Tacrolimus Significantly Improved the Outcome of CIDP Patients With Autoantibodies Against Paranodal Proteins

doi:10.21203/rs.3.rs-956114/v1

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Tacrolimus Significantly Improved the Outcome of CIDP Patients With Autoantibodies Against Paranodal Proteins

https://doi.org/10.21203/rs.3.rs-956114/v1

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Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated disabling neuropathy. CIDP with antibodies against the paranodal proteins has a low prevalence, poor prognosis and treatment difficulty. Moreover, there is currently a lack of data on the application of immunosuppressive agents. In this retrospective observational study, we aimed to evaluated the response to tacrolimus (a immunosuppressor with high efficacy) in CIDP with autoantibodies against paranodal proteins by reviewing 5 patients received daily tacrolimus. One patient started tacrolimus treatment at the first episode and eventually achieved full clinical remission without relapse. Four patients experienced worsening during corticosteroids tapering. They gradually improved after adding oral tacrolimus except one patient relapsed again due to tacrolimus discontinuation. Moreover, 3 patients were successfully withdrawn from corticosteroids and 2 patients took corticosteroids at low maintenance dose (10mg/d) after tacrolimus treatment. Furthermore, decreased nerve conduction velocity and action potential amplitudes gradually returned to a normal level after tacrolimus and corticosteroids treatment. In conclusions, tacrolimus significantly improved the outcome of CIDP patients with autoantibodies against paranodal proteins by preventing relapses, reducing corticosteroids dependence and enhancing nerve repair. Combination therapy with corticosteroids and tacrolimus may be an effective therapeutic regimen.

Cellular & Molecular Neuroscience

chronic inflammatory demyelinating polyneuropathy

paranodal proteins

tacrolimus

outcome

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated disabling neuropathy, usually causing weakness and sensory disturbances with a progressing or relapsing-remitting course ¹. CIDP has been proven to respond well to immune therapies like corticosteroids, intravenous immunoglobulin (IVIG) and plasma exchange (PE) ¹. However, patients with autoantibodies against the paranodal proteins (neurofascin-155 (NF155), contactin-1 (CNTN1) and contactin-associated protein 1 (Caspr1)), were usually resistant to IVIG and only partial response to corticosteroids ^2–5. PE and rituximab seem to be effective, especially in patients who are resistant to treatment ^6–8. However, PE was not a good choice for maintenance treatment due to invasive procedures, venous access-related complications, high cost and limited availability of equipment ^7,8. Rituximab have limited clinical long-term application due to the high cost of regular intravenous administration and the potential higher risk of infection ^6,7. To date, oral corticosteroids is still the most widely used maintenance treatment for various subtypes of CIDP considering economy, relative efficiency and easy access ⁹. However, the effectiveness, dependence and serious side effects after long-term use of corticosteroids treatment constitute the major concerns for clinicians. Therefore, it is necessary to explore new strategy for the treatment of CIDP with autoantibodies against the paranodal proteins.

Tacrolimus (FK506) is a strong immunosuppressive agent used in various autoimmune including myasthenia gravis (MG), immune-mediated necrotizing myopathy (IMNM) and neuromyelitis optica spectrum disorder (NMOSD) and neuromyotonia ^10–13. More interestingly, previous researches have shown that tacrolimus could promote functional recovery of peripheral nerves ^14,15. Therefore, we will assess the response to tacrolimus in patients with autoantibodies against paranodal proteins.

We collected 9 patients with autoantibodies against paranodal proteins from 58 patients with CIDP (17.2%). Of the 9 patients, 1 case (1.7%) harbored anti-CNTN1 IgG4, 5 cases (8.6%) harbored anti-NF155 IgG4 and 3 cases (5.2%) harbored anti-Caspr1 IgG. Their demographics and clinical features were described in Table 1. Patients 1, 2, 3, 4 and 5 had received oral tacrolimus as a maintenance therapy. Therapeutic regimens and clinical status were shown in Figure 1. Treatment efficacy, outcome and adverse events were described in Table 2. Additionally, patients 6, 7 and 9 were treated with rituximab regularly after plasma exchange or IVIG treatment, while patients 8 was treated with plasma exchange and corticosteroids.

Table 1

Demographics and clinical features of patients with antibodies against paranodal proteins. M: male; F: female; NF155: neurofascin 155; CASPR1: contactin-associated protein 1; CNTN1: contactin-1; CSF: cerebrospinal fluid.
Patient	Sex	Age at onset (Y)	Course of disease (months)	Symptoms and signs								CSF testing		Electrophysiology				Antibodies
Patient	Sex	Age at onset (Y)	Course of disease (months)	Limb weakness	Limb numbness	Sensory ataxia	Tremor	Neuro-pathic pain	Myodynia	Tendon reflex	Other	Protein 150-450 mg/dL	Cell 0-8 10⁶/L	Sensory never lesion	Motor nerve lesion	Myelin sheath lesion	Axon lesion	Antibodies
1	M	37	2.5	yes	yes	yes	-	-	-	disappeared	weight loss	5972	2	yes	yes	yes	yes	Anti-CNTN1IgG4
2	M	57	1	yes	yes	yes	yes	yes	-	weakened	weight loss	2317	2	yes	yes	yes	yes	anti-CASPR1 IgG
3	M	22	8	yes	yes	yes	yes	-	-	weakened	-	2817	2	yes	yes	yes	yes	anti-NF155 IgG4
4	F	29	0.5	yes	yes	yes	-	-	yes	weakened	-	4268	0	yes	yes	yes	yes	anti-CASPR1 IgG
5	M	17	6	yes	yes	-	-	yes	-	disappeared	-	2733	2	yes	yes	yes	yes	anti-NF155 IgG4
6	M	34	9	yes	yes	-	-	-	-	weakened	-	5348	10	yes	yes	yes	yes	anti-NF155 IgG4
7	M	13	1.5	yes	yes	-	-	-	yes	disappeared	dysphagia weight loss	2714	0	yes	yes	yes	yes	anti-NF155 IgG4
8	M	10	2	yes	-	-	-	yes	-	weakened	-	༞3000	4	yes	yes	yes	yes	anti-NF155 IgG4
9	M	75	2	yes	yes	-	-	-	-	disappeared	-	2517	8	yes	yes	yes	yes	anti-CASPR1 IgG

Table 2

Treatment efficacy, outcome and adverse events of patients treated with tacrolimus. M: male; F: female; NF155: neurofascin 155; CASPR1: contactin-associated protein 1; CNTN1: contactin-1; CSF: cerebrospinal fluid. FK506: tacrolimus; IVIG: intravenous immunoglobulin; IVMP: intravenous methylprednisolone; DRP: difficulty in reducing prednisone. Note: The follow-up period was from the peak of disease to the last follow-up.
	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5
Treatment before FK506	IVMP Oral prednisone	IVMP Oral prednisone	IVIG, IVMP Oral prednisone	IVIG, IVMP Oral prednisone	IVIG, IVMP Oral prednisone
Reason for adding FK506	Recurrence prevention	Recurrence prevention DRP	Recurrence prevention DRP	Recurrence prevention DRP	Recurrence prevention DRP
Follow up (months)	36	9	30	21	36
Prior FK506: after FK506 Relapse ONLS score MRC score MRS score Prednisone dose	0 : 0 7 : 0 3+ : 5 4 : 0 - : 0	1 : 0 3 : 1 4- : 5 2 : 1 20 : 10	1 : 0 5 : 2 3+ : 4 4 : 2 15 : 10	2 : 0 3 : 0 4- : 5- 3 : 1 30 : 0	1 : 1 4 : 3 4 : 5- 3 : 2 0 : 0
Outcome	Clinical remission	Clinical remission	Partial clinical remission	Clinical remission	Partial clinical remission
Symptoms at the last follow-up	No	Right hand tremor	Lower limb weakness	Mild lower limbs weakness	Hand tremor Abnormal gait
Adverse events	No	Mild liver damage	No	No	Hand tremor

Patient materials

Patient 1

A 37-year-old male presented with progressive upper and lower limbs numbness and weakness for 2.5 months. He has a recent diagnosis of hyperthyroidism and was treated with methimazole. Serum CNTN1 antibody were positive with titers of 1:10. He had a severe disability with MRC grade 3+ and ONLS score 7. He was treated with intravenous methylprednisolone (IVMP) and started to take oral prednisone after the end of the course. Moreover, tacrolimus was administrated at day 4 after oral prednisone considering the possibility of relapse. During the 3-years follow-up, he presented with long-lasting improvement and were successfully withdrew from oral prednisone without any relapse (Figure 1a-1b). Moreover, electromyography was performed at the base line and 3, 7, 10, 17, 22 months after treatment. Motor conduction velocity (MCV) and compound muscle action potentials (CMAPs) amplitudes were decreased in median, ulnar and tibial nerves at the peak of illness, which were followed by gradual normalization after treatment (Figure 2a, 2c and 2e). Moreover, sensory conduction velocity (SCV) and sensory nerve action potentials (SNAP) amplitudes in the median and ulnar nerves, as well as SCV in superficial peroneal nerves showed the similar findings (Figure 2b, 2d and 2f).

Patient 2

A 57-year-old male was admitted with progressive limbs numbness and weakness and neuropathic pain for 30 days. Anti-Caspr1 antibodies were found to be positive (serum, 1:1000; cerebrospinal fluid (CSF), 1:10). His weakness gradually improved from grade 4 to grade 5 after IVMP and oral prednisone, while neuropathic pain was relieved after oral pregabalin. However, his symptoms worsened again at the second months after discharge. Although oral prednisone (40mg/d) has been resumed, he gradually developed unstable walking, deep sensory disturbances and tremor in his right hand. Then tacrolimus was given at a dose of 3 mg daily and prednisone was tapered gradually. After 6 months of follow-up, the patient’s weakness and sensory disturbances gradually relived and only the tremor in his right hand remained (Figure 1c-1d).

Patient 3

A 22-year-old male admitted with limbs numbness and weakness (especially the lower limbs) for 8 months. He was initially diagnosed with Miler-Fisher syndrome in other hospital. IVMP and IVIG completely relieved his dysphagia, hoarseness and diplopia. However, his limb weakness worsened and developed ataxia and upper limbs tremor at 8th months of oral prednisone tapering. Then tacrolimus was administrated and he improved moderately, although obvious lower limb weakness persisted (MRC grade 4) (Figure 1e-1f). Two years after tacrolimus treatment, serum autoantibodies were confirmed to be anti-NF155 IgG4 positive (1:100). He was finally diagnosed with CIDP based on clinical characteristics. For a better outcome, several intravenous rituximab and PE courses were also tried but poor response.

Patient 4

A 37-year-old female was admitted with progressive numbness and weakness (especially the lower limbs) for 15 days. She had a Guillain Barre syndrome (GBS) medical history one year ago but relieved after treatment. Anti-Caspr1 IgG autoantibodies were positive (serum, 1:32; CSF, 1:1) (Figure 3b-3c) and magnetic resonance imaging (MRI) showed significant peripheral nerves hypertrophy (Figure 3a). She presented with a severe disability and required a wheelchair at onset. Corticosteroids and IVIG effectively relieved his symptoms. Unfortunately, she worsened again after oral prednisone and three courses of IVIG. Though serological and CSF analysis showed the anti-Caspr1 antibody have changed from positive to negative (Figure 3d-3e), oral tacrolimus was still added considering the possibility of recurrent attacks. During the next 18 months of follow-up, she gradually improved without recurrence and left only mild weakness of the lower limbs (MRC grade 5-) (Figure 1g and 1h).

Patient 5

An 18-year-old male suffered from limbs weakness and numbness (especially the lower limbs) for 6 months. He was firstly diagnosed as GBS and treated with IVMP and oral prednisone after IVIG failed 4 months ago. His MRC score recovered from grade 3+ to 5-, however, the symptoms worsened after oral prednisone was completely withdrawn. Then oral prednisone was resumed and tacrolimus was administrated. His symptoms improved significantly over the next year and prednisone was successfully discontinued. His weakness worsened again in the second month after tacrolimus discontinued. Moreover, serological analysis found positive anti-NF155 IgG4 antibodies. Considering that this patient was resistant to IVIG in the previous episodes, IVMP and tacrolimus was given in this episode (Figure 1i and 1j). Although there is still a slight disability (abnormal gait and hand tremor) 9 months later, he could complete activities of daily living independently (MRS score 2).

Treatment efficacy, outcome and adverse events

At the last follow-up, 3 patients reached clinical remission (MRS score 0–1) and 2 patients achieved partial clinical remission (MRS score 2). Four cases of 5 patients experienced relapses before tacrolimus treatment. Inversely, none of them did not relapse after tacrolimus treatment, except for one patient who completely discontinued tacrolimus suffered from relapses. Additionally, 3 patients were successfully withdrawn from corticosteroids and 2 patients took corticosteroids at low maintenance dose (10mg/d) during follow up. In terms of adverse events, patient 5 developed mild but acceptable hand tremors and patient 2 had mild slight transferase elevation (less than 3 times the normal value). No severe adverse events were observed in all the patients.

In the small cohort, patient 6 who carried anti-NF155 IgG4 and received PE treatment developed severe bacteremia and thrombosis in the right internal jugular vein and right subclavian vein. For the next 3 months, he received rituximab treatment and reached partial clinical remission after follow-up for 18 months (MRS 4 → 2). Patient 7 and 8 harboring anti-NF155 IgG4 were resistant to IVIG. Then patient 7 was treated with regularly rituximab and he was completely recovered after 6 months although suffered from a transient skin rash during the treatment (MRS 2 → 0). Patients 8 was treated with PE and oral prednisone and his symptoms were significantly relieved after 3 months of follow-up (MRS 2 → 1). Patient 9 harboring anti-Caspr1 IgG were treated with IVIG, rituximab, IVMP, and oral corticosteroids. Unfortunately, the disease still gradually progressive and eventually he died of respiratory failure at 4 months after onset.

CIDP is mediated by T cell immunity and B-cell immunity [23]. T cells response not only destroy the blood-nerve barrier by producing a variety of pro-inflammatory cytokines, but also promote the activation of B cells and the production of antibodies ^1,16. In the past few years, autoantibodies against paranodal protein, like NF155, CNTN1 and Caspr1 have been found in a small subgroup of patients with CIDP. Moreover, there are significant differences in pathogenesis, clinical features and therapeutic options between patients with and without these antibodies ¹⁶. In our study, it can be observed that patients with autoantibodies against NF155, CNTN1 and Caspr1 had a male predominance (male: female: 8:1) and remarkably increased CSF total protein, usually above 2000mg/dl (normal value: 150-450mg/dl). Moreover, patients with anti-NF155 IgG4 showed a younger age at onset (median: 17; range:10-34), which was consistent with previous reports ¹⁷.

Tacrolimus is a well-known immunosuppressant by inhabiting the activation and proliferation of T cells, leading to reduction in generation of various cytokines ¹⁸. In turn, suppressed T cells further affects B cell proliferation and reduces the production of antibodies ¹⁸. Our data showed that tacrolimus significantly improved the outcome of CIDP patients with autoantibodies against paranodal proteins by preventing relapse and helping to withdrawing corticosteroids. Patient 1 started tacrolimus treatment at first attack and eventually achieved full clinical remission. Patient 2, 3, 4, and 5 were treated with daily oral corticosteroids before tacrolimus treatment. Unfortunately, all of them suffered from weakness worsening during the process of corticosteroids tapering. However, patient 2, 3 and 4 gradually improved both in ONLS score and MRC score with no relapse after adding tacrolimus on daily oral corticosteroids. Patient 5 also gradually relieved after oral tacrolimus treatment, but once tacrolimus was completely discontinued, he experienced worsening and had to accept tacrolimus and corticosteroids treatment again. Moreover, patients 1, 4 and 5 were successfully withdrew from corticosteroids treatment after tacrolimus administration, and patients 2 and 3 took corticosteroids at a low maintenance dose (10mg/d) during follow up.

Glial NF155 binds to axonal Caspr1/CNTN1 to form axon–glia junctions which are the most important functional structure of the paranodes ^7,19. Autoantibodies against NF155, CNTN1 and Caspr1 were predominantly of IgG4 subclass. Moreover, Anti-NF155 IgG4, anti-CNTN1 IgG4 and anti- Caspr1 IgG4 could targeted the paranodal region and dismantle the axo-glial interactions, leading to nerve conduction defects ^4,16,17,20. Furthermore, autoantibodies against paranode proteins are closely related to demyelination and early axonal involvement ^4,21. Consistently, all the 5 patients in our study presented with demyelination and axonal damage at onset severe in both sensory and motor nerves (Table 1). Fortunately, 5 patients had improved and achieved clinical remission or partial clinical remission after treatment (Table 2).

Patients with antibodies against NF155, CNTN1 and Caspr1 were resistant to IVIG due to the predominantly of IgG4 subclass. Corticosteroids were still considered as a therapeutic option ²⁰. In our study, 5 patients were response to corticosteroids. Moreover, nerve conduction studies of patient 1 showed that MCV, CMAP, SCV and SNAP gradually returned to baseline after tacrolimus and corticosteroids treatment, suggesting that tacrolimus and corticosteroids are helpful in repairing myelin sheath and axons. Consistently, previous clinical and animal studies have revealed that tacrolimus plays a neuroprotective role by improving nerve regeneration after peripheral nerve damage, especially axonal regeneration ^14,15,22,23. These results suggested that the combination therapy with corticosteroids and tacrolimus may be an effective regimen in CIDP patients with antibodies to paranodal proteins.

Oral tacrolimus was generally well-tolerated in the 5 patients with no severe side effects, in contrast to catheter-related bacteremia and venous thrombosis in patients who receive plasma exchange treatment, just like the patient 6. Considering the good effectiveness, safety and easy access of tacrolimus as an immunosuppressant, our group has applied tacrolimus to the long-term management of several autoimmune diseases, including IMNM, NMOSD and neuromyotonia, with high efficacy of improving symptoms and preventing relapses ^10–12.

Taken all together, our study showed that tacrolimus significantly improved the outcome of CIDP patients with autoantibodies against paranodal proteins by preventing relapses, reducing corticosteroids dependence and promoting nerve repair. Tacrolimus as an effective and easily accessible immunosuppressant, could be a good choice for treating CIDP patients with autoantibodies against paranode proteins, in combination with corticosteroids. However, this retrospective research is limited by small samples. There were differences in therapeutic regimens in different cases because of the differences of individual compliance with medical suggestions. Larger randomized controlled trials are still needed to further confirm the initial observation.

Patients

In this retrospective study, we reviewed the medical records of all patients harboring NF155, CNTN1 and Caspr1 antibodies from Jan 2018 to Apr 2021 at Tongji hospital. All patients were diagnosed according to the CIDP diagnostic criteria of the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) ²⁴. Tacrolimus was administered firstly at a routine dose of 2-3 mg/ day, and then the dose was adjusted based on patient's condition and tacrolimus trough concentrations. Autoantibodies against paranodal proteins were detected by indirect immunofluorescence test using NF155, CNTN1 or Caspr1- transfected HEK-293 cells, as previously described ²⁵.

Ethics declarations

The Medical Ethics Committee of the Tongji hospital of Tongji Medical College approved the research procedures and written informed consent was obtained from all patients. All methods were performed in accordance with the relevant guidelines and regulations.

Follow up and outcome assessment

The patient's long-term management was achieved by the out-patient follow-up and telephone follow-up. The severity of disease was evaluated by the medical research council (MRC) score (0-5) and the Overall Neuropathy Limitation Scale (ONLS) score (0-12) ²⁶. The clinical outcome was assessed by the Modified Rankin Scale (MRS) score (0-6). At the time of out-patient follow-up interviews, blood sampling was collected to monitor possible side effects of tacrolimus, including liver injury, nephrotoxicity and granulocytopenia.

Data availability

All data generated or analysed during this study are included in this published article.

Acknowledgements

The authors thank Kindstar Global company for testing the autoantibodies against paranode proteins.

Author contributions

M.Y. wrote the main manuscript text and prepared figures. S.J., L.X., H.G. and Q.Z. played a role in the acquisition of data and revising the manuscript for content. B.B. developed the concept and design of the review, supervised the work and contributed to the review revision. All authors reviewed the manuscript.

Competing Interests Statement

The authors declare that they have no competing interests.

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No competing interests reported.

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Tacrolimus Significantly Improved the Outcome of CIDP Patients With Autoantibodies Against Paranodal Proteins

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