Intravenous immunoglobulin as a treatment for severe,refractory cutaneous lupus erythematosus requiring hospitalization: Three cases and review of the literature

Dear Editor,

Patients with systemic lupus erythematosus (SLE) often suffer from cutaneous LE (CLE), which is divided into acute (ACLE), subacute (SCLE), or chronic (CCLE). ¹ Antimalarials are the cornerstone of treatment, with corticosteroids and disease modifying anti-rheumatic drugs reserved for severe cases. ¹ While intravenous immunoglobulin (IVIg) has been used to treat nearly all manifestations of SLE, there is limited evidence for the use of IVIg in treating severe, skin-predominant SLE in hospitalized patients.^2,3 Here, we describe a series of inpatients with SLE and severe cutaneous involvement refractory to standard immunosuppressants whose conditions rapidly improved with IVIg.

Case 1: A 61-year-old female with HCV-induced cirrhosis was admitted to the ICU with altered mental status and a three-day history of a generalized purpuric rash with scattered flaccid bullae and skin sloughing after completing ceftriaxone for a urinary tract infection 9 days prior (Figure 1(A) and (B)). Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN)-like ACLE was strongly favored over SJS/TEN due to the lack of mucosal involvement, malar rash sparing the nasolabial folds, and nonscarring alopecia.^4,5 Labs revealed a positive ANA and anti-dsDNA/Ro52/Ro60, pancytopenia, hypocomplementemia, and proteinuria (Table 1). Skin biopsy demonstrated mild vacuolar dermatitis. She was diagnosed with SLE and SJS/TEN-like ACLE and started on IV methylprednisolone 1 mg/kg and hydroxychloroquine. On day 3, IVIg (2 g/kg) was initiated due to progression of her skin disease (Figure 1(C)), resulting in improvement of her cutaneous disease and mental status within 3 days (Figure 1(D)).OPEN IN VIEWER

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Table 1.

Patient summary, clinical characteristics, compared to those from case series in the literature.

Reference	n	Age	Sex	Outpatient vs inpatient	Diagnosis	Systemic manifestations	Data	Treatment	Outcome
Piette et al., Arthritis Rheum (1995) 9	5	Not listed	Not listed	Outpatient	DLE	Recalcitrant DLE	Not listed	IVIg 1 g/kg divided over 2 days monthly + HCQ, steroids	3/5 showed significant improvement cutaneous lesions
DePita et al., Lupus (1997) 10	7	15–49	F	Outpatient	SLE (5 pts) SCLE (2 pts)	Malar rash, oral ulcers; SCLE lesions	ANA (5/7), dsDNA (5/7), Sm (2/7)	IVIg 300 mg/kg/d for 5 days × 12 months	Improvement in asthenia, arthralgia, myalgia, fever, and reduction of initial autoantibody titer (ANA, dsDNA, and increase in C3). No change in skin lesions.
Levy et al., Lupus (1999) 11	17 3	21–52	F M	Not listed	1 with ACLE (malar rash) and 1 with anti-malarial-resistant DLE	SLE with at least 4 ACR criteria (several with anemia, thrombocytopenia, arthralgia, proteinuria) and 2 with CLE	Pre-treatment auto-Abs not listed	IVIg 400 mg/kg/d for 5 days monthly for 1–8 months + HCQ 400 mg/d	17/20 patients with responses SLAM score decreased from 193 > 4 in 9/20 patients Responders tended towards abnormal complement/auto-Abs before IVIg
Généreau et al., Arch. Derm. (1999) 12	1	30	F	Outpatient	SCLE and ACLE (without SLE) refractory to antimalaria	Mild leukopenia, thrombocytopenia	Thrombocytopenia, SSA	IVIg 2 g/kg/month + HCQ 400 mg/d + topical betamethasone	Improvement within 3 months and disappearance of lesions in 6 months
Goodfield et al., J. Derm Treat (2004) 13	10 2	24–62 42–48	F M	Outpatient	5 with SCLE, 5 with disseminated DLE, 1 with SLE and DLE, 1 with bullous LE (all refractory)	Arthritis, 1 with membranous nephropathy, two with APLS, 2 with vasculitis and Sjogren’s	ANA (12/12) and Ro or La (8/12)	IVIg 1 g/kg/d for 2 days followed by 400 mg/kg/monthly for 6 months + Prednisone 5–10 mg/d	5 pts with complete clearing, 2 with partial, and 3 with limited response. Greater efficacy in SCLE patients
Kreuter et al., Acta Derm Venerol (2005) 14	1	55	F	Outpatient	SCLE (refractory)	SCLE (face and upper trunk), livedo reticularis alopecia, periungual telangiectasia, Raynaud’s	ANA, Ro/SSA, La/SSB, Rf, decreased C3/C4	IVIg 1 g/kg/d for 3 days for 3 cycles followed by 0.5 g/kg/d for 3 days for 3 cycles + Prednisone 12.5 mg (Failed HCQ 4 mg/kg/d, Prednisone 30-150 mg/d, and AZA 150 mg/day)	Clearance of SCLE by cycle 3, with new lesions after 6th IVIg cycle when prednisone taper to 10 mg/d
Lampropoulos et al., Clin. Rheum. (2007) 15	3	43, 40, 35	F	Inpatient	SLE/SCLE (1); SCLE (2)	Lupus nephritis, SCLE refractory to IV MP 60 mg/d, HCQ, Tacrolimus; SCLE refractory to HCQ and mepacrine; SCLE refractory to MTX, HCQ, and IV MP	ANA/Ro/La, dsDNA, decreased C3/C4; ANA, Ro/Rf; weakly positive for ANA, Ro	IVIg 400 mg/kg/d for 5 days Post IVIg maintenance: MMF 1.5 g/day + HCQ 400 mg/d (1 pt) Topical tacrolimus (1 pt) MMF + tacrolimus followed by acitretin (1 pt)	Significant improvement in rash in affected areas for all 3 patients 2nd patient required additional 20 g single dose IVIg for full remission 3rd patient required additional 3 months of IVIg
Ky et al., Derm. Reports. (2015) 16	15 1	15–70	F M	Outpatient	CLE refractory to typical systemic treatments (HCQ, prednisone, dapsone)	Not provided	Not provided	IVIg 500 mg/kg/d for 4 days for 3 months (monotherapy)	5/16 with decrease in CLASI-A that persisted for 6 months; 3/16 had a flare which recovered in 1 month
Tenti et al. Autoimm. Reviews, (2018) 3	1	65	F	Outpatient	DLE	None	ANA (speckled)	IVIg 400 mg/kg/d for 3 days for 6 months + HCQ 400 mg/d + Prednisone tapered from 5 mg/d to 2.5 mg/d	Resolution of diffuse rash with IVIg
This paper	1	61	F	Hospitalized for altered mental status, cystitis, and diffuse purpuric rash with malar involvement, flaccid bullae, and skin sloughing occurring 3 days after rash onset	ACLE/SLE	Pancytopenia, proteinuria	ANA, dsDNA, Ro52, Ro60, negative HSV1/2 Biopsies: spongiotic and mild vacuolar interface dermatitis (abdomen and left thigh), negative DIF	IVIg 2 g/kg divided over 5 days and RTX after ineffective 5-day treatment with IV MP	Significant improvement in cutaneous disease and mental status within 3 days of IVIg initiation
	2	19	F	Hospitalized for rapidly worsening DLE/SCLE	DLE/SCLE/SLE	Alopecia, Arthritis, pericarditis, hypocomplementemia, proteinuria, stage IV lupus nephritis	ANA, dsDNA, Sm, RNP, Ro52, Ro60Biopsies: DLE (right cheek), exuberant vacuolar interface dermatitis (left central back), positive DIF	IVIg 2 g/kg divided over 4 days (previously on HCQ, prednisone, belimumab, and cyclophosphamide)	CLASI-Activity improved from 33 to 3 following 1 cycle; residual inflammation and erythema resolved by 3rd cycle
	3	37	F	Hospitalized for photo- distributed rash with vesicles, focal skin sloughing occurring 9 days after onset of rash, oral ulcers, and elevated LFTs after tuberculosis treatment	ACLE/SLE	Alopecia, arthritis, leukopenia, hypocomplementemia, APLS, lupus cerebritis	ANA, dsDNA, Ro, La, RNP, negative HSV 1/2, negative mycoplasmaBiopsy: mild vacuolar interface dermatitis, pigment incontinence (neck), negative DIF	IVIg 2 g/kg divided over 5 days (in setting of tuberculosis treatment and failure to improve with IV MP)	Significant improvement in cutaneous disease within 3 days of IVIg initiation

Abbreviations: ACLE = Acute cutaneous lupus erythematosus; SLE = systemic lupus erythematosus; ANA = Anti-nuclear antibody; dsDNA = double stranded DNA antibody; Ro52 = Ro52 antibody; Ro60 = Ro60 antibody; DIF = direct immunofluorescence; IVIg = intravenous immunoglobulin; RTX = rituximab; IV MP = intravenous methylprednisolone; DLE = discoid lupus erythematosus; Sm = Smith antibody; RNP = ribonuclear protein antibody; HCQ = hydroxychloroquine; LFT = liver function test; APLS = anti-phospholipid syndrome; La = La antibody; Auto-Abs = autoantibodies; SLAM score = Systemic Lupus Activity Measure (SLAM) score; MTX = methotrexate; CLASI-A = Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity (CLASI-A); MMF = mycophenolate mofetil.

Case 2: A 19-year-old female with SLE (ANA, anti-dsDNA/Sm/RNP/Ro52/Ro60, hypocomplementemia, alopecia, arthritis, pericarditis, stage IV lupus nephritis) and DLE presented to the ED with rapidly worsening DLE and features of SCLE despite hydroxychloroquine, prednisone, belimumab, and recent cyclophosphamide therapy. Following one cycle of IVIg, her CLASI-Activity improved from 33 to 3 (Figure 1(E) and (F)).

Case 3: A 37-year-old female with SLE (ANA, anti-dsDNA/Ro/La/RNP, alopecia, arthritis, lupus cerebritis, leukopenia, hypocomplementemia) was admitted for a generalized dusky rash with scattered overlying vesicles and violaceous patches on the face, oral ulcers, lymphadenopathy, and elevated liver enzymes 10 days after initiating treatment for active tuberculosis. Her exam was concerning for ACLE versus severe cutaneous adverse reaction, including DRESS syndrome and SJS/TEN. Accentuation of her rash in photo-distributed areas, involvement of only one mucosal surface (oral), gradual rather than acute development of foci of denuded skin, non-scarring alopecia, and lack of eosinophilia favored ACLE versus DRESS or SJS/TEN.^4,5 Initial skin biopsy revealed full-thickness epidermal necrosis. However, repeat biopsy, physical exam, and laboratory studies were consistent with ACLE (Table 1). She continued to develop flaccid vesicles despite IV methylprednisolone 2 mg/kg (Figure 1(G) and (H)). IVIg was added to minimize immunosuppression given her untreated active tuberculosis and resulted in improvement of her disease within 3 days (Figure 1(I)). As with Case 1, rapid disease improvement with IVIg further supported the diagnosis of ACLE versus SJS/TEN, which often progresses even with steroids and IVIg.

Nine out of 10 prior reports describe clinical improvement in patients with CLE treated with IVIg. Only two describe the efficacy of IVIg for acute facial CLE (Table 1). However, none describes the use of IVIg for patients with SLE with severe, skin-predominant disease requiring hospitalization. Here, we show that IVIg may be an effective and safe therapy for such patients, particularly in those with high autoantibody burdens. While the predominant mechanism of action of IVIg in CLE is unknown, IVIg exerts diverse immunomodulatory activities. In cases of CLE driven by autoantibodies, IVIg may mitigate disease by saturating the neonatal Fc receptor, thereby reducing the half-life of autoantibodies. In ACLE, anti-CD95 (FAS) antibodies in IVIg preparations may block the CD95-CD95 L interactions involved in keratinocyte death and acantholysis. ⁶ In CCLE/SCLE, which are known to have an elevated Type I interferon signature, ⁷ IVIg has been shown to outcompete pathogenic immune complexes from binding to Fcγ receptor IIa on cutaneous plasmacytoid dendritic cells, thereby blunting downstream activation of toll-like receptors 7 and 9 that otherwise stimulate production of interferon-α. ⁸ Future studies on the use of IVIg could inform additional management and treatment strategies.