Joint stiffness in a phantom limb: evidence of central nervous system involvement in rheumatoid arthritis

OBJECTIVE: The nature and cause of perceived joint stiffness (PJS), a well-established and defining symptom of rheumatoid arthritis (RA), remains unclear. We hypothesized that changes in the central nervous system (CNS) may determine and maintain this subjective experience of stiffness in a limb even after it is amputated. To test this hypothesis, patients with a phantom limb (PL) who had experienced characteristic RA stiffness prior to amputation were systematically investigated. METHODS: Three patients with a current diagnosis of RA and lower limb amputation were investigated to determine the nature and pattern of pain and stiffness in their PL and intact limb. In addition to standard physical examination, pain and stiffness severity was measured using visual analogue scales for both limbs. The duration and timing of stiffness were also recorded for each limb. RESULTS: In all three cases, the pattern of perceived RA stiffness was similar for the intact limb and the PL. All three patients described stiffness in their PL which mirrored that of physical RA joint symptoms in terms of quality, frequency, diurnal variation, location, distribution and response to medication [non-steroidal anti-inflammatory drug (NSAID), corticosteroid, opiate and disease-modifying anti-rheumatic drug (DMARD)]. Unilateral exercise (or attempted exercise) relieved stiffness only in the limb being exercised. CONCLUSION: The extent to which the subjective experience of perceived stiffness could be dissociated from the assumed original peripheral source was strikingly illustrated in RA patients with phantom limbs. We suggest that the PJS characteristic of RA is generated and maintained by secondary plastic changes in the CNS, although causally related to the initial peripheral rheumatoid disease process.     

Unusual central nervous system involvement of rheumatoid arthritis: successful treatment with steroid and azathioprine

Central nervous system involvement of rheumatoid arthritis (RA) frequently develops in patients who had a long-term history of RA, irrespective of the disease activity of systemic arthritis, and it has a high mortality rate despite treatment. Since clinical symptoms and radiologic signs are rather nonspecific, in short of doing biopsy, the diagnosis of rheumatoid meningitis is one of exclusion. However, the strongly positive rheumatoid factor in the cerebrospinal fluid is quite specific. We here report a 70-year-old man who had not been diagnosed as RA before he was admitted with neurological findings, who was diagnosed as RA later and successfully treated with prednisolone and azathioprine.     

An unusual central nervous system involvement in rheumatoid arthritis: combination of pachymeningitis and cerebral vasculitis

Severe primary central nervous system (CNS) involvement such as vasculitis and pachymeningitis can rarely occur in rheumatoid arthritis (RA) even in the absence of systemic disease activation. The authors illustrate a female patient with well-controlled RA who presented with headaches, encephalopathy, seizures and relapsing focal neurological deficits. Primary rheumatoid cerebral vasculitis and pachymeningitis were diagnosed based on suggestive brain magnetic resonance (MR) imaging, MR angiography, cerebrospinal fluid analysis and cerebral angiography. MR showed abnormal leptomeningeal enhancement and hyperintense FLAIR signal in the cortical subarachnoid spaces consistent with pachymeningitis. Cerebral angiography findings were consistent with vasculitis. Aggressive treatment resulted in significant clinicoradiological resolution. Cerebral vasculitis is a rare but certain manifestation of RA. This complication can be diagnosed in the presence of suggestive angiographic and CSF findings. The condition may be steroid resistant, and needs to be treated more aggressively.     

Central nervous system involvement as a major manifestation of rheumatoid arthritis

A 58-year-old woman with an 8-year history of seropositive rheumatoid arthritis was admitted with right hemiparesis, history of seizures, fever, weight loss and headaches. Her blood tests revealed the presence of rheumatoid factor, elevated C-reactive protein and anti-cyclic citrullinated peptide antibodies (>200 RU/ml). Examination of cerebrospinal fluid demonstrated pleocytosis (118 cells/mm³, predominantly lymphocytes) with elevated protein level (58 mg/dl); cultures were negative. Magnetic resonance imaging findings were suggestive for meningoencephalitis. Short course of high-dose corticosteroids and cyclophosphamide led to clinical improvement. Rheumatoid vasculitis was probably responsible for neurological symptoms.     

Anti-cyclic citrullinated peptide antibody in the cerebrospinal fluid in patients with rheumatoid arthritis who have central nervous system involvement

Clinical Rheumatology - Central nervous system (CNS) involvement, including encephalopathy, encephalitis, leptomeningitis, and pachymeningitis, in rheumatoid arthritis (RA) is rather rare. We...     

Correction to: Anti-cyclic citrullinated peptide antibody in the cerebrospinal fluid in patients with rheumatoid arthritis who have central nervous system involvement

Clinical Rheumatology - The authors regret that the original published version of the above article contained errors. The authors requested that these be noted.     

Nephropathic cystinosis with central nervous system involvement

Nephropathic cystinosis is associated with end-stage renal failure, retinal damage, and hypothyroidism. Patients may now survive past the first decade of life with the use of dialysis and renal transplantation. Examination of a 24-year-old woman with this disorder revealed ovarian failure, mildly abnormal results on a glucose tolerance test, intermittent confusion, short-term memory loss, and cerebral atrophy on computerized axial tomography. Autopsy examination at age 25 years revealed cystine storage in multiple tissues including the atrophic ovaries, pancreatic islet cells, the aorta, and the brain. Dysfunction of multiple organ systems may develop in patients with cystinosis who survive into adulthood. This emphasizes the need for a systemic therapy for cystinosis.     

Whipple's disease with destructive arthritis,abdominal lymphadenopathy,and central nervous system involvement

We describe a patient with Whipple's disease who had an unusual erosive and destructive polyarthritis, massive abdominal lymphadenopathy, asymptomatic central nervous system involvement, and rare manifestations of orbital pseudotumor and orchitis with epididymitis. Taking oral therapy with trimethoprim-sulfamethoxazole he had recurrent flares of orbital pseudotumor, an episode of orchitis with epididymitis, and persistent polymerase chain reaction T. whipplei-positive cerebrospinal fluid. Resolution was achieved with a one month course of intravenous ceftriaxone and a 6 month course of azithromycin, and no relapse occurred during 24 months of followup.     

Central nervous system involvement in rheumatoid arthritis patients and the potential implications of using biological agents

Central nervous system (CNS) involvement is quite unusual in patients with rheumatoid arthritis (RA), although cerebral vasculitis, rheumatoid nodules and meningitis have all been reported, and patients with RA may also have CNS comorbidities such as stroke and neuro-degenerative and demyelinating syndromes. It has been found that biological drugs, especially anti-tumour necrosis factor-alpha (anti-TNF-α) drugs, slightly increase the risk of developing demyelinating diseases, and they are consequently discouraged in patients with multiple sclerosis and related disorders. Furthermore, the risk of opportunistic CNS infections is increased in immunosuppressed patients.To review the current literature concerning CNS involvement in patients with RA (including RA-related forms and comorbidities) and the incidence of new-onset CNS diseases in patients with RA undergoing biological treatment (anti-TNF or non-anti-TNF drugs), the Medline database was searched using the key words ‘rheumatoid arthritis’, ‘central nervous system’, ‘anti-TNF’, ‘abatacept’, ‘tocilizumab’, ‘rituximab’ and ‘anakinra’. Abstracts not in English were excluded.We selected 76 articles published between 1989 and 2017, which were divided into four groups on the basis of whether CNS involvement was RA-related or not and according to the type of biological agent used (TNF inhibitors or other agents). The RA-related diseases included aseptic meningitis, vasculitis and cerebral rheumatoid nodules, which benefit from immunosuppressive treatments. CNS comorbidities included stroke, seizures, dementia and neuropsychiatric disorders, which have been frequently described in biological agent-naïve patients with RA, and other rarely reported neurological diseases, such as extra-pyramidal syndromes and demyelinating disorders. CNS comorbidities are relatively frequent among patients with RA and may be related to systemic inflammation or concomitant medications. The use of anti-TNF drugs is associated with the risk of developing demyelinating diseases, and CNS infections have been described in patients treated with anti-TNF and non-anti-TNF agents. Non-anti-TNF drugs may be preferred in the case of demyelinating diseases, cerebral vasculitis or neurolupus.Patients with RA may suffer from CNS involvement as a manifestation of RA or as a comorbidity. The treatment of such medical conditions should be guided on the basis of their etiopathogenesis: steroids and immunosuppressants are useful in the case of RA-related CNS diseases but are often detrimental in other situations. Similarly, the choice of biological agents in patients with RA with CNS complications should be guided by a correct diagnosis in order to prevent further complications.     

Infectious mononucleosis with severe central nervous system involvement

A case is presented of infectious mononucleosis with severe central nervous system involvement as evidenced by transitory paralyses, right homonymous hemianopia and marked rise in spinal fluid protein. Subsequently, all clinical signs and laboratory data returned to normal.     

Laryngeal involvement in rheumatoid arthritis

Laryngeal involvement was evaluated in 45 patients with moderately severe rheumatoid arthritis (RA). RA duration and severity, prior laryngeal symptoms, and abnormalities detected by concurrent indirect laryngoscopy (IL) and computerized tomography (CT) were noted and correlated with changes of basilar interstitial fibrosis (BPF) found by chest radiograph. Thirty-two percent had abnormalities detected by IL, 54% had abnormalities by CT, and 36% had BPF on chest radiographs. Comparison of these groups revealed: only two symptoms (sore throat and difficulty during inspiration) were predictive of abnormalities detected by IL; no symptoms predicted abnormalities on CT; IL and CT may show abnormalities in a large percentage of RA patients even in the absence of symptoms; IL tends to detect mucosal and gross functional abnormalities while CT detects structural lesions; BPF shown on chest radiographs in RA patients does not appear to be correlated with cricoarytenoid arthritis as defined by IL and CT.     

Pulmonary involvement in rheumatoid arthritis

The primary objective of this investigation was to assess the relationships between clinical characteristics, lung involvement, and frequency of pulmonary involvement in rheumatoid arthritis (RA). Using high-resolution computed tomography (HRCT) and pulmonary function tests (PFT), we prospectively evaluated 52 patients with RA (eight males and 44 females, mean age 53.6 years). The HRCT was abnormal in 35 patients (67.3%), the most frequent abnormalities being reticulonodular patterns, which were found in 22 patients (62.9%), ground-glass attenuation (20%), and bronchiectasis (17%). In this group of patients, PFT results were normal in 13 patients (37%). Titers of rheumatoid factor and erythrocyte sedimentation rate were significantly higher in abnormal HRCT presence. Higher Larsens score, advanced age, and severe disease were significant risk factors for lung involvement (p<0.001, p<0.01, and p<0.01, respectively) and are suggested by our data to be statistically significant predictors of lung involvement in RA.     

Laryngeal involvement in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting the synovial membrane, which causes joint damage and bone destruction. Extra-articular manifestations are numerous, involving multiple organ systems. Rheumatoid nodules are common extra-articular findings occurring in 20% RA patients. They develop most commonly in pressure areas (elbows and finger joints) and may occasionally affect internal organs including pleura, lungs, meninges, larynx, and others. Furthermore, RA affects the ear, nose, and throat, causing various otorhinolaryngological symptoms. In this report we describe two patients with RA and laryngeal involvement, mostly rheumatoid nodule formation, with a review of the literature.     

Cardiovascular involvement in rheumatoid arthritis

Cardiovascular (CV) disease morbidity and mortality are increased in patients with rheumatoid arthritis (RA) and much of the excess CV disease morbidity appears to be due to atherosclerosis. The pathogenesis of atherosclerosis (ATS) in RA is complex and there is increasing evidence that many factors including novel and traditional cardiovascular risk factors, RA treatments and the RA inflammatory disease process are involved in the development of CV disease in these patients. Of particular interest are the effects of chronic inflammation and immune dysregulation associated with RA. These have been shown to be associated with endothelial dysfunction, which is an early, potentially reversible, functional abnormality of the arterial wall. However, as several CV disease risk factors and drug prescribing are also influenced by RA disease severity it is very difficult to separate out the effects of the inflammatory disease burden on the cardiovascular system in RA.     

Heart involvement in rheumatoid arthritis

It is reported on the malignant course of a case of rheumatoid arthritis, in which the participation of the heart became the cause of death. Here it is stated that we certainly enlarge our knowledge on the participation of the heart by modern cardiological diagnostics, but therapeutically are not yet able to engage decisively in the fateful course of the systemic rheumatoid basic disease. Therefore, efforts about an early cardiologic diagnosis are at present not yet of therapeutic consequences.     

Kidney involvement in rheumatoid arthritis

Rheumatoid Arthritis (RA) is a widespread disease and its renal involvement, relatively common, is clinically significant because worsens course and mortality of the primary disease. There is still no agreement on the prevalence of renal disorders in RA: data analysis originates from different sources, as death certificates, autopsies, clinical and laboratory findings and kidney biopsies, each with its limitations. Histoimmunological studies on bioptical specimens of patients with RA and kidney damage, led to clarify prevalent pathologies. In order of frequency: glomerulonephritis and amyloidosis (60-65% and 20-30% respectively), followed by acute or chronic interstitial nephritis. Kidney injury during RA includes secondary renal amyloidosis, nephrotoxic effects of antirheumatic drugs and nephropathies as extra-articular manifestations (rheumatoid nephropathy). Amyloidosis affects survival, increases morbidity and is the main cause of end stage renal disease in patients with RA and nephropathy. Strong association between RA activity and amyloidosis needs the use of immunosuppressive and combined therapies, to prevent this complication and reduce risk of dialysis. Long-lasting and combined RA pharmacotherapy involves various renal side effects. In this review we describe NSAIDs and DMARDs (Disease-Modifying Antirheumatic Drugs) nephrotoxicity, particularly by gold compounds, D-penicillamine, cyclosporine A and methotrexate. Rare cases of IgA glomerulonephritis during immunomodulating therapy with leflunomide and TNF blocking receptor (etanercept) are reported; real clinical significance of this drug-related nephropathy will be established by development of RA treatment. In RA nephropathies, mesangial glomerulonephritis is the most frequent histological lesion (35-60 % out of biopsies from patients with urinary abnormalities and/or kidney impairment), followed by minimal change glomerulopathy (3-14%) and p-ANCA positive necrotizing crescentic glomerulonephritis.     

Imaging diagnosis of central nervous system involvement in panarteritis nodosa

Central nervous system involvement of periarteritis nodosa is a rare complication of this disease. The diagnosis of CNS manifestation in vasculitis has been improved by using imaging techniques (i.e., magnetic resonance tomography, computed tomography, positron emission tomography). A case of polyarteritis nodosa with CNS involvement is presented; the diagnostic value of magnetic resonance imaging and positron emission tomography is discussed.