11. If atlantoaxial subluxation is suspected, besides assessing the disease activity with DAS-28 score, for example (see Chap. 1), and peripheral joint X-ray, the status of the cervical spine should be assessed. Plain X-ray that includes lateral, anteroposterior, open mouth odontoid views and lateral fexion-extension dynamics is necessary to assess joint stability.

More advanced imaging is required for patients with neurological symptoms to assess multilevel disease. MRI is better than CT scan to evaluate the neurological structures as well as to provide better look at the ligamentous structures.

The mainstay of treatment is early surgical intervention before the onset of severe neurological dysfunction, appropriate and aggressive disease-modifying therapy to control the disease activity, and adequate rehabilitation services to optimize neurological outcome.

# **8.3.2 Neuropathy**

Neuropathy in patients with RA can result from nerve compression or secondary to vasculitis. When RA patients present with symptoms of mononeuropathy, it is essential to differentiate between neuropathy related to nerve compression and vasculitis as the treatment will be different.

Take appropriate history related to neurological complaints. The onset of symptoms, progression, and whether there is sensory and/or motor defcits should be checked. Check if the symptoms are all related to one nerve or multiple nerves (mononeuritis multiplex). Assess RA activity, severity with the presence of erosions on X-rays, functional decline, duration, and medications used for RA. On examination, try to identify the defcit and if you can which nerve is involved (Table 8.8). Examine all other peripheral nerves to assess whether it is a single or multiple processes. Examine the activity of RA and

**Table 8.8** Things to look for in common nerve involvements

assess deformity. Look for rheumatoid nodules. Nerve conduction studies (NCS) and electromyogram (EMG) will help to establish the diagnosis of nerve involvements. If it develops in a site of entrapment, e.g. carpal tunnel for median nerve and tarsal tunnel for posterior tibial nerve, the condition is most likely to be related to nerve compression rather than vasculitis and requires supportive care and may require surgical intervention. Neuropathy that develops in a noncompression site is related to vasculitis. Those patients may exhibit mononeuropathy or features of multiple nerve involvement (mononeuritis multiplex). Usually it happens in the setting of active erosive disease and with seropositive disease. Treatment with steroid should be initiated together with the use of disease-modifying therapy to achieve disease control. Patients with RA can also present with features of peripheral neuropathy that can be sensory, sensory-motor, or motor neuropathy. The approach to such patients will be discussed in the next part.

# **8.4 Neuropathy with Skin Rash**

When neuropathy either mononeuropathy, mononeuritis multiplex, or peripheral neuropathy occurs in a setting of skin rash, vasculitis should be considered as an etiological factor. Vasculitis is a condition that results from infammation of the blood vessels. It can be primary or secondary to other conditions, e.g. connective tissue disease, infection (hepatitis C), hypersensitivity reaction, and paraneoplastic condition. (See Chap. 19 for full details about vasculitis.)

Figure 8.7 shows the diagnostic approach to patient with neuropathy and rash.

# **8.4.1 Tips in History and Physical Examinations**

1. Identify the nature of neuropathy (sensory, sensory-motor, motor, mono, multiple versus peripheral).

**Fig. 8.7** Approach to patient with rash and neuropathy

# **8.4.2 Laboratory Investigations and Imaging Modalities**

# **8.4.3 Treatment**

**Acknowledgments** The Authors would like to thank Fahd M. Almalki, MD, for his contributions to this chapter in the previous edition. The authors also would like to thank Dr. Waleed Hafz for his assistance in the development of this chapter.

# **References**

lence using standardized defnitions. Neurology. 2002;58(8):1214–20.

matosus: an analysis of 14 cases and review of the literature. Ann Rheum Dis. 2000;59(2):120–4. Review

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**9**

# **Diagnostic Approach to Proximal Myopathy**

Hani Almoallim, Hadiel Albar, and Fahtima Mehdawi

# **9.1 Introduction**

Patients with muscle disorders are a diagnostic challenge to physicians, because of the various ways of presentation. A comprehensive approach should be followed systematically in order to reach the correct diagnosis. Weakness is a common symptom among patients including those with central or peripheral nervous systems diseases and those with muscular and/or neuromuscular diseases. Muscle weakness is not only a regular fnding in rheumatologic diseases, but in infammatory myopathies as well. This chapter focuses on skills needed to approach any patient that presents with weakness, specifcally proximal myopathy.

In addition to IIM and CTD, proximal myopathy has a wide range of differential diagnosis including drugs, alcohol, thyroid disease, hereditary myopathies, malignancy, and infections. Clinical assessment should aim to distinguish proximal myopathy from other conditions that present with weakness. Patients with proximal

H. Almoallim

Medical College, Umm Al-Qura University (UQU), Makkah, Saudi Arabia

H. Albar King Faisal Specialist Hospital & Research Center, Jeddah, Saudi Arabia

F. Mehdawi (\*) Doctor Soliman Fakeeh Hospital, Jeddah, Saudi Arabia

myopathy who need prompt attention, like those with cardiac, respiratory, or pharyngeal muscle involvement, should be identifed early and quickly.

In this chapter, the aim is to provide a systematic diagnostic approach to adult patients presenting with proximal myopathy. This is an essential step to establish the correct diagnosis in order to conduct the appropriate management.

# **9.1.1 Objectives**

By the end of this chapter, you will be able to:

# **9.2 Clinical Presentation of Proximal Myopathy**

Myopathies are diseases that primarily affect the muscles and are usually characterized clinically by weakness, fatigue, or stiffness. Symmetrical proximal muscle weakness, wasting, normal sensation, and normal stretch refexes are classical fndings in patients with myopathies particularly in IIM and myopathies associated with CTD. Aching muscle cramps can also occur. Clinical presentations sometimes can be complex, hence the need to follow a comprehensive approach to weakness.

# **9.2.1 History**

Weakness is a common complaint with different interpretations by patients. The aim of history taking is to try to defne what the patient means by "weakness." The generalized feeling of tiredness and/or fatigability is usually associated with systemic diseases like congestive heart failure, cirrhosis, and anemia. In these patients there is usually a long-standing history of a chronic disease like ischemic heart disease and/or chronic liver disease. The activity in these patients is usually limited by dyspnea, chest pain, joint pain, fever, and/or depressed mood. Long-standing chronic diseases can lead to cachexia with severe muscle atrophy, wasting, and consequent generalized weakness. The sense of generalized tiredness and/or fatigability should be differentiated

**Fig. 9.1** The four anatomic stations underlying lower motor neuron weakness

from the complaints of generalized body aches and pains in patients with fbromyalgia. The generalized body aches and pains have their own approach that is beyond the scope of this chapter.

Once it is established that the weakness is not a consequence of a non-muscular, generalized, systemic disease and there are no generalized body aches and pains, then it is essential to fnd out whether this weakness is localized to certain areas. Hemiparesis (weakness affecting upper and lower limbs on the same side of the body) should direct the history towards central nervous system diseases like stroke. Paraparesis (weakness of both lower limbs) and/or quadriparesis (weakness of the four body limbs) should limit the differential diagnosis to spinal cord and/or cerebral cortex and/or brain stem diseases. Monoparesis (weakness of one limb) is usually a disease of a peripheral nervous system including disc prolapse causing radiculopathy by compressing on a spinal nerve to peripheral nerve involvement in vasculitis. Figure 9.1 is a schematic that should be fol-

lowed while obtaining history and examining patients with weakness.

Symmetrical weakness occurs in large number of diseases including infammatory myositis, inherited muscle dystrophy, endocrine disorders, and neuromuscular junction diseases. In symmetrical and diffuse weakness, it is important to know if the weakness is proximal or distal. There are several clues in the history that point towards proximal myopathy (muscles of the trunk, shoulders, and thighs). The patient will have diffculty combing hair, diffculty climbing up the stairs, diffculty standing from a sitting position, and/or diffculty in getting up from bed. In distal myopathy, the patient will complain about diffculties while performing fne work like handling the objects by hands and driving. These patients may also present with wrist drop or foot drop. It must be noted that there are diseases affecting proximal muscles in an asymmetrical fashion like diabetic amyotrophy as well as diseases with both proximal and distal muscle weakness in symmetrical and/or asymmetrical fashion like in systemic lupus erythematosus (SLE) with myopathy and vasculitis, respectively. Inclusion body myositis, a rare IIM in elderly patients, presents with both proximal and distal myopathies simultaneously. The focus should be simply to identify the localization of the weakness, and then with comprehensive approach to history taking like what is described in Chap. 1, the differential diagnosis should be easier to obtain.

There are special characters for weakness that signify certain alerts to specifc diagnoses. Ascending pattern of weakness should direct the attention towards demyelinating diseases like acute infammatory demyelinating polyneuropathy (Guillain-Barre syndrome). Descending patterns that start centrally and proceed progressively to distal areas should direct the attention to infections like botulism. The weakness that is worsened by repetitive movement at the end of the day with double vision and drooping eyelids should direct the attention towards neuromuscular disorders like myasthenia gravis.

An extensive review of rheumatologic symptoms should follow; this was outlined thoroughly in Chap. 1. Detailed history of joint pain, skin rashes, fever, recent infections, bleeding tendencies, history suggestive of malignancies, and/or drug history (particularly statins and glucocorticoids) should all be obtained. Endocrine disorders should also be ruled out by reviewing common symptoms like neck swelling, diarrhea/ constipation, and heat/cold intolerance. Further details are found below. Detailed family history should be obtained as there are several rare hereditary myopathies that run in families (see below). A family history may also be present in other causes of weakness including dermatomyositis, polymyositis, and potassium-related paralyses. A thorough neurological history is important. Sensory defcits, impaired level of consciousness, speech or visual defect, seizure, and sphincter control should be obtained from patients with weakness. In addition, social history will further help narrow the diagnosis; thus, history of smoking, alcohol, illicit drug use, and exposure to toxins like organic phosphorus should be obtained.

There are life-threatening symptoms associated with IIM like dysphagia and nasal regurgitation resulting from skeletal muscle involvement of the pharynx and upper third of the esophagus and/or chest pain and heart failure from cardiac muscle involvement. These should be identifed promptly as they need urgent medical intervention. Breathlessness might suggest respiratory muscle involvement. Respiratory failure can occur in some diseases like Guillain-Barre syndrome, myasthenia gravis, and amyotrophic lateral sclerosis. Table 9.1 summarizes some of the common symptoms of diseases presenting with weakness.

# **9.2.2 Physical Examination**

The physical examination is an objective confrmation of the distribution and the severity of the muscle weakness. The frst step is to observe the patient doing certain activities like raising arms, standing up from a chair, or writing. This will determine if the weakness is proximal, distal, or combined. A comprehensive neurological examination should follow with higher function examination and examination of cranial nerves. You may fnd ptosis, ophthalmoplegia, and/or poor gag refex in myasthenia gravis patients. The next

**Table 9.1** Associated symptoms presented with muscle weakness

step is performing detailed motor examination. This starts with inspection of the muscle bulk and determining whether if it is normal, atrophied, or hypertrophied. In addition to observation for any fasciculation that might suggest LMND, tone, power, refexes, and gait should also be examined. Clear distinctions between signs of upper motor neuron disease (UMND) (hypertonia, hyperrefexia, and upgoing plantar response) and signs of LMND (for lesions from the anterior horn cell until muscles) (hypotonia, normal or low or absent refexes, and equivocal or downgoing plantar response) should be made. Usually with signs of UMND, patients may present with hemiparesis, paraparesis, and quadriparesis or with variable locations in the central nervous system as in multiple sclerosis. Since weakness is a prominent sign present in both UMND and LMND, it is essential to assess the power and document the degree of weakness, as well as for proper future monitoring of this disease while on

**Fig. 9.2** Clinical approach to weakness

treatment. Clinical approach to weakness is illustrated in Fig. 9.2. Grades of power are shown in Table 9.2.

Refexes are usually intact in proximal myopathy, and any signs of abnormal refexes suggest neurological cause. The last step in the neurological examination is examining sensory level. For example, in peripheral neuropathy loss of sensation is parallel to the weakness. After comprehensive neurological examination, a search for extra-muscular signs should follow. The examination of the face, hands, lower limbs, chest, and abdomen is important, since any abnormality can help in the differential diagnosis. Few signs of common diseases presenting with myopathy are shown in Table 9.3.

There are certain associations essential to be recognized while performing the physical examination. These associations may easily reveal the diagnosis without spending efforts on unnecessary investigations. Changes in the mental status, for example, with muscle weakness may indicate electrolyte imbalance. Cardiovascular assessment may reveal signs of cardiomyopathy, which is associated with some infammatory and heredi-

**Table 9.2** Grades of power

tary myopathies. Pulmonary assessment may reveal crackles of interstitial lung disease associated with some infammatory myopathies. Lymph node examination is essential as malignancies are associated with a signifcant number of IID including lymphoma. Small joint examination is essential as well to detect any tenderness and/or swelling suggestive of rheumatoid arthritis (RA) and/or systemic lupus erythematosus (SLE) associated myopathies. Skin examination is helpful: signs like Gottron's papules in dermatomyositis, erythema nodosum in sarcoidosis, and skin bronzing in adrenal insuffciency (see Dermatology chapter). Also a search for any signs possibly related to underlying malignancy like fnger clubbing, fecal occult blood, and hepatosplenomegaly should be made. Table 9.4 lists fndings with their most likely defnitive diagnosis. The vital signs should be measured to exclude any life-threatening problems. Postural hypotension can be seen in autonomic neuropathy, e.g., in diabetes mellitus and Lambert-Eaton syndrome. Also, body mass index (BMI) should be measured to assess if the patient is underweight suggestive of a malignant disease process.

# **9.3 Diferential Diagnosis of Proximal Myopathy**

Several conditions cause proximal myopathy. Myopathies can be classifed into idiopathic or acquired. The clinical history and physical exam-

**Table 9.3** Common signs with specifc myopathies

**Table 9.4** Correlation between fndings and suggestive diagnoses of weakness

ination are essential in identifying the presence of a myopathy and narrowing down the differential diagnosis. In adults a major cause of myopathy is medication like statins [1]. Myopathy due to endocrine causes, for example, thyroid disease, Cushing disease, and adrenal diseases, should be diagnosed promptly because treating the primary condition will result in resolution of the myopathy [2]. Infammatory diseases typically affect older adults including both proximal and steroid responsive disorders like polymyositis and dermatomyositis and distal and proximal myopathies with less response to steroid like inclusion body myositis. Rheumatologic disorders causing weakness, such as SLE and RA, can occur in young and elderly persons. Figure 9.3 summarizes the differential diagnosis of proximal myopathy. Further details about these disorders will be mentioned briefy in this section.

# **9.3.1 Toxins- and Drug-Induced Myopathy**

Considering toxin and drug exposure in the differential diagnosis of every single patient presenting with proximal myopathy is essential. The timely diagnosis allows for optimum recovery. There are many drugs that cause proximal myopathy, such as lipid-lowering drugs, glucocorticoids, antimalarial drugs, antiretroviral drugs, alcohol, and cocaine [1]. There is an acute presentation in drug-induced myopathy. Statin therapy associated with muscle problems is seen in approximately 10–25% of patients treated in clinical practice. Statin-induced myopathy can present as myalgia and myositis or sometimes is severe enough to cause rhabdomyolysis. The average onset of statin-induced myopathy is weeks to months. The only treatment is discontinuation of statin which results in resolution of muscle symptoms [3]. Glucocorticoids are a common cause of muscle weakness. Long-term use of glucocorticoids results in an insidious onset of proximal myopathy. Muscle enzymes are usually normal. Relief of the weakness occurs with lowering the dose of glucocorticoids [4]. Alcohol-induced myopathy generally follows a history of long-standing alcohol intake and/or consumption of large amount of alcohol. Table 9.5 summarizes pertinent features of the common causes of toxin- and drugs-induced myopathy.

# **9.3.2 Endocrine Myopathy**

Hormones play an essential role in body metabolism. Defciency or excess in most hormones will affect muscle metabolism. In endocrine-related muscle diseases, the presentation is more likely to be fatigue than true muscle weakness. The

**Fig. 9.3** Differential diagnosis of proximal myopathy

**Table 9.5** Features of toxin- and drug-induced myopathy

serum CK level is often normal (except in hypothyroidism). Nearly all endocrine myopathies respond to treatment [5].

Abnormalities in thyroid hormone can lead to a wide range of muscle diseases. For example, hypothyroid patients have frequent muscle complaints such as cramps, pain, and weakness. Almost one third of hypothyroid patients present with proximal myopathy. They present mainly with shoulder and hip muscle weakness. Treatment by thyroid replacement usually leads to resolution of symptoms and laboratory abnormalities [6]. Proximal myopathy is a very common presentation in hyperthyroid patients and may be the only symptom of the disease. Bulbar, respiratory, and even esophageal muscles may be affected, causing dysphagia and aspiration. Other neuromuscular disorders may occur in association with hyperthyroidism including hypokalemic periodic paralysis, myasthenia gravis, and a progressive ocular myopathy. Because proximal weakness is a presenting sign of hyperthyroidism and hypothyroidism, checking thyroid-stimulating hormone (TSH) is essential. Adrenal insuffciency causes muscle fatigue rather than true muscle weakness. Conn's syndrome can lead to proximal myopathy which is related to hypokalemia [7]. Pituitary disorders like acromegaly if long-standing can cause myopathy [8]. Neuromuscular complications of diabetes mellitus (DM) are mainly due to neuropathy which can be presented as asymmetrical proximal weakness. Ischemic infarction of the thigh muscles can present with severely uncontrolled diabetes [9] (see Chap. 21 (Diabetes and Rheumatology)). Table 9.6 summarizes pertinent fndings of myopathies caused by endocrine disorders.

# **9.3.3 Dystrophic Myopathies**

Dystrophic myopathies are a distinct group of inherited muscle disorders that generally present chronically. They are slowly progressive in nature resulting in muscle atrophy with exception of metabolic myopathies, where symptoms on occasion can be precipitated acutely. Each type of dystrophic myopathy has some characteristic structural abnormalities on muscle immunohistochemistry. Congenital myopathies present predominantly in the perinatal period. Some can present later in childhood, and these children may have a milder course of the disease. Multiple gene defects can give rise to similar clinical and ultrastructural phenotypes; thus, muscle immunohistochemistry should be tested to reach a fnal diagnosis. Table 9.7 shows the features of dystrophic myopathy [10].

# **9.3.4 Infammatory Myopathies**

Infammatory myopathies are a group of complex diseases of unknown etiology. The most common types are dermatomyositis, polymyositis, and inclusion body myositis. Table 9.8 represents the current classifcation for IIM. The incidence of infammatory myopathies is 5–10/million cases per year [11]. These diseases are characterized by progressive muscle weakness with extramuscular organ involvement and high serum muscle enzymes. Generally there is a female predominance 2:1, but in inclusion body myositis, the opposite is seen as it is three times more common in males [12]. The main pathophysiology is related to autoimmunity, though recent studies show that the mechanism of muscle damage is multiple and complex [13].

The clinical features of infammatory myopathy in general are muscle weakness occurring within weeks to months. The distribution of weakness is mainly proximal in dermatomyositis and polymyositis, but as the disease progresses, distal muscles may become affected. On the other hand, distal muscle weakness is the initial presentation of inclusion body myositis. The onset of polymyositis is usually after the second decade of life. Dermatomyositis has two peaks, the frst peak at around 10–15 years of age and the second peak between 40 and 70 years. Inclusion body myositis occurs after the age of 50. Table 9.9 summarizes the pathological and clinical features of the most common IID.

Dermatomyositis is known for its cutaneous manifestations. The rashes can precede, follow, or occur simultaneously with the myopathy.

**Table 9.6** Pathophysiology and characteristics of endocrine myopathies

Gottron's papules and heliotrope rash are pathognomonic features of dermatomyositis [14]. Dermatomyositis and polymyositis are also known to cause manifestations related to the cardiovascular system, respiratory system, and gastrointestinal system.

Patients diagnosed with IID tend to have a higher risk of developing malignancies. Patients with dermatomyositis or polymyositis have an increased risk of developing malignancy. Those with dermatomyositis are three to six times more likely and those with polymyositis are two to four times more likely than the normal population to develop ovarian, gastric, pancreatic, and lung cancer and non-Hodgkin lymphoma. Thus screening for malignancies is highly recommended in this population [15].

# **9.3.5 Myopathy Due to Infectious Disease**

Infectious diseases may cause an acute presentation of weakness with muscle cramps, myoglobinuria, and rhabdomyolysis. Among the infectious causes, viral infections are the most

#### **Table 9.7** Features of dystrophic myopathy

**Table 9.8** Classifcation of idiopathic infammatory myopathies

common. Myalgia is the most common symptoms, but can last up to 2–3 weeks. Usually myopathy due to viral infections is self-limiting, but severe cases may cause myoglobinuria and renal impairment.

Human immunodefciency virus (HIV) is an important differential when approaching myopathy; the condition is often referred to as HIV polymyositis. HIV polymyositis can be a presenting manifestation of HIV infection or can occur in later stages. Patients with HIV polymyositis may present with asymptomatic elevation of CK levels, or as severe muscle tenderness and muscle weakness. HIV-related myopathy appears to have a better prognosis than idiopathic infammatory myopathies. See the treatment section for how to manage HIV polymyositis.

**Table 9.9** The pathogenetic mechanisms and clinical features of the most common IID

# **9.4 Diagnostic Approach**

A thorough history and physical examination is the cornerstone to reach the diagnosis. Investigations should be tailored to screen for reversible causes of a myopathy (Fig. 9.4).

When the cause of muscle weakness is unclear, appropriate testing should be performed, and it is recommended to start with blood tests including electrolytes (potassium, calcium, phosphate, and magnesium), thyroid-stimulating hormone (TSH) level, alkaline phosphatase and 25 (OH) vitamin D level, and HIV [16].

# **9.4.1 Muscle Enzyme**

The measurement of serum levels of muscle enzymes is of critical value for the evaluation and monitoring of muscular disorders. Creatine kinase (CK), lactate dehydrogenase (LD), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and aldolase are the serum muscle enzymes that are measured in clinical practice. In patients with suspected myopathy who do not demonstrate CK elevation, testing for aldolase can be helpful, but it is less sensitive and less specifc [17].

Approach to high level of CK is demonstrated thoroughly in Table 9.10. It must be noted that CK elevation is, however, not specifc to myopathy and further testing should be performed in a comprehensive approach. Table 9.11 shows the differential diagnosis to high CK level.

While diagnosing myocardial infarction, besides symptoms and abnormal ECG fndings, there will be rise in CK-MB, the isoenzyme of CK, electrophoretically distinguished and high in concentration in the cardiac tissue. However, it is neither specifc nor sensitive as troponins [18].

**Fig. 9.4** Approach to statin-induced myopathy

CK might be falsely elevated secondary to ethnicity (can be high in Afro-Caribbean men), exercise (can remain elevated for up to 72 h), intramuscular injections, needle electromyography (EMG), medications, hypothyroidism, and motor neuron disease [16].

# **9.4.2 Rhabdomyolysis**

Muscle injury due to vigorous exercise, medication, infection, and metabolic derangements can cause rhabdomyolysis. Severe myalgia, weakness, and red to brown urine due to myoglobinuria are classical initial presenting features. Rise of CK levels is typically seen after 2–12 h of injury and reaches its maximum within 24–72 h. A decline is usually seen within 3–5 days of cessation of muscle injury. Myoglobinuria is present in 50–75% of patients at the time of initial evaluation. Thus it is recommended to perform routine dipstick urine analysis in any patient with extremely elevated CK level and myopathy. There are serious metabolic derangements that complicate this massive muscle destruction in the body. Electrolyte imbalance and acute renal failure are serious examples.

# **9.4.3 Other Tests**

In addition to CK, to diagnose rheumatologic myopathy, erythrocyte sedimentation rate (ESR) C-reactive protein (CRP), antinuclear antibody assay (ANA), rheumatoid factor, anti-doublestranded DNA, antiphospholipid antibodies, and anti-centromere antibodies should be ordered. In case of infammatory myopathy, check for anti-Jo1 antibody, directed against histidyl-tRNA synthetase. Recognition of anti-Jo1 syndrome is important because such patients can develop extra-muscular features, such as interstitial lung disease, Raynaud's phenomenon, and arthritis [19].

**Table 9.10** Approach to high CK level

**Table 9.11** Differential diagnosis to high CK level

# **9.4.4 Electromyography (EMG)**

Electromyography (EMG) is a test that is used to record muscle electrical activity and assess the nerves that control the muscles. An abnormal electromyogram can indicate a neuropathy or neuromuscular disease. Characteristic EMG fndings of myopathy include short duration and decreased amplitude of action potential unlike neuropathies that are characterized by increased duration and amplitude of action potential. Although there are no pathognomonic features that distinguish different forms of myopathy, EMG can help distinguish infammatory from non-infammatory forms of myopathy. Normal EMG examination, however, would not exclude myopathy [18]. In case of polymyositis, the site of muscle biopsy should be opposite to where the EMG was conducted [16].

# **9.4.5 Muscle Magnetic Resonance Imaging (MRI)**

MRI evaluates deep muscles not readily accessible by EMG and plays a role in the diagnostic process by identifying subclinical signs of muscle involvement. Fat-suppressed and short tau inversion recovery techniques differentiate between active myositis, pictured as edema, and chronic inactive myositis in patients with infammatory myopathy, presented as fat [20]. A secondary role for muscle MRI is to provide information about the best site for muscle biopsy by showing which muscles are involved in the myopathic process.

# **9.4.6 Muscle Biopsy**

Establishing the diagnosis of IID is essentially based on histopathological grounds. There are currently advanced therapies that can be used effectively in these patients. The justifcation of using these drugs or even steroids should be based on muscle biopsy. Open surgical biopsy is preferable to closed needle biopsy because of the patchy nature of infammation in PM and so that adequate tissue could be obtained. However, in some circumstances, the biopsy is performed by expert radiologists. Muscle biopsy is a reliable instrument in the diagnosis of PM in 85% of the patients [18]. It is an outpatient procedure that may cause pain, bleeding, infection, or sensory loss. No special preparation is required other than that patients should discontinue using anticoagulants before the procedure [21].

The best muscles to biopsy are those moderately affected by the disease process but not atrophied. Previous sites of injections, EMG examination, or trauma should be avoided. The most common biopsy sites are the deltoid, quadriceps for proximal myopathy, and gastrocnemius for distal myopathies.

Technology using genetic markers is advancing rapidly. In infammatory myopathies, immune staining for major histocompatibility classes I and II (MHC-I/II) is upregulated in myofbrils, whereas MHC-I immune staining alone is nonspecifc [22].

# **9.4.7 Screening for Malignancy**

Idiopathic infammatory myopathies PM and DM have positive relation to malignancy; retrospective studies' results justify CT of the chest, abdomen, and pelvis in addition to age-appropriate screening tests such as colonoscopy and mammography for any patient newly diagnosed. This is shown in Southeast Asia where input of otolaryngologists is invaluable due to the higher incidence of nasopharyngeal carcinoma for DM patients. Recent advances in understanding of pathogenesis of idiopathic infammatory myopathies have led to discovery of biomarkers like type 1 interferon and myeloid cell signatures to distinguish active disease from chronic injury [17].

# **9.4.8 Genetic Testing**

Genetic testing is becoming increasingly useful in confrmation of patient with muscular dystrophies and heritable myopathies. These mutations can be identifed through peripheral blood DNA analysis. Molecular testing often eliminates the need for muscle biopsy.

# **9.5 The Management of Myopathy**

# **9.5.1 Inherited Myopathy**

For most patients with congenital myopathy or muscular dystrophy, the treatment is mainly supportive. Physical therapy, occupational therapy, management of contractures, nutrition, and genetic counseling together play a role in managing congenital myopathies. In patients with Duchenne muscular dystrophy, treatment with prednisone has been shown to improve strength and muscle bulk and slow the rate of natural progression of the disease. Patients should also be monitored over time for complications related to kyphoscoliosis or involvement of cardiac, respiratory, or bulbar muscles. Finally, genetic counseling should be offered to all patients with inherited myopathy and their family members.

# **9.5.2 Acquired Myopathy**

Management of proximal myopathy depends on underlying etiology. Treatable causes should be sought and treated accordingly. Discontinuation of offending drug is likely to improve symptoms in patients with drug-induced myopathy, e.g., statins [5]. Dose reduction should be considered for those patients in whom abrupt discontinuation of drug may not be possible, e.g., steroid myopathy [6]. In HIV-related myositis, treatment with the combination of highly active antiretroviral therapy (HAART) and steroids may be benefcial.

Treatment of IIM is largely empirical because of paucity of well-controlled trials. Current evidence is mostly based on retrospective or open prospective trials involving small numbers of patients. Corticosteroids are the cornerstone in the treatment of PM and DM [19, 20]. In the absence of placebo-controlled trials, the optimal initial dose and duration of therapy are uncertain, but patients are generally started on 0.75–1 mg/ kg body weight/day of prednisolone. Intravenous pulse methylprednisolone is initially considered for those with cardiac, respiratory, or pharyngeal muscle involvement to obtain quicker response. Because maximal improvement may not be seen for several weeks, the usual practice is to start tapering the dose of prednisolone only after about 4–12 weeks, guided by clinical improvement. Many patients relapse when corticosteroids are discontinued, and therefore, a maintenance dose of 5–10 mg/day is often required for several years. About a third of patients with PM or DM, and those with IIM, might fail to show any response to prednisolone. Second-line immunosuppressive drugs are tried in patients who do not respond to corticosteroids alone and in those with progressive disease and internal organ involvement. Choice of drug is largely empirical and depends on disease severity, extra- muscular manifestations, and personal experience of treating physician, again because of paucity of wellconducted trials.

Azathioprine [23] or methotrexate is usually preferred. Intravenous immunoglobulin (Ig), the only agent for which there is positive evidence from randomized placebo-controlled trial [21, 24], is especially useful for patients with dysphagia and treatment-resistant DM. Intravenous Ig is, however, expensive and limited in availability. Cyclophosphamide, given as monthly intravenous pulses for 3–6 months, is also an option for patients with respiratory muscle weakness, interstitial lung disease, or cardiac involvement [25]. Plasmapheresis has also been studied, but was not found to be helpful in a double-blind placebocontrolled trial [26]. Rituximab, a CD20 monoclonal antibody that depletes B cells, has been reported to have a favorable effect in small openlabel uncontrolled trials [27, 28]. A new doubleblind, placebo-phase trial in refractory adult and pediatric myositis using rituximab revealed good results [29]. Tumor necrosis factor inhibitors such as infiximab, adalimumab, and etanercept are ineffective in treating IID and may cause deterioration or trigger the disease [30]. Other biological agents that may be considered as experimental treatments include alemtuzumab, which is reportedly effective in polymyositis [31], and anti-complement C3 (eculizumab), which may be effective for the treatment of dermatomyositis. Overall, the long-term outcome of infammatory myopathies has substantially improved, with a 10-year survival rate of more than 90% . Table 9.12 shows a step-by-step approach in the management of IID [32].

Input of physiotherapist is also valuable because randomized controlled trials among patients with IIM have demonstrated that exercise therapy, adapted to the patient's condition, is

**Table 9.12** Approach to treatment of infammatory myopathies

Dalakas, Marinos C. "Infammatory muscle diseases." *New England Journal of Medicine* 372.18 (2015): 1734–1747

benefcial and safe [33]. Benefts of exercise not only include improved muscle endurance, strength, and functional abilities but also prevent muscle wasting and fbrotic contractures.

**Acknowledgments** The authors would like to thank Haytham Abbas, MD, for his contributions to this chapter in the previous edition.

# **References**

The Scientifc World Journal; 2014. https://doi. org/10.1155/2014/179180.

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# **Bones and Rheumatology**

Altaf Abdulkhaliq

# **10.1 Introduction**

Bone is a target tissue in many infammatory diseases including rheumatic diseases such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), and psoriatic arthritis.

A relationship between infammation and bone disease has been established in a variety of clinical settings and animal models of infammatory disease [1–4]. It has been established that the nature of the infammatory disease can infuence on the extent and type of bone disease and that even a small rise in the level of systemic infammation can impact on bone remodeling and increase fracture risk [5].

The infammatory joint disorders, namely, rheumatic diseases, are usually accompanied with extra-articular side effects, mainly bone loss, or osteoporosis that would result in an increased risk of fractures and deformities, which are in turn associated with increased morbidity and mortality [6]. Therefore, such types of musculoskeletal diseases are considered as one of the major causes of disability around the world and can explain the enormous cost of the musculoskeletal conditions to the community.

A. Abdulkhaliq (\*)

College of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia e-mail<EMAIL_ADDRESS>
https://doi.org/10.1007/978-981-15-8323-0\_10

H. Almoallim, M. Cheikh (eds.), *Skills in Rheumatology*,

In order to easily understand the underlying pathology and mediators that affect bones in rheumatic conditions, a brief overview on bone structure, biology, physiology, and essential molecular mechanism and signaling pathways needs to be explained clearly.

# **10.2 Objectives**

# **10.3 Bone Structures**

Bone is a dynamic and highly specialized form of connective tissue, in which the extracellular components are mineralized, thus giving the property of marked rigidity and strength while retaining some degree of elasticity. Bone represents a store of calcium and other inorganic ions

**10**

<sup>©</sup> The Author(s) 2021 209

and actively contributes to the maintenance of calcium homeostasis.

Two types of bone can be identifed macroscopically: compact or cortical bone and cancellous or trabecular bone. Microscopically both types of bone have the same histological structure. Like other supporting connective tissues, bone is composed of cells and extracellular matrix that is made up of 35% of organic component and 65% inorganic component [7]. The inorganic part consists of calcium and phosphorus in hydroxyapatite crystal form, while the organic component consists of type 1 collagen and ground substance containing proteoglycan aggregates and several specifc structural glycoproteins [8] (Fig. 10.1).

# **10.4 Bone Remodeling and Bone Cells**

Bone remodeling is the lifelong process whereby old bone is removed by bone resorbing cells and subsequently replaced by new bone via the action of bone-forming cells to maintain the bone structure. Bone remodeling occurs normally in all individuals, and in adults about 25% of trabecular and 3% of cortical bone is replaced by such process each year [9]. Bone remodeling also helps to maintain mineral homeostasis via the liberation of calcium and phosphorus into the circulation. The remodeling process occurs at discrete sites on cortical and cancellous bone surfaces and involves the integrated and sequential actions of osteoclasts (bone resorbing cells) and osteoblasts (bone-forming cells), comprising anatomic structures known as basic multicellular units (BMUs).

# **10.4.1 Bone Cells**

Mesenchymal stem cells have the potential to differentiate into various cell types including osteoblasts, chondrocytes, adipocytes, myoblasts, and fbroblasts. Determination of the fnal fate of the differentiation process is determined by and depending on the signaling transcription pathways that are activated during the initial phase of differentiation of mesenchymal progenitor cells [10, 11].

Among the important signaling pathways that are responsible to direct the differentiation into osteoblast lineage are the mitogenactivated protein kinase (MAPK) and protein kinase A (PKA)-dependent pathway [12] and Wnt-signaling pathway with its related β-catenin protein [13, 14]. Moreover, of the transcriptional factors, at least two are shown to be absolutely essential for osteoblast differentiation from mesenchymal precursors including Runx2 [15–17].

The plasma membrane of activated osteoblast is rich in alkaline phosphatase and exhibits receptors for parathyroid hormone (PTH) [18], whereas the nuclei have receptors for estrogens [19], vitamin D3 [20], and glucocorticoids [21], which all are involved in the regulation of osteoblast differentiation and activity.

Osteoblasts contribute in the synthesis and secretion of new organic part of bone matrix (but not yet mineralized), called osteoid, between the secreting osteoblast layer and in contact with older bone matrix of previously formed bone. This process is referred to as *bone apposition* and is completed by further mineralization of the newly formed bone matrix (*deposition of calcium* salts into matrix), a process regulated by osteoblast too. At the end of the secreting period of osteoblasts, those osteoblasts are embedded within the bone and differentiated into osteocytes.

*Osteoclasts* originate from hematopoietic stem cells (HSCs), precisely from cells of the colony-forming unit of macrophage (CFU-M) that differentiate to multinucleated, giant, motile cells on stimulation with macrophage colonystimulating factor (M-CSF) and receptor activator of nuclear factor-kappa B "NFkB" ligand (RANKL) (Fig. 10.2).

Firstly, the osteoclast progenitors proliferate and differentiate into mononuclear preosteoclasts and then fuse with each other to form multinucleated cells. The terminal differentiation in this lineage is characterized by acquisition of mature phenotypic markers, such as the calcitonin receptor, tartrate resistant acid phosphatase (TRAP), and integrin αvβ3 [22]. The mature and active osteoclasts are characterized by a moderate

**Fig. 10.2** Pathways regulating the development of (**a**) osteoblasts and (**b**) osteoclasts**.** Hormones, cytokines, and growth factors that control cell proliferation and differentiation are shown above the arrows. Transcription factors and other markers specifc for various stages of development are depicted below the arrows. BMPs, bone morphogenetic proteins; Wnts, wingless-type mouse mammary tumor virus integration site; PTH, parathyroid hormone; Vit D, vitamin D; IGFs, insulin-like growth factors; Runx2, Runt-related transcription factor 2; M-CSF, macrophage colony-stimulating factor; PU-1, a monocyteand B lymphocyte-specifc ets family transcription factor; NFB, nuclear factor B; TRAF, tumor necrosis factor receptor-associated factors; RANK ligand, receptor activator of NFB ligand; IL-1, interleukin-1; IL-6, interleukin-6 [24]

rough endoplasmic reticulum, a well-developed Golgi apparatus, and abundant mitochondria, while the surface of their plasma membrane facing bone matrix is having ruffed border (clear or sealing zone), which is devoid of organelles but rich in actin microflaments that form a ring of contractile protein serving to attach the cell to the bone surface via integrin receptors during the resorptive process [8]. *The clear zone* is a site of adhesion of the osteoclast to the bone matrix and creates a microenvironment where bone resorption takes place. From the ruffed border, osteoclasts secrete collagenase (and other proteolytic enzymes) and pump protons (low pH) into microenvironment and thus promoting the localized digestion of matrix and the dissolving of bone mineral (calcium salt crystal), respectively.

Several systemic and local factors have infuenced osteoclasts and their bone resorption ability. In normal physiological conditions, the osteoclast activity is highly balanced by those factors. However, in pathological conditions, this balance becomes disturbed such as during excessive activation of the immune system, due to the secretion of additional pro-infammatory cytokines, produced mainly by activated T cells [23].

# **10.4.2 The Remodeling Cycle**

The remodeling cycle is comprised of four distinct phases including activation, resorption, reversal, and formation phase (Fig. 10.3). Bone remodeling starts with activation of the lining cells via increasing the surface expression of RANKL.

*In the activation phase*, RANKL interacts with its receptor RANK, thus triggering the recruitment of osteoclast progenitors to bone where they proliferate and differentiate into osteoclasts and attach tightly to the bone matrix.

Next is *the resorption phase*, when the activated osteoclasts possess ruffed borders under which the proteolytic enzymes are secreted and the *hydrogen ions are pumped* resulting in digestion of collagens and dissolving the mineralized

**Fig. 10.3** Process and phases of normal bone remodeling [26]

matrix with the formation of a resorption cavity and allowing the release of several growth factors usually stored in the bone matrix. In addition, there is an accumulation of high concentration of calcium that directly controls osteoclasts activity resulting in cell retraction [25] and movement of osteoclasts across the bone surface to resorb a new area. At the end of this stage, osteoclasts undergo apoptosis after a life span of about 3 weeks, and thus the process of remodeling requires the continual production of osteoclast precursors.

In *the reversal phase*, the remnant debris of matrix degradation will be removed, while the released growth factors including bone morphogenetic proteins (BMPs), fbroblast growth factors (FGFs), and transforming growth factor-β (TGFβ) are likely to be responsible for recruitment of osteoblasts to cover the bottom of the resorption cavity, forming osteoid tissue until the cavity is flled.

In the fnal *formation phase* of bone remodeling, osteoblasts initially synthesize the organic matrix and then preside over its mineralization, thus completing the bone remodeling process. Toward the end of this process, some osteoblasts start to fatten and become quiescent lining cells; others become embedded in the matrix and differentiate into osteocytes, while the remaining of osteoblasts will undergo programmed cell death.

# **10.4.3 Factors Infuencing Remodeling**

The rate at which new osteoblasts and osteoclasts are supplied and the timing of apoptosis of these cells are crucial determinants of bone remodeling. The development of osteoclasts and osteoblasts is controlled by growth factors and cytokines produced in the bone marrow microenvironment and is modulated by systemic hormones and immunological mechanisms [27–30]. Certain signaling pathways, systemic hormones, pro-infammatory cytokines, and growth factors are considered as fundamental regulators of bone remodeling.

Taken together, positive stimulator of osteoblast activity includes PTH, vitamin D3, IGFs, BMPs, and Wnt signaling, while those that promote osteoclast activation are monocytemacrophage colony-stimulating factor M-CSF, RANKL, IL-1, and IL-6.

Eventually, the recent discovery of osteoprotegerin (OPG) and the subsequent identifcation of its cognate ligand, OPG ligand (OPGL or RANKL), have illuminated our understanding of the molecular basis that links between osteoblastogenesis and osteoclastogenesis and thereby the rate of bone remodeling upon which other inputs (hormonal, biomechanical, etc.) operate.

# **10.4.4 RANK/RANKL/OPG System**

Despite that the principal function of the osteoblasts is to synthesize bone matrix proteins and to enhance bone mineralization, osteoblasts also play a crucial role in osteoclast biology that has been clearly demonstrated by the release of key molecules, which regulate osteoclastogenesis and bone resorption. Of these regulators are RANKL which is expressed on the surface of the osteoblast and interact with its receptor RANK [22] to mediate signals for osteoclast proliferation, differentiation, activation, and function [31] (Fig. 10.4), while OPG is acting as a decoy receptor for RANKL [32], noting that the OPG/RANK/ RANKL system accounts only for signaling of osteoblasts to osteoclasts.

The human *RANK* is a polypeptide of 616 amino acids, related to the type 1 transmembrane protein class [33], and is expressed in various tissues such as the skeletal muscle, liver, and small and large intestines. Among bone cells RANK-mRNA is exclusively expressed in osteoclast precursor cells [22, 32]. On the other hand, *RANKL* is a TNF-related cytokine that exists in both transmembrane, the predominant form, and soluble (cleaved) forms [22]. The gene expression of RANKL can be found abundantly in the skeleton and lymphoid tissues and is produced by osteoblasts, bone marrow stromal cells, and other cells under the control of various pro-resorptive growth factors, hormones, and cytokines. Moreover, osteoblasts and stromal cells produce OPG, which binds to and thereby inactivates RANKL.

**Fig. 10.4** Mechanisms of action for OPG, RANKL, and RANK [34]

Collectively, RANKL is of great importance for the development and function of osteoclasts through binding to its transmembrane-signaling receptor RANK [35]. RANK-RANKL interactions lead to pre-osteoclast recruitment, fusion into multinucleated osteoclasts, osteoclast activation, and osteoclast survival. These effects are very selective to bone and can be inhibited by the natural, soluble, decoy receptor OPG [32].

*OPG* is considered as a humoral regulator of bone resorption. It blocks osteoclast maturation and differentiation, and subsequently it can protect the bone from both normal osteoclast remodeling and ovariectomy-associated bone loss [36].

Certain human adult tissues showed a high level of OPG mRNA expression, namely, the heart, the bone, the placenta, and the thyroid gland [37]. It has been demonstrated that OPG expression is upregulated in various human osteoblastic cell systems by 1,25-dihydroxyvitamin D3, bone morphogenetic protein-2 (BMP-2), pro-infammatory cytokines such as interleukin-1 (IL-1) [38], estrogen [39], as well as transforming growth factor-β (TGF-β) [40]. However, some discrepancies were noticed in the effect of these modulators on the expression of the OPG mRNA and OPG protein levels depending on the species of the cells used and on the stage of osteoblastic differentiation. In contrast, it has been established that glucocorticoids downregulate the OPG transcript in human osteoblast and in human marrow stromal cells [41, 42], and they can suppress OPG production resulting in acceleration of osteoclastic bone resorption [43].

# **10.5 Mediators of Bone Loss in Rheumatic Diseases**

Systemic bone loss in rheumatic diseases occurs as a result of several factors including direct effects of infammation, poor nutrition, reduced lean body mass, immobility, and the effects of therapeutic agents, specifcally glucocorticoids. These mechanisms are complex and interrelated but are eventually mediated through infuencing on the bone remodeling cycle and may result in increasing bone resorption, decreasing bone formation, but most commonly affecting both of these processes.

Adding to the referred mechanisms that cause bone loss, there are background predispos**Fig. 10.5** Risk factors for osteoporosis and fractures in infammatory rheumatic diseases [44]

ing factors, which increase the risk of fractures due to bone loss, and they include age, gender, family history of osteoporosis, low body mass index (BMI), falling risk, and sedentary lifestyle (Fig. 10.5) [44].

The following sections will discuss the main underlying mechanisms that cause bone destruction in different rheumatic conditions, namely, the disease activity (infammation), immobility, and treatment with glucocorticoids are considered. Noting that each rheumatic disease has a unique effect on articular bone or on other site on skeleton whether local or generalized bone loss, however, they remarkably share common pathways of skeletal remodeling (the RANKL/OPG pathway), which is involved in the regulation of bone resorption. In addition, most human and animal studies in the feld of rheumatic arthritis have referred to the osteoclast as the principal cell type mediating bone loss in arthritis [45].

# **10.5.1 Efects of Systemic Infammation**

Infammatory process in rheumatic diseases is usually associated with skeletal destruction. The effects of infammation in induction bone loss involve two mechanisms, the role of proinfammatory cytokines and/or the role of infammatory cells.

# **<IP_ADDRESS> Role of pro-Infammatory Cytokines**

**Fig. 10.6** Illustration of the impacts of chronic infammatory disease on bone formation and resorption. A stimulatory effect is indicated by C and an inhibitory effect by K [46]

#### **<IP_ADDRESS> Role of Infammatory Cells**

considered to have an osteoclastogenic cytokine profle [52]. The presence of this lymphocyte subset prominently in infammatory arthritis could explain the tendency to local osteoclastogenesis and thus bone destruction in this condition [53].

• A subsequent to the increased bone resorption, there should be also a stimulation of bone formation because the processes of bone resorption and formation are normally tightly coupled. However, during chronic infammation, "uncoupling" of bone formation from resorption occurs with a suppressed or decreased bone formation relative to the high degree of resorption.

# **<IP_ADDRESS> Causes of Uncoupling Process**

# **The Wnt Signaling and its Antagonist, DKK1**

Studying animal models of infammatory arthritis could explain the uncoupling process via the implication of the Wnt-signaling pathway and precisely the Wnt antagonist dickkopf-1 (DKK1), in this process [54].

The canonical Wnt-signaling pathway is essential for bone development, directing differentiation of mesenchymal precursor cells into mature osteoblasts, as well as having a major role in the normal development of the skeleton in the embryo [55, 56]. The naturally occurring soluble Wnt antagonists such as DKK1, which suppress this process, are important during normal bone remodeling. This fnding has been supported by that the DKK1 knockout mice develop an increased bone mass [57] and conversely myeloma cells with aberrant DKK1 expression are associated with purely lytic lesions with little evidence of bone formation [58].

The synovial fbroblast can secrete DKK1; however, in rheumatoid arthritis, the secretion is enhanced by TNF-α, and thus the circulating levels of DKK1 have been found much elevated in those patients [54]. Thus, the secreted DKK1 from the synovium would have a suppressive effect on osteoblast maturation and on OPG function leading to inhibition of local bone formation and increased bone resorption, respectively. Understanding the mechanism of Wnt signaling and its antagonist, DKK1 (Fig. 10.7), is very important, since administration of DKK1

**Fig. 10.7** Schematic illustration of the possible role of DKK1 in the bone remodeling imbalance in infammatory joint disease. Production of DKK1 in response to TNF-α production by infammatory cells is proposed to inhibit bone formation but increase bone resorption by osteoclasts through a suppression of OPG production by osteoblasts [46]

antibody would be able to prevent bone erosions and reverse this block on osteoblast formation which resulted in a paradoxical excess of bone formation during infammation as proved by the development of new osteophytes [54].

#### **Alteration of Glucocorticoid Signaling**

The effects of glucocorticoids will be explained later in the following sections, but the current paragraph will discuss the infuence of infammation on glucocorticoid action in bone cells. Because of the intracellular metabolism of glucocorticoids by 11b-hydroxysteroid dehydrogenases (11β-HSDs) [59], it has become known that the levels of active glucocorticoids present within the circulation differ from that in the tissues. Specifcally, 11β-HSD1 enzyme is expressed on osteoblast and can increase local glucocorticoid action in these cells by converting the inactive glucocorticoids such as cortisone and prednisone to their active counterparts' cortisol and prednisolone, respectively.

Overexpression of the enzyme in osteoblasts reduces proliferation and the synthesis of bonespecifc proteins such as osteocalcin when cells are exposed to inactive glucocorticoids [60, 61]. It was reported previously by [62] that proinfammatory cytokines such as TNF-α or IL-1b can effectively induce the expression and activity of this enzyme in osteoblasts. Thus, during infammation, osteoblasts at the site of bone exposed to pro-infammatory cytokines are likely to also be exposed to high doses of locally active glucocorticoid [62, 63]. This is potentially a major mechanism by which the uncoupling process of osteoblasts and osteoclasts occurs. Overall, a high glucocorticoid level in osteoblasts will decrease bone formation through direct effects on osteoblasts [64], but it can also induce osteoclastogenesis due to upregulation of RANKL and downregulation of OPG in osteoblast precursors [42].

Studying the correlation of locally generated glucocorticoids with other proposed mechanisms of uncoupling such as DKK1 induction is essentially needed for therapeutic purposes of rheumatic diseases.

# **10.5.2 Efects of Immobility**

Immobility has consequences on all infammatory diseases specifcally neuromuscular and joint disease. The major impact on bone occurs due to uncoupling process that results in reduced bone formation and increased bone resorption [65] with overall bone loss. It has been found that osteocytes mediates mechanosensing, which means they can response to mechanical strain and maintain bony matrix via modulation of the major pathways such as the Wnt pathway that couple bone formation and resorption [66]. This effect may partly be dependent on estrogen receptor signaling, and thus hypogonadism would reduce the mechanosensing [67].

Regular exercises can maintain force on bone and thus control bone loss through mechanical stimulation. However, a more advanced approach is the administration of a vibration signal that could stimulate mechanosensing effects, which in turn will induce an anabolic response to bone [46].

# **10.5.3 Efects of Glucocorticoids**

Glucocorticoids (GCs) are frequently prescribed for patients with variety of chronic infammatory diseases such as rheumatic diseases. An excess of circulating GCs has a major negative effects on bone [64, 68, 69]. These adverse effects on bone are owing to reduced bone formation, characterized by a low mineral apposition rate that is explained by decreased numbers of osteoblasts, while bone resorption is unchanged or even elevated [70], leading to the development of glucocorticoid-induced osteoporosis (GIOP).

Overall negative effects of GCs on bone are either directly on bone cells or indirectly by affecting the bone metabolism. The underlying molecular mechanisms of GIOP include the increased apoptosis of osteoblasts and osteocytes and increased half-life time of osteoclasts, i.e., the direct effects on bone cells (Fig. 10.8) [71]. It has been reported that the increased osteoblast apoptosis results in a signifcant reduction in bone formation, while decreased osteocyte num-

**Fig. 10.8** The direct effects of glucocorticoids on bone [71]

bers result in a disturbed osteocyte-canalicular network and thus failure to respond to bone damage [72].

The process of apoptosis is induced by activating caspase-3 [73] and glycogen synthases kinase 3β (GSK3β), which suppresses the Wnt-signaling pathway by increasing the production of DKK-1, the Wnt pathway inhibitor [74, 75].

In addition to the increased apoptosis of osteoblasts, GCs impair osteoblast function by suppressing osteoblast differentiation [76] via interfering with both the bone morphogenetic protein (BMP) pathway and the Wnt-signaling pathway.

Moreover, recent studies proposed that high doses of GCs cause a shift of bone marrow stromal cells, the precursor cells of osteoblasts, to differentiate toward adipocytes instead of osteoblasts. This is mainly achieved either through an increased expression of the peroxisome proliferator-activated receptor-γ2 (PPR- γ2) and repression of the osteogenic transcription factor Runt-related protein 2 [77] or via suppression of AP-1, a process that not only mediates anti-infammatory actions but also reduces bone strength [78].

In contrast to increased apoptosis of osteoblasts and osteocytes, GCs therapy would reduce the apoptosis of osteoclasts by extending their life span through upregulation of RANKL and suppression of OPG [42].

Likewise direct effects on osteoblasts, osteocytes, and osteoclasts, GCs have indirect effects on bone (Fig. 10.9). Previous studies asserted that GCs impair bone metabolism by inhibiting both the gastrointestinal absorption and the renal tubular reabsorption of calcium, leading to hypocalcaemia and the subsequent hyperparathyroidism [71]. Recent reports referred that GCs have infuenced the bone mineralization by decreasing the production of important proteins for matrix formation, namely, osteocalcin and type 1 collagen [69]. Furthermore, GCs can cause steroid myopathy [79] [4] that may increase the risk of falling and thus indirectly increase the fracture risk.

**Fig. 10.9** The indirect effects of glucocorticoids on bone [71]

# **10.6 Common Bone Diseases Associated with Rheumatic Disease**

**Osteoporosis-related fragility fractures** represent one of the most important complications that may occur in patients with rheumatic diseases; obviously, these fractures may contribute to an important decrease in quality of life, and hence osteoporosis becomes increasingly recognized as an eminent public health problem.

Osteoporosis is a metabolic bone disease characterized by both low bone density (mass) and low bone quality, which includes not only microarchitecture deterioration of bone tissue but also alterations in bone remodeling, damage accumulation (e.g., microfractures), and mineralization. These changes in bone density and quality enhance bone fragility with a consequent increase in fracture risk after minimal trauma. Osteoporosis is caused by an imbalance between bone formation and resorption with in favor of bone resorption over bone formation, leading to altered bone remodeling.

The reduction in bone mass can be quantifed by measurement of bone mineral density (BMD) using dual-energy x-ray absorptiometry (DXA), which is the diagnostic method of osteoporosis [80]. Therefore, osteoporosis can be defned by DXA result when T score is ≤2.5 (i.e., bone density is 2.5 standard deviation below estimated peak BMD for the population), whereas osteopenia is defned when a T score is between −1 and −2.5.

# **10.6.1 Rheumatoid Arthritis and Bone Loss**

**Rheumatoid arthritis (RA) is characterized by three types of bone lesions: periarticular osteopenia, bone erosions, and osteoporosis:**

Within 6 months of disease onset, less than 50% of patients showed radiographic erosions, while almost 70% of the patients have erosions detected by MRI [81–83] and may be accompanied by bone edema, where CD34+ cells and potential osteoclast precursors [84] can be found during joint aspiration.

• *Osteoporosis* in RA is mainly characterized by marked loss of bone in the hip and the radius, while the axial bone is scarce, a pattern not similar to that of postmenopausal osteoporosis. In addition, several cross-sectional studies reported a lower bone mineral density (BMD) in patients with RA, with a twofold increase in osteoporosis compared to age- and sex-matched controls.

# **<IP_ADDRESS> Predisposing Factor of Osteoporosis in RA**

In addition to the risk factors of osteoporosis (Fig. 10.5), other factors may also contribute in RA, such as muscle wasting, glucocorticoids therapy, and disease duration. Interaction between several factors should be considered, for example, additional muscle wasting contributes to increased immobilization [85].

#### **<IP_ADDRESS> Pathological Process**

that have been found in RA and involve in upregulating RANKL, with subsequent activation of osteoclastogenesis, include TNF-α, IL-1, IL-6, and IL-17 [88, 89].

# **<IP_ADDRESS> Management of Bone Loss in RA**

# **10.6.2 Systemic Lupus Erythematosus and Bone Loss**

# **<IP_ADDRESS> Predisposing Factors of Bone Loss in SLE**

#### **<IP_ADDRESS> Pathological Process**

• Chronic systemic infammation is a cause of bone loss in SLE, where the activated infammatory cells at sites of infammation produce a wide spectrum of cytokines that stimulate local and generalized bone resorption.

**Table 10.1** Summary of risk factors for osteoporosis in patients with SLE [101]

#### Risk factors for osteoporosis in patients with SLE

#### **Non-modifable risk factors**

#### **Modifable risk factors**

# **Risk factors specifc for systemic lupus**

#### **erythematosus**

studies showed an association between organ damage and reduced BMD [111], and because prolonged active SLE usually causes organ damage in the patients, this fnding suggests that disease activity contributes to reduced BMD in SLE. Moreover, the Hopkins Lupus Cohort study [112] has established that low complement C4 levels (a measure of active disease) were a predictor of low spine BMD among patients with SLE.

# **<IP_ADDRESS> Management of Bone Loss in SLE**

**Table 10.2** ACR 2010 Recommendations on counseling for lifestyle modifcation and assessment of patients starting glucocorticoids at any dose of >3 months duration

ACR 2010 recommendations on counseling for lifestyle modifcation

a Recommendations for calcium and vitamin D supplementation are for any dose or duration of glucocorticoids, rather than a duration of 3 months

# **10.6.3 Ankylosing Spondylitis and Bone Loss**

**Infammation in ankylosing spondylitis (AS)** is characterized by **subchondral bone marrow edema with subchondral bone** *erosive lesions* and eventually to **subchondral new** *bone formation* through the articular cartilage and ossifcation of the periarticular ligaments [85].

*Bone edema* is accounted as a sign of infammatory activity and may affect limited or extensive parts of vertebrae (Fig. 10.10). Recent studies suggested a possible sequence of events of new bone formation in AS, as follows: frst erosions at the site of infammation, followed by repair reaction, and subsequently ended by new bone formation (10).

• *For instance*, at the corners of the vertebral bodies, there might be *marginal erosive lesions* with adjacent subchondral edema and sclerosis (Romanus lesion). Also, a new periosteal intraosseous *bone formation* was found and provided the typical picture of squaring of the vertebrae [85].

**<IP_ADDRESS> Fracture Risk in AS Subsequent results to bone changes in AS lead to an increase in bone loss (osteoporosis) and bone fragility and therefore increased the risk of bone fractures.**

ing fracture, structural damage of the spine and the disease activity are other signifcant contributors to hyperkyphosis [123].

# **<IP_ADDRESS> Management of Bone Loss in AS**

**Fig. 10.10** Sites of bone edema, bone loss, and bone erosion in AS [85]

decreased in AS patients taking NSAIDs, which could relieve the infammatory back pain and stiffness and thus improving the physical activity that helped in maintaining bone mass and reducing the risk of falling and subsequent fracture [126, 127]. In addition, it has recently been suggested that NSAIDs may also inhibit the formation and growth of syndesmophytes of AS in the spine via interfering with the prostaglandin metabolism. Therefore, if the divergent inhibitory effects of NSAIDs on osteoporotic fractures (bone loss) and progression of syndesmophytes (bone formation) can be confrmed, this would be an important clue in further explaining pathophysiological mechanisms in AS.

• In contrast to the treatment of osteoporosis in patients with RA, treatment of osteoporosis in patients with AS is not yet common. Data supporting the effcacy of this treatment in AS are rare. Of all bisphosphonates, alendronate and risedronate are found to be effective in increasing BMD in men. Alendronate and risedronate signifcantly increase BMD in both vertebrae and femur, with a signifcant reduction of vertebral fractures [128, 129]. More recently teriparatide was tested with the same aims, but only a positive effect on BMD could be shown [130]. It is clear that there is a need for evidence-based knowledge in these felds in the near future. Our studies highlight the need to develop strategies to identify high-risk patients with AS. Research on the treatment of osteoporosis to prevent vertebral fractures in these patients is urgently needed.

# **10.6.4 Glucocorticoid-Induced Osteoporosis (GIOP)**

Steroids are widely used in the medical practice to treat various diseases such as asthma, systemic connective tissue diseases, and other autoimmune diseases and in addition to rheumatic diseases. Treatment with GCs results in bone loss within 1 month after initiation of the therapy but primarily occurs in the trabecular bone, so that it mainly increases the risk of vertebral fracture rather than non-vertebral fractures [79]. Fractures are considered the most clinically relevant risk of prolonged steroid therapy.

GIOP is a common type of secondary osteoporosis which occurs at any age and in both men and women. It has been known that one loss in GIOP is biphasic, with a rapid reduction in BMD of 6–12%\* which occurs followed by a slower annual loss of about 3%\* for as long as the glucocorticoids are administered [131, 132].

#### **<IP_ADDRESS> Impact of GIOP**

# **<IP_ADDRESS> Approaching Managements of Patients with GIOP**

	- Afterward, ACR 2017 recommendations have been released for GIOP prevention and treatment, based on the balance of relative benefts and harms of the treatment options and highly considering the quality

of the evidence and patients' values and preferences [138]. Therefore, due to limited evidence on the benefts and harms of interventions in GC users, most recommendations in ACR 2017 guidelines are conditional or of good clinical practice. The strength of the recommendations is based on the fracture risk categories in GC-treated patients [138].

	- Complete blood cell count.
	- Serum calcium and phosphorus.
	- Serum 25-hydroxyvitamin D.
	- Serum-free testosterone in males.
	- Estradiol in premenopausal women.
	- Renal Function Tests specifcally 24-hour urinary calcium and sodium.
	- Liver function test, because healthy liver is important for synthesis of sex hormones.

FRAX is a unique model that is considered in calculating the risk of the following factors, **age, sex, race,** family history, the BMD, and the usage of BMD, but excludes the dosage and the evaluation of the risk factors of falls and the presence or absence of prevalent vertebral deformities, although they are known as risk factors for fractures. The output of FRAX calculation is a 10-year probability of hip fracture and the 10-year probability of a major osteoporotic fracture (clinical spine, forearm, hip, or shoulder fracture) [140].

• Based on the risk factors shown in Fig. 10.11 as well as the FRAX results, adult patients receiving GC can be classifed into low-, moderate-, and high-risk categories accordingly (Fig. 10.12). The ACR 2017 recommendations for GIOP prevention and treatment have addressed, in addition to all adults' categories (< 40 years and > 40 years of age), special populations, namely children, people with organ transplants, women of childbearing potential, and people receiving very high-dose GC treatment.

• Therefore, the primary implication of ACR 2017 recommendation is to clarify that all clinicians treating patients with GCs have to be aware of the GIOP risk, identify patients at high fracture risk (Fig. 10.12), and be able to provide the appropriate treatment [138].

• Moreover, the assessment of fracture risk may not only be useful in treatment decisions, but also in improving patients' treat-

**Fig. 10.12** Fracture risk categories in GC-treated patients [138]

ment compliance that would provide the patients a better insight into their future fracture risk.

# **<IP_ADDRESS> Recommendations for Fracture Risk Assessment and Reassessment of Patient with GIOP**

These recommendations are considered as good practice recommendations.

• Initial fracture risk assessment:

**For all adults and children**, an initial clinical fracture assessment should be performed as soon within six months of the initiation of long-term GC treatment. This clinical assessment should include the following:

hypogonadism, secondary hyperparathyroidism, thyroid disease, family history of hip fracture, history of alcohol use [at > 3 units/day] or smoking), and other clinical comorbidities.

– A physical examination including measurement of weight and height, detailed examination of musculoskeletal system, and other clinical fndings of undiagnosed fracture (e.g., spinal tenderness, deformity, and reduced space between lower ribs and upper pelvis).

**For adults >40 years old**, the initial absolute fracture risk should be evaluated using FRAX with correction of GC dose and BMD (if available) as prompt as possible but within at least six months of starting the GC therapy (Fig. 10.13) [138].

**For adults <40 years old**, BMD testing should be done as promptly as possible but at least within 6 months of starting the GC treatment if the patient has a history of previous OP fracture(s) (high risk) or if the patient has

**Fig. 10.13** Initial fracture risk assessment [138]

other signifcant OP risk factors (Fig. 10.13) [138].

• Reassessment of fracture risk:

**For all adults and children**, if GC therapy is used continuously, a clinical fracture risk reassessment (as referred earlier) should be performed every 12 months. For detailed pathways of reassessment of clinical fracture risk in adults <40 and ≥40 years of age, refer to Fig. 10.14 [138].

# **<IP_ADDRESS> Recommendations for Initial Treatment and Prevention of GIOP**

• In addition to adjusting the pharmacologic treatment of GIOP, optimizing the dose of calcium and vitamin D uptake and counseling lifestyle modifcation are included within both the ACR 2010 and the ACR 2017 recommendations for treating patients with GIOP.

**Fig. 10.14** Reassessment of fracture risk [138]

	- All adults >40 years of age, they are divided into women >40 years old but not of childbearing potential, and men >40 years old, who are at moderate to high risk of fracture (Fig. 10.15).
	- Adults <40 years of age, includes (women not of childbearing potential and men) with a history of OP fracture, or those continuing GC treatment (>6 months at a dose of >7.5 mg/day), who have either a hip or spine BMD with Z score <−3 or DXA result reveals bone loss of >10%/year at the hip or spine (Fig. 10.15).
	- Special populations that have further subgroups including (Table 10.4):

Women who meet criteria for moderateto-high risk of fracture and are of childbearing potential but do not plan to become pregnant within the period of OP treatment and are using effective birth control or are not sexually active.

Adults >30 years of age who are receiving very high-dose GC treatment (initial prednisone dose of >30 mg/day [or equivalent GC exposure] and a cumulative annual dose of >5 gm) (Table 3 of main reference).

Adults who have received an organ transplant and who are continuing treatment with GCs.

GC-treated children at 4–17 years of age are further subdivided into two groups (Table 10.4).

# **<IP_ADDRESS> Rationale of Pharmacotherapy of GIOP**

**Fig. 10.15** Initial pharmacologic treatment for adults [138]. Recommended doses of calcium and vitamin D are 1000–1200 mg/day and 600–800 IU/day (serum level ≥20 ng/mL), respectively. Lifestyle modifcations include a balanced diet, maintaining weight in the recommended range, smoking cessation, regular weight-bearing and resistance training exercise, and limiting alcohol intake to 1–2 alcoholic beverages/day. Very high-dose glucocorti-

coid (GC) treatment was defned as treatment with prednisone ≥30 mg/day and a cumulative dose of >5 gm in the past year. The risk of major osteoporotic (OP) fracture calculated with the FRAX tool should be increased by 1.15, and the risk of hip fracture by 1.2, if the prednisone dose is .7.5 mg/day (e.g., if the calculated hip fracture risk is 2.0%, increase to 2.4%)

phonates but is more expensive [143] and can be used if bisphosphonate is not appropriate.

• If neither oral nor IV bisphosphonates nor teriparatide treatment is appropriate, denosumab should be used rather than the patient receiving no additional treatment beyond calcium and vitamin D. Denosumab is a humanized monoclonal antibody to RANKL and is useful for GC-treated patients with renal insult but with stable serum Ca+2 levels and are not candidates for bisphosphonates or teriparatide. Denosumab has been approved for the prevention of vertebral and non-vertebral fractures, in women with postmenopausal osteoporosis [144]. Moreover, it was revealed that denosumab therapy increased spine and hip BMD and reduced bone turnover markers for 12 months in patients received GC [145]. A recent randomized, doubleblind, comparative study of denosumab and risedronate in patients ≥19 years of age taking prednisolone ≥7.5 mg/ day for ≥3 months reported that denosumab signifcantly increased spine and femoral BMD compared to risedronate [146].

• If none of these medications is appropriate for postmenopausal women, raloxifene [selective estrogen receptor modulator (SERM)] should be used rather than the patient receiving no additional treatment beyond calcium and vitamin D. The order of the preferred treatments **Table 10.4** Recommendations for initial treatment for prevention of GIOP in special populations of patients beginning long-term GC therapy [138]

*GIOP* glucocorticoid (GC)-induced osteoporosis, *IV* intravenous

was established according to a comparison of effcacy (fracture reduction), toxicity, and cost.

# **<IP_ADDRESS> Follow-up Treatment Recommendations**

Initial treatment failure is defned if the osteoporotic fracture occurs after 18 months of treatment initiation with oral bisphosphonate or if there is signifcant BMD reduction (≥10%/year) at follow-up. Various categories of treatment failure of GIOP are explained in Table 10.5 with appropriate recommendations according to the reassessment of fracture risk status.

# **10.7 Summary**

Chronic infammatory diseases, namely, rheumatic diseases such as rheumatoid arthritis, systemic lupus erythematosus, and ankylosing spondylitis, are commonly associated with extraarticular side effects, including bone loss and fractures. Osteoporosis-related fragility fractures represent one of the most important adverse outcomes that may occur in patients with rheumatic diseases. These fractures may contribute to a signifcant decrease in quality of life and thus would have a great impact on the economic status of the society.

#### **Table 10.5** Recommendations for follow up treatment for prevention of GIOP [138]

Recommendations for follow-up treatment for prevention of GIOP according to reassessment of fracture risk Adults age ≥40 years continuing GC treatment who have had a fracture that occurred after ≥18 months of treatment with an oral bisphosphonate or who have had a signifcant loss of bone mineral density (≥10%/year) [Defnition of

Treatment Failure] Treat with another class of OP medication (teriparatide or denosumab; or, consider IV bisphosphonate if treatment failure is judged to be due to poor absorption or poor medication adherence) with calcium and vitamin D over calcium and vitamin D alone or over calcium and vitamin D and continued oral bisphosphonate. Conditional recommendation because of very low-quality evidence comparing benefts and harms of the compared treatment options in this clinical situation.

Adults age ≥40 years who have completed 5 years of oral bisphosphonate treatment and who continue GC treatment and are assessed to be at moderate-to-high risk of fracture:

 Continue active treatment, without drug holiday, (with an oral bisphosphonate beyond 5 years or switch to IV bisphosphonate [if concern with regard to adherence or absorption] or switch to an OP treatment in another class) over calcium and vitamin D alone.

 Conditional recommendation because of very low-quality data on benefts and harms in GC-treated patients, but moderate-quality data in the general OP literature on benefts and harms of continuing treatment with oral bisphosphonates past 5 years for people at high risk of fracture.

Adults age ≥40 years taking an OP medication in addition to calcium and vitamin D who discontinue GC treatment and are assessed to be at low risk of fracture:

 Discontinue the OP medication but continue calcium and vitamin D over continuing the OP medication. Conditional recommendation made by expert consensus; evidence informing it too indirect for the population and very low-quality.

Adults age ≥40 years taking an OP medication in addition to calcium and vitamin D who discontinue GC treatment and are assessed to be at moderate-to-high risk of fracture:

Complete the treatment with the OP medication over discontinuing the OP medication.

 Strong recommendation for high-risk patients based on expert consensus that patients who are at high risk should continue an OP treatment in addition to calcium and vitamin D.

 Conditional recommendation for moderate-risk patients because of lower fracture risk compared to potential harms.

The concept of osteoimmunology elucidates in depth the links between the immune system and bone physiology. The predisposing factors that cause the underlying pathology of bone loss in rheumatic patients are multifactorial. In addition to the traditional background fracture risks, such as age, BMI, and gender, there are potential bone loss mediators that substantially increase fracture risk in these patients. Of these common mediators are infammation (high disease activity), immobility, and treatment with glucocorticoids. Other mediators would contribute in bone loss in rheumatic patients and may include poor nutrition, the increase of catabolic state, and the decrease in reproductive hormones (hypogonadism) in both men and women.

These effector mediators appear to interact in a complex and synergistic way to reinforce each other through various mechanisms that act on a shared common pathway, the bone remodeling cycle. The net result of these mediators is the production of a wide spectrum of cytokines that stimulate local and/or generalized bone resorption and that inhibit (as in RA) or stimulate (as in AS) bone formation. For instance, during the infammatory process, the Wnt-signaling antagonist (DKK-1) is secreted from the synovial fbroblast and inhibits osteoblast maturation and OPG function leading to suppression of local bone formation. Therefore, administration of anti DKK-1 would be useful to prevent bone erosions and reverse the inhibition on bone formation. However, immobility will suppress the mechanosensing process of osteocytes leading to uncoupling of bone formation and bone resorption through the Wnt-signaling pathway.

Although GCs are frequently prescribed for the rheumatic patients, they have a great adverse impact on bone quality leading to GIOP. The overall effects of GCs on bone are either directly on bone cells or indirectly by affecting the bone metabolism, both of which result in enhancing bone resorption and decreasing bone formation. Inhibition of bone formation by GCs occurs by increasing the osteoblast and osteocyte apoptosis and/or impairing osteoblast function via suppressing the BMP pathway and the Wntsignaling pathway. On the other hand, GCs can stimulate bone resorption by reducing osteoclast apoptosis via upregulation of RANKL and inhibition of OPG.

GIOP is a signifcant clinical complication that occurs as a result of adverse effects of the prescribed GCs for patients with rheumatic disease. ACR 2010 had set several recommendations updated that of ACR 2001 for evaluating and monitoring patients, who has just initiated or received GCs for/or more than 3 months duration. However later, ACR 2017 recommendations have been released and aimed to standardize the classifcation of patients at risk of GC induced fracture (Fig. 10.12). So that the appropriate recommendations can be applied on each category, while reducing the risk and burden of radiological testing and the anti-fracture therapy. Therefore, all clinicians treating patients with GCs should be aware of these fracture risks and identify the patient's level of fracture risk according to the ACR 2017 guidelines for assessment and reassessment of fracture risks. The recommendations of anti-fracture pharmacotherapy in order of preference, for prevention and treatment of GIOP, were based on their effcacy, potential harms, and cost. Hence, oral bisphosphonates were recommended as preferred frst-line therapy over other recommended anti-fracture therapies.

Taking together, the salient approach for early diagnosis of rheumatic diseases would be very crucial and of great help in diminishing the magnitude of bone destruction that occur during the pathogenesis of these diseases and therefore preventing further bone erosion and osteoporosis. Finally, GIOP is a medical problem that patients should be aware of its fracture risk and clinicians should consider evaluating the fracture risks for all GC-treated patients and actively prevent reduction of bone mass.

**Acknowledgments** The author of this chapter is grateful to the medical student Somayya Khan for her efforts in drawing some of this chapter's fgures. The authors also would like to thank Dr. Waleed Hafz for his assistance in the development of this chapter.

# **References**

1. Spector TD, Hall GM, McCloskey EV, Kanis JA. Risk of vertebral fracture in women with rheumatoid arthritis. BMJ. 1993;306:558.

disease. Endocr Rev. 2008;29(2):155–92. Epub 2007 Dec 5. Review

bone mineral density and lean body mass. Osteoporos Int. 2006;17:105–8.

women with systemic lupus erythematosus. Clin Rheumatol. 2009;28:579–85.

Erratum in: Arthritis Care Res (Hoboken). 2012 Mar;64(3):464. PubMed PMID: 20662044].

**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

M. Cheikh (\*) · N. Bahabri Doctor Soliman Fakeeh Hospital,

e-mail<EMAIL_ADDRESS>
Jeddah, Saudi Arabia

# **Fever and Rheumatology**

Mohamed Cheikh and Nezar Bahabri

# **11.1 Introduction**

In all the patients with rheumatic diseases, fever should prompt an immediate and thorough evaluation. There are different disorders that can cause fever and arthritis. Fever that is thought to be due to active rheumatic disease is seen in over 50% of patients with SLE30. However, it can be also related to or a sequel of an infectious process. There are many infectious diseases with rheumatological manifestations. The aim of this chapter therefore is to address variable relationships of fever with patients with arthritis. Fever of unknown origin will be addressed as some systemic rheumatic disease may present with fever. It is always a dilemma when an established patient with arthritis presents with fever. What should you do? This issue is addressed with a suggested diagnostic approach that guides you in a stepwise manner until you reach to the defnitive diagnosis.

A quick review of rheumatological manifestations of some infections is presented. This is to widen your knowledge about this area in medicine and not to ignore common viruses, for example, in your differential diagnosis of fever and arthritis. Vaccination is quite an ignored aspect of clinical practice among patients with arthritis.

The objective of this chapter is to provide a systemic approach to patient with fever and arthritis.

Specifc objectives:

By the end of the chapter the reader should be able to:

**11**

<sup>©</sup> The Author(s) 2021 241 H. Almoallim, M. Cheikh (eds.), *Skills in Rheumatology*, https://doi.org/10.1007/978-981-15-8323-0\_11

# **11.2 Fever of Unknown Origin (FUO)**

# **11.2.1 Defnition [**28**]**

# **11.2.2 Epidemiology**

The epidemiology of FUO has changed over time due to scientifc and technologic advances (better imaging, more advanced organism isolation, and more understanding of connective tissue disease). A prospective multicenter study on fever of unknown origin showed the following distribution: connective tissue diseases 22%, infection 16%, malignancy 7%, miscellaneous 4%, no diagnosis 51%.

# **Box 11.1 Initial evaluation for FUO**

# **11.2.3 General Principles in the Treatment of FUO (**Table 11.2**)**

Physician should explain to the patient that FUO is a well-known entity, and it needs time for investigation to decrease anxiety of the patient. Empiric therapy with antimicrobial or glucocorticoids *should not* be given to stable patients with FUO because it often obscure or delay the diagnosis [29]:

There are some exceptions where patient with FUO should be treated empirically. The exceptions are:

Figure 11.1 shows a suggested algorithm to approach a patient with FUO.

**Epidemiology**: Table 11.1 shows the etiologies of FUO.

**Table 11.1** Etiologies of FUO [1–27]

Biopsy

**Fig. 11.1** Suggested algorithm to approach patient with FUO

# **11.2.4 Tips in FUO**

# **11.3 Fever and Rheumatology**

# **11.3.1 Introduction**

Approach to fever is a very challenging in a patient with rheumatic disease as it could be an infection, disease activity, or medication side effect. Fever that is thought to be due to active disease is seen in over 50% of patients with SLE [30]. On the other hand, fever is a rare presentation of RA disease activity. Infections are often diffcult to diagnose and treat in this group of patient because of the following reasons:

1. Clinical manifestations of infections are often indistinguishable from the underlying disease and vice versa [52–55].

In patient with rheumatoid arthritis, bone and joints, skin, soft tissues, and the respiratory tract are the most frequently involved sites in infectious processes [33]. In patients with chronic infammatory rheumatic or autoimmune diseases without arthritis, infections of the respiratory tract are the most common site. **Finally, ascribing fever to the underlying rheumatological disease itself in an immunosuppressed patient should be done only after reasonable and good efforts have been made to exclude infection.** Figure 11.2 shows suggested algorithm to approach a patient with rheumatic disorder presenting with fever.

Risk factors for infection in a patient with rheumatic disease include:

**Fig. 11.2** Suggested algorithm to approach a patient with rheumatic disorder presenting with fever

Points to consider in the approach to this group of patients:

fever. It is rather a collective clinical and laboratory fnding with good clinical judgment.

sideration when evaluating the white blood cell count in a febrile immunosuppressed patient because:

	- Procalcitonin has higher diagnostic value than CRP for the detection of bacterial sepsis in patients with autoimmune disease, and the test for procalcitonin is more specifc than sensitive 32.
	- Procalcitonin test is not recommended to be used in isolation as a rule-out tool 32.

# **11.4 Fever in Rheumatology Patient**

# **11.4.1 History**

Careful and through history including:

# **11.4.2 Physical Examination (**Table 11.3**)**

Complete physical examination includes:

[39–57, 59–99].

**Table 11.3** Possible pathogens by the predominant immune system defect caused by pharmacological agent used in the treatment of rheumatic disease [37–38]

# **11.5 Rheumatologic Manifestation of Infectious Diseases**

# **11.5.1 Introduction**

Rheumatologic manifestations of infectious diseases are well-recognized and relatively common. This topic will review the most common infectious diseases associated with rheumatologic manifestations*. An overview of each infectious agent is presented separately*.

# **<IP_ADDRESS> Hepatitis B Virus Arthritis [**104**]**

Evidences have shown that four rheumatologic syndromes are linked with hepatitis B virus infection.

Clinical and laboratory features of each syndrome will be described below.

# **<IP_ADDRESS> Acute Hepatitis B and Arthritis**

The symptoms are abrupt in onset, and they are composed of low-grade fever, a symmetrical polyarthritis which might be additive or migratory in pattern, morning stiffness, and other constitutional symptoms. The most common joints involved are the knees and small joints of the hands, but any peripheral joint might be involved with either arthralgia or frank arthritis. It may last from several days to several months**.**

# **<IP_ADDRESS> Chronic Active Hepatitis B**

Chronic active hepatitis is linked with joint discomfort and occasional rash. The joints

**Table 11.4** Causes of CXR abnormalities in patient with rheumatic diseasea

a The appearance or progression of pulmonary disease following the initiation or intensifcation of immunosuppressive therapy should always prompt a thorough evaluation for a possible infectious cause

**Table 11.5** (continued)

(continued)

**Table 11.5** (continued)

**Table 11.5** (continued)

**Table 11.6** Rheumatic manifestations of hepatitis B virus

abnormality usually manifest as arthralgias which have a feeting nature which have a feeting nature (Table 11.6).

#### **<IP_ADDRESS> Polyarteritis Nodosa**

# **<IP_ADDRESS> Essential Mixed Cryoglobulinemia**

It has the following clinical features: nonthrombocytopenic purpura upon exposure to cold, diffuse arthralgia, and generalized weakness and hepatosplenomegaly; rarely it is associated with neuropathy and gangrene.

# **11.5.2 Hepatitis C Virus Arthritis**

Hepatitis C virus (HCV) is associated with many rheumatologic manifestations including those related to joints, muscles, and connective tissue resulting from the body's immune system interaction with the infectious agent antigens with the subsequent immune complex formation that will be deposited in various parts of the body eliciting an infammatory reaction that damage the involved organs. Patients who are infected with HCV often have no symptoms. Anyone newly diagnosed with arthritis or cryoglobulinemia should be tested for HCV infection. Also, there are certain drugs used in the treatment of HCV infection, e.g., interferon can worsen a related rheumatologic disease.

Arthritis is noted in 2 to 20% of HCV patients [107, 108]. The arthritis takes the form of evanescent rheumatoid-like picture in two-thirds of the cases and an oligoarthritis pattern in the rest. Rheumatologic manifestations include painful joints and muscle and fatigue, "the frst and most common complain," and less commonly patients might have joint swelling and vasculitis.

Cryoglobulinemia happens when cryoglobulins (which are abnormal immunoglobulin) precipitate in cold temperature. It may affect the blood vessels specially during cold weather leading to "'Raynaud's phenomenon." [105, 106] The diagnosis of HCV can be made by fnding HCV Immunoglobulins or by detecting the virus RNA.

**Table 11.7** Rheumatic manifestations of Parvovirus B19 infection

# **11.5.3 Parvovirus B19 Arthropathy**

Parvovirus B19 is the cause of ffth disease "slapped cheeks" or erythema infectiosum. The disease manifests by rash, arthritis/arthralgia, laboratory abnormalities, and other connective tissue diseases like syndrome. It may mimic systemic lupus (SLE) both in children and adults (Table 11.7) [109, 110].

Arthritis/arthralgia may accompany or follow the skin eruption. The rheumatologic symptoms may persist for weeks to rarely months with resolution, but recurrences are reported [111, 112].

The diagnosis of acute parvovirus infection is made by fnding IgM antibody, while IgG antibody is evidence of preexisting exposure. Acute phase reactant, i.e., erythrocyte sedimentation rate and C-reactive protein are occasionally elevated. The leukocyte remains normal, but in some cases, rheumatoid factor and antinuclear antibody may be present in the acute period.

# **11.5.4 Dengue Virus**

• The classical features of dengue virus (DV) are acute febrile illness, headache, and muscle and **joint pain**. It is also referred to as "breakbone fever." [114] **Arthralgia occurs in 60 to 80% of the patients infected with DV.**

Investigations may reveal leucopenia, thrombocytopenia, and elevated liver enzymes. A small percentage of patients may have potentially lethal forms known as hemorrhagic fever and dengue shock syndrome [115].

# **11.5.5 Septic Arthritis**

It is a bacterial infection of the joint that is usually curable with treatment, but morbidity and mortality are still signifcant specially in patients who have underlying rheumatoid arthritis, patients who have prosthetic joints, elderly patients, and patients who have severe and multiple comorbidities. Incidence of septic arthritis 10 cases per 100,000 patient-years in general population in Europe [116]. Incidence of septic arthritis in patients with rheumatoid arthritis.

*(Based on prospective British Society for Rheumatology Biologics Register)*

1.8 cases per 1,000 patient-years in 3,673 patients taking non-biologic disease-modifying antirheumatic drugs, where 4.2 cases per 1,000 patient-years in 11,881 patients taking anti-tumor necrosis factor therapy.

Usually it is monoarthritis, but up to 20% of patients have infection in >1 joint "polyarticular." [116] The joints mostly affected are knee (which is the most common affected joint approximately 50%) followed by the hip, shoulder, and then elbow [120]. In IV drug users, axial skeletal joints are mainly involved often with *Staphylococcus aureus*.

The most common causes of septic arthritis in adults are: [116]

In IV drug users, septic arthritis is frequently duo to methicillin-resistant Staphylococcus (MRSA), mixed infections, fungal infections, or unusual organisms [116]. Patients may have *1–2 weeks* history of joint pain, tenderness, warmth, redness, restricted motion, loss of function, and fever. Joint-related risk factors for infection are joint prosthesis, intra-articular injection, and joint trauma [119]. **Fever** occurs in about one-third of patients [116]. "**Large joints in legs (hips and knees) are the typical sites of infection.**" [116–118] Septic arthritis is diagnosed by clinical signs (hot, red, tender, swollen, restricted) with any of the following:

# **11.5.6 Poncet's Disease (Reactive Arthritis Associated with Tuberculosis) [121]**

There is a new pattern of reactive arthritis associated with tuberculosis (TB), identifed as Poncet's disease (PD) or tuberculous rheumatism, which is a sterile reactive arthritis that can emerge during any stage of acute TB infection. In a retrospective case series study, seven cases of Poncet's disease were identifed:

	- of multiple sites.

The resolution of the arthritis was with symptomatic treatment and continuation of anti-TB drugs. PD may manifest in a variable pattern during the course of active tuberculous infection. Physicians should be aware of this rare complication associated with a common disease to prevent delay in diagnosis and initiation of appropriate treatment.

# **11.6 Vaccination in Adult Patient with Autoimmune Infammatory Rheumatic Diseases (AIIRD)**

# **11.6.1 Introduction**

It is well known that vaccination is one of the most effective measures to prevent infections and as discussed earlier in this chapter patient with autoimmune infammatory rheumatic diseases is at increased risk of infection compared to the normal population with the respiratory tract being the most affected organ [122, 123]. However, vaccination of immunocompromised patients is challenging both regarding effcacy and safety. The effcacy of vaccinations in patients with AIIRD may be reduced, and there is a potential risk of fares of the underlying AIIRD following vaccination. The two major issues to consider in vaccine administration of this group of patients are what is the expected immune response following vaccination and what are the potential for worsening the underlying disease.

**Table 11.8** Vaccinations by type

# **11.6.2 General Rules**

All inactivated vaccines can be administered safely to persons with AIIRD whether the vaccine is a killed whole organism or a recombinant, subunit, toxoid, polysaccharide, or polysaccharide protein-conjugate vaccine. Live viral and bacterial vaccines should be avoided whenever possible in immunosuppressed patients with AIIRD because it might lead to severe infection in immunocompromised patients (Table 11.8). Table 11.9 shows vaccinations recommendations in adult patient with autoimmune infammatory rheumatic diseases (AIIRD).

**Table 11.9** Vaccination recommendation in AIIRD \* [124–127]

a Vaccination in patients with AIIRD should ideally be administered during stable disease. *AIIRD* autoimmune infammatory rheumatic disease, *MTX* methotrexate, *AZA* azathioprine [31, 128, 129, 130, 131, 132]

**Acknowledgments** The Authors would like to thank Abdullah Sakkat, MD, for his contributions to this chapter in the previous edition.

# **References**

multicenter study of 167 patients with FUO, using fxed epidemiologic entry criteria. The Netherlands FUO Study Group. Medicine (Baltimore). 1997;76:392.

patients with systemic lupus erythematosus. Clin Exp Rheumatol. 1999;17:737–40.

**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

**12**

# **Thrombosis in Rheumatological Diseases**

Fozya Bashal

# **12.1 Introduction**

Venous thromboembolism (VTE) is a disease of blood coagulation that occurs in the veins, most often in the calf veins frst, from where it may extend and cause deep vein thrombosis (DVT) or pulmonary embolism (PE). The frst described case of venous thrombosis that we know of dates back to the thirteenth century, when deep vein thrombosis was reported in the right leg of a 20-year-old man [1].

The risk of thrombosis is infuenced by both genetic and environmental factors. The risk factors for venous thrombosis are immobility, major surgery, underlying medical conditions like malignancies, medication use such as hormonal therapies, obesity, and genetic predisposition. In contrast to that, the major risk factor for arterial thrombosis is atherosclerosis [2].

In 1859, a German scientist, Rudolf Virchow, elucidated the mechanism of pulmonary embolism and hence deduced the major pathogenic determinants for DVT and PE, named as Virchow's triad that comprised (1) blood stasis, (2) changes in the vessel wall, and (3) hypercoagulability. This triad still applies, with essentially all prothrombotic factors, whether systemic or molecular, infuencing one of these three mechanisms [3] (Fig. 12.1).

DVT and PE are extremely common medical problems, and they are among the major cause of morbidity and death worldwide [3].

About 1–2 per 1000 individuals are affected by VTE per year with PE being the lethal complication and is associated with a high mortality rate that exceeds 15% in the frst 3 months after diagnosis [4].

Although disturbance of the coagulation and anticoagulation mechanisms is a very important risk factor for VTE, several studies suggest the role of innate immunity in the development of VTE [4].

Venous thrombosis results from multiple interactions between acquired and inherited risk factors [4].

In this chapter, we discuss the association of thrombosis with autoimmune rheumatologic disorders. The pathophysiology of thrombosis, effects of infammation, endothelial dysfunction, some novel factors on promoting thrombosis in different rheumatic disorders, diagnostic strategies for thromboembolic disease, and its treatment, management, as well as preventive measures will be addressed in detail. This chapter is useful for students, residents, fellows, and physicians interested in learning about rheumatic disease and thrombosis. The main objective of this chapter is to make the readers able to achieve the following goals:

F. Bashal (\*)

College of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia e-mail<EMAIL_ADDRESS>
<sup>©</sup> The Author(s) 2021 263

H. Almoallim, M. Cheikh (eds.), *Skills in Rheumatology*, https://doi.org/10.1007/978-981-15-8323-0\_12

**Fig. 12.1** Virchow's triad and some infammatory changes and their association with venous and arterial thrombosis

To achieve these purposes, this chapter is written in three sections.

In Sect. 2 of this chapter, we will discuss the mechanism and pathophysiology of thrombosis in individual rheumatic disorders, i.e., systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), rheumatoid arthritis (RA), vasculitis, and Behçet's disease; this includes the effects and role of different medications used specifcally in rheumatic disorders in promoting or preventing thrombosis.

In Sect. 3, we discussed in general the approach and the strategies for diagnosing VTE (DVT and PE) and arterial thrombi in different autoimmune rheumatic disorders.

In Sect. 4, we will discuss updates about the management of thrombosis in rheumatic diseases and recommendations for prophylaxis and secondary thrombosis prevention in rheumatic disorders.

# **12.2 Pathophysiology of Thrombosis in Rheumatic Disorders**

Arterial and venous thrombosis and systemic infammatory diseases are highly linked, and the systemic infammation promotes an extensive cross-link to exist between infammation and hemostasis [5]. Systemic infammation disturbs the natural tight balance between the procoagulants and the anticoagulants in the blood by release of certain infammatory markers and cytokines like tumor necrosis factor alpha (TNFα) and interleukin-1 (IL-1) and interleukin-6 (IL-6) that fnally promote a prothrombotic state [5] (Fig. 12.2).

Infammation is a common feature of many rheumatic and immune-mediated disorders; systemic infammation modulates thrombotic responses by suppressing fbrinolysis, upregulating procoagulants, and downregulating anticoagulants. Several studies indicate the role of innate immunity in promoting thrombosis as it was shown that coagulation and innate immunity have a common evolutionary origin; this leads to the concept that the immune system and coagulations system are linked [4]. These fndings conclude that autoimmune disorders such as SLE, APS, Behçet's disease, RA, and vasculitis syndromes like Wegener's granulomatosis have been linked to an increased risk of venous thrombosis [4].

RA, as well as other types of arthritides and connective tissue diseases, are associated with accelerated atherosclerosis and increased cardiovascular morbidity and mortality [6].

Chronic systemic infammation predisposes to accelerated atherosclerosis, a risk that is wellknown in systemic lupus erythematosus (SLE) and in rheumatoid arthritis (RA) patients [7].

The mechanisms for an enhanced and premature atherosclerosis in autoimmune rheumatic disorders such as RA, SLE, and systemic sclerosis (SS) include chronic infammatory process, immune dysregulation, and the classical risk fac-

**Fig. 12.2** Close relationship between mechanisms of infammation and thrombosis in Rheumatic diseases

tors; this explains the very high risk of cardiovascular disease in patients with SLE and RA and some other autoimmune diseases [8].

The coagulation factor XII (FXII, Hageman factor) activity correlates with fbrinolysis [9]. Some studies had found the association between pulmonary embolism and decreased levels of FXII; one study was done on large cohort of patients in Japan with different rheumatic disorder reports that FXII reduction coexisted with the presence of antiphospholipid antibodies (a PL) in most thrombotic patients with rheumatic disorders; they conclude the presence of anti-FXII autoantibodies as a cause of FXII defciency in the presence of aPL antibodies [9].

# **12.2.1 SLE and Thrombosis**

Thrombosis in SLE is multifactorial, and hence SLE patients are at signifcantly increased risk of thrombosis and atherosclerosis. Arterial and/ or venous thrombosis is a well-known clinical entity in SLE, with a prevalence *>*10%. This prevalence may even exceed 50% in high-risk patients [10]. The incidence of thrombosis in SLE patients according to two studies was 26.8 and up to 51.9 per 1000 patient-years, according to the disease duration [10]. Other study reported that the incidence of thrombosis was 36.3 per 1000 patient years [10]. In a 10-year prospective cohort study of patients with SLE, the most frequent causes of death were active SLE (26.5%), thrombosis (26.5%), and infection (25%), with thrombosis dominating the second 5-year period of follow-up [11]. Patients with SLE have thrombosis at an early age than the age of thrombosis occurrence in the general population, with the incidence being increased in the frst year, which may be explained by high disease activity, circulating immune complexes, cytotoxic antibodies, or a higher infammatory state at frst year of SLE diagnosis [10].

Thrombosis is the most frequent cause of death in SLE. With its frequent manifestation in patients with SLE, thrombosis contributes signifcantly to high morbidity and mortality [11].

Several studies showed that atherosclerotic cardiovascular and cerebrovascular diseases are more common causes of late deaths than active SLE itself. Some studies revealed that subclinical coronary heart disease and carotid plaque were present in a signifcantly higher proportion of SLE patients than in control subjects of similar age and sex with similar risk factors. Compared with individuals without SLE, the risk of myocardial infarction in SLE patients is 2–50 times higher, and the risk of stroke is 2–10 times higher. The prevalence of symptomatic coronary heart disease in SLE patients has been reported to be 6–20%, depending on the characteristics of the cohort, disease duration, study design, prevalence of antiphospholipid antibodies (aPL), and ethnic composition. 3–15% of SLE patients have a nonfatal stroke [12].

# **<IP_ADDRESS> Risk Factor and Etiology of Thrombosis in SLE**

#### **Infammation and Disease Activity**

Infammation promotes thrombosis through its several effects on blood coagulation [10, 13].

Infammation induces the expression of tissue factor (TF), which is an important factor in coagulation initiation [10, 13]. The production of plasminogen activator inhibitor (PAI) is upregulated in infammation which leads to decreased fbrinolysis activity and increases the risk of thrombosis [10]; high levels of C-reactive protein (CRP) released in infammatory conditions facilitate the interaction between the monocyte and the endothelial and promote plasminogen activator inhibitor-1 (PAI-1) and TF [13]. In infammation, fbrinogen, an acute phase reactant, is secreted in higher concentrations which further increase the risk of thrombosis in patients with SLE [13]. Infammation impairs protein C pathway and decreases protein S level, thus worsening the risk of thrombosis in SLE patients who might have thrombotic events early in the disease as compared to patients without SLE [10, 13]. It was found that SLE patients with lupus nephritis have a high disease activity and infammation, and this is associated with increase risk of DVT and renal vein thrombosis; they also frequently have systemic hypertension and hyperlipidemia which further worsen thrombotic risk [10].

#### **Antiphospholipid (aPL) Antibodies**

aPL antibodies are type of autoantibodies that directed towards phospholipid binding proteins, anionic phospholipids, or a combination of the two [9]; they include anticardiolipin antibodies (ACA), lupus anticoagulant (LA), and anti ß2-glycoprotein I (anti-ß2-GPI) [14]. aPL antibodies induce platelet activation, interfere with coagulation inhibitors such as protein C, inhibit antithrombin and fbrinolysis, and then initiate the formation of a thrombus [10]; they are associated with an increased risk of arterial and venous thrombosis in addition to recurrent pregnancy loss in which they comprise an antiphospholipid syndrome (APS) which could occur as a primary disease (primary APS) or associated with several autoimmune disorders, most frequently in SLE patients, where it is named as secondary APS [15]. Lupus anticoagulant is considered as signifcant risk factor for stroke and myocardial infarction [10] as well as a strongest predictor of thrombosis [15].

There is a signifcant occurrence of aPL antibodies among SLE patients [16]; about one-third of patients with SLE show aPL positivity, but not all of them have the clinical presentation of thrombosis or APS [14].

In one retrospective study of 42 SLE patients, 60% were positive for one or two aPL antibodies, but only 27% of them (10 patients) had a history of APS. The most common clinical presentation was DVT/PE in eight patients. Less common was arterial thrombosis and pregnancy loss. One patient with a history of PE developed autoimmune hemolytic anemia. Another patient without history of DVT/PE presented with thrombocytopenia [16].

The risk of thrombosis in LA and ACA positive patients has been addressed by many researchers. In patients with SLE, 42% of LA-positive and 40% of ACA-positive individuals had a history of thrombosis; in contrast, the prevalence of thrombosis in LA-negative or ACA-negative SLE patients was only10–18% [10].

APS is the main cause of thrombosis and a major predictor of irreversible organ damage and death in SLE patients [15].

ACA might be transiently positive, or persistently positive, and considered signifcant when it tests positive on at least two occasions, 12 weeks apart. The risk of thrombosis was signifcantly higher in persistently positive ACA antibodies (33% risk) versus 3% risk in those with transiently positive ACA as shown in the prospective, observational cohort study by A Martinez-Berriotxoa et al. (2007) [15].

In all patients with SLE, even if there are no clinical manifestations, aPL antibodies should be done as they are considered part of American College of Rheumatology (ACR) classifcation criteria for SLE, and they have been associated with increased risk of thrombosis [10], as the frst presentation can be fatal presenting with a CVA. Diagnosis allows prophylactic measures to be instituted in high-risk situations, e.g., prolonged immobility and postoperative states; increased awareness of APS should lead to earlier recognition of associated episodes and laboratory screening for all SLE patients to allow for prophylactic anticoagulation in high-risk situations [16].

# **Protein C and S and Antithrombin Defciencies**

They are rare but carry a higher risk for venous thrombosis [10].

#### **Factor V Leiden**

Activation of factor V leads to the formation of a cross-linked fbrin clot. Factor V Leiden (FVL) is the most common inherited risk factor for venous thrombosis in the general population and is an important factor for thrombosis in patients with SLE. FVL polymorphism is considered to be risk variant for thrombosis and confers resistance to activated protein C, thus shifting the balance towards thrombosis in the clotting cascade. FVL variant is found in 20–60% of patients with idiopathic DVT but without SLE. Patients with SLE and/or aPL positivity who have the FVL polymorphism have at least two times the odds of thrombosis compared to patients without this polymorphism. This observation places FVL to be an independent risk factor for thrombosis in SLE [11].

#### **Hyperhomocysteinemia**

Hyperhomocysteinemia is a strong and independent factor for increased risk of atherosclerosis, mainly of the carotid and coronary arteries, as well as venous thrombosis to some extent [10, 17]. 27.3% of SLE patients with thrombosis have hyperhomocysteinemia, which is signifcantly higher than those without thrombosis in whom it is detected at 16.9% [10]. Patients with shortened APTT have a hypercoagulable state and were found to have high levels of homocysteine that place them at a higher risk of thrombotic events, as shown in a study done by T. M. K. Refai et al. (2002) [17]. In this study, the researchers found that 21% of SLE patients had elevated levels of homocysteine; interestingly, the level was higher in male patients more than in female ones and also those on prednisolone; they observed that lupus patients with hyperhomocysteinemia had a threefold increase in odds ratio of thrombotic episodes. This is partly because of the direct toxic effect of homocysteine on endothelium and partly indirect effects, such as induction of a vascularendothelial-cell activator, promotion of vascular smooth muscle proliferation, and an inhibitory effect on endothelial cell growth; these fndings support the hypothesis that hyperhomocysteinemia is an independent risk factor for thrombosis in young patients with SLE [17].

#### **Traditional Risk Factors**

Smoking is associated with worse outcome and mainly venous thrombosis by inducing endothelial damage; patients with SLE may have hypertension (HTN), diabetes mellitus (DM), and dyslipidemia which predispose them to thrombotic events. Older patients have more endothelial damage and vascular morbidity, and hence age is considered to be a risk factor for thrombosis in SLE [10].

# **<IP_ADDRESS> Medication and Thrombosis in SLE**

• Glucocorticoids have been used frequently in SLE; they mediate endothelial damage and hence lead to accelerated atherosclerosis; high doses of glucocorticoids are associated with abnormalities of the coagulation system [10]. Chronic glucocorticoid consumption has been reported to increase plasma von Willebrand factor (VWF) levels, endothelial dysfunction, increased oxidative stress, and insulin resistance. Glucocorticoids use also increases (PAI-1); it was found that secretion of t-PA levels is limited in patients receiving glucocorticoids, which further worsen the coagulation system and cause hypercoagulable state which further enhances thrombosis risk in SLE patients [18].

Table 12.1 summarizes the risk factors of thrombosis and accelerated atherosclerosis in SLE patients.

# **12.2.2 RA and Thrombosis**

RA is a common chronic systemic infammatory disease with worldwide distribution. There is

**Table 12.1** Risk factors of thrombosis and accelerated atherosclerosis in SLE patients

increased incidence of premature cardiovascular disease (CVD) and venous thrombosis in patients with rheumatoid arthritis and hence increased premature mortality and death on average 2.5 years earlier in community-based studies and approximately 18 years earlier in hospital-based studies than non-RA patients [20, 21]. The risk of VTE in patients with RA is increased to more than threefold than non-RA, as shown by Bacani A et al. (2012); they found that RA patients had a higher VTE cumulative incidence at 10 years than non-RA patients (6.7 in RA versus 2.8 in non-RA), and the risk of VTE was signifcantly higher within 90 days following hospitalization [20]. RA patients showed a higher age- and sexadjusted increased risk of mortality (60%) and thromboembolic events (30%–50%) during a 5-year follow-up compared to non-RA patients. Similarly signifcant elevated risks (70% for death and 30%–40% for thromboembolic events) were seen when compared to OA patients. Several studies have shown that RA patients are 30%–60% more likely to suffer a cardiovascular event [19].

# **<IP_ADDRESS> Risk Factor and Etiology of Thrombosis in RA**

#### **Lifestyle in RA**

Patients with RA are physically less active due to their disease, and they may suffer from obesity, diabetes mellitus (DM), and hypertension that may result from medication use like steroids; some of RA patients are smokers as well; all these factors contribute to the accelerated atherosclerosis in RA subjects. Obesity is a timedependent risk factor for development of VTE in RA patients, as shown by Bacani et al. in their study [20].

#### **Infammation**

RA is characterized by a chronic infammation that results in impaired immune system as well as persistent endothelial dysfunction, which predisposes to vascular wall damage and accelerated atherosclerosis. Such damage can be detectable by ultrasound measurement of carotid intimamedia thickness (IMT) in a preclinical stage of the disease. Carotid IMT in RA patients is associated with markers of systemic infammation and disease duration [22]. CD4+ are subsets of T cells that lack surface CD28 molecule (CD4 + CD28-) and expand when stimulated by endothelial autoantigens, in a subgroup of RA patients. Moreover, they infltrate the atherosclerotic plaques and pose high pro-infammatory and tissue-damaging properties which promote vascular injury. The role of these cells in contributing to early development of atherosclerosis in RA has been confrmed by recent studies which showed that RA patients with CD4 + CD28- cell expansion have a higher degree of endothelial dysfunction and a higher carotid IMT than patients without expansion of these cells [22].

# **High Disease Activity and High Levels of Infammatory Markers**

RA patients with high ESR and/or high CRP were found to have increased carotid artery IMT as well as increased probability of vessel plaque, which supports hypotheses of the relationship between systemic infammation and atherosclerosis. ESR primarily refects increased fbrinogen levels in response to systemic infammation. The association between fbrinogen, as measured by the ESR, and increased carotid IMT suggests that infammation-coagulation interactions may also have a role in atherogenesis. CRP is produced by the liver in response to interleukin-6, an earlier infammation mediator, and can be found in the atheromatous lesions, suggesting its pathogenic role in atherothrombosis [23]; CRP is an independent risk factor for atherothrombotic disease [19].

#### **Hospitalization**

The relative risk factor for VTE is increased within 90 days post-hospitalization in RA patients. Orthopedic surgeries are reported to be a timedependent cofactor risks for VTE development in RA patients that may develop within 90 days following lower extremity arthroplasty [20].

#### **aPL Antibodies**

RA patients may develop APL antibodies in 5%–75%, which increases the risk of VTE in these patients [20].

## **TNF-α**

It causes endothelium damage and promotes blood coagulation through monocyte activation by increasing the TF levels [19].

# **Fibrinogen, VWF, Tissue Plasminogen Activator (t-PA) Antigen, and D-Dimer**

Levels of these thrombotic variables are signifcantly higher in patients with RA [21].

# **Leukocytosis, Thrombocytosis, Increasing Platelet Activity, and Low Serum Albumin**

These infammatory markers are associated with increased cardiovascular risk and accelerated atherosclerosis in RA patients [19, 21].