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Granulomatosis with polyangiitis and intravenous immunoglobulins: A case series and review of the literature
AUTREV-01696; No of Pages 6 Autoimmunity Reviews xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
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Review
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Giacomo Maria Guidelli ⁎, Sara Tenti, Nicola Antonio Pascarelli, Mauro Galeazzi, Antonella Fioravanti
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Rheumatology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Italy
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a r t i c l e
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Article history: Received 5 March 2015 Accepted 20 March 2015 Available online xxxx
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Keywords: Granulomatosis with polyangiitis ANCA-vasculitis Intravenous immunoglobulins
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Granulomatosis with polyangiitis and intravenous immunoglobulins: A case series and review of the literature☆
a b s t r a c t
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Granulomatosis with polyangiitis, formerly known as Wegener's granulomatosis or disease, is a systemic, necrotizing small-vessel vasculitis, belonging to the group of anti-neutrophil cytoplasm antibody vasculitis. The therapeutic strategy includes, in most cases, corticosteroids associated, at least in severe forms of the disease, with immunosuppressive agents: cyclophosphamide and rituximab to induce remission, methotrexate, azathioprine and mycophenolate mofetil to prevent relapses. Intravenous immunoglobulins represent an alternative adjuvant therapy. We described 5 cases of patients with granulomatosis with polyangiitis treated with monthly high-dose intravenous immunoglobulins (500 mg/kg/daily for 3 consecutive days for 9 months). No patients experienced adverse reactions, and 4 patients (80%) achieved a complete remission after 9 courses of this therapy, which was maintained also 3 months later, although we are unable to determine whether improvement in outcomes was a direct result of the IVIG. We also discussed the beneficial effects of intravenous immunoglobulins in patients suffering from granulomatosis with polyangiitis, reporting the previously published data. © 2015 Elsevier B.V. All rights reserved.
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Introduction . . Methods . . . 2.1. Case 1 . 2.2. Case 2 . 2.3. Case 3 . 2.4. Case 4 . 2.5. Case 5 . 3. Results . . . . 4. Discussion . . Conflict of interest . Take-home messages References . . . . .
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Contents
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1. Introduction
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Granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis or disease, is a systemic, necrotizing smallvessel vasculitis, belonging to the group of anti-neutrophil cytoplasm
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☆ Key message: IVIG could represent a useful adjuvant therapy in granulomatosis with polyangiitis. ⁎ Corresponding author. Tel.: +39 0577233345; fax: +39 057740450. E-mail address: [email protected] (G.M. Guidelli).
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antibody (ANCA) vasculitis, with microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome; EGPA) [1–4]. Although there are no validated diagnostic criteria, the American College of Rheumatology (ACR) published classification criteria in 1990 [5,6]. GPA is characterized by granulomatous necrotizing inflammatory lesions of the upper and/or lower respiratory tract, often associated with pauci-immune glomerulonephritis which in some cases can progress rapidly, resulting in a significant loss of renal function. The reported incidence of GPA varies from 2 to 12 per million people and the prevalence from 24 to 157 per million people [3,4,7,8].
http://dx.doi.org/10.1016/j.autrev.2015.03.005 1568-9972/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Guidelli GM, et al, Granulomatosis with polyangiitis and intravenous immunoglobulins: A case series and review of the literature, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.03.005
51 52 53 54 55 56 57 58 59 60
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2.1. Case 1
107 109 110
In this case, a male patient, GPA was diagnosed at the age of 58. The disease involved, since the early phases, muscles, lung (pulmonary infiltrates) and skin (purpura), associated with a positivity of c-ANCA. He was treated with oral CS (prednisone 25 mg/day) and CYC per os
t1:1 t1:2
Table 1 Patients' data.
86 87 88 Q7 89 90 91 92 93 94 95 96 97
101 102 103
108
C
84 85
E
82 83
R
80 81
R
78 79
O
76 77
C
74 75
N
72 73
U
70 71
2.2. Case 2
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At the age of 34, this Caucasian woman was referred to an ENT specialist for pain in the right ear; a diagnosis of mastoiditis was made and she underwent surgical treatment. After a few months, she developed constitutional symptoms (low fever, fatigue and arthralgia). Laboratory tests showed an increased of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and a positivity of c-ANCA. After the diagnosis of GPA, the patient was initially treated with methylprednisolone 80 mg/day and pulse intravenous (i.v.) CYC 500 mg/month for one year. The disease was persistent without any new/worse clinical event, so CS was progressively reduced to 20 mg/day, and maintenance therapy with MMF (2 g/day) was started. At the age of 42 she presented two episodes of cytomegalovirus pneumonia within a year. MMF was stopped for three months, and meanwhile i.v. ganciclovir was administered. After the first month of antiviral therapy, IVIG therapy at the dosage of 500 mg/kg/day for three consecutive days each month for 9 months was introduced.
118
2.3. Case 3
134
At the age of 48, a Caucasian male developed fatigue, joint pain and fever. Laboratory tests revealed increased of acute phase reactants (ESR and CRP), proteinuria (3 g/day) and a positivity of c-ANCA; a histological confirmation of GPA was obtained by kidney biopsy. Initially, seven sessions of plasmapheresis and induction immunosuppression (500 mg i.v. methylprednisolone for 3 days, steroid taper-off, 0.5 g CYC i.v. twice within two months) were applied leading to a partial remission of GPA. At the age of 62 he presented peripheral cytopenia (WBC 2.32 × 103/μL, PLT 87 × 103/μL), probably induced by CYC which was promptly discontinued; prednisolone (10 mg/day) was administered for one month and MMF was introduced as a new maintenance immunosuppressive therapy, in association with IVIG therapy at the dosage of 500 mg/kg/day for three consecutive days each month for 9 months.
135 136
2.4. Case 4
148
A 43-year old woman was diagnosed with GPA with upper and lower respiratory tract involvement, renal failure, positive for c-ANCA. No renal biopsy was performed. Moreover a previous MRI showed a brain involvement with microvascular inflammatory lesions in various stages of development. She was on therapy with prednisone 25 mg/day and AZT 100 mg/day. Two years later, she was admitted to our emergency department for a recent history of dyspnea on moderate exertion, fever and cough. She denied a familiar history of cardiac disease. She was not a smoker. On admission, she complained about constrictive chest pain during moderate effort; ECG was compatible with acute myocardial
149
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104 105
This series comprises 5 patients (3 males and 2 females) admitted to Rheumatology Unit of Siena University, Italy, affected by GPA (Table 1). The diagnosis was achieved through a combination of clinical assessment, serological tests for ANCA (qualitative assays by indirect immunofluorescence and quantitative analysis by ELISA) and histological analysis, according to 1990 ACR criteria [5].
68 69
O
100
67
R O
2. Methods
65 66
111 112 Q8
P
99
63 64
at the dosage of 100 mg/day. At the age of 64 he developed an opportunistic lung infection sustained by Aspergillus spp., diagnosed by bronchoalveolar lavage. CYC was discontinued; antimicotic therapy with oral itraconazole 100 mg/daily was started, for one month. We introduced IVIG therapy at the dosage of 500 mg/kg/day for three consecutive days each month for 9 months.
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98
The broad spectrum of clinical manifestations is heterogenous. Granulomatous ear, nose and throat (ENT) lesions are the most typical manifestations of the disease. Two-thirds of patients have pulmonary involvement, with bilateral parenchymal nodules and/or alveolar haemorrhage, while rapidly progressive glomerulonephritis is noted in 40 to 100% of patients. Other clinical features are represented by pachymeningitis, mononeuritis multiplex and sensorimotor polyneuropathy, palpable purpura and episcleritis. The typical ANCA pattern associated with GPA using indirect immunofluorescence (IIF) is cytoplasmic (c-ANCA) recognising the autoantigen proteinase 3 (PR3, PR3-ANCA). c-ANCA is approximately detected in 90% of the cases, and they can be used to help diagnosis [1–4,9]. GPA treatment should be adapted to several factors and standardization chosen after a careful analysis of classification, predictable outcome, aetiology, pathogenesis, severity and age. The therapeutic strategy comprises, in most cases, corticosteroids (CS) associated, at least in severe forms of the disease, with immunosuppressive agents. Among them, although many points concerning dose, duration, and route need to be clarified, cyclophosphamide (CYC) represents the conventional therapy for inducing remission. Recently, from April 2011, also rituximab (RTX) was approved by FDA to induce remission in patients with GPA and MPA. Subsequently, the principle agents that are used to maintain remission are methotrexate (MTX) and azathioprine (AZT). Mycophenolate mofetil (MMF), deoxyspergualin, and leflunomide are other drugs that have shown promise in maintenance of remission [10,11]. In addition, the safety and efficacy of agents involved in the immune response, such as intravenous immunoglobulins (IVIGs), were investigated in vasculitis patients. For decades, IVIGs have shown potent therapeutic efficacy in patients with ANCA-positive vasculitis [12–16]. Also the British Society for Rheumatology (BSR), in 2007, regarding ANCA-vasculitis considered IVIG as “an alternative therapy in patients with refractory disease or in patients for whom conventional therapy is contra-indicated, for example, in the presence of infection, in the severely ill patient or in pregnancy” [17]. The aim of this article was to retrospectively assess the efficacy and tolerability of IVIG (Kedrion®) administration in 5 patients with GPA admitted to our Rheumatology Unit during the years 2006–2013, and also discuss the previously published data in this field.
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2
t1:3 t1:4
Patients (no.)
Gender
Age at diagnosis
Age at IVIG start
Last therapy before IVIG
Organ involvement
Reason for IVIG introduction
t1:5 t1:6 t1:7 t1:8 t1:9
1 2 3 4 5
M F M F M
58 34 48 43 70
64 42 62 45 74
CS + CYC CS + MMF CYC + CS AZT + CS CS pulses + RTX
Lung, muscle, skin ENT, lung, kidney Skin, kidney, lung Joint, ENT, lung Lung, ENT, upper airways, bowel
Opportunistic lung infection by Aspergillus spp. Recurrent lung infections by CMV Cytopenia CYC-induced Ischaemic cardiac pain and cardiac failure GPA-related Ischaemic bowel involvement and peripheral neuropathy
t1:10
CS = corticosteroids, CYC = cyclophosphamide, MMF = mycophenolate mofetil, ENT = ear, nose, throat, AZT = azathioprine, RTX = rituximab.
Please cite this article as: Guidelli GM, et al, Granulomatosis with polyangiitis and intravenous immunoglobulins: A case series and review of the literature, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.03.005
113 114 115 116
119 120 121 122 123 124 125 126 127 128 129 130 131 132 133
137 138 139 140 141 142 143 Q9 Q10 144 145 146 147
150 151 152 153 154 155 156 157 158
G.M. Guidelli et al. / Autoimmunity Reviews xxx (2015) xxx–xxx
3. Results
195 196
203 204
After the ninth IVIG infusion 4 patients were in complete remission, according to the BVAS, while partial remission (defined as at least 75% improvement in BVAS without complete resolution of disease activity) was recorded in the fifth patient. These findings persisted immodified also at the visit of three month follow-up. During the nine courses of IVIG administration, no severe or life-threatening adverse events (AEs) related to this therapy were recorded. The only AEs observed could be classified as mild, such as headache (2 patients, 40%), flushing and nausea (2 patient, 40%). While flushing and nausea spontaneously resolved, both headaches needed the administration of 1000 mg of
t2:1 t2:2
Table 2 Summary of available studies, designed ad hoc for IVIG in GPA.
185 186 187 188 189 190 191
197 198 199 200 201 202
C
183 184
E
181 182
R
179 180
R
177 178
N C O
175 176
U
173 174
208 209
F
194
171 172
Conventional treatment of GPA consists of CS, usually in combination with immunosuppressive agents. While CYC represents the cornerstone therapy to induce remission, maintenance therapy typically consists of AZT or MTX, which is prescribed for at least 12–18 months. Despite optimal treatment regimens, relapses occur in approximately 50% of GPA patients after 5 years of follow-up [8,10,20]. IVIG treatment has been used for decades and its use has still not been superseded in certain rheumatologic diseases [21]. In fact, despite the introduction of newer immunomodulatory drugs, there has been an ever-increasing number of clinical indications for which IVIG has been tried. Immunoglobulins are plasma proteins secreted by plasma cells, forming a major component of the adaptive immune system. IVIG is a blood product prepared from plasma, each batch prepared from a pool of 10,000–20,000 donations. The ability of IVIG to regulate autoantibody production by B cells through idiotype–anti-idiotypic reactions made this an attractive treatment option for systemic vasculitis in the 1990s. In vitro studies showed that F(ab′)2 fragments of IVIG could block ANCA binding to antigen in a dose-dependent fashion [22–27]. Our study reflects a single-centre experience about the use of IVIG in GPA. It comprises five patients which, during the course of the vasculitis, were treated with a long-term IVIG course, at high dosage (500 mg/kg/daily for three consecutive days each month for 9 consecutive months). Although no current guidelines exist about the duration, frequency or optimal dose of IVIG we selected this infusional regimen on the basis of published data [12–16,28]. In our patients, IVIG represented an adjuvant therapy, in association with CS, until immunosuppressive agents were no longer contraindicated, due to a comorbidity (i.e. infections) or iatrogenic side effect (i.e. cytopenia CYC-induced). The result of IVIG therapy was well-tolerated and the safety profile was good, with only moderate and transient AEs. These AEs did not preclude the subsequent IVIG course in any patient. No patients experienced relapses of the disease during the period of IVIG treatment and the three-month follow-up. Four patients were in complete remission, with a BVAS of 0, since after the 9th month. We conducted a search of the literature in January 2015 (the period examined was 1993–2015). Medline was searched using the term “intravenous immunoglobulin” in combination with “Wegener's granulomatosis” and “granulomatosis with polyangiitis”. Papers written in languages other than English and those not reporting distinction among generic ANCA vasculitis, were excluded. A 2009 Cochrane review (recently updated) [29] identified only one randomized clinical trial (RCT) with 34 participants who were equally and randomly assigned to receive IVIG (a single course of 400 mg/kg daily for 5 days) or placebo in addition to AZT and CS for remission
O
192 193
A 44 year old female was admitted to our outpatient clinic for an eight week history of lethargy, polyarthralgia, vasculitic skin rash, and distal sensory and motor polyneuropathy. Laboratory analysis showed normal results on full blood count and urinalysis but an elevated erythrocyte sedimentation rate (79 mm/h; normal 0–35 mm/h) and positive c-ANCA. Chest radiograph was normal. A diagnosis of GPA was made and intravenous methylprednisolone (250 mg/kg/month) and RTX (1 g at basal time and two weeks later every six months) were introduced. Four years later the patient developed severe abdominal pain with signs of peritonitis. Plain film and computed tomography of the abdomen confirmed pneumoperitoneum. At laparotomy, multiple mid-ileal ischaemic perforations with extensive ischaemic involvement of the left and transverse colon were seen. One metre of small bowel was resected with ileoileal anastomosis and extended left hemicolectomy and a transverse end colostomy. Histological examination of the resected areas showed ulcerations and vasculitis in medium-sized arteries. Postoperatively, the patient was continued on i.v. methylprednisolone 1 g for five days followed by dexamethasone 16 mg intravenously daily and IVIG therapy at the dosage of 500 mg/kg/day for three consecutive days each month for 9 months was introduced. We recorded patients' medical data, at baseline (time of first IVIG infusion), after nine months (at the end of IVIG courses) and after one year. The Birmingham Vasculitis Activity Score (BVAS) modified for Wegener granulomatosis was recorded to specifically evaluate vasculitis activity [18,19].
207
R O
169 170
165
4. Discussion
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2.5. Case 5
163 164
D
168
161 162
acetaminophen. No patient worsened previous disease features, and 205 no new signs or symptoms GPA-related were observed. 206
T
166 167
ischaemia; troponin I and myoglobin were higher than normal. The coronary angiography showed a diffuse coronary artery disease without haemodynamically significant stenosis with the exception of a 90% stenosis of the proximal portion of the left anterior descending artery, engaging the emergence of the first diagonal branch, treated with percutaneous transluminal coronary angioplasty (PTCA) with position of stent. AZT was promptly stopped and after 2 months IVIG therapy at the dosage of 500 mg/kg/day for three consecutive days each month for 9 months was introduced.
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159 160
3
t2:3
Author
Year
Study design
Number of patients treated with IVIG
IVIG protocol
Results
t2:4
Martinez et al. [13]
2008
22 (19 GPA, 3 EGPA)
0.5 mg/kg/day for 4 consecutive days, monthly for 6 months
Complete remission of relapsed ANCA-vasculitis in 13 of 22 pts at month 9. Good safety and tolerability.
t2:5 Q1
Jayne et al. (13)
1996
Multicentre, prospective, open label Observational
6 (3 GPA, 3 EGPA)
0.5 mg/kg/day for 4 consecutive days
t2:6
Jayne et al. [15]
1993
Open label
14 (8 GPA, 6 MPA)
0.4 mg/kg/day for 5 consecutive days
t2:7
Richter et al. [16]
1995
Open label
15 (14 EGPA, 1 GPA)
Single/multiple courses of 30 g daily for 5 consecutive days (10 pts one course, 2 pts 2 courses, 3 pts 3 courses)
Sustained remission for at least 1 year in 4/6 pts in the absence of CS and CYC Clinical benefit has been reported in 13/14 pts, sustained remission in 8. 9/15 pts experienced clinical benefits, none complete remission.
t2:8
Repeated courses of IVIG at 4-week intervals were no more effective than single courses.
Please cite this article as: Guidelli GM, et al, Granulomatosis with polyangiitis and intravenous immunoglobulins: A case series and review of the literature, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.03.005
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Conflict of interest
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expressed on lymphocytes and monocytes, modulation of dendritic cell maturation and restoration of idiotypic–anti-idiotypic networks [52,53]. The potential mechanism of IVIG in vasculitis is unclear; IVIG contains antibodies which bind to the variable regions of ANCA autoantibodies and inhibit their binding to autoantigens and IVIG inhibits ANCA-induced neutrophil activation and cytokine release in vitro [54, 55]. It reduces TNF-α and IL-1 release, leading to an antiinflammatory effect [12]. Several limitations should be considered when interpreting our findings. First, we used a case series design (with no standardized treatment protocol prior to or during IVIG courses), and statistical testing was not performed; thus, our findings may be attributed to chance. Second, we are unable to determine whether improvement in outcomes was a direct result of the IVIG administration or due to other factors such as the CS concomitant therapy. Third, patient assessment occurred at completion of the IVIG course and again 3 months later, and longer followup is needed to assess maintenance of treatment gains. In conclusion, while scientific evidence supported by RCTs is lacking, IVIG therapy could be recommended not only as single course, but also as long term protocol in treating ANCA vasculitis. To confirm this hypothesis there is a need of future RCT double dummy design and a minimal length of 1 year, although the high cost of IVIG (one dose at 2 g/kg for a 70 kg patient = $8400) nowadays represents an important hurdle [29]. On the other hand, evident advantages of IVIG compared to other agents in the conventional immunosuppressive and biologic armamentarium are the drug's good safety profile and the steroid sparing properties [56–59].
Table 3 Summary of the studies reporting the use of IVIG in GPA patients.
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t3:1 t3:2 t3:3
Author (Ref.)
Year of publication
Study design
t3:4
Croft et al. [30]
2014
t3:5 t3:6 t3:7 t3:8 t3:9
Abtahi et al. [31] Wiwatwongwana et al. [32] Alfhaily et al. [33] Kim et al. [34]
2012 2012
Retrospective study Case report Case report
2009 2008
Case report Case report
1 1
t3:10
Arlet et al. [35]
2008
Case report
1
t3:11 t3:12 t3:13
Aries et al. [36] Ozbalkan et al. [37] Bellisai et al. [38]
2006 2006 2004
Case report Retrospective study Case report
1 2 1
t3:14 t3:15 t3:16
Ulinski et al. [39] Masterson et al. [40] Kamali et al. [41]
2005 2004 2005
Case report Case report Retrospective study
1 1 4
t3:17
Delevaux et al. [42]
2002
Case report
1
t3:18 t3:19 t3:20
Reinhold-Keller et al. [43] Taylor et al. [44]
2000
Retrospective study
1999
Case report
1
t3:21 t3:22 t3:23 t3:24
Adlakha et al. [45] Chakravarty et al. [46] Finkel et al. [47] Richter et al. [48]
1995 1994 1994 1993
Case report Case reports Case report Case series
1 1 1 8
R
R
O
N
C
Q2
U
Number of patients treated with IVIG 1
1 1
10
287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312
The authors declare no conflict of interest, nor any financial interest. 314
C
T
maintenance. This study was a prospective, randomized, double-blind, placebo-controlled, multicenter trial. There were no significant differ255 ences between adjuvant IVIG and adjuvant placebo in mortality, serious 256 AEs, time to relapse and infection rates. The authors demonstrated that 257 a single course of high-dose IVIG reduces disease activity in ANCA258 vasculitis where active disease persists, but the benefit of IVIG was not 259 maintained beyond 3 months [12]. Other than this sole RCT, 4 studies 260 have been ad hoc conducted to assess the efficacy of IVIG in GPA 261 (Table 2) [13–16] reporting clinical benefits and good tolerance in the 262 majority of these patients. Furthermore, 18 anecdotal reports have 263 showed the efficacy of IVIG in a heterogenous population affected by 264 GPA (Table 3) [30–48], while 3 reports did not point out any beneficial 265 effect [49–51]. 266 Kamali et al. [49] described the case of a young patient affected by 267 GPA with intra-alveolar haemorrhage who developed end-stage renal 268 disease requiring haemodialysis, despite CS, CYC and IVIG therapy. 269 Lamprecht et al. [50] reported the history of a GPA patient who 270 underwent partial pneumonectomy because of cavitation of granulo271 mas resulting in massive pseudocaverns followed by IVIG therapy that 272 did not result in sustained remission. Finally, Blum et al. [51] analysed 273 the cases of two patients suffering from GPA with ocular involvement 274 treated with IVIG after other several failed therapies; although the sys275 temic disease was under control, the ocular symptoms of both patients 276 worsened during and after IVIG treatment. In one case an adverse effect 277 consisting of retinal vasculitis was noted on two occasions. 278 Different mechanisms of action have been proposed to explain the 279 beneficial effects of IVIG on autoimmune diseases, including modulation 280 of Fc receptor expression on leukocytes and endothelial cells, interac281 tion with complement proteins, modulation of the synthesis and release 282 of cytokines and chemokines, modulation of cell proliferation and apo283 Q12 ptosis, remyelination, neutralization of circulating antibodies, selection 284 of immune repertoires, interaction with other cell surface molecules
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253 254
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4
IVIG protocol
Reason for IVIG introduction
5 day course (dosage not reported) 2.5 g for 5 days 400 mg/kg for 4 consecutive days every 3 weeks 500 mg daily for 3 days 400 mg/kg for 5 consecutive days (total 2 courses) 1 g/kg daily
Disease relapse in pregnancy
30 g/day for 5 consecutive days 400 mg/day for 5 days 400 mg/day for 3 consecutive days each month Not reported 2 mg/kg monthly 400 mg/day for 5 consecutive days monthly Different dosages during the six years of therapy described 150 g/month 0.5 g/kg/day for four consecutive days 500 mg/kg/day for 4 days 400 mg/kg/day for 5 days 400 mg/day for 5 consecutive days 30 g/day for 5 consecutive days
Infectious comorbidity (mucomycosis) Iatrogenic effect (CYC induced leucopenia) Active phase of disease in pregnancy New onset of disease in pregnancy Disease relapse (aneurysm located on the superior pancreatic-duodenal artery and multiple microaneurysms in the hepatic and renal artery branches, parietal thickening of the small bowel and splenic infarction) Infectious comorbidity (CMV infection) Resistant to conventional therapy Resistant to conventional therapy Disease relapse (central nervous system involvement) New onset of disease in pregnancy 3 patients resistant to conventional therapy and one infectious comorbidity (CMV chorioretinitis) Associated common variable immunodeficiency Resistant to conventional therapy Disease relapse (central nervous system involvement) plus infectious comorbidity (cystitis) Resistant to conventional therapy Resistant to conventional therapy Infectious comorbidity (parvovirus B19 infection) 6 patients resistant to conventional therapy and 2 CYC induced cystitis
Please cite this article as: Guidelli GM, et al, Granulomatosis with polyangiitis and intravenous immunoglobulins: A case series and review of the literature, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.03.005
G.M. Guidelli et al. / Autoimmunity Reviews xxx (2015) xxx–xxx
315 316
Take-home messages
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• IVIG therapy could be recommended as a long term protocol in treating ANCA-vasculitis. • IVIGs, compared to conventional immunosuppressive agents, present a better drug's good safety profile and steroid sparing properties.
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[1] Scott DG, Watts RA. Systemic vasculitis: epidemiology, classification and environmental factors. Ann Rheum Dis 2000;59:161–3. [2] Falk RJ, Gross WL, Guillevin L, Hoffman GS, Jayne DR, Jennette JC, et al. Granulomatosis with polyangiitis (Wegener's): an alternative name for Wegener's granulomatosis. Arthritis Rheum 2011;63:863–4. [3] Lane SE, Watts R, Scott DG. Epidemiology of systemic vasculitis. Curr Rheumatol Rep 2005;7:270–5. [4] Mohammad AJ, Jacobsson LT, Westman KW, Sturfelt G, Segelmark M. Incidence and survival rates in Wegener's granulomatosis, microscopic polyangiitis, Churg–Strauss syndrome and polyarteritis nodosa. Rheumatology (Oxford) 2009;48:1560–5. [5] Fries JF, Hunder GG, Bloch DA, Michel BA, Arend WP, Calabrese LH, et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis. Summary. Arthritis Rheum 1990;33:1135–6. [6] Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 2013;65:1–11. [7] Merkel PA, Lo GH, Holbrook JT, Tibbs AK, Allen NB, Davis Jr JC, et al. Brief communication: high incidence of venous thrombotic events among patients with Wegener granulomatosis: the Wegener's Clinical Occurrence of Thrombosis (WeCLOT) study. Ann Intern Med 2005;142:620–6. [8] Commarmond C, Cacoub P. Granulomatosis with polyangiitis (Wegener): clinical aspects and treatment. Autoimmun Rev 2014;13:1121–5. [9] Radice A, Bianchi L, Sinico RA. Anti-neutrophil cytoplasmic autoantibodies: methodological aspects and clinical significance in systemic vasculitis. Autoimmun Rev 2013;12:487–95. [10] Mukhtyar C, Guillevin L, Cid MC, Dasgupta B, de Groot K, Gross W, et al. EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis 2009;68:310–7. [11] Hellmich B, Flossmann O, Gross WL, Bacon P, Cohen-Tervaert JW, Guillevin L, et al. EULAR recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis: focus on anti-neutrophil cytoplasm antibody-associated vasculitis. Ann Rheum Dis 2007;66:605–17. [12] Jayne DR, Chapel H, Adu D, Misbah S, O'Donoghue D, Scott D, et al. Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity. Q J Med 2000;93:433–9. [13] Martinez V, Cohen P, Pagnoux C, Vinzio S, Mahr A, Mouthon L, et al. Intravenous immunoglobulins for relapses of systemic vasculitides associated with antineutrophil cytoplasmic antibodies. Arthritis Rheum 2008;58:308–17. [14] Jayne DR, Lockwood CM. Intravenous immunoglobulin as sole therapy for systemic vasculitis. Br J Rheumatol 1996;35:1150–3. [15] Jayne DR, Esnault VL, Lockwood CM. ANCA anti-idiotype antibodies and the treatment of systemic vasculitis with intravenous immunoglobulin. J Autoimmun 1993; 6:207–19. [16] Richter C, Schnabel A, Csernok E, De Groot K, Reinhold-Keller E, Gross WL. Treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis with high-dose intravenous immunoglobulin. Clin Exp Immunol 1995;101:2–7. [17] Lapraik C, Watts R, Bacon P, Carruthers D, Chakravarty K, D'Cruz D, et al. BSR and BHPR guidelines for the management of adults with ANCA associated vasculitis. Rheumatology (Oxford) 2007;46:1615–6. [18] Luqmani RA, Bacon PA, Moots RJ, Janssen BA, Pall A, Emery P, et al. Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. QJM 1994;87: 671–8. [19] Merkel PA, Seo P, Aries P, Neogi T, Villa-Forte A, Boers M, et al. Vasculitis Clinical Research Consortium; OMERACT 7 Special Interest Group. Current status of outcome measures in vasculitis: focus on Wegener's granulomatosis and microscopic polyangiitis. Report from OMERACT 7. J Rheumatol 2005;32:2488–95. [20] Jayne D, Rasmussen N, Andrassy K, Bacon P, Tervaert JW, Dadoniené J, et al. European Vasculitis Study Group. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 2003;349:36–44. [21] Miescher SM, Kasermann F. The future of immunoglobulin therapy: an overview of the 2nd international workshop on natural antibodies in health and disease. Autoimmun Rev 2013;12:639–42. [22] Lockwood CM. New treatment strategies for systemic vasculitis: the role of intravenous immunoglobulin therapy. Clin Exp Immunol 1996;104:77–82. [23] Vaitla PM, McDermott EM. The role of high-dose intravenous immunoglobulin in rheumatology. Rheumatology (Oxford) 2010;49:1040–8. [24] Sherer Y, Levy Y, Fabrizzi F, Shoenfeld Y. Immunomodulation of various autoimmune diseases by intravenous immunoglobulin. Drugs Today (Barc) 1999;35:513–8. [25] Sherer Y, Levy Y, Shoenfeld Y. Intravenous immunoglobulin (IVIG) therapy in autoimmune disease-SLE, antiphospholipid syndrome, vasculitis. What is New?; 1999 1–5 [http://www.rheuma21st.com/archives/cutting_edge_immunoglobulin.html (16.09.99)].
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Nat Clin Pract Rheumatol 2006;2: 511–5. [37] Ozbalkan Z, Kiraz S, Ozturk MA, Ertenli AI, Apras S, Calguneri M. Wegener's granulomatosis: clinical and laboratory results of a university hospital study of 20 patients from Turkey. Clin Rheumatol 2006;25:358–63. [38] Bellisai F, Morozzi G, Marcolongo R, Galeazzi M. Pregnancy in Wegener's granulomatosis: successful treatment with intravenous immunoglobulin. Clin Rheumatol 2004; 23:533–5. [39] Ulinski T, Martin H, Mac Gregor B, Dardelin R, Cochat P. Fatal neurologic involvement in pediatric Wegener's granulomatosis. Pediatr Neurol 2005;32:278–81. [40] Masterson R, Pellicano R, Bleasel K, McMahon LP. Wegener's granulomatosis in pregnancy: a novel approach to management. Am J Kidney Dis 2004;44: e68–72. [41] Kamali S, Cefle A, Sayarlioglu M, Gul A, Inanc M, Ocal L, et al. Experience with monthly, high-dose, intravenous immunoglobulin therapy in patients with different connective tissue diseases. Rheumatol Int 2005;25:211–4. 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[47] Finkel TH, Török TJ, Ferguson PJ, Durigon EL, Zaki SR, Leung DY, et al. Chronic parvovirus B19 infection and systemic necrotising vasculitis: opportunistic infection or aetiological agent? Lancet 1994;343:1255–8. [48] Richter C, Schnabel A, Csernok E, Reinhold-Keller E, Gross WL. Treatment of Wegener's granulomatosis with intravenous immunoglobulin. Adv Exp Med Biol 1993;336:487–9. [49] Kamali S, Kasapoglu E, Aktürk F, Gül A, Inanc M, Ocal L, et al. Eosinophilia and hyperimmunoglobulinemia E as the presenting manifestations of Wegener's granulomatosis. Clin Rheumatol 2003;22:333–5. [50] Lamprecht P, Voswinkel J, Lilienthal T, Nolle B, Heller M, Gross WL, et al. Effectiveness of TNF-alpha blockade with infliximab in refractory Wegener's granulomatosis. Rheumatology (Oxford) 2002;41:1303–7. [51] Blum M, Andrassy K, Adler D, Hartmann M, Völcker HE. Early experience with intravenous immunoglobulin treatment in Wegener's granulomatosis with ocular involvement. Graefes Arch Clin Exp Ophthalmol 1997;235:599–602. [52] Gelfand EW. Intravenous immune globulin in autoimmune and inflammatory diseases. N Engl J Med 2012;367:2015–25. [53] Tenti S, Guidelli GM, Bellisai F, Galeazzi M, Fioravanti A. Long-term treatment of antiphospholipid syndrome with intravenous immunoglobulin in addition to conventional therapy. Clin Exp Rheumatol 2013;31:877–82. [54] Rossi F, Jayne DR, Lockwood CM, Kazatchkine MD. Anti-idiotypes against antineutrophil cytoplasmic antigen autoantibodies in normal human polyspecific IgG for therapeutic use and in the remission sera of patients with systemic vasculitis. Clin Exp Immunol 1991;83:298–303. [55] Shoenfeld Y, Gershwin ME. Intravenous immunoglobulin new indications and mechanisms of action. Clin Rev Allergy Immunol 2005;29:165–6.
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[58] Zandman-Goddard G, Krauthammer A, Shoenfeld Y. The steroid-sparing effect of intravenous immunoglobulin in patients with autoimmune diseases. Expert Rev Clin Immunol 2007;3:773–80. [59] Seite JF, Shoenfeld Y, Youinou P, Hillion S. What is the contents of the magic draft IVIg? Autoimmun Rev 2008;7:435–9.
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Contents lists available at ScienceDirect
Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
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Review
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Giacomo Maria Guidelli ⁎, Sara Tenti, Nicola Antonio Pascarelli, Mauro Galeazzi, Antonella Fioravanti
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Rheumatology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Italy
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Article history: Received 5 March 2015 Accepted 20 March 2015 Available online xxxx
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Keywords: Granulomatosis with polyangiitis ANCA-vasculitis Intravenous immunoglobulins
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Granulomatosis with polyangiitis and intravenous immunoglobulins: A case series and review of the literature☆
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Granulomatosis with polyangiitis, formerly known as Wegener's granulomatosis or disease, is a systemic, necrotizing small-vessel vasculitis, belonging to the group of anti-neutrophil cytoplasm antibody vasculitis. The therapeutic strategy includes, in most cases, corticosteroids associated, at least in severe forms of the disease, with immunosuppressive agents: cyclophosphamide and rituximab to induce remission, methotrexate, azathioprine and mycophenolate mofetil to prevent relapses. Intravenous immunoglobulins represent an alternative adjuvant therapy. We described 5 cases of patients with granulomatosis with polyangiitis treated with monthly high-dose intravenous immunoglobulins (500 mg/kg/daily for 3 consecutive days for 9 months). No patients experienced adverse reactions, and 4 patients (80%) achieved a complete remission after 9 courses of this therapy, which was maintained also 3 months later, although we are unable to determine whether improvement in outcomes was a direct result of the IVIG. We also discussed the beneficial effects of intravenous immunoglobulins in patients suffering from granulomatosis with polyangiitis, reporting the previously published data. © 2015 Elsevier B.V. All rights reserved.
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Introduction . . Methods . . . 2.1. Case 1 . 2.2. Case 2 . 2.3. Case 3 . 2.4. Case 4 . 2.5. Case 5 . 3. Results . . . . 4. Discussion . . Conflict of interest . Take-home messages References . . . . .
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Contents
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1. Introduction
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Granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis or disease, is a systemic, necrotizing smallvessel vasculitis, belonging to the group of anti-neutrophil cytoplasm
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☆ Key message: IVIG could represent a useful adjuvant therapy in granulomatosis with polyangiitis. ⁎ Corresponding author. Tel.: +39 0577233345; fax: +39 057740450. E-mail address: [email protected] (G.M. Guidelli).
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antibody (ANCA) vasculitis, with microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome; EGPA) [1–4]. Although there are no validated diagnostic criteria, the American College of Rheumatology (ACR) published classification criteria in 1990 [5,6]. GPA is characterized by granulomatous necrotizing inflammatory lesions of the upper and/or lower respiratory tract, often associated with pauci-immune glomerulonephritis which in some cases can progress rapidly, resulting in a significant loss of renal function. The reported incidence of GPA varies from 2 to 12 per million people and the prevalence from 24 to 157 per million people [3,4,7,8].
http://dx.doi.org/10.1016/j.autrev.2015.03.005 1568-9972/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Guidelli GM, et al, Granulomatosis with polyangiitis and intravenous immunoglobulins: A case series and review of the literature, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.03.005
51 52 53 54 55 56 57 58 59 60
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2.1. Case 1
107 109 110
In this case, a male patient, GPA was diagnosed at the age of 58. The disease involved, since the early phases, muscles, lung (pulmonary infiltrates) and skin (purpura), associated with a positivity of c-ANCA. He was treated with oral CS (prednisone 25 mg/day) and CYC per os
t1:1 t1:2
Table 1 Patients' data.
86 87 88 Q7 89 90 91 92 93 94 95 96 97
101 102 103
108
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84 85
E
82 83
R
80 81
R
78 79
O
76 77
C
74 75
N
72 73
U
70 71
2.2. Case 2
117
At the age of 34, this Caucasian woman was referred to an ENT specialist for pain in the right ear; a diagnosis of mastoiditis was made and she underwent surgical treatment. After a few months, she developed constitutional symptoms (low fever, fatigue and arthralgia). Laboratory tests showed an increased of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and a positivity of c-ANCA. After the diagnosis of GPA, the patient was initially treated with methylprednisolone 80 mg/day and pulse intravenous (i.v.) CYC 500 mg/month for one year. The disease was persistent without any new/worse clinical event, so CS was progressively reduced to 20 mg/day, and maintenance therapy with MMF (2 g/day) was started. At the age of 42 she presented two episodes of cytomegalovirus pneumonia within a year. MMF was stopped for three months, and meanwhile i.v. ganciclovir was administered. After the first month of antiviral therapy, IVIG therapy at the dosage of 500 mg/kg/day for three consecutive days each month for 9 months was introduced.
118
2.3. Case 3
134
At the age of 48, a Caucasian male developed fatigue, joint pain and fever. Laboratory tests revealed increased of acute phase reactants (ESR and CRP), proteinuria (3 g/day) and a positivity of c-ANCA; a histological confirmation of GPA was obtained by kidney biopsy. Initially, seven sessions of plasmapheresis and induction immunosuppression (500 mg i.v. methylprednisolone for 3 days, steroid taper-off, 0.5 g CYC i.v. twice within two months) were applied leading to a partial remission of GPA. At the age of 62 he presented peripheral cytopenia (WBC 2.32 × 103/μL, PLT 87 × 103/μL), probably induced by CYC which was promptly discontinued; prednisolone (10 mg/day) was administered for one month and MMF was introduced as a new maintenance immunosuppressive therapy, in association with IVIG therapy at the dosage of 500 mg/kg/day for three consecutive days each month for 9 months.
135 136
2.4. Case 4
148
A 43-year old woman was diagnosed with GPA with upper and lower respiratory tract involvement, renal failure, positive for c-ANCA. No renal biopsy was performed. Moreover a previous MRI showed a brain involvement with microvascular inflammatory lesions in various stages of development. She was on therapy with prednisone 25 mg/day and AZT 100 mg/day. Two years later, she was admitted to our emergency department for a recent history of dyspnea on moderate exertion, fever and cough. She denied a familiar history of cardiac disease. She was not a smoker. On admission, she complained about constrictive chest pain during moderate effort; ECG was compatible with acute myocardial
149
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This series comprises 5 patients (3 males and 2 females) admitted to Rheumatology Unit of Siena University, Italy, affected by GPA (Table 1). The diagnosis was achieved through a combination of clinical assessment, serological tests for ANCA (qualitative assays by indirect immunofluorescence and quantitative analysis by ELISA) and histological analysis, according to 1990 ACR criteria [5].
68 69
O
100
67
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2. Methods
65 66
111 112 Q8
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99
63 64
at the dosage of 100 mg/day. At the age of 64 he developed an opportunistic lung infection sustained by Aspergillus spp., diagnosed by bronchoalveolar lavage. CYC was discontinued; antimicotic therapy with oral itraconazole 100 mg/daily was started, for one month. We introduced IVIG therapy at the dosage of 500 mg/kg/day for three consecutive days each month for 9 months.
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The broad spectrum of clinical manifestations is heterogenous. Granulomatous ear, nose and throat (ENT) lesions are the most typical manifestations of the disease. Two-thirds of patients have pulmonary involvement, with bilateral parenchymal nodules and/or alveolar haemorrhage, while rapidly progressive glomerulonephritis is noted in 40 to 100% of patients. Other clinical features are represented by pachymeningitis, mononeuritis multiplex and sensorimotor polyneuropathy, palpable purpura and episcleritis. The typical ANCA pattern associated with GPA using indirect immunofluorescence (IIF) is cytoplasmic (c-ANCA) recognising the autoantigen proteinase 3 (PR3, PR3-ANCA). c-ANCA is approximately detected in 90% of the cases, and they can be used to help diagnosis [1–4,9]. GPA treatment should be adapted to several factors and standardization chosen after a careful analysis of classification, predictable outcome, aetiology, pathogenesis, severity and age. The therapeutic strategy comprises, in most cases, corticosteroids (CS) associated, at least in severe forms of the disease, with immunosuppressive agents. Among them, although many points concerning dose, duration, and route need to be clarified, cyclophosphamide (CYC) represents the conventional therapy for inducing remission. Recently, from April 2011, also rituximab (RTX) was approved by FDA to induce remission in patients with GPA and MPA. Subsequently, the principle agents that are used to maintain remission are methotrexate (MTX) and azathioprine (AZT). Mycophenolate mofetil (MMF), deoxyspergualin, and leflunomide are other drugs that have shown promise in maintenance of remission [10,11]. In addition, the safety and efficacy of agents involved in the immune response, such as intravenous immunoglobulins (IVIGs), were investigated in vasculitis patients. For decades, IVIGs have shown potent therapeutic efficacy in patients with ANCA-positive vasculitis [12–16]. Also the British Society for Rheumatology (BSR), in 2007, regarding ANCA-vasculitis considered IVIG as “an alternative therapy in patients with refractory disease or in patients for whom conventional therapy is contra-indicated, for example, in the presence of infection, in the severely ill patient or in pregnancy” [17]. The aim of this article was to retrospectively assess the efficacy and tolerability of IVIG (Kedrion®) administration in 5 patients with GPA admitted to our Rheumatology Unit during the years 2006–2013, and also discuss the previously published data in this field.
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t1:3 t1:4
Patients (no.)
Gender
Age at diagnosis
Age at IVIG start
Last therapy before IVIG
Organ involvement
Reason for IVIG introduction
t1:5 t1:6 t1:7 t1:8 t1:9
1 2 3 4 5
M F M F M
58 34 48 43 70
64 42 62 45 74
CS + CYC CS + MMF CYC + CS AZT + CS CS pulses + RTX
Lung, muscle, skin ENT, lung, kidney Skin, kidney, lung Joint, ENT, lung Lung, ENT, upper airways, bowel
Opportunistic lung infection by Aspergillus spp. Recurrent lung infections by CMV Cytopenia CYC-induced Ischaemic cardiac pain and cardiac failure GPA-related Ischaemic bowel involvement and peripheral neuropathy
t1:10
CS = corticosteroids, CYC = cyclophosphamide, MMF = mycophenolate mofetil, ENT = ear, nose, throat, AZT = azathioprine, RTX = rituximab.
Please cite this article as: Guidelli GM, et al, Granulomatosis with polyangiitis and intravenous immunoglobulins: A case series and review of the literature, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.03.005
113 114 115 116
119 120 121 122 123 124 125 126 127 128 129 130 131 132 133
137 138 139 140 141 142 143 Q9 Q10 144 145 146 147
150 151 152 153 154 155 156 157 158
G.M. Guidelli et al. / Autoimmunity Reviews xxx (2015) xxx–xxx
3. Results
195 196
203 204
After the ninth IVIG infusion 4 patients were in complete remission, according to the BVAS, while partial remission (defined as at least 75% improvement in BVAS without complete resolution of disease activity) was recorded in the fifth patient. These findings persisted immodified also at the visit of three month follow-up. During the nine courses of IVIG administration, no severe or life-threatening adverse events (AEs) related to this therapy were recorded. The only AEs observed could be classified as mild, such as headache (2 patients, 40%), flushing and nausea (2 patient, 40%). While flushing and nausea spontaneously resolved, both headaches needed the administration of 1000 mg of
t2:1 t2:2
Table 2 Summary of available studies, designed ad hoc for IVIG in GPA.
185 186 187 188 189 190 191
197 198 199 200 201 202
C
183 184
E
181 182
R
179 180
R
177 178
N C O
175 176
U
173 174
208 209
F
194
171 172
Conventional treatment of GPA consists of CS, usually in combination with immunosuppressive agents. While CYC represents the cornerstone therapy to induce remission, maintenance therapy typically consists of AZT or MTX, which is prescribed for at least 12–18 months. Despite optimal treatment regimens, relapses occur in approximately 50% of GPA patients after 5 years of follow-up [8,10,20]. IVIG treatment has been used for decades and its use has still not been superseded in certain rheumatologic diseases [21]. In fact, despite the introduction of newer immunomodulatory drugs, there has been an ever-increasing number of clinical indications for which IVIG has been tried. Immunoglobulins are plasma proteins secreted by plasma cells, forming a major component of the adaptive immune system. IVIG is a blood product prepared from plasma, each batch prepared from a pool of 10,000–20,000 donations. The ability of IVIG to regulate autoantibody production by B cells through idiotype–anti-idiotypic reactions made this an attractive treatment option for systemic vasculitis in the 1990s. In vitro studies showed that F(ab′)2 fragments of IVIG could block ANCA binding to antigen in a dose-dependent fashion [22–27]. Our study reflects a single-centre experience about the use of IVIG in GPA. It comprises five patients which, during the course of the vasculitis, were treated with a long-term IVIG course, at high dosage (500 mg/kg/daily for three consecutive days each month for 9 consecutive months). Although no current guidelines exist about the duration, frequency or optimal dose of IVIG we selected this infusional regimen on the basis of published data [12–16,28]. In our patients, IVIG represented an adjuvant therapy, in association with CS, until immunosuppressive agents were no longer contraindicated, due to a comorbidity (i.e. infections) or iatrogenic side effect (i.e. cytopenia CYC-induced). The result of IVIG therapy was well-tolerated and the safety profile was good, with only moderate and transient AEs. These AEs did not preclude the subsequent IVIG course in any patient. No patients experienced relapses of the disease during the period of IVIG treatment and the three-month follow-up. Four patients were in complete remission, with a BVAS of 0, since after the 9th month. We conducted a search of the literature in January 2015 (the period examined was 1993–2015). Medline was searched using the term “intravenous immunoglobulin” in combination with “Wegener's granulomatosis” and “granulomatosis with polyangiitis”. Papers written in languages other than English and those not reporting distinction among generic ANCA vasculitis, were excluded. A 2009 Cochrane review (recently updated) [29] identified only one randomized clinical trial (RCT) with 34 participants who were equally and randomly assigned to receive IVIG (a single course of 400 mg/kg daily for 5 days) or placebo in addition to AZT and CS for remission
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A 44 year old female was admitted to our outpatient clinic for an eight week history of lethargy, polyarthralgia, vasculitic skin rash, and distal sensory and motor polyneuropathy. Laboratory analysis showed normal results on full blood count and urinalysis but an elevated erythrocyte sedimentation rate (79 mm/h; normal 0–35 mm/h) and positive c-ANCA. Chest radiograph was normal. A diagnosis of GPA was made and intravenous methylprednisolone (250 mg/kg/month) and RTX (1 g at basal time and two weeks later every six months) were introduced. Four years later the patient developed severe abdominal pain with signs of peritonitis. Plain film and computed tomography of the abdomen confirmed pneumoperitoneum. At laparotomy, multiple mid-ileal ischaemic perforations with extensive ischaemic involvement of the left and transverse colon were seen. One metre of small bowel was resected with ileoileal anastomosis and extended left hemicolectomy and a transverse end colostomy. Histological examination of the resected areas showed ulcerations and vasculitis in medium-sized arteries. Postoperatively, the patient was continued on i.v. methylprednisolone 1 g for five days followed by dexamethasone 16 mg intravenously daily and IVIG therapy at the dosage of 500 mg/kg/day for three consecutive days each month for 9 months was introduced. We recorded patients' medical data, at baseline (time of first IVIG infusion), after nine months (at the end of IVIG courses) and after one year. The Birmingham Vasculitis Activity Score (BVAS) modified for Wegener granulomatosis was recorded to specifically evaluate vasculitis activity [18,19].
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165
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2.5. Case 5
163 164
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168
161 162
acetaminophen. No patient worsened previous disease features, and 205 no new signs or symptoms GPA-related were observed. 206
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ischaemia; troponin I and myoglobin were higher than normal. The coronary angiography showed a diffuse coronary artery disease without haemodynamically significant stenosis with the exception of a 90% stenosis of the proximal portion of the left anterior descending artery, engaging the emergence of the first diagonal branch, treated with percutaneous transluminal coronary angioplasty (PTCA) with position of stent. AZT was promptly stopped and after 2 months IVIG therapy at the dosage of 500 mg/kg/day for three consecutive days each month for 9 months was introduced.
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159 160
3
t2:3
Author
Year
Study design
Number of patients treated with IVIG
IVIG protocol
Results
t2:4
Martinez et al. [13]
2008
22 (19 GPA, 3 EGPA)
0.5 mg/kg/day for 4 consecutive days, monthly for 6 months
Complete remission of relapsed ANCA-vasculitis in 13 of 22 pts at month 9. Good safety and tolerability.
t2:5 Q1
Jayne et al. (13)
1996
Multicentre, prospective, open label Observational
6 (3 GPA, 3 EGPA)
0.5 mg/kg/day for 4 consecutive days
t2:6
Jayne et al. [15]
1993
Open label
14 (8 GPA, 6 MPA)
0.4 mg/kg/day for 5 consecutive days
t2:7
Richter et al. [16]
1995
Open label
15 (14 EGPA, 1 GPA)
Single/multiple courses of 30 g daily for 5 consecutive days (10 pts one course, 2 pts 2 courses, 3 pts 3 courses)
Sustained remission for at least 1 year in 4/6 pts in the absence of CS and CYC Clinical benefit has been reported in 13/14 pts, sustained remission in 8. 9/15 pts experienced clinical benefits, none complete remission.
t2:8
Repeated courses of IVIG at 4-week intervals were no more effective than single courses.
Please cite this article as: Guidelli GM, et al, Granulomatosis with polyangiitis and intravenous immunoglobulins: A case series and review of the literature, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.03.005
210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 Q11 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252
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Conflict of interest
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expressed on lymphocytes and monocytes, modulation of dendritic cell maturation and restoration of idiotypic–anti-idiotypic networks [52,53]. The potential mechanism of IVIG in vasculitis is unclear; IVIG contains antibodies which bind to the variable regions of ANCA autoantibodies and inhibit their binding to autoantigens and IVIG inhibits ANCA-induced neutrophil activation and cytokine release in vitro [54, 55]. It reduces TNF-α and IL-1 release, leading to an antiinflammatory effect [12]. Several limitations should be considered when interpreting our findings. First, we used a case series design (with no standardized treatment protocol prior to or during IVIG courses), and statistical testing was not performed; thus, our findings may be attributed to chance. Second, we are unable to determine whether improvement in outcomes was a direct result of the IVIG administration or due to other factors such as the CS concomitant therapy. Third, patient assessment occurred at completion of the IVIG course and again 3 months later, and longer followup is needed to assess maintenance of treatment gains. In conclusion, while scientific evidence supported by RCTs is lacking, IVIG therapy could be recommended not only as single course, but also as long term protocol in treating ANCA vasculitis. To confirm this hypothesis there is a need of future RCT double dummy design and a minimal length of 1 year, although the high cost of IVIG (one dose at 2 g/kg for a 70 kg patient = $8400) nowadays represents an important hurdle [29]. On the other hand, evident advantages of IVIG compared to other agents in the conventional immunosuppressive and biologic armamentarium are the drug's good safety profile and the steroid sparing properties [56–59].
Table 3 Summary of the studies reporting the use of IVIG in GPA patients.
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t3:1 t3:2 t3:3
Author (Ref.)
Year of publication
Study design
t3:4
Croft et al. [30]
2014
t3:5 t3:6 t3:7 t3:8 t3:9
Abtahi et al. [31] Wiwatwongwana et al. [32] Alfhaily et al. [33] Kim et al. [34]
2012 2012
Retrospective study Case report Case report
2009 2008
Case report Case report
1 1
t3:10
Arlet et al. [35]
2008
Case report
1
t3:11 t3:12 t3:13
Aries et al. [36] Ozbalkan et al. [37] Bellisai et al. [38]
2006 2006 2004
Case report Retrospective study Case report
1 2 1
t3:14 t3:15 t3:16
Ulinski et al. [39] Masterson et al. [40] Kamali et al. [41]
2005 2004 2005
Case report Case report Retrospective study
1 1 4
t3:17
Delevaux et al. [42]
2002
Case report
1
t3:18 t3:19 t3:20
Reinhold-Keller et al. [43] Taylor et al. [44]
2000
Retrospective study
1999
Case report
1
t3:21 t3:22 t3:23 t3:24
Adlakha et al. [45] Chakravarty et al. [46] Finkel et al. [47] Richter et al. [48]
1995 1994 1994 1993
Case report Case reports Case report Case series
1 1 1 8
R
R
O
N
C
Q2
U
Number of patients treated with IVIG 1
1 1
10
287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312
The authors declare no conflict of interest, nor any financial interest. 314
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maintenance. This study was a prospective, randomized, double-blind, placebo-controlled, multicenter trial. There were no significant differ255 ences between adjuvant IVIG and adjuvant placebo in mortality, serious 256 AEs, time to relapse and infection rates. The authors demonstrated that 257 a single course of high-dose IVIG reduces disease activity in ANCA258 vasculitis where active disease persists, but the benefit of IVIG was not 259 maintained beyond 3 months [12]. Other than this sole RCT, 4 studies 260 have been ad hoc conducted to assess the efficacy of IVIG in GPA 261 (Table 2) [13–16] reporting clinical benefits and good tolerance in the 262 majority of these patients. Furthermore, 18 anecdotal reports have 263 showed the efficacy of IVIG in a heterogenous population affected by 264 GPA (Table 3) [30–48], while 3 reports did not point out any beneficial 265 effect [49–51]. 266 Kamali et al. [49] described the case of a young patient affected by 267 GPA with intra-alveolar haemorrhage who developed end-stage renal 268 disease requiring haemodialysis, despite CS, CYC and IVIG therapy. 269 Lamprecht et al. [50] reported the history of a GPA patient who 270 underwent partial pneumonectomy because of cavitation of granulo271 mas resulting in massive pseudocaverns followed by IVIG therapy that 272 did not result in sustained remission. Finally, Blum et al. [51] analysed 273 the cases of two patients suffering from GPA with ocular involvement 274 treated with IVIG after other several failed therapies; although the sys275 temic disease was under control, the ocular symptoms of both patients 276 worsened during and after IVIG treatment. In one case an adverse effect 277 consisting of retinal vasculitis was noted on two occasions. 278 Different mechanisms of action have been proposed to explain the 279 beneficial effects of IVIG on autoimmune diseases, including modulation 280 of Fc receptor expression on leukocytes and endothelial cells, interac281 tion with complement proteins, modulation of the synthesis and release 282 of cytokines and chemokines, modulation of cell proliferation and apo283 Q12 ptosis, remyelination, neutralization of circulating antibodies, selection 284 of immune repertoires, interaction with other cell surface molecules
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IVIG protocol
Reason for IVIG introduction
5 day course (dosage not reported) 2.5 g for 5 days 400 mg/kg for 4 consecutive days every 3 weeks 500 mg daily for 3 days 400 mg/kg for 5 consecutive days (total 2 courses) 1 g/kg daily
Disease relapse in pregnancy
30 g/day for 5 consecutive days 400 mg/day for 5 days 400 mg/day for 3 consecutive days each month Not reported 2 mg/kg monthly 400 mg/day for 5 consecutive days monthly Different dosages during the six years of therapy described 150 g/month 0.5 g/kg/day for four consecutive days 500 mg/kg/day for 4 days 400 mg/kg/day for 5 days 400 mg/day for 5 consecutive days 30 g/day for 5 consecutive days
Infectious comorbidity (mucomycosis) Iatrogenic effect (CYC induced leucopenia) Active phase of disease in pregnancy New onset of disease in pregnancy Disease relapse (aneurysm located on the superior pancreatic-duodenal artery and multiple microaneurysms in the hepatic and renal artery branches, parietal thickening of the small bowel and splenic infarction) Infectious comorbidity (CMV infection) Resistant to conventional therapy Resistant to conventional therapy Disease relapse (central nervous system involvement) New onset of disease in pregnancy 3 patients resistant to conventional therapy and one infectious comorbidity (CMV chorioretinitis) Associated common variable immunodeficiency Resistant to conventional therapy Disease relapse (central nervous system involvement) plus infectious comorbidity (cystitis) Resistant to conventional therapy Resistant to conventional therapy Infectious comorbidity (parvovirus B19 infection) 6 patients resistant to conventional therapy and 2 CYC induced cystitis
Please cite this article as: Guidelli GM, et al, Granulomatosis with polyangiitis and intravenous immunoglobulins: A case series and review of the literature, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.03.005
G.M. Guidelli et al. / Autoimmunity Reviews xxx (2015) xxx–xxx
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Take-home messages
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• IVIG therapy could be recommended as a long term protocol in treating ANCA-vasculitis. • IVIGs, compared to conventional immunosuppressive agents, present a better drug's good safety profile and steroid sparing properties.
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