Peripheral neuropathies of the forearm and hand in rheumatoid arthritis: diagnosis and options for treatment

Although the clinical hallmark of rheumatoid arthritis (RA) involves inflammatory joint disease, extra-articular manifestations may be evident in 20% of patients. Among them neurologic features involving both the peripheral and central nervous system are one of the more common, but little has been noticed about it in clinic. The same mechanisms participating in joint destruction, synovial inflammation, and vasculitis contribute to the various RA neurological complications. In this article, we reviewed clinical outcomes of peripheral neuropathies of the upper extremity associated with RA and discussed the proper diagnosis and operative indication. Magnetic resonance imaging and electrophysiological examination are the best tools to lead the final diagnosis of nerve palsy secondary to RA synovial cyst. Such neuropathies require consideration in the differential diagnosis of wrist and hand disability. Surgical decompression is recommended at prompt timing if neurophysiologic studies demonstrate denervation or significant motor abnormalities, or sensory symptoms progress despite adequate medication.     

Thallium and arsenic poisoning in a small midwestern town

Thallium and arsenic have been used as a means of criminal poisoning. Although both manifest characteristically with peripheral neuropathies, thallium is associated with alopecia and arsenic with gastrointestinal symptoms. We describe the symptoms, physical findings, diagnostic test results, and outcomes in a group of men poisoned with thallium and arsenic. Seven patients had evidence of elevated thallium levels, and 2 patients had elevated arsenic and thallium levels. The most commonly reported symptoms included myalgias, arthralgias, paresthesias, and dysesthesias. Five patients developed alopecia. All patients with symptoms and peripheral neuropathies had characteristic blackening of their hair roots. Initially treated with dimercaptosuccinic acid, patients were switched to multiple-dose activated charcoal after testing revealed thallium poisoning. By 6 months, all patients' symptoms and peripheral neuropathies improved, but 5 patients had ongoing psychiatric problems. Thallium remains a means of criminal poisoning and should be considered in any patient with a rapidly progressing peripheral neuropathy with or without alopecia.     

Peripheral neuropathy and inborn errors of metabolism in adults

Although they are classically viewed as paediatric diseases, it is now recognized that inborn errors of metabolism (IEMs) can present at any age from childhood to adulthood. IEMs can involve the peripheral nervous system, mostly as part of a more diffuse neurological or systemic clinical picture. However, in some cases, the neuropathy can be the unique initial sign. Here, based on our personal experience and on a comprehensive literature analysis, we review IEMs causing neuropathies in adults. Diseases were classified according to the predominant type of neuropathies into (1) acute neuropathies, (2) mononeuropathy multiplex, (3) chronic axonal polyneuropathies, (4) chronic demyelinating polyneuropathies, (5) small-fibre neuropathies, and (6) lower motor neuron disease.     

Cranial and peripheral neuropathy in rheumatoid arthritis with special emphasis to II,V, VII,VIII and XI cranial nerves

Background: Cranial neuropathy in rheumatoid arthritis (RA) is relatively rare compared to the frequently reported peripheral neuropathy. Methods: We investigated the occurrence of subclinical cranial and peripheral nerve involvement in 55 patients with RA. Results: Patients had a mean age of 43.1 years and a mean duration of illness of 6.4 years. All patients presented with electrophysiological findings suggestive of peripheral neuropathy. In addition, 69.1% of them had entrapment neuropathies, in which carpal tunnel syndrome was the most common (54.6%). Sensorimotor neuropathy at sites other than usual entrapment sites was diagnosed in 70.9%, while bilateral distal sensory neuropathy in lower limbs was identified in 29.1%. Among cranial nerves examined, optic and vestibulocochlear neuropathies were common (29.1% of eyes and 40% of ears examined). Spinal accessory neuropathy was reported in 21.8% of records. Neither facial nor trigeminal nerves were affected. Electrophysiological characteristics of neuropathies were indicative of axon loss. Significant association was identified between neuropathy and patients’ ages (P < 0.01), duration of the illness (P < 0.001), presence of rheumatoid nodules (P < 0.001) and disease stages (P < 0.001). Conclusions: Our results indicate that cranial and non‐compressive neuropathies are not uncommon in RA. This extends the pathologic disease spectrum. We do not confirm, but suggest the contribution of chronic immune‐mediated vasculitis and/or neurotoxicity in RA neuropathies. Of clinical importance, subclinical neuropathy may never progress and/or be of clinical significance, which contradicts that of comparable diseases, such as systemic lupus erythematosus. Advances in genetics implicate a complex immune genetics which controls susceptibilities and adaptive molecular mechanisms as a culprit of phenotypical heterogenicity among related diseases.     

Characteristics of diffuse large B cell lymphomas in rheumatoid arthritis

OBJECTIVE: Patients with rheumatoid arthritis (RA) are at increased risk of malignant lymphomas, with a correlation between RA disease severity and lymphoma risk, most pronounced for diffuse large B cell lymphomas (DLBCLs), which also constitute the majority of RA-associated lymphomas. DLBCLs can be further subdivided into germinal center (GC)-like and non-GC-like subtypes, with different cellular origins and prognoses. This study was undertaken to investigate whether RA displays a specific association with any of the DLBCL subtypes. METHODS: We identified 139 patients with DLBCLs within a population-based case-control study of 378 RA patients with lymphoma. The DLBCLs were examined for CD10, Bcl-6, and interferon regulatory factor 4 expression patterns, subclassified into GC and non-GC subtypes, and then correlated with clinical parameters. RESULTS: We found a statistically significant predominance of the non-GC subtype (97 patients; 70% of all DLBCLs). These patients more often had an advanced stage of lymphoma at diagnosis and had a worse 5-year overall survival rate (16% versus 33%) compared with patients with the GC subtype. There was a strong association with RA disease activity in both subtypes, with >70% of the GC and non-GC cases occurring in RA patients with the highest overall disease activity scores. CONCLUSION: These findings suggest that severe RA is particularly associated with the non-GC subtype of DLBCL, and indicate a critical role of activated peripheral B cells as the cells of origin in these lymphomas.     

Beyond the joints

Although arthritis is the most notable component, rheumatoid arthritis (RA) is a systemic inflammatory disorder where extra-articular manifestations are common; among them, central and peripheral nervous system involvement is frequent and associated with significant morbidity and, in some cases, reduced life span. It may produce a myriad of symptoms and signs ranging from subtle numbness in a hand, to quadriparesis and sudden death. Central and peripheral neurologic manifestations may arise from structural damage produced by RA in diarthroidal joints, by the systemic inflammatory process of the disease itself or by the drugs used to treat it. Neurologic syndromes may appear suddenly or developed slowly through months, and emerge early or after years of having RA. Neurologic manifestations may be easily overlooked or incorrectly assigned to peripheral arthritis unless the attending physician is aware of these complications. In this article, we review neurologic involvement in RA patients with emphasis on clinical approach for early detection.     

Concomitant neurological and orthopaedic diseases in the presence of peripheral arterial disease: a prospective study

BACKGROUND: The symptoms of peripheral arterial disease (PAD) can be masked by neurological or orthopaedic diseases with identical symptoms, which may result in faulty therapy decisions, if the diagnosis is solely based on the reported complaints and angiographic or duplex ultrasonographic findings. A prospective study was therefore performed to find out how often established PAD is accompanied by neurological or orthopaedic pictures that can blend into the PAD symptoms. PATIENTS AND METHODS: The examination was performed in 235 patients with PAD of Fontaine's stages II to IV, 125 were women and 110 men; the mean age was 71 years (41 to 95 years). They were systematically examined for angiologic, neurological and orthopaedic diseases. RESULTS: 44% of the patients enrolled in the study suffered from a neurological disease, 45% from an orthopaedic disease and 24.7% from both a neurological and an orthopaedic disease. The frequency of concomitant diseases depended on the stage of PAD. In Fontaine's stage II, alterations due to arthrosis or arthritis were found in 12% of the patients, peripheral neuropathies in 14%, radiculoneuropathies in 16% and malpositions of the foot in 16%. In Fontaine's stage III, arthrosis and arthritis were predominant at a percentage of 38.5%; peripheral neuropathies were diagnosed in 15.4% of the patients. Patients with Fontaine's stage IV most often showed peripheral polyneuropathies at 42.1% and malpositions of the foot at 28.4%. CONCLUSIONS: Because of the frequency of neurological and orthopaedic pictures with identical symptoms, a differential diagnosis before the initiation of a PAD therapy is imperative.     

Oesophageal motor activity in rheumatoid arthritis: a clinical and manometric study

Oesophageal motor function was clinically and manometrically investigated by means of a low-compliance system in 24 nonselected rheumatoid arthritis (RA) patients and 15 healthy controls. Dysphagia was referred by 37.5% of RA patients. Oesophageal motor abnormalities were discovered to be significantly present in a high percentage (62.5%) of patients with RA. However, there was no correlation between oesophageal motor abnormalities and any disease characteristic. It is concluded that a high percentage of RA patients have an oesophageal motor dysfunction, even in the absence of dysphagic symptoms.     

A case of rheumatoid nodule formation within the central nervous system and review of the literature

We describe nodule formation within the central nervous system (CNS) in a patient with seropositive rheumatoid arthritis (RA). Review of 13 previous reports of CNS rheumatoid nodule formation suggests that the clinical course is usually one of longstanding seropositive disease. Correlation of neurologic signs and symptoms with anatomic lesions has frequently been tenuous. We conclude that CNS nodules are a rare extraarticular feature of RA which, although often of uncertain clinical significance, should be considered as a possible etiology when neurologic dysfunction occurs in the RA patient.     

Chronic widespread pain in the spectrum of rheumatological diseases

Fibromyalgia (FM) is a rheumatic disease characterised by musculoskeletal pain, chronic diffuse tension and/or stiffness in joints and muscles, fatigue, sleep and emotional disturbances and pressure pain sensitivity in at least 11 of 18 tender points. There are currently no instrumental tests or specific diagnostic markers, and the characteristic symptoms of the disease overlap those of many other conditions classified in a different manner. FM is often associated with other diseases that act as confounding and aggravating factors, including primary Sj?gren's syndrome (pSS), systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). It has been reported to coexist in 25% of patients with RA, 30% of patients with SLE and 50% of patients with pSS. Its clinical diagnosis is not easy because FM-like symptoms are frequent, and its differential diagnosis with other causes of chronic diffuse pain is difficult. This is even more true in the case of patients who are positive for antinuclear antibodies (ANAs) because, although sensitive, ANA positivity is not specific for SLE or connective tissue diseases, and can also be found in 10-15% of FM patients. Furthermore, composite indices such as the disease activity score (DAS)-28, which are widely used in everyday clinical practice and clinical trials, may be insufficient to evaluate real inflammatory activity in patients with RA associated with chronic pain syndromes such as FM, and can lead to an overestimate of disease activity in RA. The presence of diffuse pain in autoimmune rheumatic diseases compromises the quality of life of the patients, although overall mortality is not increased. A misdiagnosis harms the patients and the community. Rheumatologists should be able to recognise and distinguish primary and secondary FM, and need new guidelines and instruments to avoid making mistakes.     

Importance des troubles cognitifs en médecine interne : physiopathologie, évaluation,prise en charge. L’exemple du lupus systémique

Systemic diseases, which are in France mainly monitored in internal medicine, affect multiple organs or tissues. While cutaneous or articular manifestations are the most common, neurological involvement is often associated with severity. Diagnosis of peripheral (e.g, neuropathies) or central (e.g, myelitis) nervous disorders is quite easy through clinical examination and dedicated complementary tests. However, neuropsychological manifestations that affect cognition, including memory, attention, executive functions or reasoning, are difficult to diagnose, sometimes trivialized by practitioners. Their causes are often numerous and interrelated. Nevertheless, these cognitive manifestations are closely related to patients’ quality of life, affecting their social life, family dynamics and professional integration but also the treatment adherence. The purpose of this review, focused on the example of systemic lupus erythematosus, is to raise awareness of cognitive dysfunction in systemic diseases including their management from diagnosis to treatments. The final aim is to go further into setting up research groups and care programs for patients with cognitive impairment followed in internal medicine.     

Peripheral neuropathy with necrotizing vasculitis in rheumatoid arthritis

Objective. To examine the clinicopathologic features of the noncompressive neuropathies in rheumatoid arthritis (RA). Methods. We studied 32 patients with RA and peripheral neuropathy whose nerve and/or muscle biopsy specimens exhibited necrotizing vasculitis. Morphologic analysis of nerve specimens included light and electron microscopy studies and teased fiber preparation. Survival was evaluated, and the prognostic values of clinical, biologic, and pathologic features were assessed by Cox proportional hazards model. A prognostic assessment based on the significant variables was devised to estimate the probability of survival of any individual patient. Results. Epi and/or perineurial vasculitis was observed with the same frequency in the 17 patients with sensory and motor deficit and the 15 patients with sensory neuropathies and was associated with axonal degeneration of an average of 77.7% of the nerve fibers. The mean followup was 7.2 years, and the overall survival rate at 5 years was 57%. A full prolonged remission of the vasculitis was observed in 53% of the patientsrelapse occurred in 25%. The factors correlated with mortality, in decreasing order of significance, were clinical cutaneous vasculitis (P = 0.0003), neuropathy affecting 3 or 4 limbs (P = 0.03), and depressed level of C4 (P < 0.05). The prognostic assessment indicated a wide range of 5-year probabilities of survival, from <1% to 93%. Conclusion. Necrotizing vasculitis is responsible for the different patterns of noncompressive neuropathies in RA, including mononeuritis multiplex and distal symmetric sensory or sensorimotor neuropathy. Cutaneous vasculitis, multifocal neuropathy, and depressed C4 level were the 3 independent variables which best predicted mortality. We propose a prognostic assessment according to these variables, to stratify patients to receive more aggressive or less aggressive therapy.     

Neurologic manifestations of infection with human immunodeficiency virus. Clinical features and pathogenesis

Subacute encephalitis caused by infection of the central nervous system by the human immunodeficiency virus (HIV) is the most frequent cause of neurologic dysfunction in patients with the acquired immunodeficiency syndrome (AIDS). This disorder results in progressive cognitive, motor, and behavioral abnormalities in at least two thirds of patients with AIDS. Pathologic evidence of subacute encephalitis is found in 90% of these patients at autopsy. Human immunodeficiency virus is also the etiologic agent of aseptic meningitis, a disease that can occur at the time of seroconversion. Other neurologic disorders frequently associated with HIV include peripheral neuropathies and vacuolar myelopathy. Thus, HIV is neurotropic and may enter the central nervous system early in the course of infection. Neurologic disease may be the only clinical manifestation of HIV infection. Although mechanisms of pathogenesis are unclear, cells of monocyte-macrophage lineage may be important in viral spread to and within the central nervous system. Effective antiviral therapy will probably require penetration of drugs across the blood-brain barrier.     

Diagnosis and pathogenesis of CNS lupus

Summary The central nervous system (CNS) is clinically involved in approximately 40% of all systemic lupus erythematosis (SLE) patients. Minor psychiatric symptoms and abnormalities on neuropsychological testing are being detected with increasing frequency. This review summarizes current thinking concerning the diagnosis and pathogenesis of CNS lupus. The main symptoms of CNS lupus can be diffuse (generalized seizures, psychosis) or focal (stroke, peripheral neuropathies). Neuropsychiatric symptoms often occur in the first year of SLE, but are rarely the presenting symptoms of the disease. In studies on the pathology of CNS lupus, vasculopathy, infarcts and haemorrhages are often observed, whereas vasculitis is rare. Endocardial lesions and mural thrombi have also been reported in 33–50% of CNS lupus patients. In fliagnostic imaging of the CNS, magnetic resonance imaging (MRI) scans often provide evidence for edema or small infarcts, both in focal and diffuse CNS lupus, whereas computerized tomography (CT) scans only show gross abnormalitites. The first reports on position emission tomography (PET) scans in CNS lupus patients show decreased glucose uptake in the brain. The cerebral blood flow decreases during active diffuse and focal CNS lupus. The blood-brain barrier is somewhat more frequently impaired in diffuse CNS lupus. Intrathecal IgG and IgM production is observed in 25–66% of all CNS lupus patient. Various specificities of autoantibodies have been observed in CNS lupus. Of these, anticardiolipin (ACA) antibodies show a well-documented association with focal involvement of the CNS in SLE. These antibodies could cause thrombosis by interfering with the protein C pathway of fibrinolysis. In addition, they are associated with endocardial and valvular heart disease, which is often observed in SLE and which could cause ombolism. The relation between ACA and diffuse CNS lupus is not yet clear. Low-avidity anti-DNA antibodies are also found in CNS lupus, possibly because of their fross-reaction with cardiolipin. Antineuronal antibodies and lymphocytotoxic antibodies have been associated with diffuse CNS lupus and abnormalities on neuropsychological testing. However, the population of these antibodies is rather heterogeneous and it has not been possible to assess a common target antigen. Therefore, it is still obscure whether there is also a second immune-mediated mechanism responsible for the development of the diffuse form of CNS lupus.     

Findings in the peripheral motor system following stimulation of the motor nerve roots: polyradiculitis, amyotrophic lateral sclerosis and polyneuropathy

The peripheral nervous system was stimulated over the vertebral column by brief, high-voltage condenser discharges. Potentials from proximal and distal muscles were recorded. We examined healthy subjects (N = 28), patients suffering from ALS (N = 5), from polyradiculitis (N = 6), and polyneuropathies (N = 8). In ALS latencies were slightly (in most cases less than 20%), in polyradiculitis latencies were markedly increased (30-40% on average). The latencies of patients suffering from polyneuropathies showed a variable pattern of vulnerability. Moreover, we could show that this method is frequently capable to quantify deficits in the peripheral nervous system when F-waves are absent.     

Use of a chimeric monoclonal anti-CD4 antibody in patients with refractory rheumatoid arthritis

Objectives. To evaluate the safety, immunogenicity, and biologic effects of chimeric monoclonal anti-CD4 (cM-T412) in patients with refractory rheumatoid arthritis (RA), and to obtain preliminary data on the clinical response to this treatment. Methods. Twenty-five patients with active refractory RA were treated with incremental doses (10 to 700 mg) of cM-T412 in an open-label, escalating-dose phase I trial. Results. Infusion with cM-T412 was followed by an immediate, rapid decline in CD4+ T cells. The level of circulating CD4+ T cells remained depressed in most patients even at 6 months posttreatment. Following antibody infusion, proliferative responses of peripheral blood lymphocytes to mitogens and antigens were determined; mitogen and antigen responses were decreased compared with pretreatment responses. Mitogen responses tended to return to baseline values more rapidly than did responses to antigen. Adverse events included fever (19 patients), which was associated with myalgias, malaise, and asymptomatic hypotension; these symptoms were self-limited and appeared to correlate with transient elevations in interleukin-6. No significant human antibody response to the cM-T412 variable region was detected; only 2 patients developed transiently low levels of antibodies reactive with cM-T412. Significant clinical improvement, defined as ≥50% decrease in tender joint counts compared with baseline, was noted in 43% of patients at 5 weeks and 33% at 6 months following cM-T412 infusion. Conclusions. Treatment of refractory RA with cM-T412 appears to be safe and is associated with sustained decreases in circulating CD4+ T cell counts and depressed in vitro T cell responses. No significant human antichimeric antibody response was detected. Nonblinded assessment of clinical end points suggests that treatment with cM-T412 may have beneficial effects in these patients with refractory RA. A double-blind clinical trial is warranted to determine its clinical efficacy in treating RA.     

Cardiovascular and pupillary autonomic nervous dysfunction in patients with rheumatoid arthritis - a cross-sectional and longitudinal study

OBJECTIVES: Patients with inflammatory diseases often demonstrate autonomic nervous dysfunction. This study was initiated to investigate cardiovascular (CAD) or pupillary autonomic dysfunction (PAD) in patients with rheumatoid arthritis (RA). METHODS: Between 1997 and 1998, 33 RA patients were examined for characteristics, and parameters of CAD and PAD. In a longitudinal part of this study, thirty patients have been re-evaluated 8.3 +/- 0.1 yr later (response rate = 91%). RESULTS: A total of 18 patients (60%) demonstrated either CAD or PAD. The prevalence of CAD was 6/30 (20%) and the prevalence of PAD was 15/30 (50%). Of all cardiovascular tests, the Ewing test demonstrated the worst results (13/30 patients were below the 5th percentile). Similar as in other diseases, several RA patients demonstrated autonomic nervous hyperreflexia with values above the 95 th percentile (relative variation coefficient: 7/30; respiratory sinus arrhythmia measure: 12/30; Valsalva measure: 1/30; Ewing measure: 0/30; latency time of pupillary light reflex: 5/30; maximal pupillary area: 0/30). During the 8-year observation period, 4/30 RA patients died. Non-survivors as compared to survivors had increased heart rate variation in the respiratory arrhythmia test (p= 0.038, hyperreflexia) but largely decreased heart rate variation in the Ewing test (p= 0.009, hyporeflexia). Non-survivors as compared to survivors demonstrated more frequent pupillary autonomic dysfunction (100% vs. 42%, p= 0.035). CONCLUSION: This study demonstrates that CAD and PAD were frequent in patients with RA. Patients with a poor test result in the Ewing test and PAD might have an increased risk of death. This study in RA patients demonstrates similar results as in patients with diabetes mellitus.     

Hepatitis C virus and peripheral neurological complications in Egyptian patients

Background and study aimsNeurological complications in HCV-infected patients occur predominantly in the peripheral nervous system. Vasculitic neuropathy is the most firmly linked neurologic illness associated with HCV infection. This type of neuropathy occurs frequently in the presence of cryoglobulinemia. HCV-related cranial neuropathies have been also reported. This study was conducted to investigate the various peripheral neurological complications of chronic hepatitis C infection and their possible pathogenetic mechanisms.Patients and methodsThis study was conducted on 160 patients with chronic hepatitis C infection comprised two subgroups: group I, composed of 80 chronic hepatitis C patients with clinically apparent neurological complication(s), and group II, composed of 80 chronic hepatitis C patients neurologically asymptomatic. Patients were subjected to clinical evaluation, estimation of hepatitis markers, cryoglobulins, anticardiolipin antibodies, antinuclear antibodies and nerve conduction studies.ResultsPeripheral neuropathies represented the most commonly encountered neurological disorders, occurring in 25 patients (31.25%). The sensory peripheral neuropathy was the most common type, representing 32% of neuropathic patients (8/25). A statistically significant difference was found between groups I and II regarding the presence of cryoglobulin and anticardiolipin antibody, being more common in group I. Antinuclear antibody was more common in group I than in group II. Results of nerve conduction studies showed nerves were more affected in group I and in cryoglobulin and ANA positive patients.ConclusionPeripheral neuropathies represent the most common HCV-related peripheral neurological disorders especially when associated with cryoglobulins and ANA antibodies.     

Pharyngo-esophageal motility disturbances in patients with myotonic dystrophy.

BACKGROUND: Esophageal motility is often disturbed in patients with myotonic dystrophy. The esophageal motor derangement pattern and its correlation with esophageal and peripheral motor symptoms is not well defined. Our aims were to evaluate: 1) pharyngo-esophageal motor abnormalities in these patients; 2) the relationship between motor involvement and clinical manifestations; and 3) the correlation between pharyngo-esophageal motility abnormalities and peripheral neuromuscular involvement. METHODS: We compared data from 18 patients and 18 healthy controls. Neuromuscular affectation was quantified with a five-point muscular disability rating scale. Pharyngo-esophageal symptoms were assessed with a directed questionnaire, whereas motility was evaluated by means of manometry. RESULTS: Myotonic dystrophy patients had diminished pharyngeal contraction amplitude, upper esophageal sphincter basal pressure, and esophageal body contraction amplitude compared with the control group (P < 0.001). No signs of esophageal myotony were evident. Simultaneous esophageal waves after more than 40% of liquid swallows were found in 80% of patients. No relationship between esophageal manometric alteration and esophageal or peripheral motility symptoms was elicited. CONCLUSION: In patients with myotonic dystrophy pharyngo-esophageal motility is severely deranged in both amplitude and coordination. These abnormalities may be present even if symptoms referred by the patient or the severity of the disease is not remarkable.     

Balancing the autonomic nervous system to reduce inflammation in rheumatoid arthritis

Imbalance in the autonomic nervous system (ANS) has been observed in many established chronic autoimmune diseases, including rheumatoid arthritis (RA), which is a prototypic immune‐mediated inflammatory disease (IMID). We recently discovered that autonomic dysfunction precedes and predicts arthritis development in subjects at risk of developing seropositive RA. In addition, RA patients with relatively high vagus nerve tone (higher parasympathetic parameters, measured by heart rate variability) respond better to antirheumatic therapies. Together, these data suggest that the ANS may control inflammation in humans. This notion is supported by experimental studies in animal models of RA. We have found that stimulation of the so‐called cholinergic anti‐inflammatory pathway by efferent electrical vagus nerve stimulation (VNS) or pharmacological activation of the alpha7 subunit of nicotinic acetylcholine receptors (α7nAChR) improves clinical signs and symptoms of arthritis, reduces cytokine production and protects against progressive joint destruction. Conversely, increased arthritis activity was observed in alpha7nAChR knockout mice. These studies together with previous work in animal models of sepsis and other forms of inflammation provided the rationale for an experimental clinical trial in patients with RA. We could for the first time show that an implantable vagus nerve stimulator inhibits peripheral blood cytokine production in humans. VNS significantly inhibited TNF and IL‐6 production and improved RA disease severity, even in some patients with therapy‐resistant disease. This work strongly supports further studies using a bioelectronic approach to treat RA and other IMIDs.