Immunoadsorption Therapy in Patients With Multiple Sclerosis With Steroid-Refractory Optical Neuritis

Michael J Koziolek; Desiree Tampe; Matthias Bühr; Hassan Dihazi; Klaus Jung; Dirk Fitzner; Reinhard Klinge; Gerhard A Müller; Bernd Kitze

Disclosures

J Neuroinflammation. 2012;9(80)

Abstract and Introduction

Abstract

Background In multiple sclerosis relapses refractory to intravenous corticosteroid therapy, plasma exchange is recommended. Immunoadsorption (IA) is regarded as an alternative therapy, but its efficacy and putative mechanism of action still needs to be established.
Methods We prospectively treated 11 patients with multiple sclerosis who had optical neuritis and fulfilled the indications for apheresis therapy (Trial registration DE/CA25/00007080-00). In total, five IA treatments were performed using tryptophan-IA. Clinical activity (visual acuity, Expanded Disability Status Scale, Incapacity Status Scale), laboratory values and visual evoked potentials were measured before, during and after IA, with a follow-up of six months. Moreover, proteomic analyses were performed to analyze column-bound proteins as well as corresponding changes in patients' sera.
Results After the third IA, we detected an improvement of vision in eight of eleven patients, whom we termed responders. Amongst these, the mean visual acuity improved from 0.15 ± 0.12 at baseline to 0.47 ± 0.32 after the third IA (P = 0.0252) up to 0.89 ± 0.15 (P < 0.0001) at day 180 ± 10 after IA. Soluble interleukin-2 receptor decreased in responders (P = 0.03), whereas in non-responders it did not. Proteomic analyses of proteins adsorbed to IA columns revealed that several significant immunological proteins as well as central nervous system protein fragments, including myelin basic protein, had been removed by IA.
Conclusions IA was effective in the treatment of corticosteroid-refractory optic neuritis. IA influenced the humoral immune response. Strikingly, however, we found strong evidence that demyelination products and immunological mediators were also cleared from plasma by IA.

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Abstract and Introduction
Background
Methods
Results
Discussion
Conclusions
References

Table 1. Clinical baseline characteristics of the participants
Parameter	Total (n = 11)	Responder (n = 8)	Non-responder (n = 3)
Gender
Female	7 (64%)	5 (62%)	2 (67%)
Male	4 (36%)	3 (38%)	1 (33%)
Age	33.6 ± 10.5	29.6 ± 9.2	44.3 ± 8.0
	(19.0 to 55.0)	(19.0 to 47.0)	(39.0 to 55.0)
Body mass index	25.5 ± 3.0	22.9 ± 2.6	26.2 ± 4.0
	(20.1 to 30.7)	(22.0 to 30.7)	(20.1 to 25.7)
Relapse rates in the past 12 months (median and range)	2	2	1
	(1 to 4)	(1 to 4)	(1 to 2)
Baseline Expanded Disability Status Scale	4	3.5	4
	(2 to 7.5)	(2 to 7.5)	(3 to 4)
Days after onset of relapse	26.6 ± 14.6	29.3 ± 15.6	19.3 ± 10.1
	(10.0 to 60.0)	(10.0 to 60.0)	(10.0 to 30.0)
Days after initiation of corticosteroid therapy	10.8 ± 6.9	12.3 ± 6.6	7.0 ± 7.2
	(1.0 to 20.0)	(3.0 to 20.0)	(1.0 to 15.0)
Cumulative dose of prednisolone equivalents (g)	9.5 ± 3.7	8.6 ± 3.7	12.0 ± 2.6
	(4.0 to 15.0)	(4.0 to 15.0)	(10.0 to 15.0)
Duration of disease (years)	3.5 ± 4.9	5.7 ± 2.9	2.7 ± 9.0
	(0.0 to 16.0)	(0 to 7.0)	(0.0 to 16.0)
Initial disease modifying therapy	3 (27.3%)	2 (25%)	1 (33.3%)
Interferon beta	2 (18.2%)	2 (25%)	0 (0%)
Glatiramer acetate	1 (9.1%)	0 (0%)	1 (33.3%)

Descriptive values are shown either as absolute numbers (frequencies) or mean ± standard deviation (minimum–maximum), except for baseline EDSS and relapse rates which are shown as medians and ranges.

Table 2. Moderate adverse events occurring during immunoadsorption that were classified as being related to vascular access, the immunoadsorption procedure or immunosuppression
	Patients (n = 11)	Immunoadsorption therapies (n = 55)
Vascular access-related
Central venous catheter exit site infection	1 (9.1%)	1 (1.8%)
Jugular vein thrombosis	1 (9.1%)	1 (1.8%)
Side effects during immunoadsorption therapy
Chest pain	1 (9.1%)	1 (1.8%)
Dyspnoe	1 (9.1%)	1 (1.8%)
Transient hypotension	4 (36.5%)	5 (9.1%)
Urticaria	1 (9.1%)	1 (1.8%)
Putatively related to immunosuppression both by steroids and immunoadsorption
Febrile infection	2 (18.2%)	2 (3.6%)

Table 3. List of identified proteins from immunoadsorption column elutes pooled from five patients with multiple sclerosis after the first immunoadsorption therapy
Protein name	Gene name	UniProt	SwissProt	Nominal mass	PMF-score
Alpha-1-antitrypsin	SERPINA1	A1AT HUMAN	57.5	46878	94
Apolipoprotein A-I	APOA1	APOA1 HUMAN	56.6	30759	152
Apolipoprotein A-IV	APOA4	APOA4 HUMAN	56.6	45371	67
CD5 antigen-like	CD5L	CD5L HUMAN	56.8	39603	120
Cleavage stimulation factor, subunit, tau variant	CSTF2T	CSTFT HUMAN	57.2	64624	57
Clusterin	CLU	CLUS HUMAN	56.8	53031	160
Complement C1r	C1R	C1R HUMAN	57.5	81606	72
Complement factor I	CF1	CFA1 HUMAN	56.8	68072	86
Complement factor H	CFH	CFAH	57.1	143680	61
Complement factor H-related protein 2	CFHR2	FHR2 HUMAN	57.4	30631	60
Complement C4-A	C4A	CO4A	57.4	192650	213
Fibrin alpha C term fragment		gi 223057	NCBI nr	14443	85
Fibrinogen alpha chain	FGA	FIBA HUMAN	57.1	95656	103
Fibrinogen beta chain	FGB	FIBB HUMAN	57.1	56577	170
Fibrinogen gamma chain	FGG	FIBG HUMAN	57.2	52106	146
Gelsolin	GSN	GELS HUMAN	57.2	86043	95
Histidine-rich glycoprotein	HRG	HRG HUMAN	57.0	60510	152
Huntingtin-associated protein 1	HAP1	HAP1 HUMAN	57.5	76208	65
Kininogen 1	KNG1	KNG1 HUMAN	56.8	72996	96
Transthyretin	TTR	TTHY HUMAN	56.6	15991	89
Immunoglobulin alpha-1 chain C region	IGHA1	IGHA1 HUMAN	57.4	37631	130
Immunoglobulin lamda chain C region	IGLC1	LAC HUMAN	57.4	11230	218
Immunoglobulin mu chain C region	IGHM	IGHM HUMAN	57.4	49960	90
Immunoglobulin kappa constant protein		gi 49258112		25915	78
Immunoglobulin kappa chain, C region	IGCK	IGCK HUMAN	57.2	11773	287
Immunoglobulin kappa light chain variable region		gi 48475436	NCBI nr	21251	80
Immunglobulin kappa light chain VLJ region		gi 21669479	NCBI nr	29086	76
Inter-alpha-trypsin inhibitor	ITIP	ITIH4 HUMAN	57.5	103521	67
Monoclonal immunoglobulin M antibody light chain		gi 41388186	NCBI nr	26008	65
Microtubule-actin crosslinking factor 1	MACF	MACF1	57.0	623626	57
Mps one binder kinase activator-like2A	MOBKL2A	MOL2A	57.0	25676	55
Myelin basic protein	MBP	MBP HUMAN	56.6	33097	55
Malate dehydrogenase cytoplasmic	MDH1	MDHC HUMAN	56.6	36631	57
Plasminogen	PLG	PLMN HUMAN	56.6	93247	89
Serum albumin	ALB	ALBU HUMAN	57.5	71317	101
Serum amyloid P-component	APCS	SAMP HUMAN	57.5	25485	68
Small ubiquitin-related modifier	SUMO1	SUMO1 HUMAN	57.2	11607	59
Transmembrane and tetratricopeptide repeat-containing protein 1	TMTC1	TMTC1 HUMAN	57.2	88209	62
Zinc finger protein basonuclin-2	BNC2	BNC2 HUMAN	57.2	1236677	62
Zinc fincer protein 706	ZNF706	ZN706 HUMAN	57.4	8606	64
39 S ribosomal protein L13 mitochondrial	MRPL13	RM13 HUMAN	57.0	20736	58

Gene names, accession number and identification score are given. PMF: peptide mass finger printing.

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