedIVIg IVIg for for livedoid livedoid vasculopathy
FIG. 1. Clinical improvement after one cycle of intravenous immunoglobulins (IVIg) and three cycles of IVig in patient 5 (A, before E(3)U(3)P(3); B, after 1 cycle E(3)U(3)P(2); C, after three cycles E(2)U(2)P(1)) E: erythema, U: ulceration, P: pain.
FIG. 2. Graph showing the difference in clinical scores after each cycle of intravenous immunoglobulins (IVIg) in seven patients (*p < 0.05).
the others were well controlled by conventional therapy, such as aspirin, pentoxifylline, dipyridamole, clopidogrel, and danazol. In patient 2, after a mild recurrence following IVIg, only two months of oral medication was necessary for complete clearance of all skin lesions, and she has remained disease-free ever since, for 9 years now. Patient 7 experienced recurrence after 17 months and was re-administered one cycle of 2 g/kg IVIg, after which LV lesions remained stable for 10 months. However, patient 1 experienced recurrence periodically, especially in the spring/ summer season. She has been followed up for over 9 years, and she was re-administered IVIg for six times in total, mostly without any concomitant oral therapy, with interval 1 year and 7 months, 11 months, 3 years and 11 months, 1 year and 2 months, 11 months, and 5 months, respectively. This case demonstrates that after three cycles of
IVIg monthly, refractory LV can be managed well with annual IVIg with/without concomitant conventional treatment. The latest disease-free interval period was 5 months, but clinical score was only 3 (erythema 1, ulceration 1, pain 1), and she responded well to only 1 g/kg of IVIg. Over the years, she consistently preferred IVIg to conventional treatment despite the cost difference because of the quick response (within 1 week) and far superior long-lasting efficacy of IVIg and hence higher quality of life. During IVIg infusion, blood pressure and electrocardiography were monitored. The only side effects were nausea/vomiting and headache, which were controlled by reducing the speed of infusion.
Discussion LV is classified as occlusive vasculopathy with minimal or no inflammation. Therefore, therapies that modulate or interfere with microcirculatory disturbances show effect, whereas topical, systemic, and intralesional steroid has little or no effect in LV (1). Many therapeutic strategies have been employed, including drugs stimulating endogenous fibrinolytic activity (danazol), antiplatelet agents (aspirin, dipyridamole, cilostazol, clopidogrel, ticlopidine hydrochloride), vasodilators (nifedipine, cilostazol, nicotinic acid), hemorheologicals (pentoxifylline), anticoagulants (warfarin, enoxaparin), modulation of lymphocyte response (phototherapy UVA, cyclosporine A, methotrexate, azathioprine, colchicine, sulfasalazine), prostanoids (alprostadil,
289 3
al. Kim et al.
beraprost, iloprost), oral factor-X inhibitor (rivaroxaban), hyperbaric oxygen, and IVIg (2–4). IVIg is highly purified preparation of IgG obtained from pooled human plasma. Its mode of action is not fully understood, but it can be hypothesized that in addition to its anti-inflammatory properties, it might exert anticoagulation effects through inhibition of thrombogenic effects of antiphospholipid antibodies, inhibitory effects on platelet adhesion, and modulation of endothelial function (5–8). Proposed mechanisms of actions of IVIg include: the modulation of Fc receptor expression, the elimination of circulating immune complexes and autoantibodies, the inhibition of complement-mediated damage, the modulation of cytokine production and release, the blockade of Fas ligand, and the reduction of thromboxane A2 and endothelin synthesis accompanied by an increase in prostacyclin secretion (9). Furthermore, the broad spectrum of specificities of IVIg, representing thousands of healthy donors that cannot be found in any one individual, creates a new immune realm in the recipient individual, and this partly explains the superb efficacy of IVIg compared with conventional therapy. In all of our patients LV improved with significant difference in clinical scores, and six out of seven patients reached a score of 0 or 1 after 2∼3 cycles of IVIg. There have been three case series of LV treated with IVIg thus far (10–12). The results of our series are similar to the previous reports in that three cycles of monthly IVIg was effective and improvement in pain was achieved faster and was more significant compared with erythema and ulceration (p = 0.041). However, in Kreuter et al.’s study, the dose of IVIg in one cycle was less than 2 g/kg (1.0 or 1.5 g/kg) and the follow-up period was short (3 months). The present series is meaningful in that the follow-up period was longer (1 year 9 months to 9 years and 2 months) and that the disease severity was greatly lowered after two to three cycles of IVIg with prolonged effect. The case series that Monshi et al. reported had a long follow-up period of 5.3 years, but 5 of 11 patients received IVIg as the first-line therapy and thus one cannot compare the effects of IVIg with conventional therapies. Limitations of this study include its retrospective nature and the limited number of patients. However, considering the rarity of the disease and fairly long follow-up period and the fact that it is the first Asian case series with the largest number
290 4
of patients of LV treated with IVIg, we believe our experience is worth sharing. Because of the high cost and need for hospitalization, IVIg may not be suitable as the initial treatment of LV. However, its prompt, dramatic, and prolonged effect supports IVIg to be a safe and effective treatment option in severe, refractory livedoid vasculopathy. Funding sources: None. Conflict of interest: No conflict of interest.
References 1. Criado PR, Rivitti EA, Sotto MN, de Carvalho JF. Livedoid vasculopathy as a coagulation disorder. Autoimmun Rev 2011: 10: 353–360. 2. Frances C, Barete S. Difficult management of livedoid vasculopathy. Arch Dermatol 2004: 140: 1011. 3. Nakamura S, Kishibe M, Nishi K, Hashimoto Y, Takeda K, Mizumoto T, Iizuka H. Livedoid vasculopathy; favorable clinical response with low dose warfarin. Eur J Dermatol 2011: 21: 1011–1012. 4. Pitarch G, Rodriguez-Serna M, Torrijos A, Oliver V, Fortea JM. Treatment of livedoid vasculopathy with short-cycle intravenous immunoglobulins. Acta Derm Venereol 2005: 85: 374–375. 5. Gelfand EW. Intravenous immune globulin in autoimmune and inflammatory diseases. N Engl J Med 2012: 367: 2015– 2025. 6. Frostegard AG, Su J, von Landenberg P, Frostegård J. Effects of anti-cardiolipin antibodies and IVIg on annexin A5 binding to endothelial cells: implications for cardiovascular disease. Scand J Rheumatol 2010: 39: 77–83. 7. Inagaki M, Yamada K. Inhibitory effects of high doses of intravenous gamma-globulin on platelet interaction with the vessel wall in Kawasaki disease. Acta Paediatr Jpn 1991: 33: 791–798. 8. Pierangeli SS, Espinola R, Liu X, Harris EN, Salmon JE. Identification of an Fc gamma receptor-independent mechanism by which intravenous immunoglobulin ameliorates antiphospholipid antibody-induced thrombogenic phenotype. Arthritis Rheum 2001: 44: 876–883. 9. Mouthon L, Kaveri SV, Spalter SH, Lacroix-Desmazes S, Lefranc C, Desai R, Kazatchkine MD. Mechanisms of action of intravenous immune globulin in immune-mediated diseases. Clin Exp Immunol 1996: 104 (Suppl. 1): 3–9. 10. Bounfour T, Bouaziz JD, Bezier M, Petit A, Viguier M, Rybojad M, Bagot M. Intravenous immunoglobulins in difficult-to-treat ulcerated livedoid vasculopathy: five cases and a literature review. Int J Dermatol 2013: 52: 1135–1139. 11. Kreuter A, Gambichler T, Breuckmann F, Bechara FG, Rotterdam S, Stücker M, Altmeyer P. Pulsed intravenous immunoglobulin therapy in livedoid vasculitis: an open trial evaluating 9 consecutive patients. J Am Acad Dermatol 2004: 51: 574–579. 12. Monshi B, Posch C, Vujic I, Sesti A, Sobotka S, Rappersberger K. Efficacy of intravenous immunoglobulins in livedoid vasculopathy: long-term follow-up of 11 patients. J Am Acad Dermatol 2014: 71: 738–744.
C 2015 Wiley Periodicals, Inc. V © 2015 Wiley Periodicals, Inc.
DERMATOLOGIC DERMATOLOGIC THERAPY THERAPY ISSN ISSN1396-0296 1396-0296
THERAPEUTIC HOTLINE: HOTLINE THERAPEUTIC SHORT PAPERS Pulsed intravenous immunoglobulin therapy in refractory ulcerated livedoid vasculopathy: seven cases and a literature review Eun Jee Kim*, So Young Yoon†, Hyun Sun Park*, Hyun-Sun Yoon* & Soyun Cho* *Department of Dermatology, Seoul National University Boramae Hospital and †Clean-up Dermatologic Clinic, Seoul, Korea
ABSTRACT: Livedoid vasculopathy (LV) is a thrombotic vasculopathy of the skin of unknown origin. No treatment has been validated in this indication, but case reports demonstrated successful use of intravenous immunoglobulins (IVIg) in LV. We assessed the efficacy and tolerability of 2 g/kg IVIg therapy every month for 2∼3 cycles in patients with refractory LV. We analyzed the efficacy, side effects and recurrence after long-term follow-up (51.9 ± 14.0 months) in seven patients with LV treated with 2 g/kg of IVIg. Mean clinical score of sum of erythema, ulceration and pain index (each: 0–3) was 5.7 ± 0.9 before the therapy and significantly lower after therapy (1.1 ± 0.5) (p = 0.001). Even after just one cycle of IVIg, the score decreased significantly from 5.7 ± 0.9 to 3.7 ± 0.9 (p = 0.002), especially the pain score. In one patient, LV has not recurred for over 7 years; six patients experienced recurrence after a mean of 12.7 ± 2.8 months. Out of the six patients, two patients were re-administered IVIg whereas the others were well controlled by conventional therapy. We propose that IVIg is a rapid, effective, and safe therapeutic option in LV refractory to other treatment modalities. KEYWORDS: intravenous immunoglobulin, livedoid vasculopathy
Introduction Livedoid vasculopathy (LV) is characterized by purpuric macules and papules of the lower legs and feet, sometimes ulcerated. The skin lesions heal slowly, leaving stellate, atrophic, porcelainwhite scars with surrounding hyperpigmentation Address correspondence and reprint requests to: Soyun Cho, MD, PhD, Department of Dermatology, Seoul National University Boramae Hospital, 20, Boramae Road 5-gil, Dongjak-gu, Seoul, 156-707, Korea, or email: [email protected].
and telangiectasia (atrophie blanche). Intravenous immunoglobulin (IVIg) has been used in LV, and the case reports showed good results. Herein we summarize the results of the retrospective analysis regarding the long-term efficacy and tolerability of IVIg in Korean patients with refractory LV.
Materials and methods The patients with resistant ulcerated LV who visited department of dermatology in Seoul National
287 1
288 2
20 17 6 7
F, female; FANA, fluorescent anti-nuclear antibody; M, male; PD, prednisolone; PGE1, prostaglandin E1; PT INR, prothrombin time international normalized ratio.
1 year 9 months 2 years 9 months 17 19 Yes Yes 2 3
28 5
F M
4 5
Summer Summer
Student Student
FANA 1:40 weakly positive PT INR 1.20 Normal Nurse Summer 3
23 4
F
24 3
F
5
Summer
Student
FANA 1:40 weakly positive Normal Office worker Summer 3
39 43 1 2
F
Oriental medicine Pentoxifylline, danazol, PGE1
2 years 1 months 12 Yes 3
4 years 5 months No 3
2 years 5 Yes 3
19 4 Yes Yes 3 3
Pentoxifylline Aspirin, nifedipine, pentoxifylline Aspirin, pentoxifylline, colchicine Methyl PD, pentoxifylline, hyperbaric oxygen Does not know Normal Normal Tailor Housewife Summer None 1 10
Previous therapy Lab findings Occupation Sex Age Patient
F F
Recurrence
Time till recurrence (months) IVIg cycles Seasonal worsening Disease duration (year)
A total of seven patients with mean age of 27.7 ± 3.7 years were treated by IVIg (Table 1). The LV lesions in all patients were either unresponsive or minimally responsive to conventional oral treatment (Table 1). Six patients underwent three cycles, and one underwent two cycles. In all patients, significant regression of skin lesions was observed after IVIg (Fig. 1). Mean clinical score was 5.7 ± 0.9 before IVIg and 1.1 ± 0.5 after two to three cycles of IVIg (p = 0.001) (Fig. 2). Even after just one cycle, score decreased dramatically (p = 0.002) (Fig. 2). In one patient, LV did not recur for 4 years and 5 months, but six patients experienced recurrence (12.7 ± 2.8 months) (Table 1). Out of the recurred patients, two (patients 1 and 7) retook IVIg whereas
Table 1. Summary of the patients’ clinical course
Results
Total follow-up period
Boramae Hospital between January 2005 and September 2014 were enrolled. All patients underwent biopsy, which revealed segmental hyalinization, endothelial proliferation, thrombosis of dermal vessels without neutrophilia or leukocytoclasia, consistent with LV. We assessed demographic data, occupation, general medical history, disease duration before diagnosis, seasonal worsening, previous and concomitant treatments and total follow-up period through retrospective chart review. Laboratory findings including complete blood cell count, routine blood chemistry testing, urine analysis, thrombophilia screen (prothrombin time, bleeding time, activated partial thromboplastin time, fibrinogen), C-reactive protein, anti-streptolysin O, and vasculitis screen (antinuclear antibody, anti-DNA antibody, antineutrophilic cytoplasmic antibody, rheumatoid factor, lupus anticoagulant, C3, C4, cold agglutinin, cryoglobulin) were reviewed to rule out peripheral vascular diseases and inflammatory vasculitis. The treatment protocol of IVIg was 2 g/kg divided over 3–5 days monthly repeated for 2∼3 cycles. The outcome evaluation was performed according to a semi-quantitative clinical scoring, consisting of the summation of erythema, ulceration, and pain index (0–9). Erythema score was graded as none (0), mild (1), moderate (2) or severe (3), and ulceration score was graded as none (0), epidermis (1), dermis (2), or subcutaneous (3). Finally, pain score was graded as none (0), mild (1), moderate (2), or severe (3). We used paired t-test and Friedman’s test using the Statistical Package for the Social Sciences (SPSS; SPSS, Inc.., Chicago, IL, USA) software to compare scores. A p-value less than 0.05 was considered significant.
9 years 2 months 8 years 1 months
al. Kim et al.
Pulsed PulsedIVIg IVIg for for livedoid livedoid vasculopathy
FIG. 1. Clinical improvement after one cycle of intravenous immunoglobulins (IVIg) and three cycles of IVig in patient 5 (A, before E(3)U(3)P(3); B, after 1 cycle E(3)U(3)P(2); C, after three cycles E(2)U(2)P(1)) E: erythema, U: ulceration, P: pain.
FIG. 2. Graph showing the difference in clinical scores after each cycle of intravenous immunoglobulins (IVIg) in seven patients (*p < 0.05).
the others were well controlled by conventional therapy, such as aspirin, pentoxifylline, dipyridamole, clopidogrel, and danazol. In patient 2, after a mild recurrence following IVIg, only two months of oral medication was necessary for complete clearance of all skin lesions, and she has remained disease-free ever since, for 9 years now. Patient 7 experienced recurrence after 17 months and was re-administered one cycle of 2 g/kg IVIg, after which LV lesions remained stable for 10 months. However, patient 1 experienced recurrence periodically, especially in the spring/ summer season. She has been followed up for over 9 years, and she was re-administered IVIg for six times in total, mostly without any concomitant oral therapy, with interval 1 year and 7 months, 11 months, 3 years and 11 months, 1 year and 2 months, 11 months, and 5 months, respectively. This case demonstrates that after three cycles of
IVIg monthly, refractory LV can be managed well with annual IVIg with/without concomitant conventional treatment. The latest disease-free interval period was 5 months, but clinical score was only 3 (erythema 1, ulceration 1, pain 1), and she responded well to only 1 g/kg of IVIg. Over the years, she consistently preferred IVIg to conventional treatment despite the cost difference because of the quick response (within 1 week) and far superior long-lasting efficacy of IVIg and hence higher quality of life. During IVIg infusion, blood pressure and electrocardiography were monitored. The only side effects were nausea/vomiting and headache, which were controlled by reducing the speed of infusion.
Discussion LV is classified as occlusive vasculopathy with minimal or no inflammation. Therefore, therapies that modulate or interfere with microcirculatory disturbances show effect, whereas topical, systemic, and intralesional steroid has little or no effect in LV (1). Many therapeutic strategies have been employed, including drugs stimulating endogenous fibrinolytic activity (danazol), antiplatelet agents (aspirin, dipyridamole, cilostazol, clopidogrel, ticlopidine hydrochloride), vasodilators (nifedipine, cilostazol, nicotinic acid), hemorheologicals (pentoxifylline), anticoagulants (warfarin, enoxaparin), modulation of lymphocyte response (phototherapy UVA, cyclosporine A, methotrexate, azathioprine, colchicine, sulfasalazine), prostanoids (alprostadil,
289 3
al. Kim et al.
beraprost, iloprost), oral factor-X inhibitor (rivaroxaban), hyperbaric oxygen, and IVIg (2–4). IVIg is highly purified preparation of IgG obtained from pooled human plasma. Its mode of action is not fully understood, but it can be hypothesized that in addition to its anti-inflammatory properties, it might exert anticoagulation effects through inhibition of thrombogenic effects of antiphospholipid antibodies, inhibitory effects on platelet adhesion, and modulation of endothelial function (5–8). Proposed mechanisms of actions of IVIg include: the modulation of Fc receptor expression, the elimination of circulating immune complexes and autoantibodies, the inhibition of complement-mediated damage, the modulation of cytokine production and release, the blockade of Fas ligand, and the reduction of thromboxane A2 and endothelin synthesis accompanied by an increase in prostacyclin secretion (9). Furthermore, the broad spectrum of specificities of IVIg, representing thousands of healthy donors that cannot be found in any one individual, creates a new immune realm in the recipient individual, and this partly explains the superb efficacy of IVIg compared with conventional therapy. In all of our patients LV improved with significant difference in clinical scores, and six out of seven patients reached a score of 0 or 1 after 2∼3 cycles of IVIg. There have been three case series of LV treated with IVIg thus far (10–12). The results of our series are similar to the previous reports in that three cycles of monthly IVIg was effective and improvement in pain was achieved faster and was more significant compared with erythema and ulceration (p = 0.041). However, in Kreuter et al.’s study, the dose of IVIg in one cycle was less than 2 g/kg (1.0 or 1.5 g/kg) and the follow-up period was short (3 months). The present series is meaningful in that the follow-up period was longer (1 year 9 months to 9 years and 2 months) and that the disease severity was greatly lowered after two to three cycles of IVIg with prolonged effect. The case series that Monshi et al. reported had a long follow-up period of 5.3 years, but 5 of 11 patients received IVIg as the first-line therapy and thus one cannot compare the effects of IVIg with conventional therapies. Limitations of this study include its retrospective nature and the limited number of patients. However, considering the rarity of the disease and fairly long follow-up period and the fact that it is the first Asian case series with the largest number
290 4
of patients of LV treated with IVIg, we believe our experience is worth sharing. Because of the high cost and need for hospitalization, IVIg may not be suitable as the initial treatment of LV. However, its prompt, dramatic, and prolonged effect supports IVIg to be a safe and effective treatment option in severe, refractory livedoid vasculopathy. Funding sources: None. Conflict of interest: No conflict of interest.
References 1. Criado PR, Rivitti EA, Sotto MN, de Carvalho JF. Livedoid vasculopathy as a coagulation disorder. Autoimmun Rev 2011: 10: 353–360. 2. Frances C, Barete S. Difficult management of livedoid vasculopathy. Arch Dermatol 2004: 140: 1011. 3. Nakamura S, Kishibe M, Nishi K, Hashimoto Y, Takeda K, Mizumoto T, Iizuka H. Livedoid vasculopathy; favorable clinical response with low dose warfarin. Eur J Dermatol 2011: 21: 1011–1012. 4. Pitarch G, Rodriguez-Serna M, Torrijos A, Oliver V, Fortea JM. Treatment of livedoid vasculopathy with short-cycle intravenous immunoglobulins. Acta Derm Venereol 2005: 85: 374–375. 5. Gelfand EW. Intravenous immune globulin in autoimmune and inflammatory diseases. N Engl J Med 2012: 367: 2015– 2025. 6. Frostegard AG, Su J, von Landenberg P, Frostegård J. Effects of anti-cardiolipin antibodies and IVIg on annexin A5 binding to endothelial cells: implications for cardiovascular disease. Scand J Rheumatol 2010: 39: 77–83. 7. Inagaki M, Yamada K. Inhibitory effects of high doses of intravenous gamma-globulin on platelet interaction with the vessel wall in Kawasaki disease. Acta Paediatr Jpn 1991: 33: 791–798. 8. Pierangeli SS, Espinola R, Liu X, Harris EN, Salmon JE. Identification of an Fc gamma receptor-independent mechanism by which intravenous immunoglobulin ameliorates antiphospholipid antibody-induced thrombogenic phenotype. Arthritis Rheum 2001: 44: 876–883. 9. Mouthon L, Kaveri SV, Spalter SH, Lacroix-Desmazes S, Lefranc C, Desai R, Kazatchkine MD. Mechanisms of action of intravenous immune globulin in immune-mediated diseases. Clin Exp Immunol 1996: 104 (Suppl. 1): 3–9. 10. Bounfour T, Bouaziz JD, Bezier M, Petit A, Viguier M, Rybojad M, Bagot M. Intravenous immunoglobulins in difficult-to-treat ulcerated livedoid vasculopathy: five cases and a literature review. Int J Dermatol 2013: 52: 1135–1139. 11. Kreuter A, Gambichler T, Breuckmann F, Bechara FG, Rotterdam S, Stücker M, Altmeyer P. Pulsed intravenous immunoglobulin therapy in livedoid vasculitis: an open trial evaluating 9 consecutive patients. J Am Acad Dermatol 2004: 51: 574–579. 12. Monshi B, Posch C, Vujic I, Sesti A, Sobotka S, Rappersberger K. Efficacy of intravenous immunoglobulins in livedoid vasculopathy: long-term follow-up of 11 patients. J Am Acad Dermatol 2014: 71: 738–744.
