A Systematic Review of Peripheral and Central Nervous System Involvement of Rheumatoid Arthritis, Systemic Lupus Erythematosus, Primary Sjögren’s Syndrome, and Associated Immunological Profiles

Table 2

Characteristics of the selected clinical trials focusing on PNS and CNS complications of SLE, pSS, and RA.

Authors/year	Type of study	Sample characteristics (sex, years in median or mean ± SD)	Type of CNS involvement % () of patients	Type of PNS involvement	Clinical associations with immunological profiles
SLE patients
Schneebaum et al., 1991 [9]	Cohort	269 patients with SLE	Depression 88% (), 45% psychosis ()	NM	The serum level of anti-P antibodies correlates with the activity of psychiatric disease
Isshi and Hirohata, 1998 [10]	Cohort	87 SLE patients	Psychosis 39% (), nonpsychotic CNS lupus 29,9% ()	NM	Serum anti-P levels were significantly elevated in patients with lupus psychosis compared with those with non-CNS SLE or those with nonpsychotic CNS lupus
Tzioufas et al., 2000 [11]	Cohort	28 patients with NPSLE	Psychiatric disorders 25% (), grand mal seizures 14,2% (), focal signs 46,4% ()	NM	Overall prevalence of anti-P antibodies in active CNS disease patients was statistically and significantly higher, as compared to unselected SLE patients
Kasitanon et al., 2002 [12]	Cohort	91 patients with NPSLE (90 F, 1 M, 30,7 ± 10,9)	Seizures 58,3% (), psychosis 14,3% (), acute confusion state 12% (), cerebral infraction 2,2% (), abnormal consciousness 6,6% (), transverse myelitis 6,6% (), aseptic meningitis 2,2% ()	MM 3,3% (), polyneuropathy 2,2% ()	Patients with NPSLE had significantly more cutaneous vasculitis and less arthritis than those without NPSLE
Sanna et al., 2003 [13]	Cohort	185 patients with NPSLE	Headache 24% (), CD 14.5% (), mood disorders 16.7% (), cognitive disorders 10.8% (), seizures 8.3% (), psychosis 7.7% (), anxiety 3.7% (), acute confusional state 3.7% ()	NM	The presence of aPL was associated with NP manifestations
Chiewthanakul et al., 2012 [14]	Cohort	97 patients with NPSLE (84 F, 13 M, 35.1 ± 11.7)	Seizures 33% (), CD 23,7% (), psychoses 24% (), myelopathy 6,2% (), headaches 2% (), mood disorders 1% ()	13 patients with polyneuropathy 77% (), GB 7,7% (), mononeuropathy 7,7% (), cranial neuropathy 7,7% ()	ANA and antibodies to dsDNA did not correlate with NP manifestations
Závada et al., 2013 [15]	Cohort	50 patients with NPSLE (5 M, 45 F 43 years (±16))	Cognitive disorder 50% (), mood disorder 28% (), CD 26% (), headache 26% (), seizure 22% (), psychosis 16% (), aseptic meningitis 4% ()	Polyneuropathy 8% (), cranial neuropathy 6% (), mononeuropathy 4% (), transverse myelitis 2% ()	NMO-IgG/AQP4-Ab in NPSLE were present only in a patient with TM and were not detectable in NPSLE patients with other neurological manifestations
Hanly et al., 2004 [16]	Cohort	111 patients with SLE (96 F, 15 M, 44.7 ± 1.2 years)	Headaches 9% (), CD 3,6% (), mood disorders 3,6% (), cognitive dysfunction 2,7% (), acute confusional state 2,7% (), psychoses 2,7% (), seizures 0,9% (), anxiety 0,9% (), aseptic meningitis 0,9% ()	Cranial neuropathy 1,8% (), polyneuropathy 1,8% ()	No correlations were found
Kluz et al., 2007 [17]	Cohort	15 F mean age: 38.33 ± 11.02 years with SLE	Organic brain syndrome 13,3% (), cranial nerve disorder 6,6% (), headache 6,6% (), seizures 6,6% ()	NM	CNS complications were associated with aPL antibodies in patients with severe disease activity and microangiopathic complications compared with those with less active disease
Briani et al. 2009 [18]	Cohort	85 SLE patients (NM sex and mean age)	Headache 41,2% (), CD 12,3% (), epilepsy 11,8% (),; psychiatric disorders 3% (), myelopathy 2,4% ()	Symmetric polyneuropathy 20% (), mononeuropathy 15,3% (), median nerve 3,6% (); sciatic nerve 3,6% () involvement, MM 2,4% ()	Abs to ribosomal P proteins are associated with psychosis and MM
Florica et al., 2011 [19]	Case-control (retrospective)	207 SLE patients, F 86.3% (125 SLE-related PN 35.2 ± 14.4 years and 82 non-SLE-related PN 38.6 ± 15.4)	NM	PM 11,1% (), cranial neuropathy 12,5% (), MM 9,2% (), CIDP 0,9% ()	There was no significant difference in lupus serology; such as antinuclear antibody, anti-double-stranded DNA; antibody, and antibodies to the extractable nuclear antigens between the two groups
Hirohata et al., 2014 [20]	Cohort	72 patients with NPSLE (49 with diffuse NPSLE 38.3 ± 14.4, 23 with neurological syndromes or peripheral neuropathy 42.0 ± 15.2) 32 M, 50 F	Diffuse NPSLE: acute confusional state 38,7% (), anxiety 6,1% (), cognitive disorder 6,1% (), psychosis 14,2% (); focal NPSLE: headache 8,7% (), movement disorder 8,7% (), seizure 8,7% (), aseptic meningitis 4,3% (), demyelinating syndrome 4,3% ()	Polyneuropathy 4,3% ()	Anti-Sm and anti-RNP in CSF and sera were elevated in NPSLE compared with non-SLE control
SS patients
Spezialetti et al., 1993 [21]	Cohort	77 patients with pSS	Severe depression 13% (), psychosis 8% (), cognitive dysfunction 69% ()	NM	No correlation between CNS diseases, including the presence of anti-ribosomal P antibodies
Alexander et al., 1994 [22]	Cohort	Group 1: 52 SS patients; Group 2: 49 patients	Group 1: focal CNS disease 60% ( = 26/43), nonfocal CNS disease 22% ( = 2/9); Group 2: focal CNS disease 63% ( = 19/30), nonfocal CNS disease 37% ( = 7/19)	Not available	Anti-Ro antibodies were positive in 48% of patients with CNS compared to only 24% of all patients with pSS
Delalande et al., 2004 [23]	Cohort	82 patients (65 F, 17 M 48,6 years)	Seizures 8,5% (), cognitive dysfunction 11% (), encephalopathy 2,4% (), optic neuropathy 15% (), MS 28% ()	SMN 34,1% (), cranial neuropathy 19,5% (), MN 8,5% (), myositis 2,4% (), polyradiculoneuropathy 1,2% ()	Anti-Ro/SSA or anti-La/SSB antibodies were more frequently observed in patients with PNS involvement than in those with CNS involvement
Pittock et al., 2008 [24]	Cohort	14 patients with SS/SLE with neurological manifestations	NM	NM	SSA, SSA, ANA, and dsDNA antibodies were found in these patients but not NMO-IgG
Sène et al., 2011 [25]	Cohort	120 patients with pSS (106 F, 14 M 50.4 ± 14.0)	NM	SMN 23% (), ASN 10% (), NSN 67% ()	Patients with NSN with lower prevalence of ANA (60% versus 90%; ), anti-SSA (Ro) (40% versus 72%; ), anti-SSB (La) (15% versus 41%; ), RF (37% versus 67%; ), and hypergammaglobulinemia (35% versus 64%; )
Jamilloux et al., 2014 [26]	Cohort	420 patients with pSS (377 F, 43 M, 53.6 ± 14.8)	Acute ischemic stroke-like symptoms 1,4% (), dysarthria 0,2% (), seizures 0,2% (), cerebellar ataxia 0,4% () central neuronitis 0,4% (), acute encephalopathy 2,1% (), cognitive impairment 0,4% (), aseptic meningitis 0,2% (), transverse myelitis (), optic neuritis 1,2% (), MS-like syndrome 1,2% (),; cerebral venous thrombosis; 0,2% ()	SMN 0,6% (), MM 0,7% (), SN 4,5% (), SGN 2,1% (), DPN 0,2% (), cranial neuropathy 1,9% ()	Patient with SN had more frequent cryoglobulinemia and lymphopenia () but lower prevalence of anti-Ro/SSA antibodies and hypergammaglobulinemia ()
Morreale et al. 2014 [27]	Cohort	120 patients (12 M, 108 F; 58.3 ± 14.2 years)	Headache 46.9% (), cognitive disorder 44.4% (), mood disorders 38.3% ()	NM	Headache, cognitive disorders, and psychiatric symptoms were significantly associated with anti-SSA
RA
Sivri and Güler-Uysal, 1999 [28]	Cohort	33 RA patients (28 F, 5 M; 46.7 ± 13.7 years)	NM	6% () carpal tunnel syndrome, 18% () MM	No correlation between neuropathy and RF

number of patients, F: female, M: male, SD: standard deviation, pSS: primary Sjögren syndrome, RA: rheumatoid arthritis, RF: rheumatoid factor, NMO: Neuromyelitis optica, PN: peripheral neuropathy, SMN: sensorimotor neuropathy, ASN: ataxic sensory neuropathy, NSN: nonataxic sensory neuropathy, SFN: small fiber neuropathy, PN: peripheral mononeuropathy, MM: mononeuritis multiplex, SN: sensory neuropathy, SGN: sensory ganglionopathy, DPN: demyelinating polyradiculoneuropathy, ANS: autonomous nervous symptoms, PNS: peripheral nervous system, CNS: central nervous system, CD: cerebrovascular disease, MS: multiple sclerosis, NP: neuropsychiatric disease, SLE: systemic lupus erythematosus, aPL: antiphospholipid antibodies, CIDP: chronic inflammatory demyelinating polyradiculoneuropathy, AIDP: acute inflammatory demyelinating polyradiculoneuropathy, focal CNS disease: one or more fixed focal clinical deficits of brain or spinal cord with or without psychiatric or cognitive dysfunction, nonfocal CNS disease: psychiatric or cognitive dysfunction or both without focal neurologic deficit, and NM: not mentioned; according to the 1999 ACR definition of NPSLE.