An approach to assessing immunoglobulin dependence in chronic inflammatory demyelinating inflammatory polyneuropathy

Regular immunoglobulin treatment maintains strength and prevents disability in chronic inflammatory demyelinating polyneuropathy (CIDP). Discrimination between active disease, with optimum symptom control on treatment, and disease in remission not requiring treatment is essential for therapeutic decision‐making and clinical trial design. To compare treatment cessation versus gradual dose reduction in assessment of disease activity (immunoglobulin dependence) in a cohort of stable CIDP patients on maintenance immunoglobulin treatment. An approach to restabilization of immunoglobulin‐dependent individuals is also described. Retrospective review of IVIg cessation or gradual reduction in 33 patients with stable CIDP on maintenance IVIg. Demographic, clinical and treatment data were collected; clinical monitoring data were recorded prospectively as part of routine clinical practice. A total of 21/33 patients (62.6%) were immunoglobulin dependent, (gradual dose reduction:11, cessation:10). Mean change in Inflammatory Rasch‐built Overall Disability Scale (I‐RODS) (−15, standard deviation [SD] 16) and Medical Research Council Sum Score (MRC‐SS) (−4, SD: 4) was clinically and statistically meaningful (>75% exceeded minimum clinically important differences). Mean time to deterioration was 5.0 (SD: 4.6) months, shorter in cessation group (3.5 months) than gradual reduction group (8.8 months). All patients were restabilized to previous baseline (M: 2.3, SD: 4.3 months), half within 1 week of retreatment. A total of 12 patients (37.4%) remained stable without treatment for ≥2 years (remission). A total of 50% were identified rapidly by cessation and 50% by gradual dose reduction requiring mean 4.8 (SD: 2.8) years follow‐up and costing £113 623 per person Ig spend. No predictors of disease activity were identified. A treatment cessation trial with close clinical monitoring is an efficient, cost‐effective and safe approach to assessing disease activity in CIDP.

In clinical practice, it is important to identify those individuals who no longer need maintenance Ig treatment to remove the potential for serious Ig-related adverse events, such as thromboembolism, and reduce waste of an expensive product with limited supply. 5,6 In research, particularly in the setting of therapeutic trials, participants with active (Ig-dependent) disease are essential to avoid inflation of the placebo effect. A meta-analysis of RCTs in CIDP revealed a 48% placebo effect when the primary endpoint was relapse or clinical deterioration and 11% placebo response when the primary endpoint was an improvement. Although some of this may be explained by patient expectation and conditioning, the sensitivity of outcome measures and incorrect identification of Ig-dependency likely plays a role. 7 There is consensus opinion in CIDP treatment that close clinical monitoring with validated outcome measures should guide Ig dosing and frequency of maintenance Ig treatment. 8 Here, we examined differing approaches to assessment of Ig dependence/disease activity in clinically stable patients on maintenance Ig therapy for CIDP in one specialist centre over a 10-year period. We explored the impact on clinical scores and time to decision with sudden treatment cessation vs gradual dose titration. The restabilization of Ig-dependent individuals is also described.

| METHODS
We identified all patients with definite or possible diagnosis of CIDP according to the European Federation of Neurological Societies/ Peripheral Nervous System guidelines in whom a formal assessment of Ig dependence was performed in the last 10 years. 8 Here, we present data on demographics, disease duration, clinical and neurophysiological information, Ig maintenance regimen, with baseline and follow-up outcome measures in response to Ig dependence challenge. Ig dependence was tested either by gradual dose reduction or immediate treatment cessation. All data were prospectively recorded as per routine departmental practice by the peripheral nerve specialist consultant team at the National Hospital of Neurology and Neurosurgery (NHNN), London.
The MRC-SS has been consistently used throughout this period, as well as subjective patient reported peri-dose fluctuation. The IVIg treatment was restarted. Nadir was marked by date of retreatment. We documented response to retreatment, time to and dose needed to achieve previous baseline.
Those who did not decline were defined as Ig independent (in remission) and were routinely reviewed at 6 to 12 monthly intervals for at least 2 years after treatment discontinuation. The decision and approach to Ig dependency assessment were determined by the treating neurologist, with patient approval and in accordance with national Ig guideline. 10 This study was approved by the University College London Hospital Trust clinical governance ethics and consent framework. Individual patient consent was not required for this service evaluation project.

| Statistical analysis
We present descriptive statistics for group (Ig dependent, Ig independent, cessation, gradual reduction) demographics, baseline clinical, therapeutic and neurophysiological characteristics. We provide mean  Figure 2A). I-RODS change exceed MCID in the majority (6/8 where recorded).
F I G U R E 2 Ig dependence challenge outcomes in Ig-dependent patients (active) There was no difference in magnitude of deterioration in scores between approaches, but numbers in each group were limited.

| Predictors of Ig dependence/independence
We compared the demographic, clinical, electrophysiological and therapeutic characteristics of Ig-independent and Ig-dependent patient groups, and no statistically significant differences were identified.
There was no difference in disease course and no difference in the number of diagnostic criteria fulfilled.

| DISCUSSION
This study demonstrates safe and effective methods for differentiating between CIDP patients on maintenance IVIg with active disease vs those in remission. Restabilization to previous baseline was achieved in all Ig-dependent patients. Close clinical monitoring with appropriate outcome measures was sufficient to provide reliable objective evidence for Ig dependence and response in active CIDP.
We did not identify any patient, disease, investigational or treatmentrelated factors that predict disease remission/activity or Ig independence/dependence.
We suggest treatment cessation as a feasible method of promptly, definitively, and safely assessing disease activity. This approach avoids prolonged uncertainty on disease status in the individual and saves on average £100 000 per person Ig spend. Time to restabilization was slightly shorter after demonstrable decline via the gradual dose reduction approach. There were no other differences between the two approaches.  17 There is no consensus on how to interpret and act on changes in scores and decisionmaking is at the clinician's discretion. This study highlights the workload and complexity associated with these decisions. It is unclear how often to attempt cessation trials, and understandably, clinicians may be reluctant to try another cessation trial in patients who were difficult to stabilize after a relapse. We did not formally collect data on patients' impression of change (PIC) while assessing disease activity, but other groups have shown a strong correlation between changes in disability scores and changes in quality-of-life measures so excessive cessation attempts should be avoided in Ig-dependent individuals. 18 Recent work on novel, objective serological biomarkers of disease activity in inflammatory neuropathies is a very promising development in this area. 19 Our retrospective study has several limitations as it evaluates a heterogenous population managed by a group of neuromuscular specialists over a lengthy timespan. We now apply the Lunn et al protocol for IVIg dosing and are vigilant about cessation trials through a dedicated IVIg clinic. 9 The monitoring of CIDP and MMN has evolved; disease-specific RODS scales and grip strength by vigorimeter were not measured on all included patients from onset. However, we consider this cohort of patients to represent a clinically realistic sample of patients with CIDP and MMN who might attend a specialist neuromuscular centre.

| CONCLUSION
Monitoring disease activity remains challenging in CIDP. This study did not identify any obvious predictors of clinical activity/Ig dependence in a cohort of patients on maintenance Ig treatment. However, disease remission can mimic well-controlled active disease and currently treatment withdrawal with close clinical monitoring is the only way of differentiating between these states. Immediate treatment cessation is an effective and safe approach to establishing disease activity, and clinicians should consider this in their treatment algorithms for patients with inflammatory neuropathies.