Psychiatric Issues in Rheumatology

Vice-Chairman, Department of Psychiatry Professor of Psychiatry, Medicine, and Surgery, Chairman, Consultation/Liaison Psychiatry, Virginia Commonwealth University Medical Center

General Principles of Diagnosis and Assessment

The mental status examination is the most sensitive, available, and least expensive tool for assessing neuropsychiatric status in rheumatologic disorders. Neuropsychologic testing provides a more detailed, sensitive assessment of cognitive function but it is not specific to particular rheumatologic disorders. Laboratory studies help rule out infection and confirm the presence of active rheumatologic disease. High disease activity increases the likelihood of central nervous system (CNS) involvement; however, the absence of systemic disease activity does not rule out CNS involvement.

When rheumatology patients have neuropsychiatric symptoms, lumbar puncture is indicated to rule out CNS infection and assess the degree of disease activity in the CNS. In patients without CNS infection, cerebrospinal fluid (CSF) pleocytosis and increased CSF protein are suggestive of CNS involvement by SLE or other rheumatologic disease.³ CSF studies should include oligoclonal bands, which are present in only a small number of disorders, including neurosyphilis, Lyme disease, multiple sclerosis, Sjögren’s syndrome, and CNS SLE. While magnetic resonance imaging (MRI) is the best available imaging technique for identifying focal CNS lesions in patients with rheumatologic disorders and neuropsychiatric symptoms, it cannot reliably differentiate acute from old lesions.³

Psychiatric disorders, especially depression, often remain unrecognized and undertreated in patients with rheumatologic disorders due partly to a tendency to focus on the physical aspects of disease and to misperceive depression and anxiety disorders as normal reactions to chronic illness. Diagnosing depression is also complicated because there is an overlap in symptoms of depression and rheumatologic disorders (eg, fatigue, weight loss, insomnia, and lack of appetite).

General Principles of Treatment

When rheumatologic diseases affect the CNS, the primary treatment is corticosteroids when the pathophysiology is thought to be neuronal injury or inflammation resulting from autoantibodies, and anticoagulants when hypercoagulability is involved (eg, the anticardiolipin antibody syndrome). When corticosteroids are ineffective, other immunosuppressive agents may be helpful.

For primary psychiatric disorders, cognitive and behavioral psychotherapies have been effective in reducing psychologic distress and pain and improving coping and functioning in rheumatologic disorders.⁴ In choosing an antidepressant, it often makes sense to give preference to those with greater analgesic activity, ie, serotonin norepinephrine reuptake inhibitors and tricyclic antidepressants. Drug interactions with psychiatric medications are generally not a problem with current first- and second-line treatments for rheumatologic disorders.

Rheumatoid Arthritis

Rheumatoid arthritis is a chronic disorder characterized by persistent inflammatory synovitis, typically involving peripheral small joints in a symmetrical pattern, which can eventually result in destruction of the joint. Approximately one-fifth of patients with rheumatoid arthritis have a psychiatric disorder and a similar number have subsyndromal psychiatric symptoms. Neuropsychiatric manifestations in rheumatoid arthritis can arise through four processes, including direct CNS involvement, secondary effects of the illness or its treatments, emotional reactions to chronic illness, and comorbid primary psychiatric illness.

Despite the common extra-articular manifestations associated with rheumatoid arthritis, neurologic complications are not common. When present, the most common is peripheral neuropathy. Direct involvement of the CNS is rare. Atlanto-axial subluxation may occur, resulting in transverse myelitis, and is the most serious neurologic complication of rheumatoid arthritis. Vasculitis in rheumatoid arthritis can involve cerebral vessels, resulting in cerebral ischemia or infarction, and has been associated with acute and chronic brain syndromes.⁵

Most psychiatric symptoms in patients with rheumatoid arthritis are emotional reactions to having a painful potentially disabling and immobilizing chronic illness adversely affecting work, family, social life, and leisure activity. Social support that might help to offset the stress of rheumatoid arthritis may be less available because of limited mobility. Social support is important to patients with rheumatoid arthritis and is associated with use of more adaptive coping strategies, greater perception of ability to control the disease, and less psychologic distress. However, rheumatoid arthritis disrupts social networks and social support, especially in those with disease of greatest duration and disability.¹

Cross-sectional studies in rheumatoid arthritis have shown that the magnitude of depression is associated with the severity of pain and the degree of functional disability, and depression may even be an independent risk factor for mortality in rheumatoid arthritis.⁶ Depressed rheumatoid arthritis patients perceive their illness as more hopeless compared with nondepressed rheumatoid arthritis patients.⁷ The mechanisms by which depression influences pain and disability in rheumatoid arthritis are poorly understood. Although depression and psychologic stress have been shown to result in immune dysfunction, there is no evidence to suggest that depression increases the pain and disability of rheumatoid arthritis by changing the underlying inflammation. A more likely explanation lies in adverse effects of depression and anxiety on pain perception, catastrophizing and other negative illness cognitions, adherence, health-seeking behaviors, and healthcare utilization as in other chronic illnesses.¹

Systemic Lupus Erythematosus

SLE is an autoimmune disorder of unknown cause characterized by immune dysregulation with tissue damage caused by pathogenic autoantibodies, immune complexes, and T lymphocytes, with 90% of cases in women of childbearing age. SLE may involve one or multiple organ systems. Common clinical manifestations include cutaneous lesions, constitutional symptoms, arthritis, pericarditis/pleuritis, renal disease, neuropsychiatric disorders, and hematologic disorders.

CNS involvement is a major cause of morbidity and mortality in SLE. Neuropsychiatric manifestations range from stroke, seizures, headaches, neuropathy, transverse myelitis, and movement disorders to cognitive deficits, depression, mania, anxiety, psychosis, and delirium. Psychiatric syndromes in SLE can be caused by direct CNS involvement; infection, other systemic illness, or drug side effects; reaction to chronic illness; or comorbid primary psychiatric illness.^3,8

The two mechanisms of CNS injury in SLE are both mediated by antibodies; they are neuronal injury and microvasculopathy.^3,8 Antineuronal antibodies have been associated with psychosis, depression, delirium, coma, and cognitive dysfunction. In contrast, antiphospholipid antibodies cause focal deficits (strokes) and cognitive dysfunction. These two pathogenic mechanisms may be mutually reinforcing. Microvascular endothelial injury in the CNS may increase the permeability of the blood-brain barrier, leading to influx of autoantibodies and further CNS damage.

With the possible exception of cognitive dysfunction, psychiatric manifestations of SLE are mostly reversible with corticosteroid treatment. Even cognitive deficits sometimes respond to corticosteroids.⁹ However, most focal neurologic events are irreversible and some patients experience progressive cognitive impairment, often with cerebral atrophy.³

Common psychologic reactions to having SLE include grief, depression, anxiety, regression, denial, and invalidism. Social isolation is reinforced by self-consciousness about appearance and by public ignorance about SLE. Patients fear worsening disease, cognitive impairment, stroke, renal failure, becoming disabled and a burden on their families, and death.

Although stress may cause an SLE flare, it is also likely, if not inevitable, that SLE flares cause stress. It is often perceived that stress precipitates onset or exacerbation of SLE symptoms, but this has received little study. There is some evidence of stress-induced immune dysregulation in SLE.³

Psychiatric Disorders in Systemic Lupus Erythematosus

The American College of Rheumatology (ACR) developed standardized nomenclature for neuropsychiatric SLE,¹⁰ including psychiatric disorders psychosis, acute confusional state, cognitive dysfunction, anxiety disorder, and mood disorders. However, these categories do not match those in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision.¹¹

Cognitive dysfunction is the most common neuropsychiatric disorder in patients with SLE, occurring in up to 80%.^9,12 On neuropsychologic testing, even patients who have never had overt neuropsychiatric symptoms are often found to have cognitive impairment. Depression is the second most common neuropsychiatric disorder in SLE, with a prevalence of almost 50%.^3,12 Diagnosing depression in SLE is confounded by the overlap between depressive symptoms and those associated with SLE or its treatment. Anxiety is quite common in SLE patients, often as a reaction to the illness. In patients with SLE, the most common cause of mania is corticosteroid therapy. Psychosis in SLE patients can be a manifestation of direct CNS involvement, and in some but not all studies, it has been linked to antiribosomal-P antibodies. Delirium (“acute confusional state” in the ACR criteria) is common in severe SLE and is a result of CNS lupus, medications, infection, or other comorbid medical disorders. Personality changes have been reported in SLE patients whose disease has damaged the frontal or temporal lobes.

Most laboratory tests relevant to SLE (eg, serum antinuclear antibody [ANA], anti-deoxyribonucleic acid antibodies, complement levels) do not seem to correlate with CNS SLE activity. Testing for antiphospholipid antibodies (including lupus anticoagulant and anticardiolipin) is important, particularly in patients with focal symptoms, because the results may influence treatment and prognosis.¹³ Patients with antiphospholipid syndrome are treated primarily with anticoagulation rather than corticosteroid or cytotoxic therapy. Antiribosomal-P antibodies have been linked to psychosis, but have a low positive predictive value.³

Distinguishing corticosteroid-induced psychiatric reactions from a flare of CNS SLE is a well-recognized but still difficult challenge. Given the risk of untreated CNS SLE, and the likelihood that corticosteroids will alleviate such flares and only temporarily exacerbate corticosteroid-induced psychiatric reactions, an empirical initiation or increase of corticosteroids is often the most prudent intervention.³ (Corticosteroid-induced psychiatric reactions are discussed below.)

Differential Diagnosis of Neuropsychiatric Disorders in Systemic Lupus Erythematosus

The differential diagnosis of neuropsychiatric SLE includes Sjögren’s syndrome, mixed connective tissue disease, multiple sclerosis, rheumatoid arthritis, sarcoidosis, hepatitis C, polyarteritis nodosa, microscopic angiitis, temporal arteritis, Wegener’s granulomatosis, Behçet’s disease, chronic fatigue syndrome, fibromyalgia, and somatization disorder. Several cases of factitious SLE have been reported but none had serologic evidence of an autoimmune disorder.¹⁴ Drug-induced SLE has been reported with phenothiazines (particularly chlorpromazine), carbamazepine, divalproex, other anticonvulsants, and lithium, and may include positive ANAs and antiphospholipid antibodies; however, CNS manifestations are rare.³ If the offending drug is discontinued, lupus symptoms typically resolve within weeks, although the ANA may remain positive for over a year.

Osteoarthritis

Osteoarthritis is the most common joint disease, most often idiopathic and/or the result of trauma (acute or chronic), although it also may occur in a variety of metabolic and endocrine disorders. Psychologic disorders in patients with osteoarthritis arise either as a reaction to the pain, disability, and resulting life difficulties related to the osteoarthritis, or for reasons independent of the osteoarthritis.

Osteoarthritis appears less closely associated with depression than is rheumatoid arthritis. When depression does occur in patients with osteoarthritis, it has been associated with younger age, less education, higher pain, and greater self-reported impact of the osteoarthritis.^1,15 Anxiety and hopelessness are associated with functional disability. Most importantly, improvement in treatment of depression in patients with osteoarthritis results in reduced pain and disability.¹⁶

Sjögren’s Syndrome

CNS involvement in Sjögren’s syndrome can be focal (cerebellar ataxia, vertigo, ophthalmoplegia, cranial nerve involvement) or diffuse (encephalopathy, aseptic meningoencephalitis, dementia, or psychiatric manifestations).¹ Focal lesions are visible on MRI and most frequently involve white matter in the frontal and temporal lobes. Cognitive deficits are common, particularly impairment in attention and concentration. Those with recognized neuropsychiatric manifestations may progress to dementia. Psychiatric manifestations usually take the form of affective disturbances (depression, hypomania) or anxiety.¹⁷

Systemic Sclerosis (Scleroderma)

While CNS damage is uncommon in systemic sclerosis, psychiatric symptoms are not, with approximately 50% of patients reporting symptoms of depression and approximately one-fifth clinically depressed. Body image dissatisfaction is common, contributing to psychologic distress and impairment.¹⁸

Temporal (Giant-Cell) Arteritis

Neuropsychiatric manifestations of temporal arteritis result from either ischemic or hemorrhagic events involving arteries supplying blood to the CNS. The clinical presentation depends on the location and extent of the insult. Resultant dysfunction can be focal (eg, stroke leading to specific motor or sensory deficit) or diffuse, resulting in impairment of consciousness. Affective symptoms are frequent and visual hallucinations are particularly common, which can progress to permanent visual loss. Treatment with high-dose steroids is indicated as soon as the diagnosis is made on clinical grounds, before results of arterial biopsy (which can be falsely negative) are available, to prevent progression of the disease resulting in irreversible blindness or other serious CNS injury.

Polymyositis

CNS vasculitis can occur in polymyositis, resulting in neuropsychiatric manifestations. As with SLE and temporal arteritis, the clinical features of neuropsychiatric involvement secondary to vasculitis depend on the site and extent of the vasculitic lesions.

Behçet’s Disease

Neuropsychiatric involvement occurs in 10% to 20% of cases of Behçet’s disease. Aseptic meningitis or meningoencephalitis may occur acutely. Later manifestations include personality change, chronic meningoencephalitis, and motor signs. Depression and anxiety are common. Dementia is common in advanced Behçet’s disease.¹⁹

Secondary Causes of Neuropsychiatric Symptoms
in Rheumatologic Disorders

Because rheumatologic disorders or their treatment may result in immunosuppression, CNS and systemic infections are common causes of neuropsychiatric symptoms. These include cryptococcal, tubercular, meningococcal, and Listeria meningitis; herpes encephalitis; neurosyphilis; CNS nocardiosis; toxoplasmosis; brain abscesses; and progressive multifocal leukoencephalopathy. Other etiologies of neuropsychiatric manifestations in rheumatologic disorders include uremia, hypertensive encephalopathy, cerebral lymphoma, and medication side effects, as well as comorbid medical or psychiatric disorders and psychologic reactions to illness.

Psychiatric side effects of selected medications used in treating rheumatologic disorders are shown in the Table. Psychiatric side effects are most common with corticosteroids; rare with methotrexate, cyclophosphamide azathioprine, leflunomide, and mycophenolate mofetil; and have not been reported with penicillamine or gold salts.

Mood disorders, including depression, mania, and mixed dysphoric episodes, are the most common psychiatric adverse event of corticosteroids, often accompanied by psychotic symptoms. Delirium and psychosis (without mood symptoms) are less common. Cognitive dysfunction also has been reported. The incidence of corticosteroid-induced psychiatric symptoms is dose related, occurring at rates of approximately 1% in patients receiving <40 mg/day of prednisone, 5% in those receiving 40–80 mg/day, and 20% in those receiving >80 mg/day.²⁰ The onset of psychiatric symptoms is usually within the first 2 weeks (and in 90%, within the first 6 weeks) of initiating or increasing corticosteroids.

Adjunctive treatment with antipsychotics, antidepressants, and mood stabilizers can be helpful, depending on the particular psychiatric symptom constellation. Tapering of corticosteroids, which may not be possible, usually leads to remission of psychiatric side effects, but too rapid tapering or discontinuation of corticosteroids can also cause adverse psychiatric and systemic effects by precipitating a flare of the rheumatologic disease, iatrogenic adrenal insufficiency, and/or even a corticosteroid withdrawal syndrome. Corticosteroid withdrawal syndrome is manifested by headache, fever, myalgias, arthralgias, weakness, anorexia, nausea, weight loss, and orthostatic hypotension, and sometimes depression, anxiety, agitation, or psychosis.²¹ Symptoms respond to an increase or resumption of corticosteroid dosage.

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