Abstract
Stiff Person Syndrome (SPS), a rare autoimmune neurologic disorder characterized by fluctuating muscle spasms and rigidity, is mediated by autoantibodies to glutamic acid decarboxylase (GAD) antibodies. Symptoms of SPS have been shown to improve after administration of intravenous immunoglobulin (IVIG) however, there is a paucity of information regarding use of SCIg in SPS. Four patients with Stiff Person Syndrome were treated with SCIgPro20 for a period between 31 to 101 months. Most reactions were local and mild. All patients reported improvement in spasticity, and 2 patients reported improvement in seizure frequency. SCIgPro20 was well tolerated in patients with SPS and was associated with improvement in symptoms.
INTRODUCTION
Stiff Person Syndrome (SPS) is a rare neurologic disorder characterized by fluctuating muscle spasms and rigidity. It is mediated mainly by autoantibodies to glutamic acid decarboxylase (GAD65), and to a lesser extent, by antibodies to amphiphysin, gephyrin, glycine receptor, and others. There is a high prevalence of co-existing autoimmune disorders, and has recently been described in association with common variable immunodeficiency (CVID) [1, 2]. Symptoms of SPS have been shown to improve after administration of intravenous immunoglobulin (IVIG) [3]. However limited information exists regarding use of subcutaneous immunoglobulin (SCIG) in SPS, including a single case series of 2 patients [4].
SCIG use is reported in several autoimmune conditions [5]. SCIgPro20, a 20%liquid immunoglobulin G (IgG) product stabilized with L-proline, is lic-ensed for subcutaneous administration in adults and children≥two years who have primary immunodeficiency disease (PIDD) and as maintenance therapy in adults with chronic inflammatory demyelinating polyneuropathy [6]. SCIgPro20 is efficacious, can be administered at home, is associated with fewer systemic side effects than IVIG, often requires no pre-medications, and maintains stable steady-state IgG levels [5]. We describe the use of SCIgPro20 in 4 patients with SPS and PIDD.
A multi-center retrospective chart review included 4 patients with SPS treated with SCIgPro20. We examined safety and efficacy by assessing adverse effects and change in symptom frequency. Other study assessments included patient characteristics, indications for switch to SCIG, clinical and laboratory course while on SCIgPro20, and characteristics of infusions including dosage, number of infusion sites, and duration of infusion. The study was approved by the Institutional Review Board, and procedures involving experiments on human subjects are done in accord with the ethical standards of the Committee on Human Experimentation of the institution in which the experiments were done or in accord with the Helsinki Declaration of 1975.
CASE PRESENTATIONS
Patient demographics and immunologic characteristics are shown in Table 1. All patients were diagnosed with SPS based on previously reported criteria including characteristic symptoms and pres-ence of GAD65 autoantibodies [1]. Patient #1 had neck and lower extremity stiffness, and episodic spasms including bilateral legs, torso, and neck. Her ambulation was limited. Patient #2 and #3 had mild generalized stiffness, and did not have episodic spasms. Patient #4 experienced bilateral leg stiffness, severe intermittent spasms including coronary, esophageal and bilateral leg muscle spasms. The patient could not ambulate for long distances. None of the 4 subjects had respiratory involvement. All subjects were female, and the average age at diagnosis was 37 (range 12–55) years. Three subjects were diagnosed with CVID and 1 subject with selective IgA deficiency with specific antibody deficiency (SAD) in the context of baseline immunoglobulins, vaccine responses when available, and infection history, all prior to the diagnosis of SPS. Two of 4 subjects had associated autoimmune conditions. Lymphocyte subsets and proliferative responses were normal in all subjects except a decreased response to candida and tetanus antigen stimulation in Patient #1. Patients were observed from 31 to 101 months while receiving weekly SCIgPro20. Four patients received a total of 1,196 infusions. The average number of infusions per patient was 299 (range 124–436). All 4 patients diagnosed with PIDD prior to SPS received IVIG for treatment of PIDD before the start of SCIgPro20. In 2 patients, the SCIgPro20 dose was established using the package insert suggested conversion factor of 1.37 when switching from IVIG [5]. The cumulative monthly SCIgPro20 dosage was 680 (range 472 –1,200) mg/kg/4 weeks compared to 600 (range 400–1000) mg/kg/3-4 weeks of IVIG prior to SCIgPro20 treatment. The average weekly volume infused of SCIgPro20 per patient was 60 (range 40–90) mL. The median number of infusion sites was 4 (range 3–8). Calculated infusion rates (mL/hr) per site averaged 8.9 (range 3.8–16.7). The average infusion time for 4 patients was 100 (range 40–180) minutes. Only one patient currently receives premedication (diphenhydramine, acetaminophen) prior to SCIgPro20 infusions. Reasons for switch to SCIG was patient preference (n = 2), inadequate control of spasticity associated with SPS (n = 1), and systemic side effects associated with IVIG (n = 1) including migraine headaches and aseptic meningitis.
Demographic, immunologic, and infusion characteristics of patients with Stiff Person Syndrome
Pt. = patient; CVID = common variable immunodeficiency; GAD = glutamic acid decarboxylase (GAD65); IVIG: intravenous immunoglobulin; NA = not available; PIDD = primary immunodeficiency disease; sIgA = selective IgA deficiency; SAD = specific antibody deficiency; DPH = diphenhydramine; APAP = acetaminophen; F = female; W = white (Caucasian); & = two different laboratories utilized as indicated by different units; * = abnormal value; # = post immunization with pneumococcal polysaccharide vaccine PPSV23.
All patients reported subjective (no formal assessment) improvement in spasticity associated with SPS. Prior to immunoglobulin therapy, Patient #1 received clonazepam, which was changed to diazepam with mild improvement in symptoms. Following discontinuation of diazepam, her symptoms returned and she was restarted on diazepam and subsequently re-ceived rituximab after initiation of SCIgPro20. She had improvement in her gait and could ambulate longer distances. Interestingly, seizure frequency im-proved for both the patient with autoimmune epilepsy (Patient #2), as well as Patient #1 who has an otherwise unspecified seizure disorder. Patient #2 became seizure free for more than one year and returned to work. Improvement was also reported in gait disturbance and motor function (n = 1), migraine headaches (n = 1), and distal paresthesia (n = 1). Patient #4 received levetiracetam, as well as clonazepam, tramadol, and tizanidine for exacerbations of symptoms. She had considerable improvement in her symptoms to the point she could trek and climb up slopes. No coronary or esophageal spasms were reported during immunoglobulin treatment.
Local reactions were mild in 3 patients. One patient reported no adverse events. Other reported adverse events were chills, headache, and exacerbation of an underlying illness (chronic urticaria). Patient 1 discontinued SCIgPro20 in favor of IVIG due to provider preference.
DISCUSSION
This is the largest retrospective study to examine SCIG use in SPS patients, including SPS patients with associated PIDD. All patients previously rec-eived IVIG at an average dose of 600 (range 400–1000) mg/kg every 3-4 weeks, while the average SCIgPro20 dose was 680 (range 472–1,200) mg/kg/4 weeks. This was similar to the two patients in the other study of patients with SPS who were treated with doses of 40–100 grams/4 weeks of SCIG [4]. Improvements in PIDD symptoms attained on IVIG were sustained on SCIgPro20. The average IgG level while receiving IVIG was 898 (range 503–1416) mg/dL compared to 1176 (range 1080–1350) mg/dL during SCIgPro20 treatment. This difference could be related to higher steady state levels and/or dose adjustment factor (1.37, n = 2 patients) seen with SCIgPro20 compared to IVIG. In all patients, SCIgPro20 was well tolerated with minimal adverse effects, similar to reports of tolerability of SCIG [4, 5]. Three patients currently remain on SCIgPro20.
All 4 subjects reported improvement in SPS symptoms while on SCIgPro20. The manufacturer has not established immunoglobulin induction and maintenance dosing in SPS, however the reported immunomodulatory dose of IVIG is 2 g/kg monthly [3]. The lower actual dose may reflect dosing closer to replacement doses for PIDD. This suggests the immunomodulatory effects of immunoglobulin may be achieved at doses closer to replacement dosing for PIDD, however further prospective studies are required to determine whether this concept is valid for all with SPS. Three of 4 patients received concomitant medications to treat their SPS, and could have contributed to observed improvement in symptoms.
The mechanism of action of SCIG in SPS remains unknown. It is possible that immunoglobulin inhibits autoantibody to GAD65, although relative amounts of these autoantibodies did not appear to change over time (data not shown) in patients receiving SCIG, similar to a previous report describing use of high-dose IVIG [3], despite patient-reported improvement in symptoms. Higher doses of immunoglobulin (≥2 gm/kg) may impact the acute antibody-mediated phase of autoimmune neurological diseases, while lower doses such as≤1 gm/kg may affect the chronic phase involving T cells and dendritic cells [5].
SCIgPro20 was well tolerated and the low systemic side effect profile of SCIG has been associated with improvement in quality of life in patients with autoimmune neurological diseases and those with PIDD [5, 7]. SCIG allows flexibility in dosing, home infusions, and no requirement for venous access; these benefits contributed to SCIG preference over IVIG in this study and the other study of SCIG in SPS [4]. In select patients, immunosuppressants including steroid-sparing agents have been weaned or discontinued in patients on SCIG [5]. Limitations of the study include small sample size, no standardized system for characterizing and quantifying response to treatment and adverse effects, including quality of life measures, and temporal limitations. Additionally, we have limited data to make conclusions about IgG and anti-GAD65 levels in relation to treatment with SCIgPro20.
In summary, SCIgPro20 was well tolerated and associated with improvement in symptoms in SPS patients. All patients had associated PIDD, and dosing range on SCIgPro20 reflected replacement dosing closer to that given for PIDD. Larger studies are needed to further characterize clinical and laboratory response to SCIG products in a more diverse patient population.
CONCLUSIONS
Subcutaneous immunoglobulin therapy with IgPro20 may be considered as an alternative to intravenous immunoglobulin in patients with Stiff Person Syndrome. SCIgPro20 was well tolerated with most local reactions reported as mild and was associated with improvement in spasticity. Larger studies are needed to confirm the efficacy and safety of SCIGPro20, as well as objective tools to verify the subjective improvement in spasticity experienced by patients.
Footnotes
ACKNOWLEDGMENTS
Funding source: This study was supported through an Investigator Initiated Research grant awarded to Niraj Patel, funded by CSL Behring LLC, King of Prussia, PA, USA. Dr. Ty Prince is on Speaker’s Bureau for CSL Behring. Drs. Olivia Francis and Avni Joshi have no COI. Dr. Guha Krishnaswamy has research funding from CSL Behring and receives biannual royalties from UpToDate Medicine. Dr. Niraj Patel receives research funding from Takeda and CSL Behring, and is on Speaker’s Bureau for Takeda and CSL Behring