Efficacy and safety of intravenous immunoglobulin for treating refractory livedoid vasculopathy: a systematic review

Search strategy

This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. ⁹ The final literature search was conducted on 7 December 2021 using the PubMed, Cochrane, and Embase online electronic databases for articles concerning IVIG therapy in LV patients. The search terms included the following: ‘livedoid vasculopathy’, ‘livedoid vasculitis’, ‘livedo vasculitis’, ‘atrophie blanche’, ‘white atrophy’, ‘segmental hyalinizing vasculitis’, ‘intravenous immunoglobulin’, ‘IVIG’, and ‘immunoglobulin’. The search strategy used was as follows: (‘livedoid vasculopathy’ OR ‘livedoid vasculitis’ OR ‘livedo vasculitis’ OR ‘atrophie blanche’ OR ‘segmental hyalinizing vasculitis’ OR ‘white atrophy’) AND (‘intravenous immunoglobulin’ OR ‘IVIG’ OR ‘immunoglobulin’). The timeline was from inception of the search engine to December 2021. Articles were restricted to papers that were written in English only. No other filters or automated tools were used in the search process. In addition, all the references of screened articles were searched for further high-quality studies. The ethics approval and informed consent were not applicable in this systematic review.

Study selection

The initial search process yielded 39 articles from the PubMed, Cochrane, and Embase online electronic databases, removing 20 duplicating records. Another two articles were from references of screened articles. Two investigators independently screened the abstracts of all 41 identified records and selected articles for full-text review. The PRISMA flow figure demonstrating the process of literature search and study selection is shown in Figure 1.

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Figure 1.

The PRISMA flow figure demonstrating the process of literature search and study selection.

The inclusion criteria were as follows: (1) LV patients with a confirmed diagnosis depending on their typical clinical and pathological manifestations in accordance with the main LV diagnostic criteria; ¹⁰ (2) LV patients receiving IVIG therapy; (3) studies involving efficacy and safety of IVIG therapy in LV, and recording detailed relevant information like dosage, cycles, frequency, clinical response, and adverse events; (4) article types including research articles, case series, case report, and correspondence; and (5) English articles only.

The exclusion criteria were as follows: (1) uncertain LV diagnosis; (2) details in the general data and about the treatment like dosage, cycles, frequency, clinical response, and adverse events were all vaguely recorded; (3) review articles or editorial articles; or (4) articles written in languages other than English.

According to the inclusion and exclusion criteria, 24 records were excluded due to following reasons: (1) not published in English languages (n = 1); (2) review articles (n = 2); (3) irrelevant subjects (n = 18); and (4) lack details in treatment (n = 3). A total of 17 eligible articles were enrolled in this systematic review, among them 3 articles were studies, and 14 articles were case reports and case series.

We assessed the risk of bias according to the Cochrane handbook of systematic reviews of interventions. Due to enrollment of case reports and case series in this systematic review, overreporting or overestimating of specific results may bias the analysis. However, considering disease rarity and limited evidence on IVIG therapy in LV, we included these case reports and case series.

Data extraction

After carefully screening and reviewing, the following data were extracted from the included studies: first author’s name, year, country, number of patients, mean age, gender, comorbidities, screening for thrombophilic factors, previous treatment, dose, frequency, duration, efficacy of the IVIG therapy, combination treatment, recurrence, and adverse events (Tables 1 and 2). Screening for thrombophilic factors mainly included protein C, protein S, antithrombin III, activated protein C resistance, lipoprotein(a), homocysteine, antinuclear antibody, anticardiolipin antibody, lupus anticoagulant, and several single nucleotide polymorphisms that were related to hypercoagulability, the thrombosis-like coagulation factor V Leiden mutation, and plasminogen activator inhibitor-1 promoter homozygosity.

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Table 1.

Demographic and general data of LV patients enrolled.

No.	Authors	Year	Country	Patients	Age	Gender (M/F)	Comorbidities	Thrombophilic factors	Previous treatment
1	Levy et al. 8	1999	Israel	2	30 (24–36)	0/1	NA	NA	ASP, NSAID, CTX, AZA, GC, warfarin, heparin, local plastic surgery
2	Amital et al. 11	2000	Israel	1	36	0/1	NA	NA	NA
3	Ravat et al. 7	2002	United Kingdom	2	38 (30–46)	0/2	Antiphospholipid syndrome	1 patient	ASP, GC, AZA, danazol, stanazolol, dapsone, dipyridamole, ketanserin, nicotinic acid, guanethidine, nicotinamide, intralesional triamcinolone
4	Schanz et al. 12	2003	Germany	1	43	0/1	None	NA	GC, ASP, PTX, heparin
5	Kreuter et al. 13	2004	Germany	9	37.89 (22–55)	2/7	None	None	GC, ASP, PTX, PUVA, AZA, heparin
6	Pitarch et al. 14	2005	Spain	1	19	0/1	NA	None	ASP, PTX, GC, dipyridamole, nadroparin, potassium iodine
7	Tuchinda et al. 15	2011	United States	1	33	0/1	NA	1 patient	tPA infusion
8	Bounfour et al. 16	2013	France	5	43 (21–73)	1/4	None	None	GC, MTX, PTX, LMWH, ASA, clopidogrel, colchicine, dapsone
9	Monshi et al. 6	2014	Austria	11	29.91 (19–60)	4/7	HTN; COPD; RA; DM; polyneuropathy; mononeuritis multiplex	3 patients	ASP, GC, LMWH, AZA, oral anticoagulation
10	Kim et al. 17	2015	Korea	7	27.71 (17–43)	1/6	NA	1 patient	ASP, PTX, GC, PGE1, HBOT, nifedipine, colchicine, danazol
11	Vieira et al. 18	2016	Portugal	1	58	0/1	NA	None	GC, gabapentin
12	Yoshioka et al. 19	2018	Japan	1	51	0/1	SLE	1 patient	GC, AZA, antiplatelet
13	Ozden et al. 20	2020	Turkey	9	45.89 (25–68)	0/9	HTN; DM; stroke	NA	GC, ASA, MTX, LMWH, colchicine, diosmin, mycophenolate sodium
14	Scarpone et al. 5	2020	Germany	2	33.5 (28–39)	0/2	Polyneuropathy	NA	PTX, LMWH, ASA, MTX, GC, CTX, AZA, etoricoxib, enoxaparin, cyclosporine
15	Dinescu et al. 21	2020	Romania	1	41	0/1	None	NA	GC, LMWH, sulodexide, colchicine, peripheral vasodilators, antiplatelet drugs, sulfasalazine, danazol
16	Kofler et al. 22	2021	Germany	25	66.4 (46–83)	15/10	HTN; DM; RA; SLE; malignant tumor; peripheral arterial disease; thrombosis	7 patients	GC, ASA, LMWH, rivaroxaban, apixaban
17	Takahagi et al. 23	2021	Japan	1	60	0/1	NA	NA	GC, CTX, ASP, warfarin, beraprost

ASA, acetylsalicylic acid; ASP, aspirin; AZA, azathioprine; COPD, chronic obstructive pulmonary disease; CTX, cyclophosphamide; DM, diabetes mellitus; F, female; GC, glucocorticoid; HBOT, hyperbaric oxygen therapy; HTN, hypertension; LMWH, low-molecular-weight heparin; M, male; MTX, methotrexate; NA, not available; NSAID, nonsteroidal anti-inflammatory drugs; PGE1, prostaglandin E1; PTX, pentoxifylline; PUVA, psoralen and UV-A; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; tPA, tissue plasminogen activator.

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Table 2.

Efficacy and safety of IVIG in the treatment of LV.

No.	Authors	Dosage per cycle	Frequency	Duration	Responded patients	Efficacy	Recurrence	Combination treatment	Adverse events
1	Levy et al. 8	0.4 g/kg for 5 days	4 weeks and gradually prolonged	NA	2 patients	Significant resolution of lesions and pain since 3 cycles; CTX non-dependent after 6 cycles	NA	NA	NA
2	Amital et al. 11	NA	NA	NA	1 patient	Significant resolution of lesions and pain	NA	NA	NA
3	Ravat et al. 7	0.4 g/kg for 5 days; 1 g/kg for 1 day	4 weeks; 6 weeks and gradually prolonged	NA	2 patients	Ulcers healed and pain relief in 4 weeks	NR 1 year	None	None
4	Schanz et al. 12	0.5 g/kg for 4 days	4 weeks and gradually prolonged	5 cycles	1 patient	Remarkable effect after 3 cycles	NR more than 10 months	None	NA
5	Kreuter et al. 13	0.5 g/kg for 2–3 days	4 weeks and gradually prolonged	Median 7.6 cycles (2–22 months)	8 patients	A dramatic relief of pain after first 2 cycles	NR 3 months	Systemic immunosuppressive treatment	Headache, nausea
6	Pitarch et al. 14	0.4 g/kg for 5 days; 0.7 g/kg for 3 days	6 weeks	2 cycles	1 patient	Ulcers healed completely in 4 weeks	NR	GC	None
7	Tuchinda et al. 15	0.5 g/kg	2 weeks	NA	1 patient	Responded to IVIG	NA	None	NA
8	Bounfour et al. 16	1 g/kg for 2 days	4 weeks	Median 4.4 (3–6) cycles	4 patients	Remarkable improvement on pain and ulcers at 4 weeks	3 patients relapsed; median 10.7 months	ASP, GC, MTX, clopidogrel	Headache
9	Monshi et al. 6	2 g/kg over 2–3 days	4 weeks	6–15 cycles	10 patients a	Pain relief in 80% after 2 cycles; disease severity improved after 6 cycles	8 patients relapsed in 1.8–50.4 months; NR in 26.7–59.1 months	ASP, LMWH, oral anticoagulation	Headache, nausea
10	Kim et al. 17	2 g/kg over 3–5 days	4 weeks	2–3 cycles	7 patients	Responded to IVIG, especially pain relief	6 patients relapsed in median 12.67 months (4–19 months); 1 patient NR for 7 years	NA	Headache, nausea/vomiting
11	Vieira et al. 18	2 g/kg over 5 days	4 weeks	NA	1 patient	Pain, dysesthesia and ulcers improved	Relapsed after 8 years	Warfarin	NA
12	Yoshioka et al. 19	0.4 g/kg for 5 days	Once	1 cycle	1 patient	Ulcers improved in 6 weeks	NA	Warfarin	NA
13	Ozden et al. 20	2 g/kg over 3 days	4 weeks	3–6 cycles	9 patients	Complete response in 6 patients(3–6 months), partial response in 3 patients; pain and ulcers started to improve after first cycle	2 patients relapsed in 6 months	Anticoagulants	Headache, fatigue, temporary changes in blood pressure
14	Scarpone et al. 5	1 g/kg over 2 days; 2 g/kg over 2 days	4 weeks and gradually prolonged	Median 25 (6–44) cycles	2 patients	Ulcers completely healed in 1 patient; dysesthesias regressed in 1 patient	1 patient NR	ASA, clopidogrel, cyclosporine, dalteparin	Headache, nausea
15	Dinescu et al. 21	NA	4 weeks	NA	1 patient	Complete remission of ulcer after 6 cycles	NA	NA	NA
16	Kofler et al. 22	2 g/kg over 5 days	25–28 days	Median 6.8 (1–45) cycles	24 patients	Complete remission in 17 patients after median 4.4 (1–14) cycles	2 patients relapsed less than 3 months	ASP, heparin, oral anticoagulants	Headache, nausea, dizziness, circulatory problems
17	Takahagi et al. 23	1.75 g/kg over 5 days	10 weeks	2 cycles	1 patient	Prompt improvement on pain and ulcers	NR 7 years	NA	None

ASA, acetylsalicylic acid; ASP, aspirin; CTX, cyclophosphamide; GC, glucocorticoid; LMWH, low-molecular-weight heparin; MTX, methotrexate; NA, not available; NR, no recurrence.

a

A total of 10 patients responded to IVIG: 9 patients achieved remission after 3 cycles; 1 refractory patient successfully retreated after 6 years with 7 cycles.

General results

Eighty LV patients from 17 studies, case series, and case reports who received IVIG treatment were included. Among them, 24 patients (30%) were men and 56 patients (70%) were women, with a male-to-female ratio of 1:2.33. The median age of LV patients in this systematic review was 46.64 years, ranging from 17 to 83 years. The comorbidities for LV patients are summarized in Table 3. Hypertension (n = 22) and diabetes mellitus (n = 9) were the first and second most common comorbidities that were recorded in the selected articles. Other documented comorbidities included autoimmune diseases [e.g. systemic lupus erythematosus (n = 3), rheumatoid arthritis (n = 5), and antiphospholipid syndrome (n = 1)], thrombotic diseases [e.g. stroke (n = 1), thrombosis (n = 6), and peripheral arterial disease(n = 4)], neuropathy [e.g. polyneuropathy (n = 3) and mononeuritis multiplex (n = 1)], chronic obstructive pulmonary disease (n = 1), and malignant tumor (n = 6). Screening for thrombophilic factors was conducted in 63 LV patients. Fourteen LV patients (22.22%) had at least one thrombophilic factor that was mentioned above. Most LV patients receiving IVIG therapy were intractable cases, and they had been previously treated with multiple medications but had a poor response or had frequent recurrences. The previous therapeutic medications are mainly divided into the following categories: glucocorticoid, immunosuppressive agents, nonsteroidal anti-inflammatory drugs, anticoagulants, antiplatelet drugs, vasodilator drugs, and other treatments such as hyperbaric oxygen therapy and local plastic surgery (Table 1).

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Table 3.

Details about comorbidities in LV patients.

Comorbidities	Patients
Hypertension	22
Diabetes mellitus	9
Systemic lupus erythematosus	3
Rheumatoid arthritis	5
Antiphospholipid syndrome	1
Stroke	1
Thrombosis	6
Peripheral arterial disease	4
Polyneuropathy	3
Mononeuritis multiplex	1
Chronic obstructive pulmonary disease	1
Malignant tumor	6

Efficacy of IVIG

Among the 80 LV patients who received IVIG treatment, 75 LV patients responded well to this therapy. In addition, one refractory LV patient was resistant to IVIG therapy in the initial disease episode but was successfully retreated with IVIG for a relapse 6 years later. ⁶ Overall, the total effective rate of IVIG therapy in LV patients was as high as 95% (76/80) in the published studies. IVIG therapy was generally effective in treating refractory LV patients who were resistant to previous treatment, and it was also effective in patients with new-onset LV when IVIG was used for the initial treatment. Among the five LV patients who had not been prescribed any treatment before they received IVIG therapy for the first time, four of them achieved a favorable clinical response. ⁶ There was no significant difference in the efficacy of IVIG therapy in LV patients with and without thrombophilic factors.

The curative effect of IVIG therapy in LV is mainly reflected in the following aspects: (1) IVIG acted quickly to resolve pain in LV patients after one to three cycles of treatment, as described in the published studies. In four articles, the earliest pain remission began to appear during the first cycle of IVIG therapy.^7,16,20,23 Eighty percent of pain was resolved after two IVIG cycles in a long-term follow-up study of 11 LV patients; ⁶ (2) ulceration healing usually lagged behind pain resolution. The resolution of skin ulcerations lasted from 1 to 14 cycles in the published studies;^{6,7,8,12,14,16,19–23} (3) neurological symptoms such as numbness and hypoesthesia caused by ischemic nerve damage are common in LV. ²⁴ However, conventional medications have little influence on LV neuropathy. In addition to the efficacy of IVIG on pain and ulcerations, there was also improvement in dysesthesia along with IVIG treatment maintenance;^5,18 and (4) because LV frequently recurs, using IVIG reduced the patient’s dependence on conventional medications such as glucocorticoids and immunosuppressive agents that have multiple severe side effects when used in the long term. Levy et al. ⁸ described an LV patient who was no longer dependent on cyclophosphamide after six cycles of IVIG therapy.

Frequency and dosage of IVIG

The initial frequency of IVIG therapy was 4-week intervals in most articles,^{5–8,12,13,16–18,20,22} except for two articles (including two patients) in which the IVIG dose information was vague.^11,21 There were also a few LV patients who received IVIG as a single shot or at 2-week, 6-week, and 10-week intervals.^{7,14,15,19,23} The interval for IVIG therapy was gradually prolonged on the basis of its efficacy and the patients’ response. The details in doses and duration of maintenance phase were limited and mainly depended on clinical experience of dermatologists and disease activity. In maintenance phase, some LV patients paused IVIG therapy directly after receiving 1–3 cycles,^17,19,23 or gradually prolonged their intervals for IVIG infusions to 6-week, 8-week, or even 4- to 6-month interval.^5,7 Conventional treatments like anticoagulants or antiplatelet medications were gradually applied as combination therapy in maintenance phase.

The total monthly dose of IVIG ranged from 1 to 2.1 g/kg body weight, which could be divided into a high-dose IVIG group (2–2.1 g/kg body weight) and a low-dose IVIG group (1–1.5 g/kg body weight). Here, we demonstrated the detailed information about dosage, duration, treatment outcomes, and adverse events of low-dose and high-dose IVIG groups in Table 4. Sixty-five LV patients [84.42% (65/77)]^{5,6,7,8,12,14,16–20,22} received high-dose IVIG therapy, whereas 12 LV patients [15.58% (12/77)]^5,7,13,15 received low-dose IVIG therapy. The IVIG dose in one LV patient decreased to 1 g/kg body weight after a dramatic clinical response at the initial dose of 2 g/kg body weight, but this led to a less dramatic improvement. ⁷ Compared with the low-dose IVIG group, ¹³ the high-dose IVIG group achieved remission in fewer cycles, indicating that it was a more effective LV treatment. ⁶

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Table 4.

Detailed information about dosage, duration, treatment outcomes, and adverse events of low-dose and high-dose IVIG groups.

Authors	Patients	Dosage per cycle	Duration	Treatment outcome	Adverse effect
High-dose group
Scarpone et al. 5	1	2 g/kg over 2 days	NA	Skin lesions healed completely	Headache, nausea
Monshi et al. 6	11	2 g/kg over 2–3 days	6–15 cycles	Pain relief in 80% after 2 cycles; disease severity improved after 6 cycles	Headache, nausea
Ravat et al. 7	1	0.4 g/kg for 5 days	NA	The patient respond to 2 g/kg for the first cycle and tried 1 g/kg with less dramatic improvement, subsequent doses were 2 g/kg	NA
Levy et al. 8	2	0.4 g/kg for 5 days	NA	Significant resolution of lesions and pain since 3 cycles; CTX non-dependent after 6 cycles	NA
Schanz et al. 12	1	0.5 g/kg for 4 days	5 cycles	Remarkable effect after 3 cycles	NA
Pitarch et al. 14	1	0.4 g/kg for 5 days; 0.7 g/kg for 3 days	2 cycles	Ulcers healed completely in 4 weeks	None
Bounfour et al. 16	5	1 g/kg for 2 days	Median 4.4 cycles	Remarkable improvement on pain and ulcers at 4 weeks	Headache
Kim et al. 17	7	2 g/kg over 3–5 days	2–3 cycles	Responded to IVIG, especially pain relief	Headache, nausea/vomiting
Vieira et al. 18	1	2 g/kg over 5 days	NA	Pain, dysesthesia and ulcers improved	NA
Yoshioka et al. 19	1	0.4 g/kg for 5 days	1 cycle	Ulcers improved in 6 weeks	NA
Ozden et al. 20	9	2 g/kg over 3 days	3–6 cycles	Pain and ulcers started to improve after first cycle	Headache, fatigue, temporary changes in blood pressure
Kofler et al. 22	25	2 g/kg over 5 days	Median 6.8 cycles	Complete remission in 17 patients after median 4.4 cycles	Headache, nausea, dizziness, circulatory problems
Low-dose group
Scarpone et al. 5	1	1 g/kg over 2 days	NA	Symptoms improved quickly, dysesthesias regressed	Headache
Ravat et al. 7	1	1 g/kg for 1 day	NA	2 g/kg IVIG for the first cycle and 1 g/kg IVIG for subsequent infusions led to healing of active lesions and relief of pain	NA
Kreuter et al. 13	9	0.5 g/kg for 2–3 days	Median 7.6 cycles	A dramatic relief of pain after first 2 cycles	Headache, nausea
Tuchinda et al. 15	1	0.5 g/kg every 2 weeks	NA	Responded to IVIG	NA

CTX, cyclophosphamide; IVIG, intravenous immunoglobulin; NA, not available.

LV patients receiving a dose of 2–2.1 g/kg body weight IVIG therapy could also be classified as a conventional daily dose group (0.4–0.5 g/kg body weight per day) and a high daily dose group (over 0.5 g/kg body weight per day) on the basis of their daily dose of IVIG per cycle. Except for the vague description of the daily dose per cycle in one study, ¹⁷ among the LV patients who received high-dose IVIG therapy (2–2.1 g/kg body weight per cycle), 27 of these LV patients received a high daily dose of IVIG that was more than 0.5 g/kg body weight per day, while 31 LV patients received a conventional daily dose of IVIG, which was 0.4–0.5 g/kg body weight per day. Although the sample size is relatively small, LV patients who received a high daily dose of IVIG seemed to achieve faster resolution of pain and ulcerations compared with LV patients who received the conventional daily dose.^6,14,16,20

Recurrence

Twenty-three patients experienced recurrence in this systematic review.^{5,6,16–18,20,22} Among them, the shortest recurrence period after suspending IVIG treatment was less than 3 months, and the longest interval with no recurrence was 8 years. After achieving complete remission, two LV patients had a relapse less than 3 months after discontinuing IVIG therapy. ²² With maintenance IVIG and warfarin treatment, one LV patient relapsed after 8 years, after which she was successfully treated with rituximab. ¹⁸

Adverse events

IVIG therapy was well tolerated in most of LV patients. Adverse events that were recorded were moderate. The most common adverse event in IVIG therapy was headache, which occurred in 11 LV patients during IVIG therapy in this systematic review, and these adverse events were usually mild and resolved spontaneously.^{5,6,13,16,17,20,22} Overall, the incidence of headache for LV patients during IVIG therapy was 13.75% (11/80). Other adverse events included nausea, vomiting, fatigue, dizziness, temporary changes in blood pressure, and circulatory problems.^{5,6,13,17,20,22}