Table 2.

The use of intravenous immunoglobulins in rheumatologic diseases

Disease	Ref.	Study design	Intervention including dose and IVIg preparation used	Number of patients	Results/response
Systemic lupus erythematosus (SLE) systemic flare-up	[36]	Controlled trial	IVIg 0.4 g/kg for 5 days, between 1 and 8 monthly courses (mean 5; ISIVEN-Instituto Sierovaccinogeno, Italiano ISI SpA.)	20 patients with active SLE	Beneficial clinical response in 17 out of 20 pts (p < 0.0001); especially in arthritis, fever, thrombocytopenia, and CNS lupus
	[37]	Uncontrolled multicenter trial	IVIg 0.4 g/kg for 5 days	13 females with acute exacerbation of SLE	After IVIg treatment, the modified European Consensus Lupus Activity Measurement (mECLAM) declined in 12 out of 13 pts by ≥3 points (p = 0.0002)
	[38]	Uncontrolled trial	30 g of sulfonated IVIg preparation on days 1–4 and 21–24	12 patients with mild-to-moderate active SLE	Within 6 weeks, the mean Systemic Lupus Activity Measure (SLAM) score declined from 7.3 to 5.25 (p < 0.01); in a minority, this effect lasted 5–12 months
	[19]	Retrospective trial	Review of medical records of patients with SLE that were treated with low-dose IVIg (0.5 g/kg) for several courses	62 patients	Clinical improvement in most disease manifestations including pericarditis; not including thrombocytopenia and alopecia
Lupus myocarditis	[39]	Case series	IVIg 0.4 g/kg per day for 5 days, in addition to CP or MMF (given to 2 patients)	3 patients with lupus myocarditis and severe deterioration in contractile functions; high-dose CS had little effect	Marked clinical improvement; decreased need for CS
	[40]	Case report	IVIg 0.4 g/kg per day for 5 days	1 patient with lupus myocarditis refractory to CS	Marked improvement of severe cardiac dysfunction after one course of IVIg
SLE and thrombocytopenia	[41]	Retrospective trial	IVIg 2 g/kg for 2 to 5 days	31 patients with severe thrombocytopenia associated with SLE refractory to PD treatment	A transient response was observed in 20 patients (65%); no sustained response was observed
Subacute cutaneous lupus erythematosus (SCLE)	[42]	Case series	IVIg with starting doses of 1 g/kg for 2 days, followed by 0.4 g/kg monthly, until disease resolution or for 6 months	12 patients with resistant SCLE	5 patients had complete or near-complete clearing of their skin disease; two had partial improvement and 3 had limited responses
	[43]	Case series	IVIg 0.3 g/kg per day for 5 days each month for 12 months	7 patients with skin disease (5 had systemic LE; two had SCLE)	IVIg was unable to control cutaneous disease efficiently
	[44]	Case series	IVIg	3 patients with SCLE resistant to topical and systemic therapy	Good response
	[45]	Case report	IVIg 2 g/kg monthly	30-year-old woman with SCLE	Good response
Various manifestations of SLE	[46]	Various case reports	Different IVIg preparations and doses	26 patients with specific lupus manifestations refractory to standard Tx.: autoimmune hemolytic anemia (2), acquired factor VIII inhibitors (2), acquired von Willebrand disease (2), pure red cell aplasia(3), pancytopenia (1), myelofibrosis (1), pneumonitis (2), pleural effusion (1), pericarditis (2), myocarditis (2), CNS lupus (6), peripheral neuropathy (1), polyradiculoneuropathy (1)	Improvement of SLE-related condition
For lupus nephritis, see kidney section
For Kawasaki disease, see cardiology section
Kikuchi Disease	[47]	Case report	IVIg 0.4 g/kg per day for 3 days	A 35-year-old patient with Kikuchi, refractory to steroids and thalidomide	A definite improvement in her facial swelling occurred within 4 days, followed by gradual but complete resolution of lymphadenopathy over the subsequent 8 weeks, despite stopping steroid medication
	[48]	Case report	IVIg 1 g/kg per day for 2 days, plus PD (2 mg/kg per day)	2 children who had Kikuchi complicated with hemophagocytic syndrome	One responded dramatically; second case responded partially to IVIg and fully after PD was added
Still’s disease	[49]	Uncontrolled trial	Patients received monthly IVIg	7 patients unresponsive or poorly responsive to nonsteroidal anti-inflammatory drugs	5 patients responded after 4–6 treatments; 2 failed to respond
	[50]	Uncontrolled trial	Between 1 and 8 IVIg monthly infusions with a dose of 1 g/kg per day for 2 days	7 patients suffering from adult Still's disease	All patients improved but relapsed after 3–24 months
	[51]	Case report	2 courses of IVIg 1 g/kg for 2 days	23-year-old patient with flare-up of disease while taking salicylates at gestational week 22	Significant clinical and laboratory improvement
Granulomatous arteritis (GA, Wegener's granulomatosis)	[52]	Multicentered RCT	14 patients received IVIg 2 g/kg in 5 days (sandoglobulin Novartis) vs. 14 placebo	34 patients with ANCA-associated vasculitis (GA or MPA), refractory to CS or CP	Reduction in Birmingham Vasculitis Activity Score of 50% in 14/17 and 6/17 of the IVIg and placebo groups, respectively
	[53]	Uncontrolled trial	Patients received IVIg (Sandoglobulin)	14 patients with GA who responded poorly to standard therapy	All patients were in full and partial remission after 8 weeks; clinical benefit was maintained a year later
	[54]	Uncontrolled trial	Single or multiple courses of IVIg, 30 g/day, over 5 days	15 patients with GA who responded poorly to standard therapy	40% of patients benefited from IVIg treatment but without complete remission
	[55]	Uncontrolled trial	Monthly IVIg, 0.4 g/kg for 5 days, 1–6 cycles (Isiven Instituto Sierovaccinogeno, Italiano ISI SpA.)	10 patients with GA, CSS, or undifferentiated vasculitis which were refractory to standard treatment	IVIg treatment was found beneficial in 6 out of the 10 patients
	[56]	Uncontrolled trial	IVIg 0.5 g/kg per day for 4 days; Sandoglobulin (Sandoz, Basel, Switzerland)	3 patients with GA not treated with immunosuppressants before	One patient had full remission; one had transitional response; one had no response
Microscopic polyangitis (MPA)	[57]	Uncontrolled trial	IVIg 0.4 g/kg per day for 5 days, before or along with CS or CP (kenketsu velilon-I, Teijin Co., Ltd., Tokyo or kenketsu Glovenon-I, Nihon pharmaceutical Co., Ltd., Tokyo, Japan)	30 patients with MPA plus rapidly progressive glomerulonephritis	At 6 months, renal and general survival were 92% and 93%, respectively, compared to 70% and 74% with conventional therapy in other studies
	[56]	Uncontrolled trial	IVIg 0.5 g/kg per day for 4 days (Sandoglobulin, Sandoz, Basel, Switzerland)	3 patients with MPA not treated with immunosuppressants before	One patient had full remission; one had transitional response; one had no response
	[53]	Uncontrolled trial	Patients received IVIg (Sandoglobulin)	11 patients with MPA who responded poorly to standard therapy	8 weeks after IVIg, all patients were in full and partial remission, clinical benefit was maintained 12 months later in most patients
Churg–Strauss syndrome (CSS)	[58]	Controlled trial	All patients received PS and CP in severe cases; 9 received monthly PP, followed by IVIg 1 g/kg for 2 days (Ig vena N IVH; Sclavo, Siena, Italy)	18 patients with CSS	After 12 months, all patients in the IVIg group and 4 (44%) in the control group were in remission; a significant favorable outcome was kept after 3 years (p < 0.01)
	[59]	Case series	Daily IVIg 0.4 g/kg for 5 days	5 patients with cardiac CSS who showed poor response to PS ± CP	Neuropathy improved; EF of patients improved from 35.2% to 61% (p < 0.02)
	[55]	Case report	5–6 courses of monthly IVIg, each course 0.4 g/kg for 5 days (Isiven Instituto Sierovaccinogeno, Italiano ISI SpA.)	2 patients with CSS, nonresponsive to standard treatment	First patient had no improvement; second patient had clinical and laboratory improvement and was steroid-spared
Autoimmune hepatitis (AIH)	[60]	Case report	IVIg was initiated because of adverse affects of long-term steroid therapy	A patient with chronic AIH	Immediate clinical, serological, and histological improvement
Autoimmune features in hepatitis C virus (HCV) infection	[61]	RCT	IVIg 0.4 g/kg for 5 days, and then IFN alpha 3 times a week, compared to treatment with IFN alpha alone	42 patients with HCV and autoimmune phenomena	A higher percentage of patients who received IFN alpha plus IVIg showed complete virological and histological responses
Henoch–Schönlein purpura (HSP)	[62]	Cohort study	IVIg 1 g/kg for 2 days, every month for 3 months (Biotransfusion, Roissy, France)	11 adult patients with severe IgA nephropathy (9 idiopathic, 2 with HSP)	Substantial improvement in glomerular filtration rate and kidney functions; 2 patients with HSP had resolution of other systemic symptoms
	[63]	Case report	IVIg (Tegelines) 1 g/kg per day for 2 days	A 10-year-old boy with HSP and severe abdominal manifestations refractory to treatment with CS	Digestive symptoms disappeared within 3 days
	[64]	Case report	Patient was treated with IVIg	A 26-year-old woman with HSP with nephrotic syndrome refractory to CS	Dramatic resolution
	[65]	Case report	IVIg (polyglobulin N containing maltose) 0.4 g/kg, for 2 days	46-year-old man with HSP and MPGN	Developed hemolysis and rapid deterioration renal function
	[66]	Case report	IVIg 1 g/kg for 2 days	56-year-old man with HSP and severe digestive manifestations	The patient's purpura and abdominal syndrome improved dramatically
Mixed connective tissue disease (MCTD)	[67]	Case report	IVIg 0.4 g/kg for 5 days	A woman with MCTD and fasciitis	Quick improvement of her symptoms and decreased CRP
	[68]	Case report	Patient was treated with IVIg	A 69-year-old man with MCTD and nonresponsive skin eruptions	Successful control of disease
Systemic sclerosis (SSc)	[69]	Controlled trial	IVIg 0.4 g/kg daily for 5 days, monthly for 3–6 cycles	15 patients with SSc	Treatment resulted in significant improvement in quality of life (p = 0.03) and a decrease in Rodnan skin score (p < 0.001)
	[70]	Case series	IVIg 0.4 g/kg daily for 5 days	5 patients with diffuse SSc	Marked long-term improvement in skin thickness from 2 weeks of treatment (p < 0.01)
	[71]	Controlled trial	Monthly IVIg 0.4 g/kg for 4 days, for 6 months	7 female patients with SSc (5 limited, 2 diffuse), with a severe refractory joint involvement	Significant improvement in joint swelling and pain (p < 0.03), as well as skin score (p < 0.003), after 6 months of therapy
	[72]	Case report	3–6 cycles of IVIg 0.4 g/kg for 5 days; ISIVEN (Instituto Sierovaccinogeno, Italiano ISI SpA, Italy)	3 patients with rapid deteriorating SSc refractory to treatment	All patients had a significant decrease in their skin score
For scleromyxedema, see dermatology section
For Evan's syndrome, see hematology section
Juvenile rheumatoid arthritis (JRA)	[73]	Multicentered RCT	Bimonthly IVIg 1.5–2.0 g/kg for the first 2 months, then monthly for up to 6 months (Iveegam, Immuno AG, Vienna) after 3 and a half months was switched to placebo	25 patients with resistant JRA	19 (76%) had moderate to large improvement; the group which switched to placebo showed rapid loss of this effect
	[74]	RCT	Patients were additionally treated with high-dose IVIg or MP	20 patients with JRA treated with MTX and CS	Clinical effects were rapid in both groups
	[75]	Retrospective cohort	IVIg monthly for 3–54 months	27 patients with systemic JRA	20 patients responded after 6 months, especially systemic features and CS dependence
	[76]	Controlled trial	High-dose IVIg	16 children with severe juvenile chronic arthritis	Mild–moderate systemic, articular and laboratory improvement in most patients
Rheumatoid arthritis (RA)	[77]	RCT	IVIg 5 g/kg every 3 weeks for 6 courses vs albumin	20 patients with refractory RA	No significant differences between treatment groups were noted during the 18-week trial
	[78]	Controlled trial	Patients were treated with IVIg	11 patients with refractory RA	In 6 patients, clinical results were impressive; lasting responses could be achieved in 3 patients only
	[79]	Case report	IVIg 1 g per day for 2 days, monthly for 3 months	4 patients with severe refractory RA who have failed at least 4 second-line drugs	None of the patients improved or worsened
	[80]	Case report	IVIg 0.4 g/kg for 5 days	A 50-year-old woman with acute systemic RA refractory to treatment with CS, CP, or PP	Clinical improvement 3 days after IVIg treatment
Sjögren's disease	[81]	Case series	3 monthly courses of IVIg 0.4 g/kg body for 5 days	5 Sjögren patients complicated with ataxic sensory neuropathy, refractory to CS or PP	4 patients showed remarkable improvement, 2 of whom responded after the first course
	[82]	Case report	IVIg 0.4 g/kg for 5 days	A patient with long-standing Sjögren's that developed a painful sensory neuropathy	Remarkable clinical improvement and reduction of pain
	[83]	Case report	IVIg 0.4 g/kg for 5 days every 3 weeks	A patient with Sjögren syndrome complicated with ataxic sensory neuropathy	Remarkable improvement that subsided after switching to CS but regained after reintroduction to IVIg despite withdrawal of CS
For antiphospholipid syndrome, see gyneco-obstetric section
Polymyositis (PM) and dermatomyositis (DM)	[84]	RCT	Received PD 25 mg plus IVIg 2 g/kg or placebo every month for 3 months	15 patients with treatment-resistant DM	Significant improvement of muscle strength (p < 0.018) and neuromuscular symptoms (p < 0.035), with IVIg treatment compared to placebo
	[85]	Controlled trial	IVIg or standard therapy	16 patients with PM or DM	Clinical and functional remission in a higher percentage (81%) that was maintained after a mean 5-year follow-up period, as compared to control group (p < 0.001)
	[86]	Controlled trial	IVIg 0.4 g/kg per day for 5 days in addition to CS (Benesis Corporation, Osaka, Japan).	15 patients with Dm (7) or PM (8), who were refractory to traditional CS therapy	Significant improvement in muscle strength, daily activity scores with no severe adverse reactions
Inclusion Body myositis (IBM)	[87]	RCT	Randomized to receive IVIg or placebo monthly for 3 months	36 patients with IBM, treated with high dose PD	No clinical significant difference
	[88]	RCT	IVIg 2 g/kg Vs placebo	22 patients with sporadic inclusion body myositis	No significant changes between groups according to modified Medical Research Council (MRC) score; mild improvement with IVIg according to Neuromuscular Symptom Score (NSS)
	[89]	RCT	IVIg 2 g/kg vs placebo monthly for 3 months	19 patients with IBM	No significant changes between the groups according to MRC score; significant improvement in swallowing with IVIg (p < 0.05)
Behcet's disease (BD)	[90]	Case series	0.4 g/kg daily of IVIg (Omr-IgG-am, a 5% solution of human normal immunoglobulin G; Omrix Biopharmaceuticals Ltd, Nes-Ziona, Israel) 5 times in the first week, an additional 3 applications in the first month, once every 20 days for the next 3 months, then every 6 weeks for 1 year	6 eyes of 4 patients with ocular BD refractory to CS and cyclosporin A	All 6 eyes of all 4 patients showed good response to IVIg therapy
	[91]	Case report	IVIg was started with 5 daily doses of 0.4 g/kg followed by reinforcement doses of 0.4 g/kg at 2-week intervals	A 28-year-old man with BD suffering from severe leg, mouth, and scrotal ulcers and phlebitis resistant to immunosuppressants	After 4 days, the ulcers started to heal; 2 months later, the patient became totally pain free and walked without limping