Peripheral Neuropathy in Systemic Autoimmune Rheumatic Diseases-Diagnosis and Treatment

Abstract

Peripheral neuropathy (PN) is frequently observed in systemic rheumatic diseases and is a challenge in clinical practice. We aimed to review the evidence on the subject and proposed a comprehensive approach to these patients, facilitating diagnosis and management. We searched the MEDLINE database for the terms (and its respective Medical Subject Headings (MeSH) terms): "peripheral neuropathy" AND "rheumatic diseases" OR "systemic lupus erythematosus", "rheumatoid arthritis", "Sjogren syndrome", and "vasculitis" from 2000 to 2023. This literature review focuses on the diagnostic workup of PNs related to systemic lupus erythematosus, Sjögren's syndrome, rheumatoid arthritis, and systemic vasculitis. For every type of PN, we provide a pragmatic flowchart for diagnosis and also describe evidence-based strategies of treatment.

Keywords: connective tissue diseases; peripheral neuropathy; rheumatic diseases; systemic vasculitis.

Figure 1

Proposed diagnostic flowchart for patients with small fiber neuropathy. Notes: Anti-SSA/Ro is the main autoantibody related to Sjögren’s syndrome and part of the contemporary diagnostic criteria. Sicca symptoms refer to the complaints related to dryness of the mouth, eyes, skin, and genital and respiratory tracts. Legend: MSG: minor salivary gland; OSS: ocular staining score (ophthalmic exam with specific dyes aiming to document and quantify eye surface’s lesions); Sch: Schirmer’s test (quantification of lacrimal flow volume by time unit); SFN: small fiber neuropathy; SLE: systemic lupus erythematosus; SM: unstimulated sialometry (simple quantification of salivary flow volume by time unit); SS: Sjögren syndrome. * Consider treating neuropathic pain and repeating functional tests after 6 months. † Consider testing for anti-DNA and anti-Sm.

Figure 2

Proposed approach for the patient with pure sensory polyneuropathy (except isolated small fiber neuropathy) or sensorimotor polyneuropathy. Notes: Anti-SSA/Ro is the main autoantibody related to Sjögren’s syndrome and part of the contemporary diagnostic criteria. Sicca symptoms refer to the complaints related to dryness of the mouth, eyes, skin, and genital and respiratory tracts. Legend: ACPA: anti-cyclic citrullinated peptide antibody; JUS: joint ultrasound; MSG: minor salivary gland; OSS: ocular staining score (ophthalmic exam with specific dyes aiming to document and quantify eye surface’s desepithelization); RA: rheumatoid arthritis; Sch: Schirmer’s test (quantification of lacrimal flow volume by time unit); SPN/SMPN: sensory polyneuropathy/sensorimotor polyneuropathy; SLE: systemic lupus erythematosus; SM: unstimulated sialometry (simple quantification of salivary flow volume by time unit); SS: Sjögren’s syndrome. * Treat neuropathy (see text) and either: (1) order anti-Sm and anti-DNA for systemic lupus erythematosus; (2) order antineutrophil cytoplasmic antibody for systemic vasculitides; or (3) reassess in 6 months. † Consider testing for anti-DNA and anti-Sm. ‡ Order rheumatoid factor and anti-cyclic citrullinated peptide antibody (if not carried out yet) for prognostic purposes.

Figure 3

Proposed approach for patients with sensory neuronopathy. Notes: Anti-SSA/Ro is the main autoantibody related to Sjögren’s syndrome and part of the contemporary diagnostic criteria. Sicca symptoms refer to the complaints related to dryness of the mouth, eyes, skin, and genital and respiratory tracts. Legend: MSG: minor salivary gland; OSS: ocular staining score (ophthalmic exam with specific dyes aiming to document and quantify eye surface’s desepithelization); Sch: Schirmer’s test (quantification of lacrimal flow volume by time unit); SGMRI: magnetic resonance imaging of salivary glands; SGUS: ultrasound of salivary glands; SM: unstimulated sialometry (simple quantification of salivary flow volume by time unit); SN: sensory neuronopathy; SS: Sjögren’s syndrome. * Consider new biopsy of minor salivary gland, because the first one might have missed the diagnosis. † Treat aggressively (see text) and consider the unusual diagnosis of systemic lupus erythematosus or rheumatoid arthritis-related sensory neuronopathy. Might order anti-cyclic citrullinated peptide antibody, anti-DNA, and anti-Sm. If negative, consider a new assessment for Sjögren’s syndrome in 6 months.

Figure 4

Proposed diagnostic flow for confirmed multiple mononeuropathy. Legend: AAV: antineutrophil cytoplasmic antibody-associated vasculitis; ANCA: antineutrophil cytoplasmic antibody; CG: serum cryoglobulin; CV: cryoglobulinemic vasculitis; DD: differential diagnosis; EGPA: eosinophilic granulomatosis with polyangiitis; HT: hypertension; MM: multiple mononeuropathy; PAN: polyarteritis nodosa; PEo: peripheral eosinophils; RF: renal failure; RV: rheumatoid vasculitis; SVV: small vessel vasculitis; UrP: urinary protein. * If immunofluorescence for antineutrophil cytoplasmic antibodies is perinuclear, confirm with anti-myeloperoxidase; if it is cytoplasmic, confirm with anti-proteinase 3. † If antineutrophil cytoplasmic antibodies are negative, dose cryoglobulins. If cryoglobulins are absent, order antineutrophil cytoplasmic antibodies. If both are negative, treat as antineutrophil cytoplasmic antibody-associated vasculitis (see text) because of the severity. ‡ Consider guiding biopsy by nerve conduction studies and electromyography, or alternatives to multiple mononeuritis, such as hereditary neuropathy with liability to pressure palsies.