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 % (n) of patients | Type of PNS involvement | Clinical associations with immunological profiles |
|---|---|---|---|---|---|
| SLE patients∗ | |||||
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| Schneebaum et al., 1991 [9] | Cohort | 269 patients with SLE | Depression 88% (n = 8), 45% psychosis (n = 29) | NM | The serum level of anti-P antibodies correlates with the activity of psychiatric disease |
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| Isshi and Hirohata, 1998 [10] | Cohort | 87 SLE patients | Psychosis 39% (n = 34), nonpsychotic CNS lupus 29,9% (n = 26) | 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 |
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| Tzioufas et al., 2000 [11] | Cohort | 28 patients with NPSLE | Psychiatric disorders 25% (n = 7), grand mal seizures 14,2% (n = 4), focal signs 46,4% (n = 13) | NM | Overall prevalence of anti-P antibodies in active CNS disease patients was statistically and significantly higher, as compared to unselected SLE patients |
|
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| Kasitanon et al., 2002 [12] | Cohort | 91 patients with NPSLE (90 F, 1 M, 30,7 ± 10,9) | Seizures 58,3% (n = 53), psychosis 14,3% (n = 13), acute confusion state 12% (n = 11), cerebral infraction 2,2% (n = 2), abnormal consciousness 6,6% (n = 6), transverse myelitis 6,6% (n = 6), aseptic meningitis 2,2% (n = 2) | MM 3,3% (n = 3), polyneuropathy 2,2% (n = 2) | Patients with NPSLE had significantly more cutaneous vasculitis and less arthritis than those without NPSLE |
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| Sanna et al., 2003 [13] | Cohort | 185 patients with NPSLE | Headache 24% (n = 78), CD 14.5% (n = 47), mood disorders 16.7% (n = 54), cognitive disorders 10.8% (n = 35), seizures 8.3% (n = 27), psychosis 7.7% (n = 25), anxiety 3.7% (n = 24), acute confusional state 3.7% (n = 12) | NM | The presence of aPL was associated with NP manifestations |
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| Chiewthanakul et al., 2012 [14] | Cohort | 97 patients with NPSLE (84 F, 13 M, 35.1 ± 11.7) | Seizures 33% (n = 32), CD 23,7% (n = 23), psychoses 24% (n = 23), myelopathy 6,2% (n = 6), headaches 2% (n = 2), mood disorders 1% (n = 1) | 13 patients with polyneuropathy 77% (n = 10), GB 7,7% (n = 1), mononeuropathy 7,7% (n = 1), cranial neuropathy 7,7% (n = 1) | ANA and antibodies to dsDNA did not correlate with NP manifestations |
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| Závada et al., 2013 [15] | Cohort | 50 patients with NPSLE (5 M, 45 F 43 years (±16)) | Cognitive disorder 50% (n = 25), mood disorder 28% (n = 14), CD 26% (n = 13), headache 26% (n = 13), seizure 22% (n = 11), psychosis 16% (n = 8), aseptic meningitis 4% (n = 2) | Polyneuropathy 8% (n = 4), cranial neuropathy 6% (n = 3), mononeuropathy 4% (n = 2), transverse myelitis 2% (n = 1) | 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 |
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| Hanly et al., 2004 [16] | Cohort | 111 patients with SLE (96 F, 15 M, 44.7 ± 1.2 years) | Headaches 9% (n = 10), CD 3,6% (n = 4), mood disorders 3,6% (n = 4), cognitive dysfunction 2,7% (n = 3), acute confusional state 2,7% (n = 3), psychoses 2,7% (n = 3), seizures 0,9% (n = 1), anxiety 0,9% (n = 1), aseptic meningitis 0,9% (n = 1) | Cranial neuropathy 1,8% (n = 2), polyneuropathy 1,8% (n = 2) | No correlations were found |
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| Kluz et al., 2007 [17] | Cohort | 15 F mean age: 38.33 ± 11.02 years with SLE | Organic brain syndrome 13,3% (n = 2), cranial nerve disorder 6,6% (n = 1), headache 6,6% (n = 1), seizures 6,6% (n = 1) | NM | CNS complications were associated with aPL antibodies in patients with severe disease activity and microangiopathic complications compared with those with less active disease |
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| Briani et al. 2009 [18] | Cohort | 85 SLE patients (NM sex and mean age) | Headache 41,2% (n = 35), CD 12,3% (n = 11), epilepsy 11,8% (n = 10), psychiatric disorders 3% (n = 6), myelopathy 2,4% (n = 2) |
Symmetric polyneuropathy 20% (n = 17), mononeuropathy 15,3% (n = 13), median nerve 3,6% (n = 3) sciatic nerve 3,6% (n = 3) involvement, MM 2,4% (n = 2) |
Abs to ribosomal P proteins are associated with psychosis and MM |
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| 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% (n = 23), cranial neuropathy 12,5% (n = 26), MM 9,2% (n = 19), CIDP 0,9% (n = 2) | 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 |
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| 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% (n = 19), anxiety 6,1% (n = 3), cognitive disorder 6,1% (n = 3), psychosis 14,2% (n = 7); focal NPSLE: headache 8,7% (n = 2), movement disorder 8,7% (n = 2), seizure 8,7% (n = 7), aseptic meningitis 4,3% (n = 1), demyelinating syndrome 4,3% (n = 1) | Polyneuropathy 4,3% (n = 1) | Anti-Sm and anti-RNP in CSF and sera were elevated in NPSLE compared with non-SLE control |
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| SS patients | |||||
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| Spezialetti et al., 1993 [21] | Cohort | 77 patients with pSS | Severe depression 13% (n = 10), psychosis 8% (n = 6), cognitive dysfunction 69% (n = 54) | NM | No correlation between CNS diseases, including the presence of anti-ribosomal P antibodies |
|
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| Alexander et al., 1994 [22] | Cohort | Group 1: 52 SS patients Group 2: 49 patients |
Group 1: focal CNS disease 60% (n = 26/43), nonfocal CNS disease 22% (n = 2/9) Group 2: focal CNS disease 63% (n = 19/30), nonfocal CNS disease 37% (n = 7/19) |
Not available | Anti-Ro antibodies were positive in 48% of patients with CNS compared to only 24% of all patients with pSS |
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| Delalande et al., 2004 [23] | Cohort | 82 patients (65 F, 17 M 48,6 years) | Seizures 8,5% (n = 7), cognitive dysfunction 11% (n = 9), encephalopathy 2,4% (n = 2), optic neuropathy 15% (n = 13), MS 28% (n = 23) | SMN 34,1% (n = 28), cranial neuropathy 19,5% (n = 16), MN 8,5% (n = 7), myositis 2,4% (n = 2), polyradiculoneuropathy 1,2% (n = 1) | Anti-Ro/SSA or anti-La/SSB antibodies were more frequently observed in patients with PNS involvement than in those with CNS involvement |
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| 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 |
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| Sène et al., 2011 [25] | Cohort | 120 patients with pSS (106 F, 14 M 50.4 ± 14.0) | NM | SMN 23% (n = 7), ASN 10% (n = 3), NSN 67% (n = 20) | Patients with NSN with lower prevalence of ANA (60% versus 90%; P = 0.003), anti-SSA (Ro) (40% versus 72%; P = 0.009), anti-SSB (La) (15% versus 41%; P = 0.039), RF (37% versus 67%; P = 0.02), and hypergammaglobulinemia (35% versus 64%; P = 0.023) |
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| 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% (n = 6), dysarthria 0,2% (n = 1), seizures 0,2% (n = 1), cerebellar ataxia 0,4% (n = 2) central neuronitis 0,4% (n = 2), acute encephalopathy 2,1% (n = 9), cognitive impairment 0,4% (n = 2), aseptic meningitis 0,2% (n = 1), transverse myelitis (n = 12), optic neuritis 1,2% (n = 5), MS-like syndrome 1,2% (n = 5), cerebral venous thrombosis 0,2% (n = 1) |
SMN 0,6% (n = 25), MM 0,7% (n = 3), SN 4,5% (N = 19), SGN 2,1% (n = 9), DPN 0,2% (n = 1), cranial neuropathy 1,9% (n = 8) | Patient with SN had more frequent cryoglobulinemia and lymphopenia (P < 0.05) but lower prevalence of anti-Ro/SSA antibodies and hypergammaglobulinemia (P < 0.05) |
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| Morreale et al. 2014 [27] | Cohort | 120 patients (12 M, 108 F; 58.3 ± 14.2 years) | Headache 46.9% (n = 30), cognitive disorder 44.4% (n = 28), mood disorders 38.3% (n = 6) | NM | Headache, cognitive disorders, and psychiatric symptoms were significantly associated with anti-SSA |
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| RA | |||||
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| Sivri and Güler-Uysal, 1999 [28] | Cohort | 33 RA patients (28 F, 5 M; 46.7 ± 13.7 years) | NM | 6% (n = 2) carpal tunnel syndrome, 18% (n = 6) MM | No correlation between neuropathy and RF |
n: 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.