Indications for IVIG in Rheumatic Diseases
Indications for IVIG in Rheumatic Diseases
IVIG has been used experimentally as last-resort therapy to treat organ-specific manifestations of lupus, and case studies have reported positive outcomes in specific areas such as neuropsychiatric lupus, panniculitis, immune cytopenias and severe serositis. Recently, with the advent of biologic agents, there have been cases where the monoclonal antibody has been efficacious where IVIG has not. It is well known that positive case reports that describe favourable outcomes for treatments are more likely to be published than those that do not and therefore the results of case reports where IVIG is used as a last resort with success should be interpreted with caution.
Two small RCTs tested the efficacy of IVIG in SLE as well as four open trials and one retrospective study. These studies include 150 patients in total. The most recent RCT investigated the response of pregnant SLE patients to IVIG compared with those given prednisolone and NSAIDs alone. Patients in the treatment group had a total of 11 infusions of IVIG (500 mg/kg every 3 weeks to 33 weeks gestation). The lupus activity in pregnancy score fell significantly, from 0.72 to 0.13, and there was no significant change in the control group (0.88–0.66). All 12 IVIG patients went to term, compared with 9 of 12 of the control group with no serious side effects, leading the authors' to conclude that IVIG improves pregnancy outcome and reduces lupus disease activity. A second RCT looked at IVIG use in LN compared with CYC. Fourteen LN patients who had already been induced into remission with i.v. CYC were randomized to receive monthly IVIG (400 mg/kg) or i.v. CYC. After a follow-up period of 18 months, there was no significant difference between IVIG and CYC in maintaining remission, leading the authors to conclude that IVIG could be an alternative treatment to CYC. However, it is recognized that significant differences between LN treatment outcomes may take 5 years to become apparent. Therefore larger-scale RCTs with longer periods of follow-up are required to accurately compare the two treatments.
Uncontrolled open trials all report positive results for IVIG. Francioni et al. looked at the treatment of chronically active lupus rather than acute flares and administered IVIG (400 mg/kg) for 5 days every month for 6–24 months. Of 12 patients, 11 showed clinical and serological improvement after treatment, although no comment was made on concurrent medication changes. Schroeder et al. also demonstrated a significant improvement in mild flares of lupus as measured by a reduction in their SLAM scores from 7.33 to 5.25 (P < 0.001) with a total of 10 infusions 20 days apart, although this improvement was only very modest considering the intensity of the infusion protocol. Levy et al. describe 20 patients with various manifestations of SLE treated with monthly IVIG (400 mg/kg/day for 5 days). Of the 20, 17 responded fully after one to eight courses of monthly IVIG, with a mean reduction in SLAM score from 19.3 to 4.0 (P < 0.0001). Encouragingly, 8 of 15 patients taking glucocorticoids were able to reduce their dose by the end of the trial. Hundt et al. studied the treatment of lupus exacerbations in 13 patients with 5 consecutive days of IVIG (400 mg/kg/day) as measured by mECLAM scores. Although concurrent glucocorticoid dose was increased in six of these patients, it was noted that the remaining seven patients, in whom the glucocorticoid dose was kept constant, were full responders with a median reduction in their mECLAM score of 8 points. When these results are taken together, they suggest that IVIG may be useful in acute flares of SLE, with most benefit seen during severe flares. They also suggest that the most common symptoms to improve are those of fatigue, fever and pain.
More recently, Zandman-Goddard et al. reported that 9 of 11 lupus patients given IVIG (400 mg/kg/day for 5 days) over 2–42 months had a full or partial response as measured by a significant reduction in SLEDAI score. Background therapy in this open study was not controlled, which of course may confound interpretation of these observations. In addition, >10% developed pulmonary embolism, representing an unacceptably high rate of serious side effects.
Finally, a larger retrospective study by Sherer et al. looked at 62 patients given IVIG as part of their treatment for lupus. Patients were treated for a variety of symptoms, including mucosal ulcers, fever, rash, pleurisy and pericarditis, with a single dose of IVIG (500 mg/kg). Good responses were noted with a reduction in SLEDAI score from 15 to 5. Overall, the results from this study were promising, although there was no information about the dosing regimen of IVIG for each patient or other treatments they were receiving, and it is clear that a more rigorous study design is required. A summary of indications for IVIG use in lupus can be found in Table 4.
APS can present as early pregnancy loss and stillbirth or arteriovenous thromboses. As of May 2012, the NDMP updated its clinical guidelines and no longer permits IVIG use in pregnancy-related problems related to APS, although its use is still permitted in catastrophic APS (CAPS) and stroke.
CAPS is a rare complication of APS that causes microthrombi and occlusions in the small vessels of multiple organs and carries a high mortality rate. Due to the rarity of CAPS, the European Forum on Antiphospholipid Antibodies set up the CAPS registry with the aim of increasing our understanding of CAPS and developing treatment strategies. The registry has shown that patients who receive prompt anticoagulation, glucocorticoids and plasma exchange with or without IVIG make the best recovery, with 75% of patients surviving, compared with ~20% with anticoagulation and glucocorticoids alone. Regarding IVIG, patients who received anticoagulants, glucocorticoids and plasma exchange had a survival rate of 78%, compared with 69% of those who also received IVIG, although this difference was not significant. As already mentioned, IVIG has been associated with thromboembolism, with an incidence rate of up to 2%. Most patients who developed thromboembolism were given high-dose IVIG at a fast rate and had multiple risk factors. It has therefore been suggested that a high dose (2 g/kg) be given over 5 days and each infusion over a minimum of 8 h, as this has been shown to reduce the risk of thromboembolism. On this basis, the current evidence does not support the use of IVIG in CAPS unless it is complicated by severe autoimmune thrombocytopenia.
Ischaemic stroke is a well-recognized complication of APS, with one in five young stroke sufferers having aPLs. No RCTs exist evaluating the use of IVIG in preventing or treating stroke associated with APS. One case study reports positive findings stating that 'the temporal association between IVIG and reversal of … neurological impairment … strongly indicates a specific effect of IVIG administration in this patient'. Tincani et al. canvassed the opinions of six experts at the International Advisory Board of the 10th International Congress on Antiphospholipid Aantibodies. Most respondents had little or no experience of using IVIG and it was mainly used where other treatments had failed or where severe thrombocytopenia coexisted. Furthermore, the British Committee for Standards in Haematology guidelines do not mention of the use of IVIG and only endorse a target international normalized ratio (INR) of 2.0–3.0 for APS prophylaxis. The lack of evidence for IVIG use certainly warrants more research in this area. However, currently, anticoagulation should only remain the mainstay of prophylaxis against arterial thrombosis in APS. IVIG should be reserved only for those severely affected by coexistent thrombocytopenia.
Systemic-onset JIA (sJIA) causes fever, arthritis, serositis and a characteristic salmon-pink macular rash. Traditional therapies have included NSAIDs, corticosteroids and MTX. A number of findings led investigators to postulate that sJIA is driven by the interleukin IL-6. These findings were confirmed by a placebo-controlled double-blind RCT comparing the anti-IL-6 antibody tocilizumab with placebo, where a significant improvement was seen over 12 weeks. The anti-IL-1β antibody canakinumab has also recently been shown to be effective in two RCTs. Other biologic therapies found to be effective include the IL-1 receptor antagonist anakinra and the anti-TNF agents adalimumab and etanercept.
IVIG has occasionally been used alongside glucocorticoids in resistant cases of sJIA, with good anecdotal evidence of efficacy from a number of studies, although the only RCT comparing IVIG with placebo in sJIA had negative results. Today its use has largely been superseded by the newer biologics, and recent guidance released by the ACR states that the use of IVIG in sJIA with fever but without active arthritis is 'uncertain for initial management'.
Granulomatosis with polyangiitis (GPA), microscopic polyangiitis and eosinophillic granulomatosis with polyangiitis (EGPA; formerly Churg–Strauss syndrome) make up the ANCA-associated vasculitides (AAVs). Induction of remission usually involves intensive treatment with CYC combined with high-dose glucocorticoids. However, CYC is associated with a risk of ovarian failure and infertility even when given in courses as short as 6 months. Rituximab has recently been shown in the Rituximab for ANCA-associated Vasculitis (RAVE) trial to be non-inferior to CYC in inducing remission. Maintenance therapy usually involves corticosteroids as well as AZA, MTX or LEF.
The toxicity of these drugs has led to IVIG being considered among other treatments. Jayne et al. reported positive results in seven treatment-resistant GPA patients who were given IVIG, with symptoms improving within 2 days–3 weeks. In another open trial by the same author, 13 of the 26 patients with GPA had complete remission and another 13 of the 26 had partial remission after 8 weeks that was maintained 12 months after treatment started. In contrast, Richter et al. found that only 6 of 15 patients had a partial response to IVIG after 4 weeks, with none going into complete remission. Subtle differences between the responders and non-responders in this trial led the authors to hypothesize that IVIG may have an effect on the vasculitic but not the granulomatous component of the disease. The first RCT examining the effect of IVIG in persistent systemic AAV found a significant response at 3 months, with a reduction of >50 % in BVAS in 14 of 17 treated patients, although this benefit did not persist beyond 3 months as the BVASs of the placebo-treated patients gradually came down to meet those of the IVIG group.
Regarding EGPA, Tsurikisawa et al. describe five patients with EGPA-associated myocarditis and heart failure who received five doses of IVIG and subsequently increased their left ventricular ejection fraction significantly. In a further open-label prospective study, 22 patients with a diagnosis of relapsed systemic AAV were induced into remission by administering six courses of monthly IVIG (500 mg/kg/day for 4 days). All patients initially responded well, with 59% remaining in remission after 9 months, suggesting that IVIG might be an important adjunct in AAV patients with refractory or relapsing disease. Recently a Cochrane review evaluated IVIG as an adjuvant therapy to glucocorticoids and immunosuppression in GPA and found insufficient evidence to support its use given its high cost and the need for repeat courses. Current guidance from the British Society for Rheumatology (BSR) and British Health Professionals in Rheumatology regarding AAVs is that IVIG 'may be considered 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'. IVIG may therefore be an important and safe bridging therapy during severe active vasculitis with coexisting immunosuppression.
Grey Indications
Lupus
IVIG has been used experimentally as last-resort therapy to treat organ-specific manifestations of lupus, and case studies have reported positive outcomes in specific areas such as neuropsychiatric lupus, panniculitis, immune cytopenias and severe serositis. Recently, with the advent of biologic agents, there have been cases where the monoclonal antibody has been efficacious where IVIG has not. It is well known that positive case reports that describe favourable outcomes for treatments are more likely to be published than those that do not and therefore the results of case reports where IVIG is used as a last resort with success should be interpreted with caution.
Two small RCTs tested the efficacy of IVIG in SLE as well as four open trials and one retrospective study. These studies include 150 patients in total. The most recent RCT investigated the response of pregnant SLE patients to IVIG compared with those given prednisolone and NSAIDs alone. Patients in the treatment group had a total of 11 infusions of IVIG (500 mg/kg every 3 weeks to 33 weeks gestation). The lupus activity in pregnancy score fell significantly, from 0.72 to 0.13, and there was no significant change in the control group (0.88–0.66). All 12 IVIG patients went to term, compared with 9 of 12 of the control group with no serious side effects, leading the authors' to conclude that IVIG improves pregnancy outcome and reduces lupus disease activity. A second RCT looked at IVIG use in LN compared with CYC. Fourteen LN patients who had already been induced into remission with i.v. CYC were randomized to receive monthly IVIG (400 mg/kg) or i.v. CYC. After a follow-up period of 18 months, there was no significant difference between IVIG and CYC in maintaining remission, leading the authors to conclude that IVIG could be an alternative treatment to CYC. However, it is recognized that significant differences between LN treatment outcomes may take 5 years to become apparent. Therefore larger-scale RCTs with longer periods of follow-up are required to accurately compare the two treatments.
Uncontrolled open trials all report positive results for IVIG. Francioni et al. looked at the treatment of chronically active lupus rather than acute flares and administered IVIG (400 mg/kg) for 5 days every month for 6–24 months. Of 12 patients, 11 showed clinical and serological improvement after treatment, although no comment was made on concurrent medication changes. Schroeder et al. also demonstrated a significant improvement in mild flares of lupus as measured by a reduction in their SLAM scores from 7.33 to 5.25 (P < 0.001) with a total of 10 infusions 20 days apart, although this improvement was only very modest considering the intensity of the infusion protocol. Levy et al. describe 20 patients with various manifestations of SLE treated with monthly IVIG (400 mg/kg/day for 5 days). Of the 20, 17 responded fully after one to eight courses of monthly IVIG, with a mean reduction in SLAM score from 19.3 to 4.0 (P < 0.0001). Encouragingly, 8 of 15 patients taking glucocorticoids were able to reduce their dose by the end of the trial. Hundt et al. studied the treatment of lupus exacerbations in 13 patients with 5 consecutive days of IVIG (400 mg/kg/day) as measured by mECLAM scores. Although concurrent glucocorticoid dose was increased in six of these patients, it was noted that the remaining seven patients, in whom the glucocorticoid dose was kept constant, were full responders with a median reduction in their mECLAM score of 8 points. When these results are taken together, they suggest that IVIG may be useful in acute flares of SLE, with most benefit seen during severe flares. They also suggest that the most common symptoms to improve are those of fatigue, fever and pain.
More recently, Zandman-Goddard et al. reported that 9 of 11 lupus patients given IVIG (400 mg/kg/day for 5 days) over 2–42 months had a full or partial response as measured by a significant reduction in SLEDAI score. Background therapy in this open study was not controlled, which of course may confound interpretation of these observations. In addition, >10% developed pulmonary embolism, representing an unacceptably high rate of serious side effects.
Finally, a larger retrospective study by Sherer et al. looked at 62 patients given IVIG as part of their treatment for lupus. Patients were treated for a variety of symptoms, including mucosal ulcers, fever, rash, pleurisy and pericarditis, with a single dose of IVIG (500 mg/kg). Good responses were noted with a reduction in SLEDAI score from 15 to 5. Overall, the results from this study were promising, although there was no information about the dosing regimen of IVIG for each patient or other treatments they were receiving, and it is clear that a more rigorous study design is required. A summary of indications for IVIG use in lupus can be found in Table 4.
APS
APS can present as early pregnancy loss and stillbirth or arteriovenous thromboses. As of May 2012, the NDMP updated its clinical guidelines and no longer permits IVIG use in pregnancy-related problems related to APS, although its use is still permitted in catastrophic APS (CAPS) and stroke.
CAPS is a rare complication of APS that causes microthrombi and occlusions in the small vessels of multiple organs and carries a high mortality rate. Due to the rarity of CAPS, the European Forum on Antiphospholipid Antibodies set up the CAPS registry with the aim of increasing our understanding of CAPS and developing treatment strategies. The registry has shown that patients who receive prompt anticoagulation, glucocorticoids and plasma exchange with or without IVIG make the best recovery, with 75% of patients surviving, compared with ~20% with anticoagulation and glucocorticoids alone. Regarding IVIG, patients who received anticoagulants, glucocorticoids and plasma exchange had a survival rate of 78%, compared with 69% of those who also received IVIG, although this difference was not significant. As already mentioned, IVIG has been associated with thromboembolism, with an incidence rate of up to 2%. Most patients who developed thromboembolism were given high-dose IVIG at a fast rate and had multiple risk factors. It has therefore been suggested that a high dose (2 g/kg) be given over 5 days and each infusion over a minimum of 8 h, as this has been shown to reduce the risk of thromboembolism. On this basis, the current evidence does not support the use of IVIG in CAPS unless it is complicated by severe autoimmune thrombocytopenia.
Ischaemic stroke is a well-recognized complication of APS, with one in five young stroke sufferers having aPLs. No RCTs exist evaluating the use of IVIG in preventing or treating stroke associated with APS. One case study reports positive findings stating that 'the temporal association between IVIG and reversal of … neurological impairment … strongly indicates a specific effect of IVIG administration in this patient'. Tincani et al. canvassed the opinions of six experts at the International Advisory Board of the 10th International Congress on Antiphospholipid Aantibodies. Most respondents had little or no experience of using IVIG and it was mainly used where other treatments had failed or where severe thrombocytopenia coexisted. Furthermore, the British Committee for Standards in Haematology guidelines do not mention of the use of IVIG and only endorse a target international normalized ratio (INR) of 2.0–3.0 for APS prophylaxis. The lack of evidence for IVIG use certainly warrants more research in this area. However, currently, anticoagulation should only remain the mainstay of prophylaxis against arterial thrombosis in APS. IVIG should be reserved only for those severely affected by coexistent thrombocytopenia.
Systemic-onset JIA
Systemic-onset JIA (sJIA) causes fever, arthritis, serositis and a characteristic salmon-pink macular rash. Traditional therapies have included NSAIDs, corticosteroids and MTX. A number of findings led investigators to postulate that sJIA is driven by the interleukin IL-6. These findings were confirmed by a placebo-controlled double-blind RCT comparing the anti-IL-6 antibody tocilizumab with placebo, where a significant improvement was seen over 12 weeks. The anti-IL-1β antibody canakinumab has also recently been shown to be effective in two RCTs. Other biologic therapies found to be effective include the IL-1 receptor antagonist anakinra and the anti-TNF agents adalimumab and etanercept.
IVIG has occasionally been used alongside glucocorticoids in resistant cases of sJIA, with good anecdotal evidence of efficacy from a number of studies, although the only RCT comparing IVIG with placebo in sJIA had negative results. Today its use has largely been superseded by the newer biologics, and recent guidance released by the ACR states that the use of IVIG in sJIA with fever but without active arthritis is 'uncertain for initial management'.
ANCA-associated Vasculitis
Granulomatosis with polyangiitis (GPA), microscopic polyangiitis and eosinophillic granulomatosis with polyangiitis (EGPA; formerly Churg–Strauss syndrome) make up the ANCA-associated vasculitides (AAVs). Induction of remission usually involves intensive treatment with CYC combined with high-dose glucocorticoids. However, CYC is associated with a risk of ovarian failure and infertility even when given in courses as short as 6 months. Rituximab has recently been shown in the Rituximab for ANCA-associated Vasculitis (RAVE) trial to be non-inferior to CYC in inducing remission. Maintenance therapy usually involves corticosteroids as well as AZA, MTX or LEF.
The toxicity of these drugs has led to IVIG being considered among other treatments. Jayne et al. reported positive results in seven treatment-resistant GPA patients who were given IVIG, with symptoms improving within 2 days–3 weeks. In another open trial by the same author, 13 of the 26 patients with GPA had complete remission and another 13 of the 26 had partial remission after 8 weeks that was maintained 12 months after treatment started. In contrast, Richter et al. found that only 6 of 15 patients had a partial response to IVIG after 4 weeks, with none going into complete remission. Subtle differences between the responders and non-responders in this trial led the authors to hypothesize that IVIG may have an effect on the vasculitic but not the granulomatous component of the disease. The first RCT examining the effect of IVIG in persistent systemic AAV found a significant response at 3 months, with a reduction of >50 % in BVAS in 14 of 17 treated patients, although this benefit did not persist beyond 3 months as the BVASs of the placebo-treated patients gradually came down to meet those of the IVIG group.
Regarding EGPA, Tsurikisawa et al. describe five patients with EGPA-associated myocarditis and heart failure who received five doses of IVIG and subsequently increased their left ventricular ejection fraction significantly. In a further open-label prospective study, 22 patients with a diagnosis of relapsed systemic AAV were induced into remission by administering six courses of monthly IVIG (500 mg/kg/day for 4 days). All patients initially responded well, with 59% remaining in remission after 9 months, suggesting that IVIG might be an important adjunct in AAV patients with refractory or relapsing disease. Recently a Cochrane review evaluated IVIG as an adjuvant therapy to glucocorticoids and immunosuppression in GPA and found insufficient evidence to support its use given its high cost and the need for repeat courses. Current guidance from the British Society for Rheumatology (BSR) and British Health Professionals in Rheumatology regarding AAVs is that IVIG 'may be considered 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'. IVIG may therefore be an important and safe bridging therapy during severe active vasculitis with coexisting immunosuppression.
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