Abstract
Introduction
While clinical trials have established the efficacy of immunoglobulin (Ig) to treat chronic inflammatory demyelinating polyneuropathy (CIDP), real-world data are limited. This study evaluated real-world effectiveness of Ig among patients with CIDP in terms of progressive use of assistive devices as a proxy for deteriorating clinical disability.
Methods
Adults diagnosed with CIDP by a neurologist from 1/2015 to 11/2021 and with a documented nerve conduction study were identified using linked medical and pharmacy claims and electronic medical record (EMR) data in the United States (US). Patients receiving Ig were propensity score matched to patients without Ig. Claims for assistive devices were used as a proxy for disability and assessed over 6-month baseline and follow-up periods. Deterioration was defined as ≥ 1 post-index claim for an assistive device indicating a higher level of disability than observed at baseline. Changes in anticonvulsant, antidepressant, and opioid use were assessed as secondary outcomes.
Results
The study sample comprised 1302 Ig-treated and non-Ig-treated matched pairs (mean age 61 years and ~ 40% female). Approximately 40% fewer Ig-treated patients had ≥ 1 level of deterioration (3.3% vs. 5.4%, p = 0.0104) and ≥ 2 levels of deterioration (3.1% vs. 5.1%, p = 0.0079) in assistive device use. Anticonvulsant (48.0–44.8%) and opioid use (39.2–33.3%; both p < 0.0001) decreased from baseline to follow-up in Ig-treated patients but remained unchanged for non-Ig-treated patients. Among patients with baseline opioid use, a higher proportion of Ig-treated patients had opioid improvement over the post-index period (41.5% vs. 32.1%, p = 0.0021).
Conclusion
Our findings support the effectiveness of Ig therapy in CIDP. The benefits of Ig seen in clinical trials of maintained or improved disability scores appear to be reflected in the real world by less deterioration in assistive device use and lesser use of anticonvulsants, antidepressants, and opioids.
Keywords: Anticonvulsants, Antidepressants, Assistive devices, Chronic inflammatory demyelinating polyneuropathy, Disability, Intravenous immunoglobulin, Opioids, Real-world evidence, Subcutaneous immunoglobulin
Key Summary Points
| Why carry out this study? |
| Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare disorder of the peripheral nervous system characterized by deteriorating physical function and clinical disability. |
| While the efficacy of immunoglobulin (Ig) treatment in CIDP is well established from clinical studies, real-world data on the effectiveness of Ig therapy are limited. |
| This study aimed to evaluate the real-world effectiveness of Ig therapy among patients with CIDP compared to similar patients who did not receive any Ig treatment in terms of progressive use of assistive devices as a proxy for deteriorating clinical disability. |
| What was learned from the study? |
| Approximately 40% fewer Ig-treated patients had ≥ 1 level of deterioration compared to matched non-Ig-treated patients (3.3% vs. 5.4%, p = 0.0104), where deterioration was defined as ≥ 1 post-index claim or record for an assistive device indicating a higher level of disability than observed at baseline. |
| Our findings support the real-world effectiveness of Ig therapy in CIDP using the real-world proxy of deterioration in assistive device use, reflecting the benefits of Ig seen in clinical trials in terms of maintained or improved disability scores. |
Introduction
Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare disorder of the peripheral nervous system, resulting in progressive weakness, impaired sensory function of the arms and legs, and loss of reflexes [1–3]. Patients with CIDP commonly experience pain, fatigue, and functional impairment which can lead to disability (e.g., difficulty walking) [3–6]. A systematic review and meta-analysis of literature through 2017 found a worldwide incidence rate of CIDP of 0.33 per 100,000 person-years and prevalence rate of 2.81 per 100,000 [7]. Misdiagnosis is a key concern and challenge in the appropriate and timely diagnosis and initiation of treatment in CIDP [8, 9].
Consensus guidelines from the European Academy of Neurology and Peripheral Nerve Society recommend intravenous (IV) immunoglobulin (Ig; IVIg) or corticosteroids as initial treatment in typical CIDP and CIDP variants [10]. Recommended maintenance treatments include IVIg, subcutaneous Ig (SCIg), or corticosteroids. A recently published Cochrane review of randomized controlled trials (RCTs) found that IVIg improved disability for at least 2–6 weeks compared with placebo [11]. In one trial, the benefit of IVIg persisted for up to 24 weeks [12]. SCIg has also been found to be efficacious as a maintenance therapy for CIDP over 24 weeks [13].
Clinical trials of therapies in CIDP have typically evaluated disability as the primary outcome measure [14]. The Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale is the preferred outcome measure of the United States (US) Food and Drug Administration (FDA) [14, 15]. The INCAT is an ordinal scale for arm and leg disability that ranges from 0 (no signs of disability) to 10 (maximum disability) [14]. A one-point change in INCAT indicates the minimal clinically important difference in CIDP. A ≥ 1 point decrease in INCAT signals improvement or response, while a ≥ 1 point increase indicates deterioration or relapse [12, 16, 17].
Efgartigimod alfa (Vyvgart® Hytrulo; Argenx, Breda, Netherlands), a neonatal fragment crystallizable (Fc) receptor blocker, is a new treatment that was approved for the treatment of CIDP by the FDA in June 2024 [18]. Other agents being investigated in CIDP include C1 complement inhibitors and Bruton tyrosine kinase inhibitors [19]. Given the recent emergence of a new therapeutic option in CIDP, along with the potential for novel therapies in the future, it is critical to understand the real-world effectiveness of current treatment options. While the efficacy of Ig to treat CIDP is well established in clinical trials, systematic evaluations of the real-world effectiveness of Ig therapy are limited [11].
Real-world studies evaluating the effectiveness of IVIg have primarily been conducted at single-center institutions with small sample sizes utilizing older data [20–25]. Analyses of claims data allow for the capture of larger and more representative CIDP study populations, but do not contain clinical disability scores (e.g., INCAT). Two claims-based studies in the US have reported markers of functional status among patients with CIDP initiating IVIg [26, 27]. Diagnosis codes for markers of impaired functional status (e.g., difficulty walking, weakness) were compared prior to and after IVIg treatment initiation [27].
The current study aimed to evaluate the real-world effectiveness of Ig therapy among patients with CIDP using medical and pharmacy claims data in the US. The primary outcome measure was the progressive use of assistive devices which served as a proxy measure for deteriorating clinical disability. Reductions in the use of anticonvulsants, antidepressants, and opioids were assessed as secondary proxy measures to indicate improvement in pain [28]. Outcomes were assessed over 6 months of treatment among patients with CIDP that initiated Ig treatment and compared to similar patients who did not receive any Ig therapy.
Methods
Data Source
This retrospective observational study leveraged US open-source claims data from IQVIA’s Longitudinal Prescription Claims (LRx) and Professional Fee Claims (Dx) databases between January 2014 and May 2022 (the ‘study period’). The LRx database encompasses over 1.6 billion retail and mail-order prescription claims, representing dispensed prescriptions from approximately 85% of retail, mail, long-term care, and specialty pharmacies. The Dx database includes approximately 1 billion professional fee claims per year, representing over 870,000 practitioners monthly, and approximately 70% of office-based and specialist physician activity in the US. Data elements in these databases include diagnoses, procedures, and office-administered drugs.
As available, patients were linked to IQVIA’s Ambulatory Electronic Medical Records (AEMR) database, sourced from an “opt-in” provider research network. AEMR includes approximately 75 million patient records from more than 40,000 physicians. In addition to information on diagnoses, procedures, and office-administered drugs, the electronic medical records (EMR) data also includes problem names (indicating patients’ symptoms, conditions, etc.).
LRx, Dx, and AEMR are de-identified and compliant with the Health Insurance Portability and Accountability Act (HIPAA), as well as the Helsinki Declaration of 1964 and its later amendments or comparable ethical standards. The study did not require patient consent or institutional review board review due to the use of de-identified, secondary data. Patients are linked across IQVIA databases through a unique IQVIA patient ID, created using a deterministic matching process and actual patient information.
Study Population
The initial study population included adult patients newly diagnosed with CIDP between January 2015 and November 2021 (the ‘selection window’) (Figs. 1,2). The first claim in Dx or record in AEMR with a diagnosis code of CIDP [International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) 357.81, International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) G61.81, Systematized Nomenclature of Medicine—Clinical Terms (SNOMED, in AEMR) 128,209,004, 444,728,005, 230,564,004] was classified as the ‘diagnosis index date’. Patients were excluded if they had a diagnosis code for CIDP in the 360 days prior to the diagnosis index date or drug codes for any Ig therapy from 360 to 90 days prior to the diagnosis index date (to ensure a newly-diagnosed population). Due to the potential challenges related to misdiagnosis of CIDP in current clinical practice, additional criteria were required to increase confidence in an accurately-diagnosed population. A second diagnosis code of CIDP was required ≥ 90 days after the diagnosis index date, and at least one of the first two CIDP diagnoses must have been from a neurologist of high relevance (with specialty of neurology, clinical neurophysiology, or neuromuscular medicine). Patients were also required to have a procedure code for a nerve conduction study or H-reflex or F-wave study between 360 days prior to 90 days after the diagnosis index date. Because open-source databases were utilized, proxies for continuous enrollment requirements were implemented, including requirements for activity (≥ 1 claim) in LRx and Dx > 360 days prior to the diagnosis index date and > 180 days after the diagnosis index date.
Fig. 1.
Study diagram: newly diagnosed patients with CIDP. AEMR Ambulatory Electronic Medical Records, CIDP chronic inflammatory demyelinating polyneuropathy, Dx Professional Fee Claims, Ig immunoglobulin, LRx Longitudinal Prescription Claims
Fig. 2.
Patient selection: newly diagnosed patients with CIDP. AEMR Ambulatory Electronic Medical Records, CIDP chronic inflammatory demyelinating polyneuropathy, Dx Professional Fee Claims, Ig immunoglobulin, LRx Longitudinal Prescription Claims
Ig Treated and Non-Ig Treated Cohorts
Patients were stratified into mutually exclusive Ig-treated and non-Ig-treated cohorts (Figs. 3,4). Patients were included in the Ig-treated cohort based on the presence of ≥ 1 claim or record for Ig [specifically, any IVIg or immune globulin subcutaneous (human), 20% liquid (Hizentra®; CSL Behring, Bern, Switzerland); IgPro20] from 90 days prior to the diagnosis index date through the end of the available follow-up (termed the ‘index date’) and with a second Ig claim or record > 60 days after the index date [29]. Ig was identified using national drug codes in LRx or Healthcare Common Procedure Coding System codes in Dx or AEMR. Patients in the Ig-treated cohort were excluded if they had any use of a non-IgPro20 SCIg or if they discontinued Ig (at the class level) within 6 months post-index (defined as a gap in any Ig therapy of ≥ 45 days).
Fig. 3.
Study diagram: Ig- and non-Ig-treated cohorts. Dx Professional Fee Claims, Ig immunoglobulin, LRx Longitudinal Prescription Claims
Fig. 4.
Patient selection: Ig- and non-Ig-treated cohorts. AEMR Ambulatory Electronic Medical Records, Dx Professional Fee Claims, Ig immunoglobulin, IgPro20 immune globulin subcutaneous (human), 20% liquid, LRx Longitudinal Prescription Claims
Patients without ≥ 1 claim or record for any Ig (any IVIg or SCIg) from 90 days prior to the diagnosis index date through the end of the available follow-up were included in the non-Ig-treated cohort. For patients in the non-Ig-treated cohort, a pseudo-index date was assigned. The median time between diagnosis and initiation of Ig in the Ig-treated cohort was applied to the diagnosis index date of the non-Ig-treated cohort to derive the pseudo-index date.
For both cohorts, patients were further required to have activity (≥ 1 claim) in LRx and Dx > 180 days post-index and pharmacy stability in LRx from 360 days prior to the diagnosis index date through the end of the 6-month post-index period. Because wheelchair use was used to identify the highest level of disability based on assistive device proxy in this study, patients with ≥ 1 claim or record indicating wheelchair use any time pre-index were excluded. Patients had a fixed 6-month pre-index (‘baseline’) period to characterize the sample, and a fixed 6-month post-index (‘follow-up’) period to assess the study outcomes of interest.
Matching
Ig-treated and non-Ig-treated cohorts were matched 1:1 using propensity score matching (PSM) and optimal matching approach [30]. Patients were balanced on the following clinically relevant demographic and baseline clinical characteristics: age group, gender, assistive device use, residential care, physical therapy, comorbidities of interest [back pain, chronic acquired polyneuropathies (not including diabetic neuropathy), chronic pain, coronary artery disease, diabetes, diabetic neuropathy, dyslipidemia, fibromyalgia, Guillain–Barré syndrome, idiopathic small fiber neuropathy, hypertension, hypothyroidism, inherited neuropathies, multiple sclerosis, neuropathic pain, and osteoarthritis], and medications of interest [anti-anxiety medications, anticonvulsants, antidepressants, central muscle relaxants, immunosuppressants (composite measure of azathioprine, corticosteroids, cyclophosphamide, cyclosporin, and mycophenolate mofetil), nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids].
Study Measures
Baseline characteristics were reported for the Ig-treated and non-Ig-treated cohorts, both pre- and post-match. Demographics (e.g., age, gender, region) were assessed on the index date. Baseline measures of disease severity and disability [e.g., emergency room (ER) visits, physician office visits, assistive device use, physical therapy] and clinical characteristics [e.g., Charlson Comorbidity Index (CCI) relevant comorbidities, relevant therapies] were assessed over the 6-month baseline period.
Study outcomes were assessed and compared between the Ig-treated and non-Ig-treated cohorts, post-match. Because claims data lack clinical disability scores (e.g., INCAT), claims or records for assistive devices were used as a proxy measure for disability, at the ordinal level, with the following order in terms of progressive (or worsening) disability: no assistive device, cane, crutch, walker, scooter, and wheelchair. Deterioration was defined as ≥ 1 post-index claim or record for an assistive device indicating a higher level of disability than observed at baseline (e.g., progression from no assistive device at baseline to cane at follow-up). Evidence of ≥ 1 level of deterioration was the primary proxy for worsening clinical disability. Patients were considered to have ≥ 2 levels of deterioration if there was ≥ 1 post-index claim or record for an assistive device indicating a level of disability at least two levels higher than observed at baseline (e.g., progression from walker at baseline to wheelchair at follow-up); this was only evaluated among patients with assistive device use at a lower level than scooter at baseline, in order to allow for ≥ 2 levels of deterioration post-index. Post-index anticonvulsant, antidepressant, and opioid use and change in use from baseline to post-index were assessed as secondary proxy measures for pain. Among patients with ≥ 1 claim or record for anticonvulsant, antidepressant, or opioid at baseline separately, improvement was defined as having no post-index claim or record of the respective medication class. Among patients with no claim or record for anticonvulsant, antidepressant, or opioid at baseline separately, deterioration was defined as having ≥ 1 post-index claim or record for the respective medication class.
Analyses
Descriptive statistics were reported for all relevant study measures. Categorical measures were reported using frequency (n) and percentage (%) and continuous measures were reported using mean, standard deviation (SD), and median. Baseline comparisons between the Ig-treated and non-Ig-treated cohorts were conducted both pre- and post-match using standardized mean differences (SMD), with SMD (absolute) ≥ 0.10 considered statistically meaningful.
For comparisons of study outcomes between the post-match cohorts, or for comparisons of change from pre- to post-index within a cohort, dependent statistical comparisons were conducted using paired t tests for continuous variables and McNemar’s test for categorical variables. Comparisons between subsets of post-match cohorts were made using appropriate independent statistical tests (e.g., t-test and chi-square test). A p value of < 0.05 was considered statistically significant. All analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC, USA).
In a sensitivity analysis, study outcomes were evaluated and compared over the 12-month post-index period among the subset of patients with evaluable 12-month follow-up and where both matched pairs were retained. Ig-treated patients were required to be persistent on any Ig over the 12-month post-index.
Results
Study Population
Initially, 109,627 patients were identified with ≥ 1 medical claim or record with a diagnosis code for CIDP between January 2015 and November 2021. After application of the eligibility criteria, there were 9276 patients newly diagnosed with CIDP. Patients were most often excluded due to the requirements to enhance confidence in the sample: 29.8% were excluded because they did not have a second diagnosis code for CIDP, and 22.3% were excluded because none of the first two CIDP diagnoses was from a neurologist with specialty of high relevance and/or because they did not have a nerve conduction study or H-reflex or F-wave study.
Of the newly diagnosed sample, 4327 patients (46.6%) were identified with use of Ig (IVIg or IgPro20) and included in the Ig-treated cohort. Almost all Ig-treated patients (95.8%) initiated Ig after the diagnosis index date (median of 48 days after) while 5.2% initiated Ig before the diagnosis index date (median of 24 days before). Of the newly diagnosed sample, 4949 patients (53.4%) were identified without any Ig use and included in the non-Ig-treated cohort. Following application of the remaining eligibility criteria, the final unmatched sample comprised 1302 Ig-treated patients and 4015 non-Ig-treated patients. Following the 1:1 PSM, all patients in the Ig-treated cohort were retained, resulting in 1302 matched pairs. Among patients in the Ig-treated cohort, nearly all (97.9%) had evidence of IVIg use at index, while the remaining 2.1% of patients in this cohort had evidence of SCIg use at index.
Baseline Characteristics
Pre-match, imbalance was observed between Ig-treated and non-Ig-treated cohorts across several relevant baseline characteristics (Table 1). Ig-treated patients had lower mean (SD) age compared to non-Ig-treated patients [61.2 (13.8) years and 65.5 (13.8) years, respectively]. Gender was well-balanced and about 40% of patients were female. Assistive device use was also well-balanced at baseline and 3.3% of Ig-treated patients and 3.5% of non-Ig-treated patients had ≥ 1 pre-index claim or record for an assistive device. The Ig-treated cohort had a lower proportion with back pain, hypertension, neuropathic pain, or osteoarthritis at baseline compared to the non-Ig-treated cohort, but a higher proportion with chronic acquired polyneuropathies (not including diabetic neuropathy). Baseline use of pre-index therapies of interest was well-balanced between the cohorts.
Table 1.
Baseline characteristics of Ig-treated and non-Ig-treated cohorts, pre- and post-match
| Pre-match | Post-match | |||||
|---|---|---|---|---|---|---|
| Characteristic | Ig-treated, N = 1302 | Non-Ig-treated, N = 4015 | SMD | Ig-treated, N = 1302 | Non-Ig-treated, N = 1302 | SMD |
| Mean age, years (SD) | 61.2 (13.8) | 65.5 (13.8) | 0.32 | 61.2 (13.8) | 61.4 (14.4) | 0.02 |
| Age group, n (%) | ||||||
| 18–44 years | 161 (12.4) | 325 (8.1) | 0.33 | 161 (12.4) | 164 (12.6) | 0.03 |
| 45–64 years | 586 (45.0) | 1305 (32.5) | 586 (45.0) | 574 (44.1) | ||
| 65–84 years | 467 (35.9) | 1918 (47.8) | 467 (35.9) | 475 (36.5) | ||
| 85+ years | 88 (6.8) | 467 (11.6) | 88 (6.8) | 89 (6.8) | ||
| Female, n (%) | 530 (40.7) | 1672 (41.6) | – 0.02 | 530 (40.7) | 521 (40.0) | 0.01 |
| Geographic region, n (%) | ||||||
| Northeast | 313 (24.0) | 895 (22.3) | 0.09 | 313 (24.0) | 294 (22.6) | 0.15 |
| Midwest | 210 (16.1) | 780 (19.4) | 210 (16.1) | 270 (20.7) | ||
| South | 529 (40.6) | 1642 (40.9) | 529 (40.6) | 504 (38.7) | ||
| West | 227 (17.4) | 641 (16.0) | 227 (17.4) | 214 (16.4) | ||
| Unknown | 23 (1.8) | 57 (1.4) | 23 (1.8) | 20 (1.5) | ||
| Medicare/Medicare Part D payer, n (%) | 461 (35.4) | 2060 (51.3) | 0.33 | 461 (35.4) | 548 (42.1) | 0.14 |
| Index year, n (%) | ||||||
| 2014–2019 | 928 (71.3) | 3169 (78.9) | 0.18 | 928 (71.3) | 1004 (77.1) | 0.13 |
| 2020–21 | 374 (28.7) | 846 (21.1) | 374 (28.7) | 298 (22.9) | ||
| ER visit, n (%) | 347 (26.7) | 1034 (25.8) | – 0.02 | 347 (26.7) | 326 (25.0) | – 0.04 |
| Physician office visit, n (%) | 1208 (92.8) | 3776 (94.0) | 0.05 | 1208 (92.8) | 1199 (92.1) | 0.03 |
| Assistive device, n (%) | 43 (3.3) | 140 (3.5%) | 0.01 | 43 (3.3) | 35 (2.7%) | – 0.04 |
| Highest level of: | ||||||
| Cane | 3 (0.2) | 10 (0.2) | 3 (0.2) | 0 (0.0) | ||
| Crutch | 2 (0.2) | 3 (0.1) | 2 (0.2) | 0 (0.0) | ||
| Walker | 36 (2.8) | 127 (3.2) | 36 (2.8) | 35 (2.7) | ||
| Scooter | 2 (0.2) | 0 (0.0) | 2 (0.2) | 0 (0.0) | ||
| Residential care, n (%) | 117 (9.0) | 379 (9.4%) | 0.02 | 117 (9.0) | 117 (9.0%) | 0.00 |
| Physical therapy, n (%) | 362 (27.8) | 1078 (26.8%) | – 0.02 | 362 (27.8) | 361 (27.7%) | 0.00 |
| Mean CCI score (SD) | 1.4 (1.7) | 1.7 (1.9) | 0.17 | 1.4 (1.7) | 1.5 (1.9) | 0.09 |
| Comorbidities, n (%) | ||||||
| Back pain | 509 (39.1) | 1877 (46.7) | 0.16 | 509 (39.1) | 497 (38.2) | – 0.02 |
| Chronic acquired polyneuropathiesa | 621 (47.7) | 1650 (41.1) | – 0.13 | 621 (47.7) | 607 (46.6) | – 0.02 |
| Chronic pain | 127 (9.8) | 370 (9.2) | – 0.02 | 127 (9.8) | 129 (9.9) | 0.01 |
| Coronary artery disease | 141 (10.8) | 552 (13.7) | 0.09 | 141 (10.8) | 151 (11.6) | 0.02 |
| Diabetes | 285 (21.9) | 985 (24.5) | 0.06 | 285 (21.9) | 297 (22.8) | 0.02 |
| Diabetic neuropathy | 169 (13.0) | 512 (12.8) | – 0.01 | 169 (13.0) | 178 (13.7) | 0.02 |
| Dyslipidemia | 396 (30.4) | 1348 (33.6) | 0.07 | 396 (30.4) | 389 (29.9) | – 0.01 |
| Fibromyalgia | 35 (2.7) | 149 (3.7) | 0.06 | 35 (2.7) | 37 (2.8) | 0.01 |
| Guillain–Barré syndrome | 150 (11.5) | 369 (9.2) | – 0.08 | 150 (11.5) | 147 (11.3) | – 0.01 |
| Idiopathic small fiber neuropathy | 271 (20.8) | 959 (23.9) | 0.07 | 271 (20.8) | 271 (20.8) | 0.00 |
| Hypertension | 549 (42.2) | 1926 (48.0) | 0.12 | 549 (42.2) | 541 (41.6) | – 0.01 |
| Hypothyroidism | 142 (10.9) | 457 (11.4) | 0.02 | 142 (10.9) | 134 (10.3) | – 0.02 |
| Inherited neuropathies | 17 (1.3) | 100 (2.5) | 0.09 | 17 (1.3) | 16 (1.2) | – 0.01 |
| Multiple sclerosis | 28 (2.2) | 84 (2.1) | 0.00 | 28 (2.2) | 22 (1.7) | – 0.03 |
| Neuropathic pain | 1178 (90.5) | 3845 (95.8) | 0.21 | 1178 (90.5) | 1172 (90.0) | – 0.02 |
| Osteoarthritis | 153 (11.8) | 669 (16.7) | 0.14 | 153 (11.8) | 151 (11.6) | 0.00 |
| Therapies of interest (≥ 5%), n (%) | ||||||
| Anti-anxiety medications | 299 (23.0) | 950 (23.7) | 0.02 | 299 (23.0) | 286 (22.0) | – 0.02 |
| Anticonvulsants | 625 (48.0) | 1915 (47.7) | – 0.01 | 625 (48.0) | 606 (46.5) | – 0.03 |
| Antidepressants | 494 (37.9) | 1476 (36.8) | – 0.02 | 494 (37.9) | 465 (35.7) | – 0.05 |
| Central muscle relaxants | 246 (18.9) | 732 (18.2) | – 0.02 | 246 (18.9) | 214 (16.4) | – 0.06 |
| Corticosteroids | 499 (38.3) | 1513 (37.7) | – 0.01 | 499 (38.3) | 483 (37.1) | – 0.03 |
| NSAIDs | 330 (25.3) | 908 (22.6) | – 0.06 | 330 (25.3) | 307 (23.6) | – 0.04 |
| Opioids | 511 (39.2) | 1576 (39.3) | 0.00 | 511 (39.2) | 486 (37.3) | – 0.04 |
| Immunosuppressantsb | 513 (39.4) | 1561 (38.9) | – 0.01 | 513 (39.4) | 499 (38.3) | – 0.02 |
CCI Charlson Comorbidity Index, ER emergency room, Ig immunoglobulin, NSAID nonsteroidal anti-inflammatory drug, SD standard deviation, SMD standardized mean difference
aInclusive of monoclonal gammopathies, toxic neuropathies, other, and unspecified; not including diabetic neuropathy
bInclusive of azathioprine, corticosteroids, cyclophosphamide, cyclosporin, mycophenolate mofetil
Post-match, Ig-treated and non-Ig-treated cohorts were well-balanced across all clinically relevant baseline characteristics (Table 1). Mean (SD) age was 61.2 (13.8) years for Ig-treated patients and 61.4 (14.4) years for non-Ig-treated patients. The Ig-treated cohort was 40.7% female and the non-Ig-treated cohort was 40.0% female. Use of assistive devices continued to be well-balanced post-match. At baseline, 3.3% of Ig-treated patients and 2.7% of non-Ig-treated patients had ≥ 1 pre-index claim or record for an assistive device. This included 2.8% and 2.7% with use of a walker, respectively, with no other higher-level device. Baseline comorbid conditions and use of therapies of interest were well-balanced between the cohorts. The most common baseline comorbidities of interest included neuropathic pain (90.0–90.5%), chronic acquired polyneuropathies (46.6–47.7%), hypertension (41.6–42.2%), and back pain (38.2–39.1%). The most common baseline therapies of interest included anticonvulsants (46.5–48.0%), immunosuppressants (including corticosteroids; 38.3–39.4%), opioids (37.3–39.2%), and antidepressants (35.7–37.9%).
Assistive Device Deterioration
Post-match, approximately 40% fewer Ig-treated patients had ≥ 1 level of deterioration in assistive device use over the 6-month post-index period compared to non-Ig-treated patients (3.3% vs. 5.4%, p = 0.0104; Fig. 5I). Among patients with baseline assistive device use at a lower level than scooter (99.8% of Ig-treated and 100.0% of non-Ig-treated), a significantly lower proportion of Ig-treated patients had ≥ 2 levels of deterioration in assistive device use (3.1% vs. 5.1%, p = 0.0079; Fig. 5ii).
Fig. 5.
Assistive device deterioration over the 6-month post-index, post-match: I Proportion of patients with ≥ 1 level of assistive device deterioration; deterioration defined as ≥ 1 post-index claim or record for an assistive device indicating a higher level of disability than observed at baseline; comparison using McNemar’s test; ii proportion of patients with ≥ 2 levels of assistive device deterioration; among the subset of patients with baseline assistive device use at a lower level than scooter; deterioration defined as ≥ 1 post-index claim or record for an assistive device indicating a level of disability at least two levels higher than observed at baseline; comparison using chi-square test. Ig immunoglobulin
Anticonvulsant, Antidepressant, and Opioid Utilization
Post-index use of opioids (proportion of patients with ≥ 1 post-index claim or record), was lower in the Ig-treated versus the non-Ig-treated cohort (33.3% vs. 37.8%, p = 0.0129). No difference between cohorts was seen for anticonvulsants or antidepressants (Fig. 6).
Fig. 6.
Anticonvulsant, antidepressant, and opioid utilization, post-match. Ig immunoglobulin
Among Ig-treated patients, the use of opioids decreased from pre- to post index (from 39.2% to 33.3%, p < 0.0001), as did the use of anticonvulsants (48.0–44.8%, p = 0.0041), while the use of antidepressants remained stable (Fig. 7I–iii). Among non-Ig-treated patients, the use of anticonvulsants and opioids remained stable, while there was an increase in the use of antidepressants (35.7–39.7%, p = 0.0001, Fig. 7I–iii).
Fig. 7.
Change in utilization, post-match: I proportion of patients with ≥ 1 anticonvulsant claim or record in the 6-month baseline period compared to the 6-month post-index period; ii proportion of patients with ≥ 1 antidepressant claim or record in the 6-month baseline period compared to the 6-month post-index period; iii proportion of patients with ≥ 1 opioid claim or record in the 6-month baseline period compared to the 6-month post-index period. Ig immunoglobulin
Among patients with no usage during the baseline period, deterioration (i.e., ≥ 1 new claim or record) was less frequent in the Ig-treated cohort versus the non-Ig cohort for anticonvulsants (12.7% vs. 16.7%, p = 0.0382) and antidepressants (9.7% vs. 13.9%, p = 0.0082). There was not a statistically significant difference for opioids (16.9% vs. 19.9%, p = 0.1321, Fig. 8).
Fig. 8.
Proportion of patients with deterioration of anticonvulsants, antidepressants, and opioids. Ig immunoglobulin
Among patients with usage during the baseline period, improvement (i.e., no post-index claim or record) was seen more frequently in the Ig-treated cohort versus the non-Ig cohort for opioids (41.5% vs. 32.1%, p = 0.0021), but not for anticonvulsants or antidepressants (Fig. 9).
Fig. 9.
Proportion of patients with improvement of anticonvulsants, antidepressants, and opioids. Ig immunoglobulin
Sensitivity Analysis
The sensitivity analysis included 678 matched pairs with a 12-month evaluable post-index period. Although a numerically lower proportion of patients in the Ig-treated cohort had ≥ 1 level of deterioration (5.5% vs. 7.2%, p = 0.1904) and ≥ 2 levels of deterioration (5.3% vs. 7.2%, p = 0.1492) in assistive device use over the 12-month post-index period compared to the non-Ig-treated cohort, these findings were not statistically significant.
Trends in the use of anticonvulsants, antidepressants, and opioids during the 12-month post-index period generally mirrored those observed during the 6-month post-index period. However, the use of opioids increased from baseline in both cohorts (Table 2).
Table 2.
Sensitivity analysis of select outcomes post-match
| 6-month baseline period | 12-month post-index period | p value | |||||
|---|---|---|---|---|---|---|---|
| Outcome | Ig-treated, N = 678 | Non-Ig-treated, N = 678 | Ig-treated, N = 678 | Non-Ig-treated, N = 678 | Comparison within Ig-treated | Comparison within non-Ig-treated | Comparison of post-index use between Ig-treated and non-Ig-treated |
| Patients with ≥ 1 level of assistive device deterioration post-index, n (%) | – | – | 37 (5.5) | 49 (7.2) | – | – | 0.1904 |
| Patients with ≥ 2 levels of assistive device deterioration post-index, n (%) | – | – | 36 (5.2) | 49 (7.2) | – | – | 0.1492 |
| Patients with ≥ 1 claim for anticonvulsants, n (%) | 326 (48.1) | 322 (47.5) | 335 (49.4) | 344 (50.7) | 0.4245 | 0.0500 | 0.6075 |
| Patients with anticonvulsant improvement post-index, n (%) | – | – | 59 (18.1) | 52 (16.1) | – | – | 0.5103 |
| Patients with ≥ 1 claim for antidepressants, n (%) | 258 (38.1) | 242 (35.7) | 274 (40.4) | 313 (46.2) | 0.0953 | < 0.0001 | 0.0321 |
| Patients with antidepressant improvement post-index, n (%) | – | – | 38 (14.7) | 20 (8.3) | – | – | 0.0241 |
| Patients with ≥ 1 claim for opioids, n (%) | 259 (38.2) | 270 (39.8) | 287 (42.3) | 338 (49.9) | 0.0444 | < 0.0001 | 0.0035 |
| Patients with opioid improvement post-index (n, %) | – | – | 83 (32.0) | 60 (22.2) | – | – | 0.0110 |
Ig immunoglobulin
Discussion
This retrospective observational study evaluated the real-world effectiveness of Ig therapy in CIDP using medical and pharmacy claims data in the US, supplemented with EMR data as available. To our knowledge, this is the first study to evaluate the real-world effectiveness of Ig using proxy measures available in claims and EMR data that mimic the INCAT, the gold standard to measure clinical disability in CIDP clinical trials. We evaluated the presence of an assistive device used for a higher level of disability than observed at baseline to indicate deteriorating clinical disability. The benefits of Ig observed in clinical trials in terms of maintained or improved disability scores appeared to be reflected in the real world [11]. In this study, we observed less deterioration in assistive device use among 1302 patients treated with Ig compared to 1302 matched patients who did not receive any Ig. We found a significantly lower proportion of Ig-treated patients (approximately 40% fewer) experienced at least one level of deterioration in assistive device use over the 6-month post-index period compared to non-Ig-treated patients. In other words, a higher proportion of Ig-treated patients were able to maintain or improve their baseline level of disability. It is an important consideration that in the current study, we were only able to evaluate deterioration in disability, not improvement, since only an initiation or escalation of use of reimbursed assistive devices and not any reduction in use is observable in claims data.
In RCTs, IVIg has demonstrated improved disability for up to 6 weeks compared with placebo [11]. Our 6-month follow-up period aligns with two RCTs of Ig which were conducted over a 24-week period. One RCT found that 54% of patients treated with IVIg [immune globulin injection (human), 10% caprylate/chromatography purified (Gamunex®-C; Grifols, Barcelona, Spain)] improved in INCAT disability score by at least one point with improvement maintained through week 24 compared to 21% of patients receiving placebo (p = 0.0002) [12, 30, 31]. In the Polyneuropathy And Treatment with Hizentra (PATH) study, IgPro20 was efficacious as a maintenance treatment in preventing disease relapse over 24 weeks compared to placebo [13].
Two prior studies utilizing real-world claims data in the US assessed functional status in IVIg-treated patients based on diagnosis codes for difficulty walking or weakness [26, 27]. One of these studies evaluated functional status markers before or on the IVIg index date and during follow-up [27]. Among 3975 patients at baseline, 30.2% had at least one diagnosis code for difficulty walking, and 30.9% had at least one diagnosis code for weakness. Among 728 patients over the 1-year follow-up, the proportion with difficulty walking remained generally consistent (29.1%) while the proportion with weakness decreased (23.4%). These findings similarly support the benefit of Ig in maintaining, and potentially improving, functional status. The authors also evaluated diagnosis codes for nerve dysfunction (e.g., abnormal reflex, abnormal response to nerve stimulation), which can be identified from electrodiagnostic testing, but found those to be infrequently coded (< 1.5%).
A few real-world studies have evaluated disability as measured by the INCAT, but these are limited to studies among smaller sample sizes using older data. In a German multicenter, prospective, non-interventional study, 148 patients with CIDP-treated with IVIg [immune globulin injection (human), 10% caprylate/chromatography purified] were followed for 2 years [25]. The mean (SD) INCAT disability score was 2.4 (1.8) at baseline and 2.5 (1.9) at the end of the follow-up, demonstrating that long-term IVIg therapy was associated with clinical stability. A retrospective analysis conducted at a German hospital of 49 patients with CIDP evaluated INCAT scores before the start of IVIg treatment and at the end of the observation period (mean 45 months) [20]. Patients gained a mean of one INCAT score further supporting the sustained beneficial effects of long-term IVIg.
Pain is a common symptom of CIDP which can further negatively impact quality of life [4]. A systematic literature review estimated a 46% prevalence of pain within the course of CIDP, when considering pain of any type caused by CIDP [32]. Among patients initiating IVIg, a retrospective US claims-based analysis found an 80.2% prevalence of neuropathic or chronic pain among patients initiating IVIg [26]. Anticonvulsants, antidepressants, and opioids are commonly used for pain management among patients with CIDP [28]. In another US claims-based analysis of patients with CIDP and controls without CIDP (790 matched pairs), 33.4% of patients used opioids in the 6 months prior to CIDP diagnosis and nearly two-thirds (60.6%) of patients with CIDP used opioids compared to one-quarter (26.8%) of controls over a 2-year follow-up [33]. The US claims-analysis described earlier that assessed functional status on IVIg also evaluated initiation of opioids as an indirect measure of CIDP pain [27]. The incidence rate of opioids after IVIg initiation was 17.6 events per 100 person-years. Avoiding long-term opioid use is an important consideration in pain management as it can lead to dependency and increased drug tolerance [34].
In the current study, baseline prevalence of neuropathic pain (94.5% of study population) and opioid use (39.3% of study population) was higher than seen in existing literature. This may be in part due to the study population being indexed at the point of Ig initiation, which may indicate worsening symptoms. Baseline anticonvulsant, antidepressant, and opioid use was well-balanced due to the matching approach. From baseline to follow-up, we observed a significant decrease in anticonvulsant and opioid use among the Ig-treated cohort, while use remained similar for the non-Ig-treated cohort. Antidepressant use remained similar within the Ig-treated cohort, but increased in the non-Ig-treated cohort. In the Ig-treated cohort, more frequent improvements (i.e., no post-index use in baseline users) were seen for opioids, and less frequent deterioration (new use in baseline non-users) were seen for anticonvulsants and antidepressants. Our secondary results suggest Ig has a beneficial effect in reducing pain, although it is unknown whether anticonvulsants, antidepressants, or opioids were prescribed specifically for CIDP-related pain or for comorbid conditions.
Our study has important strengths which are worthwhile highlighting. This is the first study to evaluate real-world effectiveness of Ig in CIDP using proxy measures that mimic the standard clinical outcome of clinical studies, although assistive devices capture primary lower extremity and not upper extremity dysfunction included in the INCAT. Nevertheless, lower extremity disability, as measured based on assistive device use in this study, is an important outcome for patients with CIDP, with implications for quality of life, productivity, and healthcare resource utilization. The data sources utilized represent a large volume of pharmacy and medical claims from pharmacies and providers in the US, across all payer types (e.g., commercial, Medicare, Medicaid, cash). Because misdiagnosis is a major challenge in CIDP, stringent eligibility criteria were applied to our sample to provide greater confidence in accurate CIDP diagnosis [7].
There are also limitations inherent to the retrospective study design and the databases employed which are of note. First, results from retrospective studies must be interpreted with caution, and in the context of findings from similar studies, because they can only establish associations and not causal relationships between therapy and outcomes. In this retrospective analysis, descriptive data generation was employed with PSM methodology to balance Ig-treated and non-Ig-treated patients in terms of baseline characteristics; however, the predictive power of the results is limited. Second, the databases utilized were open-source databases; therefore, there is a loss of visibility to healthcare activity and consumption outside of pharmacies and provider offices that participate in/contribute to the databases. Nevertheless, representation is quite high for these data sources. Third, patients were evaluated over a 6-month follow-up period which is consistent with the duration of relevant Ig clinical studies [12, 13]. Patients with Ig therapy of less than 6 months were not included. While discontinuation at less than 6 months may be due to many factors, e.g., loss of insurance coverage, this may have eliminated in part a small proportion that did not initially respond to IVIg therapy. Assessments over a longer follow-up are needed to understand the long-term effectiveness of Ig therapy. While we observed numerically meaningful outcomes among the Ig-treated cohort over the 12-month follow-up period in the sensitivity analysis, we did not observe a statistically significant impact. Due to the limited sample size with evaluable 12-month follow-up, it is not appropriate to draw any causal or conclusive interpretation due to insufficient power. Finally, while we were able to evaluate deterioration in clinical disability based on assistive device use as a proxy, it is an important limitation that we were not able to measure improvement in physical function. Claims are unlikely to be observed for an assistive device at the same level more than once, so we could not assume lack of a post-index claim or record to indicate improvement.
Conclusions
The findings from this study support the real-world effectiveness of Ig therapy in CIDP. The benefits of Ig therapy seen in clinical trials in terms of maintained or improved disability scores appear to be reflected in the real world by less deterioration in assistive device use. In addition, patients treated with Ig had greater reductions in anticonvulsant, antidepressant, and opioid use, reflecting Ig-related improvements in reducing pain. Further research is needed to investigate and validate assistive device use as a proxy outcome measure for disability in claims data, as well as to evaluate the longer-term effectiveness of Ig.
Acknowledgements
The authors thank the participants of the study.
Medical Writing/Editorial Assistance
The authors thank Kate Lovett, an employee of IQVIA at the time of writing, for her assistance with medical writing.
Author Contributions
All named authors met the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of all aspects of the work and have given their approval for this version to be published.
Conceptualization: Rajiv Mallick; Methodology: Alphonse Hubsch, Fidelia Ida, Xiang Zhang, Victoria Divino, Rajiv Mallick, Katharine Coyle, Elizabeth Langford, Betsy Lahue, Estella (Yi) Wang; Formal analysis and investigation: Katharine Coyle, Victoria Divino, Elizabeth Langford, Estella (Yi) Wang; Writing – original draft preparation: Victoria Divino; Writing – review and editing: all authors; Approval of final manuscript: all authors.
Funding
This study was funded by CSL Behring (King of Prussia, PA, USA). CSL Behring is also funding the journal’s Rapid Service Fee.
Data Availability
The data used in this study were licensed from IQVIA. These data are not publicly available. Researchers seeking access must obtain a license directly from IQVIA. Aggregated, de-identified results generated during this study may be available from the corresponding author upon reasonable request and are subject to the terms of IQVIA licensing agreement.
Declarations
Conflicts of Interest
Alphonse Hubsch, Fidelia Ida, and Xiang Zhang are current employees and shareholders of CSL Behring. Rajiv Mallick was an employee of CSL Behring at the time of writing. Katharine Coyle and Elizabeth Langford are current employees of IQVIA, which received funding from CSL Behring for this study. Victoria Divino and Estella (Yi) Wang were employees of IQVIA at the time of writing. Betsy Lahue is an employee of Alkemi, which received consulting fees from CSL Behring.
Ethical approval
This study involved use of IQVIA de-identified data, with proper permission for its use. Data were de-identified by IQVIA and comply with HIPAA and the Helsinki Declaration of 1964 and its later amendments or comparable ethical standards. The US Department of Health and Human Services does not consider analysis of de-identified secondary data to meet the definition for human subject research. Therefore, this study was exempt from federal regulations and did not require patient consent or IRB review.
Footnotes
Prior Presentation: Contents of this study were presented at the 2025 Peripheral Nerve Society Annual Meeting in Edinburgh, Scotland. This meeting was held May 17–20, 2025.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data used in this study were licensed from IQVIA. These data are not publicly available. Researchers seeking access must obtain a license directly from IQVIA. Aggregated, de-identified results generated during this study may be available from the corresponding author upon reasonable request and are subject to the terms of IQVIA licensing agreement.