Rheumatology

Molly Forlines

Mary Ann Picone

Anthony M. Iuso

Michael A. Ciaramella

Rheumatoid Arthritis and Systemic Lupus Erythematosus

Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are autoimmune diseases with rheumatologic manifestations that can often mimic the symptoms of multiple sclerosis (MS). Marrie et al recently included RA in a systematic review of epidemiological studies assessing the relation between autoimmune diseases and MS.¹ Their review included three studies (two population based) that addressed the incidence of RA in MS populations and calculated an estimated incidence of 0.21%. Additionally, they included 17 studies assessing the prevalence of RA in MS and calculated an estimated prevalence of 2.92%. Two of the studies included found the prevalence of RA before MS diagnosis to be 0.22% to 1.17%.²,³ The review also included 11 studies that assessed the relation between MS and SLE and estimated an incidence rate of SLE in MS populations to be 0.02% to 0.35% and a prevalence of 0.14% to 2.90%.¹,⁴,⁵

The analysis by Marrie et al, although not definitive, suggests that the incidence and prevalence of RA and SLE in MS is not significantly different from that of RA and SLE in the general population. However, there have been a number of similar trends found in all three autoimmune diseases. The three conditions share rheumatologic symptoms, and new evidence suggests the possibility of a similar pathogenesis between RA, SLE, and MS. Most notably, all three are significantly more likely to occur in females
than in males, particularly females of childbearing age.⁶,⁷,⁸ On a cellular level, all three are characterized by excess Th1/Th17 cytokine production, B lymphocyte involvement, and the role of tumor necrosis factor (TNF) and extracellular vesicles.³,⁹,¹⁰,¹¹

For the rheumatologist, there is a great deal of overlap between both the clinical manifestations of RA, SLE, and MS and their subsequent treatment. However, some common RA and SLE treatments can exacerbate MS symptoms and even advance the disease. The following chapter will explore the signs and symptoms of these diseases, their treatments, and the implications of some of these treatments in MS.

Rheumatoid Arthritis

RA is among the most common chronic inflammatory diseases and primarily involves the joints.¹² Like MS, RA has many extra-articular manifestations that must be considered during diagnosis and treatment, such as rheumatoid nodules, pulmonary involvement, vasculitis, and other systemic comorbidities. If left untreated, joint destruction and inflammation can lead to decreased physical function and the inability to carry out basic tasks or maintain employment.¹³ The exact etiology of RA is unknown. It appears to involve multiple cell types such as T and B cells and genes such as class II MHC genes.¹⁴

RA should be suspected if an adult patient presents with inflammatory polyarthritis. The location and duration of morning stiffness can suggest an alternative diagnosis, as patients with RA should report pain and/or stiffness in the peripheral joints (not the low back) for at least 30 minutes, with pain improving with activity.¹⁵,¹⁶ If symptoms of arthritis have been present for less than 6 weeks, they may be due to an acute viral polyarthritis rather than RA; the longer the symptoms persist, the more likely an RA diagnosis becomes. In addition to performing a complete physical examination to assess for synovitis and the presence and distribution of swollen or tender joints, the laboratory tests indicated in Table 12.1 should also be considered. Diagnosis is also confirmed by exclusion of similar diseases such as psoriatic arthritis, acute viral polyarthritis, polyarticular gout, and SLE.¹³

Systemic Lupus Erythematosus

SLE is a chronic inflammatory disease of unknown etiology that can impact virtually every organ. Like MS, SLE preferentially affects females of childbearing age and is less prominent in prepubescent and postmenopausal women, suggesting that female sex hormones may play a role in pathogenesis.⁸ Physical symptoms include mucosal ulcers, inflammatory polyarthritis, photosensitivity, and, most commonly, acute cutaneous
lupus erythema, which presents as erythema in a malar distribution over the cheeks and nose and is commonly referred to as “the butterfly rash.”17 Patients with SLE are at risk for developing neuropsychiatric manifestations, which involves depression, encephalopathy, coma, and psychosis and occurs in approximately 50% of patients with SLE.¹⁸ Like RA, SLE involves T and B cell activity and is associated with class II MHC genes.¹⁹

SLE is diagnosed based on clinical and laboratory findings, but the clinical heterogeneity and lack of pathognomonic features can deter a definitive diagnosis. Additionally, patients may present with only a few clinical indications of SLE, which often resemble other autoimmune diseases or infections.¹⁹ Demographics should be considered when evaluating a patient for SLE. Like MS, it is more common in women of childbearing age. However, MS is more common in women of European descent, whereas SLE disproportionately affects African Americans, Asians, and Hispanic Americans. In addition to routine laboratories and urinalysis, abnormalities in antinuclear antibodies, antiphospholipid antibodies, C3 and C4 or CH50 complement levels, and erythrocyte sedimentation rate and C-reactive protein levels could support a diagnosis of SLE.

How Do RA and SLE Compare With MS?

Patients with MS present with pain in the extremities but not specifically the joints.²⁰ MS is classified as an immune-mediated inflammatory demyelinating disease of the central nervous system, and clinical features are far less specific than that of RA or SLE. Patients with MS report migraines, painful tonic spasms, and neuropathic pain.²¹ The most useful diagnostic tool in support of an MS diagnosis is magnetic resonance imaging (MRI) and would demonstrate multifocal areas of demyelination with loss of oligodendrocytes and astroglial scarring. Disease progression is monitored through annual MRIs.²²

A key feature of MS is the presence of oligoclonal bands (OCBs) found in the cerebrospinal fluid (CSF) obtained during a lumbar puncture. OCBs are found in up to 95% of patients with clinically definite MS.²²,²³ A positive CSF analysis is based on the presence of OCBs or by an increased immunoglobulin G (IgG) index without an increased IgG index in blood serum; if there is an increased IgG index present in blood serum, alternative diagnoses should be considered. Apart from the presence of OCBs, the CSF appearance and pressure are normal. It should be noted that the presence of OCBs in the CSF alone is not enough to confirm a diagnosis of MS; up to 8% of CSF samples from patients without MS contain the bands.²² This is especially important given that CSF samples from patients with neuropsychiatric SLE have been shown to contain OCBs.²³ Please refer to Table 12.1 for similarities and differences in the diagnoses of these three diseases.

TABLE 12.1 DIAGNOSTIC RESULTS FOR RHEUMATOID ARTHRITIS (RA), SYSTEMIC LUPUS ERYTHEMATOSUS (SLE), AND MULTIPLE SCLEROSIS (MS)¹⁹,²²,²³,²⁴,²⁵

Test	RA	SLE	MS
Antinuclear antibody	▪ Positive in 40%-45% of patients at a dilution of 1:40 ▪ Recommended that tests be run at a dilution of 1:160	▪ Positive in virtually all patients at some time during course of disease at all dilutions ▪ If negative but suspicion of SLE high, more antibody testing necessary	▪ Insignificant at all dilutions
Rheumatoid factor (RF)	▪ Positive 50%-70% of the time ▪ Higher the titer, stronger likelihood of RA	▪ Positive in 20%-30% of patients with SLE	▪ Negative
Anti-cyclic citrullinated peptide (CCP) antibodies	▪ Positive in nearly all RA patients (>95%) ▪ Specificity for RA increases when both RF and anti-CCP are positive	▪ Negative in most patients with SLE	▪ Negative
Plain radiographs	▪ Normal early in disease ▪ Swollen joints with erosions later on	▪ Swollen joints without erosions ▪ Deformities (also present on physical examination)	▪ Unremarkable
Erythrocyte sedimentation rate and serum C-reactive protein	▪ Both elevated in RA	▪ Both elevated in SLE	▪ Unremarkable
Cerebrospinal fluid (CSF) analysis	▪ Unremarkable	▪ Oligoclonal bands found in patients with neuropsychiatric manifestations of SLE, distinguishable from those found in MS CSF analysis with antibody analysis	▪ Presence of oligoclonal bands found in 95% of patients with MS
Magnetic resonance imaging	▪ No established role in RA evaluation ▪ Could be helpful in detecting inflammatory changes or the presence of synovitis	▪ Small punctate hyperintensity focal lesions on T2-weighted images in subcortical and periventricular white matter, usual in frontal parietal regions	▪ Multifocal areas of demyelination with loss of oligodendrocytes and astroglial scarring
Electroencepha-lography	▪ No established role in RA evaluation	▪ In NPSLE, abnormal (but not specific) in 60%-91% of patients	▪ No established role in RA evaluation

Comorbidities

As demonstrated in Figure 12.1,²⁶,²⁷,²⁸,²⁹,³⁰ there is a great deal of overlap in the symptoms of these autoimmune diseases. As discussed in the chapter regarding pain in MS, determining the source of pain is necessary to determine which treatment will be the most effective.

Treatment

The primary consideration for managing the comorbidity of RA, SLE, and MS comes from balancing the effects of disease-modifying immunotherapies on each disease. Treating either of these diseases in MS requires extensive communication between the neurologist and rheumatologist regarding treatment to avoid excessive immunosuppression via disease-modifying therapies. This section will discuss both the beneficial and deleterious effects of disease-modifying antirheumatic drugs (DMARDs) and antirheumatic biologics in patients with MS (see Table 12.2 for a complete list of RA AND SLE drugs and their effect in patients with MS).

The most significant consideration in the pharmacologic management of RA in patients with MS concerns the use of anti-TNF therapies. The American College of Rheumatology (ACR) suggests using an anti-TNF therapy either alone or in combination with methotrexate once a primary DMARD (usually methotrexate) alone fails in the treatment of RA.⁴⁷
Anti-TNF therapies should not be used in the patient population with MS. Early trials using anti-TNF biologics in the patient population with MS were quickly halted owing to the finding that they worsened myelin lesions and advanced disease progression.⁴⁸,⁴⁹ It is now known that anti-TNF therapies may lead to neuroinflammation and demyelination. Anti-TNF therapies increase immune cell migration to the CNS and impair neuroprotective and regenerative functioning via inhibition of TNFR2.³¹,³²,³³,³⁴

Figure 12.1. Types of pain in multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis.

TNF is a cytokine that serves a number of important functions in homeostasis and disease pathology. The importance of TNF stems from its role as an inflammatory mediator and as a trigger of many cellular mechanisms, including induction of tissue repair, organogenesis, and inhibition of tumorigenesis. At normal physiologic levels, TNF signaling contributes to homeostasis and defense against pathogens through these mechanisms. When TNF concentrations exceed normal levels, as seen in many rheumatic diseases and cancers, it can contribute to chronic inflammation and tissue destruction. This section will focus on TNF as a target for the
treatment of rheumatic diseases and on the deleterious effect of global TNF inhibitors (TNFi) in patients with both a rheumatic disease and MS.³¹

TABLE 12.2 RHEUMATOID ARTHRITIS (RA) AND SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) DRUGS AND THEIR EFFECT ON MULTIPLE SCLEROSIS (MS) PROGRESSION³¹,³²,³³,³⁴,³⁵,³⁶,³⁷,³⁸,³⁹,⁴⁰,⁴¹,⁴²,⁴³,⁴⁴,⁴⁵,⁴⁶

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