Research ArticleSystemic Sclerosis
Open Access

Epidemiology and Treatment of Peripheral Neuropathy in Systemic Sclerosis

Bader A. AlMehmadi, Fergus Z. To, Melanie A. Anderson and Sindhu R. Johnson
The Journal of Rheumatology December 2021, 48 (12) 1839-1849; DOI: https://doi.org/10.3899/jrheum.201299

Abstract

Objective The epidemiology and treatment of peripheral neuropathy in systemic sclerosis (SSc) is poorly understood. The objectives of this study were to evaluate the incidence, prevalence, risk factors, and treatments of peripheral neuropathy in SSc.

Methods A systematic review of MEDLINE, Embase, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases for literature reporting peripheral neuropathy in SSc was performed. Studies evaluating incidence, prevalence, risk factors, and treatments were synthesized. A metaanalysis using a random effects model was used to evaluate the prevalence of peripheral neuropathy.

Results This systematic review identified 113 studies that reported 949 of 2143 subjects with at least 1 type of peripheral neuropathy. The mean age was 48.5 years. The mean time between SSc onset and detection of peripheral neuropathy was 8.85 years. The pooled prevalence of neuropathy was 27.37% (95% CI 22.35–32.70). Risk factors for peripheral neuropathy in SSc included advanced diffuse disease, anticentromere antibodies, calcinosis cutis, ischemia of the vasa nervorum, iron deficiency anemia, metoclopramide, pembrolizumab, silicosis, and uremia. There were 73 subjects with successful treatments (n = 36 restoring sensation, n = 37 restoring motor or sensorimotor function). Treatments included decompression surgery, prednisone, cyclophosphamide, carbamazepine, transcutaneous electrical nerve stimulation, tricyclic antidepressants, and intravenous Ig.

Conclusion All-cause peripheral neuropathy is not uncommon in SSc. Compression neuropathies can be treated with decompression surgery. Observational data reporting immunosuppressives and anticonvulsants to treat peripheral neuropathy in SSc are limited and conflicting. Randomized controlled trials are needed to evaluate the efficacy of these interventions.

Key Indexing Terms:

Peripheral neuropathy encompasses a wide spectrum of clinical disorders affecting sensory, motor, and autonomic peripheral nerve fibers. Most peripheral neuropathies affect all fiber types to some extent. However, a single fiber type may be predominantly or exclusively affected in some disorders. Peripheral neuropathies are also defined by the pattern of nerve fiber involvement. Some disorders involve single individual peripheral nerves (mononeuropathies), and some involve numerous individual peripheral nerves (the mononeuritis multiplex syndrome). In addition, peripheral nerve disorders can involve the brachial plexus, lumbosacral plexus, or they can involve a single root, resulting in signs and symptoms in 1 limb. This diverse array of possible etiologies can make the diagnosis of peripheral neuropathies challenging. Nevertheless, the diagnosis can be facilitated with a systematic approach that classifies the peripheral neuropathy on the basis of clinical features, taking into account the type of peripheral nerve fiber that may be involved (i.e., sensory, motor, or autonomic), the distribution or pattern of peripheral nerve fiber involvement (generalized and symmetrical vs asymmetrical and multifocal), and the mode of evolution (acute, subacute, or chronic). Nerve conduction studies can be helpful in confirming the diagnosis, and in defining the nature and extent of the peripheral neuropathy. Peripheral nerve disorders are relatively common conditions that affect 2.4% of the population.1 However, the prevalence increases to 8.0% with advancing age. Management of the peripheral neuropathy is directed first at the specific cause if it is treatable; and second at the alleviation of symptoms, including managing neuropathic pain, and bracing and physical therapy for weakness.

Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, fibrosis, and immune abnormalities.2 Affected organs include the skin, lungs, heart, digestive system, kidneys, muscles, joints, and nervous system. Neurologic involvement in SSc includes cranial, entrapment, peripheral, cutaneous, and autonomic neuropathies, whereas central nervous system (CNS) involvement includes headache, seizure, stroke, vascular disease, radiculopathy, and myelopathy. Estimates of the frequency of neurologic involvement in patients with SSc vary widely, but CNS involvement due to SSc is rare. A systematic review of the literature was conducted to synthesize data evaluating the epidemiology of peripheral neuropathy and treatment options used in SSc.

METHODS

Literature search. A literature search was conducted through the University Health Network library with the assistance of an information specialist. The search included Ovid MEDLINE from 1946 to September 2020, including the Epub Ahead of Print and In-Process and Other Non-Indexed Citations (inception to September 2020); Embase (1974 to September 2020); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) with full text (inception to September 2020). The following keywords were used in the database search: scleroderma, systemic sclerosis, CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias), sclerodactyly, Raynaud, calcinosis, peripheral nervous system diseases, peripheral neuropathy, tarsal tunnel, carpal tunnel, cubital tunnel, neuropathy, mononeuropathy, polyneuropathy, radiculopathy, and myelopathy. The search was restricted to humans, but no language restriction was applied.

Study selection. Titles and abstracts were screened by 2 investigators independently to identify studies that described peripheral neuropathy in SSc. Inclusion criteria were (1) peer reviewed observational studies (cohort and case-control studies), randomized controlled trials (RCTs), case reports, or case series; and (2) report of peripheral neuropathy by symptoms and clinical examination, nerve conduction studies, or other detection tools. The 2 independent reviews were compared, and discrepancies were resolved by consensus or inclusion of a third investigator, as needed. Mixed connective tissue disease, central neuropathy, and myelopathies were excluded.

Data abstraction. Two investigators (BAA, FZT) independently reviewed each abstract and applied the inclusion and exclusion criteria to identify relevant studies for full review. A standardized data abstraction form was used to collect data on the study design, sample size, presence of control groups, incidence, prevalence, patterns of neuropathy, risk factors, and treatment.

Outcomes. A standardized form was used to abstract the prevalence, incidence, and risk factors of peripheral neuropathy in SSc, as well as treatments and outcomes.

Statistical analysis. Metaanalyses were evaluated for heterogeneity using the Q and I2 tests.3 Influential analysis was initially conducted to see the effect of each study; the Baujat plot identified identified 2 studies that were contributing to high heterogeneity. We used the suggested criteria of 25% (low), 50% (moderate), and 75% (high) for different levels of heterogeneity. A random effects metaanalysis was performed using the Paule-Mandel estimator on the final studies,4 whereas the CIs of τ and τ2 were adjusted using the Biggerstaff and Jackson method. Prediction intervals are also reported for the random effects model.5 Publication bias was assessed visually by inspecting a funnel plot and additionally by Egger test,6 as well as Trim and Fill and Fail Safe N methods.7 Multiple metaregression was also used to assess the significance of different moderators. A P value < 0.05 was considered statistically significant. The data were analyzed using R Core Team (R Foundation for Statistical Computing).

RESULTS

Of the 6342 studies identified through a systematic review of the literature, 1138–120 were identified for full review (Figure 1). A total of 2143 subjects were included in the studies reviewed, of which 949 subjects were diagnosed with at least 1 type of peripheral neuropathy (Supplementary Table 1, available with the online version of this article). The mean age was 48.5 years. Fifty-one studies reported peripheral neuropathy in 1030 subjects with limited SSc8–15,17–29,31–33,35–40,42–60,68,74,80,83,85,88,93–95,98,99,107 and 53 studies reported peripheral neuropathy in 607 subjects with diffuse SSc (dSSc).9,10,12,18,20,22,24,25,30,31,33,35,36,38,41,44,45,48,49,51, 53–55,57,59,61–69,71,74,76–78,81,82,90,91,94,95,107,108,114–118,120 At least 5 juvenile SSc subjects with peripheral neuropathy were found in 4 studies,78,79,116,120 4 studies reported peripheral neuropathy in 22 subjects with morphea,48,79,108,113 and 3 studies reported peripheral neuropathy in 81 subjects with SSc sine scleroderma.36,54,70 Study design included 49 case reports,8,14,15,17,23,27–31,37,39,40,42,43,47,52,56,58,60,61,63–67,69,70–73,76,78–91,115,117,118 23 case series,11,16,20,22,26,31,32,34,41,46,50,62,68,77,92–95,97–99,114,120 39 observational studies,9,10,12,13,18,19,21,24,25,33,35,36,38,44,45,48,49,51,53–55,57,59,74,96, 100–106,108–113,116 and 51 studies for therapeutics.8,11,14,15,17,21,23,29,31,32,34, 37,39–43,46–48,60–62,64,66,68,69,71–74,76,81,84–86,88,90–95,99,101,102,107,114–116,118 No RCTs were identified.

PRISMA flow diagram of systematic review results. CINAHL: Cumulative Index to Nursing and Allied Health Literature; PRISMA: Preferred Reporting Items for Systematic reviews and Meta-Analyses; SSc: systemic sclerosis.
Figure 1.

PRISMA flow diagram of systematic review results. CINAHL: Cumulative Index to Nursing and Allied Health Literature; PRISMA: Preferred Reporting Items for Systematic reviews and Meta-Analyses; SSc: systemic sclerosis.

The average duration between SSc onset and the detection of peripheral neuropathy was 8.85 years. Twenty-four studies reported a neuropathy onset ranging from 3 months to 5 years before SSc was diagnosed,8,11,22,29,31,46,48,50,56,58,63,64,66,69,71,77,78,80,82,83,87,89,94,114 4 studies reported diagnosing SSc and neuropathy at the same time,34,62,93,98 and the remaining studies reported neuropathy 1 month to 59 years after the diagnosis of SSc. The most frequent modalities used to detect and assess neuropathy were history and physical examination in symptomatic subjects (n = 339),8,11,13–17,20–32,34,37,40–48,50,52,53,56–64,66–74,76–91, 93–95,97–99,101,103–105,109–111,114–116,118,120 nerve conduction studies (NCS; n = 173),8,11,13–17,20–34,37, 40–50,52,53,56–64,66–74,76–84,86,88,93,94,98,100,105,108,114,115,120 and nerve and skin biopsies (n = 117).19,21,31,35,41,42,49,52,56,64,79,82,88,89,93, 94,112,113,116,117 Imaging techniques included radiographs (6.3%),17,47,60,65,81,85,91 computed tomography scans (5.4%),17,23,72,81,90,91 ultrasound (4.5%),10,13,57,92,105 and magnetic resonance imaging (4.5%).42,57,69,91,120 Imaging modalities were mostly used where compression neuropathy was suspected.

Peripheral neuropathies were categorized as compression vs noncompression neuropathies. Compression neuropathies were reported in 26.5% of the studies.10,11,13,17,23,30,31,34,40,43,46, 47,50,56,57,60,64,72,74,77,81,84,85,90,91,95,101,105,118,120 Median nerve entrapment (carpal tunnel syndrome [CTS]) was the most common form of compression neuropathy (n = 216; Table 1).10,11,13,31,34,46,50,56,57,64,74,77,84,95,101,105,118,120 Causes of entrapment included calcinosis cutis (most common)17,47,57,60,72,85,91 and soft tissue thickening.10,13,40,74,84 Trigeminal neuralgia may also occur as a result of nerve entrapment secondary to calcinosis or tissue fibrosis.8,14,17,19,30,31,34,35,37,43,46,47,52,57–60,63,70,72–74,80–82,84,85,90,91,93,94,99,104, 111,113,116,118,120

View this table:
Table 1.

Compression and noncompression neuropathies in systemic sclerosis.

The most common type of noncompression neuropathy was trigeminal neuropathy (n = 100).9,22,23,25,26,29,31,58, 61–63,66–69,73,78,79,83,87,95,97,99,120 Several etiologies were proposed including nerve fibrosis secondary to tissue edema and vasculitis,8,13,15,19,21,27,32,34,35,39,40,48,56,57,63,73,80,88,99,113,117as well as nerve ischemia due to microangiopathy.9,10,14,15,23,24,31,33,37,44,49,52,53,57,59,73,88,94,105 Mononeuropathy was found in the majority of subjects (n = 369),9,11,13,16–19,22–24,26,27,29–34,37,39,40,46,47,50,57–60,62–70,73,74,77,78, 83–85,87,95,97–99,101,103,105,118,120 multiple mononeuropathies in 143 subjects,14–16,21,31,34,35,41,53,61,79,82,92,95,98,100,102 and polyneuropathy in 202 subjects.16,25,26,28,31,38,40,42–44,48,49,51,52,55,56,68,71,72,76,80,81,86,88–91,94,96,104, 105,109–111,114,115,117,120 When neuropathies were assessed based on small and large fibers, the most common type found was small fiber neuropathy (n = 556),9–16,18,19,21–24, 26,27,29–31,34,35,38,41,43,44,46–51,53,55,57,58,62–64,66–70,73,74,77–79,83,87,92,95, 97–104,106,109,111,113,118,120 whereas large fiber neuropathy was found in 231 subjects (data not shown).8,16,17,21,25,26,28,31–33,37,39–42,48,49,52,56,59–61, 65,68,71,72,74,76,79–82,84–86,88–92,94,96,98,100,102,105,110,115,120

Risk factors. The most frequent risk factor for compression neuropathy in SSc was calcinosis cutis.17,72,88 Risk factors for noncompression neuropathies include advanced diffuse disease, anticentromere antibodies, ischemia of the vasa nervorum, iron deficiency anemia, reduced nerve density, metoclopramide, pembrolizumab, silicosis, and uremia (Table 2).

View this table:
Table 2.

Risk factors for noncompression peripheral neuropathy in SSc.

Treatment. There were 68 patients with reported success of treatments in the literature, including 41 patients who had success in restoring sensation.8,11,14,15,17,23,34,40,42,43,48,56,60,64,73,74,84,88,90,91,101 These patients had CTS, brachial plexopathy, optic neuropathy, ulnar nerve compression, trigeminal neuropathy, axonal sensory neuropathy, lumbosacral plexopathy, cervical radiculopathy, and cauda equina. Thirty-three patients had improvement in motor or sensorimotor neuropathies.31,37,40,64,75,88,91,94,107,115 These patients had neuromyotonia, CTS, 4th nerve palsy, lumbosacral plexopathy, cauda equina, and gastric myoelectric activity abnormalities (Table 3). Out of the 68 patients, 17 had documented successful surgeries (14 for sensory neuropathies11,17,34,40,43,60,64,74,84,90,91 and 3 for sensorimotor40,64,91), and all the surgeries were performed on neuropathies caused by nerve compression.17,31,34,40,43,47,60,72,74,84,90,91,118

View this table:
Table 3.

Treatment of compression peripheral neuropathy in systemic sclerosis and outcomes.

Immunosuppression was the treatment of choice for noncompression neuropathies caused by tissue edema, vasculitis, and microangiopathy.8,15,21,32,34,39,40,73,88,94 The most commonly used medication in cases of neuropathy with successful outcomes was prednisone (n = 11), where it was used in 7 patients with sensory neuropathies (5 as monotherapy,34,48,73,88 1 in combination with cyclophosphamide [CYC],8 and 1 in combination with azathioprine15), and in 4 patients with motor neuropathies (3 as monotherapy31,88,94 and 1 in combination with CYC75). Only complete resolution of symptoms was considered a successful outcome. CYC use was reported in 4 case reports.8,65,75,119 Nonimmunosuppressive therapy for noncompression neuropathies included amitriptyline, pregabalin, gabapentin, tricyclic antidepressants, and transcutaneous electrical nerve stimulation. Treatments for compression and noncompression peripheral neuropathies are summarized in Tables 3 and 4.

View this table:
Table 4.

Treatment of noncompression peripheral neuropathy in systemic sclerosis and outcomes.

Metaanalysis. The pooled prevalence of neuropathy using the random effects model was 27.37% (95% CI 22.35–32.70) with the 95% prediction interval of 17.54–38.47%. The I2 was 19% (95% CI 0.00–58.50) with P = 0.27. Results are presented in a forest plot (Figure 2). Egger test (P = 0.65) and funnel plot showed that publication bias was not an issue in this research. The results of the Fail Safe N method (N = 1720, P = 0.05) further suggest that the conclusion of our metaanalysis may not be susceptible to publication bias. We tested different moderators (sex, publication year, age, duration of disease, and study design) to explain the 19% heterogeneity. Results of metaregression showed that collectively the amount of heterogeneity explained by all these moderators was R2 = 98.77%, but overall the tests for moderators was not significant (P = 0.67). When multimodel inference was applied to observe which predictors were important, results showed that age was the most important predictor of neuropathy, followed by male sex, then female sex, and last, duration of disease.

Forest plot of random effects model showing the pooled prevalence and prediction interval.
Figure 2.

Forest plot of random effects model showing the pooled prevalence and prediction interval.

DISCUSSION

Our study synthesizes the literature on the epidemiology and treatment of peripheral neuropathy in SSc. First, we found that peripheral neuropathy is not uncommon in SSc, with a pooled prevalence of 27.37%. Compared to a general population prevalence of 2–8%, peripheral neuropathy appears to occur more frequently in SSc. Peripheral neuropathy in SSc has several different etiologies including nerve compression by soft tissue swelling, tissue fibrosis or calcinosis cutis, traumatic injury, medication adverse effects, metabolic sequelae, and ischemia. Peripheral neuropathy was detected mostly in the first decade of the disease course (mean 8.85 yrs from the onset of SSc). Modalities most frequently used to detect peripheral neuropathy in SSc were physical examination, NCS, electromyography, and biopsy.

Peripheral neuropathy in the context of SSc can be categorized as compression or noncompression neuropathies. Calcinosis was the most-reported cause of compression neuropathy, but other causes of compression included soft tissue thickening, edema, and fibrosis. The most common entrapment neuropathy in SSc was CTS, which may present prior to the diagnosis of SSc. Compression neuropathies were mostly successful when treated by surgical decompression. Compression neuropathies, such as CTS, are well recognized in SSc and treatment well established.

In contrast, noncompression peripheral neuropathies in SSc may occur secondary to traumatic injury, adverse effects of medication, metabolic sequelae, or ischemia, and therefore have different risk factors. The noncompression peripheral polyneuropathies, consisting of sensory, mixed sensory and motor, and mononeuritis multiplex, were more common in dSSc. A symmetric, sensory polyneuropathy was the noncompression neuropathy most frequently associated with SSc. A number of risk factors and etiologies have been implicated in the development of noncompression peripheral neuropathy in SSc. Complications of organ damage in SSc have also resulted in peripheral neuropathy, including renal involvement with hypertensive and/or uremic neuropathy; gastrointestinal tract involvement with malabsorption and subsequent myelopathy; and vitamin E, cyanocobalamin, or calciferol deficiency.74,120 Peripheral neuropathy may also be caused by microangiopathy leading to nerve ischemia,14,21,35,53,68,73,74,88,94,120 or as a result of therapies used in SSc, such as colchicine and penicillamine.74,120

Mononeuropathy, or mononeuritis multiplex, may occur as a manifestation of vasculitis and was more frequent in patients with limited SSc. Since vasculitis is an uncommon manifestation of SSc, other overlapping diseases such as systemic lupus erythematosus, or a concomitant disease such as cryoglobulinemia due to hepatitis C infection, should be considered. Cranial neuropathies have also been reported in SSc. The most commonly involved cranial neuropathy was the trigeminal nerve, with dysfunction of the optic, oculomotor, trochlear, abducens, facial, glossopharyngeal, and auditory nerves. Symptoms of trigeminal neuropathy included slowly progressive unilateral or bilateral facial numbness, frequently with associated pain and paresthesia.

There are few reports of peripheral nerve pathology in patients with SSc. Findings include increased collagen and amorphous substance in the endoneurium, loss of myelinated fibers, intimal thickening, adventitial edema, diffuse hyalinosis of endoneurial and perineurial blood vessels, and necrotizing vasculitis (very rare).21,121,122 The treatment for compression peripheral neuropathy is most frequently decompression surgery. Medications used in the treatment of noncompressive peripheral neuropathies have included corticosteroids, CYC, amitriptyline, gabapentin, methotrexate, and anticonvulsants.

This comprehensive systematic review synthesizes what is known about the epidemiology and treatment of peripheral neuropathy on SSc. This may be of value to clinicians who face this clinical challenge. However, this study has a few limitations that should be considered. First, the literature reporting peripheral neuropathy in SSc is limited by the large number of case reports and the lack of RCTs. The literature describing the frequency of peripheral neuropathy in SSc is largely descriptive and of poor methodological quality. As a result, our estimate of the frequency of all-cause peripheral neuropathy is imprecise. Attempts to make estimates of peripheral neuropathy by etiology would be even more imprecise. Second, the studies were variable in their use of physician diagnosis or classification criteria for SSc as inclusion criteria. Nearly all the studies predated the most recent 2013 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for SSc. The main messages we wish to express is that all-cause peripheral neuropathy occurs in SSc and is not uncommon. Peripheral neuropathy in SSc warrants better investigation of epidemiology and treatment. We have found evidence of potential therapeutic benefit of immunosuppressive and anticonvulsive medications, and demonstrated clinical equipoise regarding the preferred treatment regimen.123

In conclusion, all-cause peripheral neuropathy appears to be more common in SSc than in the general population. Observational data suggest that compression neuropathies can be successfully treated with decompression surgery. The evidence supporting immunosuppressives and anticonvulsants to treat peripheral neuropathy in SSc is limited and conflicting. These data provide enough evidence of effect to justify RCTs to evaluate the efficacy of these interventions.

Footnotes

  • SRJ is supported by a Canadian Institutes of Health Research New Investigator Award, Gurmej Kaur Dhanda Scleroderma Research Award, and the Oscar and Elanor Markovitz Scleroderma Research Fund.

  • The authors declare that they have no competing interests relevant to this article.

  • Accepted for publication June 9, 2021.

This is an Open Access article, which permits use, distribution, and reproduction, without modification, provided the original article is correctly cited and is not used for commercial purposes.

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Keywords

EPIDEMIOLOGY
peripheral neuropathy
SCLERODERMA
SYSTEMIC SCLEROSIS

Keywords