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Abstract

Immunoglobulin (Ig) therapy is used to treat a wide range of immunodeficiencies and autoimmune diseases; While, its clinical benefit has been demonstrated in several studies, Ig therapy is associated with a risk of systemic adverse effects. As such, Onset of renal impairment, including acute renal failure, osmotic nephrosis and renal insufficiency, after immunoglobulin administration is rare, but is one of the most significant concerns related to intravenous Ig use at immunomodulatory doses. However, only few studies have investigated the safety of subcutaneous Ig (SCIg) in relation to these rare conditions. The aim of this prospective study is to describe the safety of SCIg (Gammanorm), specifically with regards to renal function, in inflammatory myopathies including mainly polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM). Twenty-four cases were included: 10 patients with PM, 6 with IBM, 5 with DM, 2 with mixed connective-tissue disease (MCTD) and 1 patient with scleromyositis. SCIg was given two to three times per week at 2 g/kg/month in all patients. Patients were treated for a mean duration of 24.6 ± 11.4 months (range 8–37 months) and received a median of 78 SCIg infusions. Renal function was stable over the study period in all patients. High-dose SCIg was well tolerated; the treatment was not withdrawn during the first year in any patient for safety issues. These results suggest that the use of high-dose SCIg is generally feasible and safe in patients with inflammatory myopathies.

Keywords

dermatomyositis high-dose therapy inclusion body myositis polymyositis renal function safety subcutaneous immunoglobulin

Key points

Immunoglobulin therapy is used for a broad range of diseases, including immunodeficiency disorders and inflammatory myopathies, While mostly prescribed off-label in autoimmune diseases such as inflammatory myopathies, immunoglobulins are generally considered as a safe therapy.

Most of the adverse events (AEs) associated with immunoglobulin administration are mild and transient. Late AEs are rare and include acute renal failure, thromboembolic events, aseptic meningitis, neutropenia, autoimmune haemolytic anaemia, skin reactions, and rare events of arthritis.

Renal impairment is one of the main concerns related to the use of high-dose immunoglobulin therapy. This manuscript reviews 24 cases treated in clinical practice and shows the renal safety of subcutaneous immunoglobulin in longstanding inflammatory myopathies.

Introduction

Immunoglobulin replacement therapy was first indicated for primary immune deficiencies; nowadays, its use has been extended to autoimmune disorders where immunoglobulins are given as an immunomodulatory therapy. Intravenous immunoglobulin (IVIg) therapy is now recommended for patients presenting with myositis refractory to corticosteroids or immunosuppressive agents.¹ It is also recommended for patients with myositis who are unable to continue immunosuppression due to adverse events, as well as those for whom such agents are contraindicated.^2–5 However, long-term IVIg therapy is associated with a risk of systemic adverse events, including renal impairment.⁶ Onset of renal impairment after immunoglobulin administration is rare, but one of the most significant concerns related to IVIg doses used in immunomodulatory diseases.⁶ The relationship between renal impairment including acute renal failure, osmotic nephrosis and renal insufficiency and the IVIg products stabilized with sucrose has been well established.^7–9 Its incidence has declined with the reduced use of IgG products containing sucrose.

Subcutaneous immunoglobulin (SCIg) has been proposed as an alternative to IVIg.^10–13 SCIg does not contain sucrose and the daily infused quantity is much lower than with IVIg, which may prevent the potential IVIG-induced nephrotoxicity. To date, there is no report of SCIg-induced renal toxicity. Moreover, systemic side effects have been shown to occur more commonly with IVIg than SCIg.⁶

SCIg is widely being used off label to treat several autoimmune diseases, such as myositis. The efficacy and safety of SCIg in patients with myositis have been reported, primarly in case series and uncontrolled studies.^10–13 Demonstrating that low-dose SCIg (0.2–0.6 g/kg/month) is effective and safe. A recently published series of 19 cases showed that the use of high-dose SCIg (2 g/kg/month) was feasible and beneficial in patients with inflammatory myopathies.¹⁴ However, renal function has not been specifically assessed in high-dose settings.

In this paper, we present a prospective series of 24 patients with myositis, treated with high-dose SCIg. The renal function was monitored thoroughly up to 1 year after treatment initiation.

Methods

Study design

This case series is based on observational, single-centre, prospective data collection between 2011 and 2014. Because the study was carried out at a single centre and according to clinical practice, it did not require ethics approval (Articles L1121-1 CSP and R1121-2: Code de la santé publique). However, although not a requirement, the study protocol was submitted to the CCTIRS before patient enrolment. Per the same regulations, an information letter was provided to all patients before enrolment, explaining the study objectives and procedures, and informing them that they could withdraw from the study at any time with no impact on their relationship with their physician or on their routine management. Patients were not included if they refused data collection or the publication of their individual information in the study report. All patients provided verbal informed consent to participate in the study and for the publication of their anonymous data.

The study objective was to assess the safety of high-dose SCIg (Gammanorm®, Octapharma, Boulogne-Billancourt, France) for the treatment of autoimmune diseases in terms of renal tolerance. All adult patients (>18 years) presented with a diagnosis of myositis and willing to receive SCIg for the treatment of autoimmune disease were included in the study. Only patients with myositis refractory to conventional treatment including high-dose corticosteroids and at least one standard immunosuppressive agent were included. For patients with inclusion body myositis (IBM), dysphagia must have been observed.

Patient evaluation

The Patients were evaluated at treatment initiation and at each subsequent routine visit, as per clinical practice. SCIg was given two to three times per week, for a total of 2 g/kg/month. The renal function was monitored at baseline before treatment initiation and monthly after SCIg initiation for up to 1 year. Monitoring included serum creatinine, glomerular filtration rate (GFR) and dipstick tests (i.e. urine test strip). GFR was estimated using the modification of diet in renal disease (MDRD) formula. In the case of abnormal dipstick results, the following tests were undertaken: proteinuria over 24 h, cytobacteriological examination of the urine (CBEU) and Addis count (i.e. number of erythrocytes, leukocytes, epithelial cells and casts) in the case of leukocyturia and haematuria.

Data collection

At treatment initiation, following data were \collected: demographics, the indication for SCIg treatment, prior and concomitant treatments, and comorbidities. Renal function measures were collected before treatment initiation, and at 3, 6 and 12 months. Information about SCIg administration was collected during the whole duration of the study.

Statistical analyses

Parameters were expressed as mean ± standard deviation (SD). Baseline values were defined as the value measured prior to treatment initiation. Endpoint values were defined as the last value measured during the treatment with SCIg.

Results

Baseline patient characteristics

A total of 24 patients were included in the study. Fifteen were women. The mean age was 53.3 ± 15.9 years (range 27–77 years). Initial diagnosis was polymyositis in 10 patients, inclusion body myositis in 6, dermatomyositis in 5, mixed connective-tissue disease (MCTD) in 2 and scleromyositis in 1 patient. Myositis diagnosis was confirmed using European Neuromuscular Centre (ENMC) criteria.¹⁵ Mean duration since diagnosis was 5.9 ± 4.9 years (range 0.7–16.1 years). Main patient characteristics are summarized in Table 1. Most patients (17/24) reported comorbidities at baseline, including Raynaud’s phenomenon (case 3), hypothyroidism (cases 6 and 12), heart failure (case 2), myofasciitis (case 11), multiple deep venous thrombosis (case 12), chronic venous insufficiency (case 7), aortic insufficiency and lupus erythematosus (case 13), hypertension (cases 2, 5, 6, 8, 9, 10, 15, 16, 18) and human immunodeficiency virus (HIV) (case 14).

Table 1.

Demographics and medical history of the 24 cases treated with subcutaneous immunoglobulin (SCIg) at initiation.

Patient no.	Sex	Age (years)	Diagnosis	Duration since diagnosis (years)	Prior treatments					Existing risk factors for renal dysfunction/pre-existing renal dysfunction
Patient no.	Sex	Age (years)	Diagnosis	Duration since diagnosis (years)	IVIg	Corticosteroids	MTX	AZA	Other*
1	Female	69	DM	7.8	Yes	Yes	Yes	Yes	yes	No
2	Female	55	PM	1.6	–	Yes	–	–	–	H/HF
3	Female	63	IBM	2.2	Yes	Yes	Yes	–	–	No
4	Female	30	DM	8.1	Yes	Yes	Yes	–	–	No
5	Female	78	IBM	7.7	Yes	–	–	–	–	A/H
6	Female	71	IBM	0.7	Yes	Yes	–	–	yes	A/H
7	Female	78	PM	10.8	–	Yes	–	–	–	A/H
8	Female	75	PM	1.0	Yes	Yes	Yes	–	–	A/H
9	Male	69	IBM	0.8	–	Yes	–	–	–	A/H
10	Female	49	PM	5.1	Yes	Yes	Yes	Yes	yes	H
11	Female	22	Scleromyositis	1.5	Yes	Yes	Yes	–	–	No
12	Female	49	MCTD	2.4	Yes	Yes	Yes	Yes	yes	No
13	Male	61	PM	10.2	Yes	Yes	–	Yes	yes	No
14	Male	52	IBM	1.2	–	–	–	–	–	Pre-existing renal dysfunction associated with HIV
15	Male	65	IBM	7.8	Yes	Yes	Yes	Yes	Yes	No
16	Female	70	IBM	3.0	–	Yes	–	–	–	A/H
17	Female	28	PM	8.4	Yes	Yes	Yes	Yes	–	No
18	Female	56	MCTD	10.5	Yes	Yes	Yes	Yes	Yes	H
19	Female	41	PM	16.1	Yes	Yes	Yes	–	Yes	No
20	Male	27	DM	1.2	–	Yes	Yes	–	–	No
21	Male	34	DM	1.8	–	Yes	Yes	Yes	–	No
22	Male	56	PM	9.8	–	Yes	Yes	–	Yes	No
23	Male	50	PM	18	–	Yes	Yes	–	Yes	No
24	Male	45	PM	4.2	Yes	Yes	Yes	Yes	Yes	D

Other treatments included rituximab, plasma exchange, immunosuppressants.

A, age > 65 years; AZA, Azathioripine; D, diabetes; DM, dermatomyositis; H, hypertension; HF, heart failure; HIV, human immunodeficiency virus; IBM, inclusion body myositis; IVIg, intravenous immunoglobulin; MCTD, mixed connective tissue disease; MTX, methotrexate; PM, polymyositis.

Most patients received prior corticosteroids (22/24), IVIg (14/24) and methotrexate (MTX) (15/24). Prior treatments are summarized in Table 1.

All renal function measures were normal prior to SCIg initiation, except for one patient (case 14) treated for interstitial nephritis associated with HIV disease. Mean creatinine level at baseline was 78.4 ± 51.4 µmol/liter (median 68), and mean estimated GFR using the MDRD formula was 108.4 ± 56.9 ml/min/1.73 m² (median 100.5 ml/min/1.73 m²). Dipstick tests were negative in all patients at baseline.

As presented in Table 1, 1 patient presented with pre-existing renal dysfunction and 10 patients presented with at least one risk factor for renal dysfunction (i.e. age > 65 years, diabetes, hypertension and heart failure).

SCIg therapy

SCIg was given two to three times per week, at 2 g/kg/month in all patients. Two patients (cases 1 and 19) received MTX concomitantly. Mean treatment duration was 24.6 ± 11.4 months (range 8–37 months), and patients received a total of 1872 SCIg injections. Mean follow-up duration for renal function monitoring was 16.1 ± 6 months.

Renal assessment

After SCIg initiation, creatinine and estimated GFR levels remained normal in all patients during the 1-year follow up. Individual measures are listed in Table 2.

Table 2.

Renal function monitoring: change in creatinine and estimated glomerular filtration rate (eGFR) over 1-year follow up.

Patient no.	Creatinine				eGFR				Change in renal function
Patient no.	Baseline	Month 1	Month 6	Month 12	Baseline	Month 1	Month 6	Month 12	Change in renal function
1	59	67	70	64.8	93	78	76	84	Stable/nonsignificant decrease
2	79.6	77.4	81.4	84.4	69	71	68	64	Stable/nonsignificant decrease
3	62	72.5	69.1	72.1	90	75	79	74	Stable/nonsignificant decrease
4	82.3	81.1	85	84	75	77	72	72	Stable/nonsignificant decrease
5	47	61	53.4	61.2	118	70	102	86	Stable/nonsignificant decrease
6	85	90.4	89.4	88	61	57	57	58	Stable/nonsignificant decrease
7	74	72	77	81.4	70	72	67	63	Stable/nonsignificant decrease
8	44.3	48.7	55.4	59	128	114	99	91	Stable/nonsignificant decrease
9	99	96	101	94.4	69	72	68	72	Stable/nonsignificant decrease
10	22	31.4	34	47	312	207	189	129	Stable/nonsignificant decrease
11	43.3	48	57.3	61.1	166	148	120	111	Stable/nonsignificant decrease
12	78	77.8	75.4	76	72	73	75	74	Stable/nonsignificant decrease
13	69.6	75.5	78.9	86.4	106	97	92	82	Stable/nonsignificant decrease
14	264	231.5	228.1	237.9	24	28	28	26	Stable/severe renal insufficiency
15	67	82	81	85	110	87	88	82	Stable/nonsignificant decrease
16	65.1	59.8	64.7	67.9	83	92	84	78	Stable/nonsignificant decrease
17	53	58	53	67.1	127	114	127	96	Stable/nonsignificant decrease
18	86	88.4	94.2	91.5	63	61	57	59	Stable/nonsignificant decrease
19	59.6	72.1	67.4	71.4	102	82	88	82	Stable/nonsignificant decrease
20	49	48.1	55	59.1	188	192	165	151	Stable/nonsignificant decrease
21	54	52.6	60.4	59	160	166	141	144	Stable/nonsignificant decrease
22	75	78	72	82	99	95	104	90	Stable/nonsignificant decrease
23	68	71	74	-	114	108	103	-	Stable/nonsignificant decrease
24	90	94	95	91	102	97	96	100	Stable/nonsignificant decrease

Mean creatinine levels were 72.7 ± 15.3 µmol/liter (median 71.5), 72.5 ± 19.3 µmol/liter (median 74) and 74.6 ± 15.6 µmol/liter (median 82) at month 1, 6 and 12, respectively. Mean estimated GFRs were 97.2 ± 42.6 ml/min/1.73 m² (median 84.5), 93.5 ± 35.5 ml/min/1.73 m² (median 88) and 85.5 ± 28.1 ml/min/1.73 m² (median 82), at month 1, 6 and 12, respectively.

Cases 10 and 11 experienced an increase in serum creatinine which was associated with muscle growth, as a response to the treatment. Gain in muscle mass was assessed using muscle strength testing and magnetic resonance imaging. Moreover, creatinine clearance levels (>140 ml/min for both cases) were within the normal range after initiation and during treatment with SCIg.

Dipstick tests remained negative in all patients during the follow up except for one patient at month 6. Case 4 experienced a low urinary tract infection due to colon bacillus, which led to leukocyturia and haematuria. The infection resolved quickly after treatment with antibiotics and the dipstick test was negative at month 12.

High-dose SCIg was well tolerated; the treatment was not withdrawn during the first year in any patients for safety issues. Renal function was stable over the study period in all patients.

Discussion

Onset of renal impairment after Ig administration is rare but is one of the most significant concerns related to IVIg use at immunomodulatory doses. Acute renal failure typically develops between a few hours to 10 days (with a median of 4.5–5 days) after the first administration of IVIg. In most patients, renal dysfunction is reversible within 4 weeks (mean time 10 days) after IVIg discontinuation.^8,9,16,17 However, in approximately 40% of patients, at least 1 day of haemodialysis is required^8,9; most patients recover within 2 weeks of hemodialysis.¹⁸ The need for dialysis is determined on an individual basis. Despite the favourable outcome observed in IVIg-related renal impairment, acute renal failure may progress to chronic renal failure¹⁷ leading to death in 8–15% of these patients.^9,19,20

Risk factors for the development of acute renal failure after IVIg administration include pre-existing renal disease, diabetes mellitus, hypertension, volume depletion (dehydration or hypovolemia), advanced age of at least 65 years, sepsis, paraproteinemia, and concomitant nephrotoxic drug usage.^{7,9,16,17,19,21} For patients with a history of renal impairment or risk factors, several precautionary measures should be implemented. These patients should be adequately hydrated prior to initiation of the IVIg infusion (approximately 6 h), and preferably up to several hours after IVIg administration.⁶ In our case series, 10 patients presented with at least one risk factor for renal insufficiency prior treatment initiation, including advanced age, hypertension, diabetes and pre-existing severe renal insufficiency, however, none of them showed a decrease in renal function throughout the duration of this study. Furthermore, patients with pre-existing renal impairment did not show any deterioration in renal function (cases 6 and 18).

The relationship between renal impairment including acute renal failure, osmotic nephrosis and renal insufficiency and IVIg products stabilized with sucrose is now well known.^7–9 The incidence of renal impairment declined with the reduced use of products containing sucrose, after the US Food and Drug Administration (FDA) required all IVIg manufacturers to revise their prescription information and to include a FDA black box warning on products containing sucrose.¹⁹

Considering the existing findings, SCIg could be proposed as an alternative to IVIg to potentially further decrease the risk of IVIg-associated nephrotoxicity.²² Compared with some IVIg products still available in the market, SCIg preparations do not contain sucrose and the daily infused quantity is much lower with SCIg than with IVIg, which may prevent the potential IVIg-induced nephrotoxicity. Taking into account that SCIg preparations do not contain sucrose, the risk of renal toxicity is empirical, and the occurrence of renal events might be related to other factors. It is also worth noting that systemic side effects for patients with primary antibody deficiencies are very rare during treatment with SCIg. Most studies reported no treatment-related serious adverse events; no patients discontinued SCIG due to treatment-related adverse events.^22,23

To date, there is no report of SCIg-induced renal toxicity. In replacement therapy for antibody deficiencies, renal function was preserved with the use of low-dose SCIg, ranging from 0.2 to 0.6 g/kg/month, as replacement therapy for antibody deficiencies.^14,24 This is supported by the present case series highlighting the safety of high-dose SCIg (2 g/kg/month). Although some patients presented existing risk factors for renal insufficiency, renal function remained stable in all patients up to 1-year follow up and no patient discontinued the SCIg treatment for safety issues.

The efficacy of high-dose SCIg (2 g/kg/month) has already been studied in patients with neurological and autoimmune diseases,¹⁴ but the safety of high-dose SCIg has not been extensively studied in these disorders. To the best of our knowledge, this small study is the first to assess renal function in patients treated with SCIg for myositis. The results highlight the safe use of SCIg in these patients with pre-existing risk factors. However, due to study limitations, including the small number of patients and the observational noncontrolled design, our findings must be considered with caution. Prospective randomized data are required to further confirm the efficacy and safety of high-dose SCIg in patients with myositis.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare that there is no conflict of interest.

References

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Assessment of renal function in patients with myositis and treated with subcutaneous immunoglobulin: a series of 24 cases

Abstract

Keywords

Key points

Introduction

Methods

Study design

Patient evaluation

Data collection

Statistical analyses

Results

Baseline patient characteristics

SCIg therapy

Renal assessment

Discussion

Footnotes

Funding

Conflict of interest statement

References