Part 3. Systemic Syndromes in Rheumatology

With a prevalence as high as 15%, chronic pain is increasingly being recognized as a common problem in children and adolescents,1 but one that is still poorly understood. This chapter describes evolving concepts of several syndromes in which musculoskeletal pain is a prominent feature. Interestingly, these pain syndromes frequently have overlapping features. However, most children can be readily diagnosed by the typical pattern of somatic complaints and the salient physical findings specific to each syndrome.

“Growing pains” are the most common cause of recurrent limb pain in childhood, and references to it have can be found in the medical literature dating back more than 150 years. Growing pains occur in children between the ages of 3 and 12, and are characterized by intermittent nighttime nonarticular aching or pain most commonly in the legs. Recent prevalence estimates vary from less than 3%2 to as many as 36.9% in 4 to 6 year olds in Australia.3 An extension of the syndrome in adolescents and adults may include restless legs syndrome. In one recent population study, the prevalence of restless legs syndrome was found to be 1.9% in 8 to 11 year olds and 2% in 12 to 17 year olds; a history of growing pains and sleep disturbances was more common in the study population.4 Interestingly, restless legs syndrome also is reported to be common in patients with fibromyalgia, another pain syndrome which is described later in this chapter.5The pathogenesis of growing pains is unknown. Despite the name, it is almost certainly not owing to growing.6 Perhaps this term is used because the condition occurs in children (who are always growing), and does not occur in adulthood (after cessation of growth). Theories have abounded about the etiology, and have included overuse, anatomic abnormalities, perfusion problems, and emotional issues, but most have not been supported by subsequent research.7-10 Recently, investigators have shown that children with growing pains may have increased pain sensitivity11 and decreased bone strength as measured by quantitative ultrasound.12

Growing pains are typically bilateral, usually occurring in the evening or at night, and not associated with limping or limited mobility. There is no history of trauma or infection, and objective findings are lacking on physical examination. The areas most frequently involved include the thighs, calves, and, occasionally, the forearms and trunk. In contrast to patients with juvenile idiopathic arthritis (JIA), who usually have more pain and stiffness when first arising in the morning, these children are usually asymptomatic in the morning.

Parents of children with growing pains report no swelling, color changes, or warmth of the affected limb. The physical examination is unrevealing. X-rays and laboratory tests may be necessary to alleviate parental concern,13 but if the clinical picture is typical, they are not necessary. In contrast to patients with juvenile idiopathic arthritis (JIA), who usually have more pain and stiffness when first arising in the morning, these children are usually asymptomatic in the morning. Typically, if testing is done, it might include the erythrocyte sedimentation rate, complete blood count and muscle enzyme determination, all of which should be normal.

If the child has a limp, is complaining of pain in or around the joint, or has an abnormal musculoskeletal exam, growing pains is probably not the correct diagnosis. A thorough investigation for known causes of joint pain should be pursued, such as infection, inflammatory arthritis, and neoplasm, as well as orthopedic and endocrine disorders. A frequent mistake is to use growing pains as a convenient diagnosis for any vague musculoskeletal complaint, rather than reserving the term for a child whose symptoms truly fit the clinical picture as outlined above.

Treatment for this condition is symptomatic. Heat, massage, and analgesics such as nonsteroidal anti-inflammatory agents or acetaminophen, have all been suggested, but none have been tested in a prospective fashion. Reassurance that growing pains have no long-term sequelae and represent a relatively benign condition is important. The most important treatment is reassurance that there is no serious organic disease and that the problem will not progress to arthritis or to other deforming conditions, despite its recurrent nature. The consensus of opinion is that growing pains have no long-term sequelae and represent a relatively benign condition.10

Hypermobility is widely prevalent in children and adolescents, and may be responsible for a wide variety of musculoskeletal complaints including benign joint hypermobility syndrome (BJHS), patellar subluxation, articular dislocation, premature osteoarthritis, and increased susceptibility to ligamentous injury. In addition to causing joint specific problems, BJHS is also now known to be associated with chronic pain, fatigue, and possibly dysautonomia in adults.14 Additional hereditary diseases that must be considered in the differential diagnosis of joint laxity include: (1) Ehlers-Danlos syndrome, (2) Marfan syndrome, (3) marfanoid hypermobility syndrome, (4) osteogenesis imperfecta, (5) Williams syndrome, and (6) inborn errors of metabolism such as homocystinuria and hyperlysinemia.

There is tremendous variability in the reported prevalence of joint hypermobility in the general population, with studies reporting incidences from as low as 2% to as high as 30%. Hypermobility appears to be more common in younger children and in females.15-18 There may be racial and ethnic differences as well, with hypermobility apparently occurring more commonly in persons of African, Asian, and Middle Eastern descent, though studies are somewhat conflicting. Estimates of the prevalence of hypermobility in children vary from 10% to 34%, declining during the school-aged years.19,20 The prevalence of pain in adults with BJHS varies between 5 to 45% depending upon the group studied.21,22 Not all hypermobile patients have pain: one recent study found that only about 5% of hypermobile adults had symptomatic benign joint hypermobility syndrome,21 but in one study of a rheumatology clinic population, as many as 45% had benign joint hypermobility syndrome if patients were systematically examined.22 Children affected by BJHS are usually school-aged and adolescents, although patients under age 5 have been described. An increased incidence of a familial tendency for joint hypermobility has been reported. The parents may report that they were loose-jointed as youngsters. Many patients consider themselves “double-jointed” and participate in activities where hypermobility may be advantageous, such as ballet or gymnastics.

Diagnosis

The 1998 Revised Brighton Criteria23 are the most recently published criteria for hypermobility. The components of the Beighton score consist of five simple maneuvers: (1) extension of the wrist and metacarpophalangeal joints so that the fingers are parallel to the dorsum of the forearm; (2) passive apposition of the thumb to the flexor aspect of the forearm; (3) hyperextension of the elbows 10 degrees or more; (4) hyperextension of the knees 10 degrees or more; and (5) flexion of the trunk with the knees fully extended so the palms rest on the floor (Fig. 207-1). Patients are scored on a 9-point scale, with one point awarded for each hypermobile site. A Beighton score of 4 or more points fulfills criteria for hypermobility. However, the use of the Beighton score to diagnose hypermobility in children may not be optimal: since children are more hypermobile than adults, it may identify as many as 50% of children as being “abnormal” in terms of excessive hypermobility.

Whether or not the Beighton hypermobility score is used, the other criterion for the diagnosis of BJHS are shown in Table 207-1. The examiner should also look for stigmata of heritable connective tissue diseases such as Marfan syndrome (Marfanoid habitus, arachnodactyly, high-arched palate, ocular abnormalities such as drooping eyelids and dislocated lens), and Ehlers-Danlos syndrome including increased elasticity of the skin, abnormal “papyraceous” scars, and a velvety texture of the skin (see Fig. 207-2).

Clinical Manifestations

The symptoms attributed to BJHS include joint and muscle pain, transient joint swelling, and subjective stiffness; these are typically worsened with increased physical activity. The joints most commonly involved are the lower extremity joints, but the back also may be affected. If joint swelling is present, consideration must be given to an inflammatory arthropathy such as juvenile idiopathic arthritis. A high frequency of hypermobility was found in a group of children with recurrent episodes of joint pain that was called juvenile episodic arthritis/arthralgia.24 These children most likely simply have hypermobility syndrome, with the swelling likely owing to edema from strain and sprain injuries rather than true joint effusions.

Congenital abnormalities of the hips including actual developmental dysplasia have also been associated with hypermobility. Anterior knee pain syndrome, a frequent diagnosis in preadolescent and adolescent patients, may be owing in some individuals to hypermobility of the patellae and genu recurvatum or genu valgus. Pes planus, which becomes apparent on weight bearing, is also common in hypermobility and may cause musculoskeletal pain that tends to improve with the use of orthotics. Chronic nonspecific back pain may also be secondary to hypermobility, and can also predispose to injuries such as spondylolysis and spondylolisthesis.

Growing evidence suggests that hypermobility is not just a “benign” problem limited to the joints. One recent study of 15 children with BHJS found that these children had increased laxity of other tissues compared to asymptomatic prepubertal children.25 Furthermore, children and adults with BJHS tend toward osteopenia25,26 and there appears to be overlap of hypermobility with chronic pain, fatigue and dysautonomia, and fibromyalgia.27-30

A recent study of 125 children with BJHS found that 48% had “clumsiness,” poor coordination, developmental motor delay, major physical limitations, and school absences because of symptoms.31 Up to 20% had recurrent joint sprains and 10% had actual subluxation/dislocation of a joint, among many other features that overlapped with collagen abnormalities such as Ehlers-Danlos and Marfan syndromes.

Basic laboratory investigations, such as a complete blood count, erythrocyte sedimentation rate, serum chemistries, thyroid function tests, and urinalysis, are usually negative unless there is an underlying inflammatory condition. A Lyme titer may be done if a joint effusion is present, and the child has spent time in an endemic area. Joint radiographs show no evidence of joint space narrowing, osteopenia, or erosive change. Invasive studies, such as arthrocentesis, arthroscopy, or biopsy are not necessary. If an arthrocentesis is done for some reason, the synovial fluid is typically noninflammatory, with less than 200 leukocytes (in contrast to that in inflammatory arthritis, which contains at least several thousand [and sometimes many more] leukocytes).

The treatment of benign joint hypermobility syndrome includes (1) explanation of joint laxity and the mechanism of pain; (2) reassurance that an underlying arthritis does not exist; (3) analgesics; (4) a physical therapy program to improve periarticular muscle strength; and (5) avoidance of activities that aggravate the musculoskeletal pain. When overpronation and pes planus are present, the use of an orthotic to correct pronation and support the arch may be helpful in normalizing the gait and deceasing lower extremity joint symptoms.18The intermittent use of nonsteroidal anti-inflammatory drugs (NSAIDs), or application of warmth or cold, may help relieve pain or stiffness in some patients. Swimming is an excellent sport to improve strength and cardiovascular endurance without excessive impact loading and strain on the supportive tissues, especially since exercise tolerance in children with benign joint hypermobility syndrome is reduced.32The rehabilitation program should address both the physical and emotional needs of the child, and in severe cases, the child will benefit from a multidisciplinary approach involving physical and occupational therapy, psychology, and podiatry. The prognosis is thought to be good in most cases if benign joint hypermobility syndrome is identified early and interventions begun prior to the development of a chronic pain syndrome.

Complex regional pain syndrome (CRPS) is characterized by pain, swelling, and disuse of an extremity associated with signs of vasomotor instability. This syndrome has had many names, including reflex sympathetic dystrophy (RSD), Sudeck atrophy, causalgia, reflex neurovascular dystrophy, and hysterical edema. The incidence of CRPS in children is not known, but the usual age of onset is between 9 and 15 years, and it is much more common in girls than boys.

Disorders precipitating complex regional pain syndrome in adult patients include infection, fracture, surgery, peripheral neuropathy, and trauma (mild to severe), but such conditions rarely antedate pediatric complex regional pain syndrome.33 Instead, the antecedent injury is usually relatively minor in relation to the severity of the complex regional pain syndrome. In one of the first series of pediatric complex regional pain syndrome, Bernstein reported that only 11 out of 24 (46%) of his cases in children had an antecedent illness or trauma.34It is much more common in the lower extremities in children as compared to adult.35-37

The patient with complex regional pain syndrome often complains of a continuous burning sensation. Typically, even gentle stroking of the skin causes marked discomfort and withdrawal of the limb, a phenomenon referred to as allodynia, which is highly characteristic of complex regional pain syndrome. The limb is usually held in a spastic posture, and the patient refuses to move it actively or passively because of pain. The patient will usually refuse to bear weight on the affected extremity. There is often diffuse swelling of the distal extremity, and vasomotor changes, including coolness or warmth, pallor or erythema, and accompanying hyperhidrosis, are present. If the complex regional pain syndrome has been present for an extended period of time, the patient may develop trophic skin changes, with alterations in the nails, hair, and pigmentation.

The pathophysiology of this syndrome is unknown, but it appears to be owing in part to immobilization. The cause of the immobilization, which is usually self-induced, remains unclear. Several authors have reported that children with complex regional pain syndrome tend to demonstrate psychosocial stress or psychopathological trends, including a tendency to somaticize.38-41 Psychotherapy is therefore thought to be as an important therapeutic intervention in many patients.

As in other pain syndromes, laboratory studies are negative in this syndrome. Bone radiographs in the adult patient characteristically reveal a patchy osteoporosis, but children do not uniformly have demineralization, and when it occurs it is usually only diffuse, mild osteopenia. Arterial Doppler ultrasonography may show decreased flow on the affected side. Bone scintigraphy utilizing 99mTc-labeled phosphate or polyphosphates may be abnormal, showing diffusely increased (and sometimes decreased) uptake in the juxta-articular tissues of the affected distal extremity. The MRI may show edema in the bones and/or marrow. These imaging abnormalities are not specific, and therefore they are not necessary to diagnose a patient with the typical signs and symptoms of complex regional pain syndrome.

Multiple treatment modalities have been suggested to break the pain cycle and to reduce increased sympathetic tone, but it is clear that early mobilization is the single most critical intervention. Therefore, the mainstay of treatment is physical therapy to encourage the child to use the affected limb.34,35,42,43 Immobilization is contraindicated and only aggravates the pain and edema. The family should be taught range-of-motion exercises that should be done frequently throughout the day. The regimen may include contrast baths with cold and heat application, and superficial desensitization techniques, such as rubbing or massaging. Patients and their families should understand that although these maneuvers will be painful initially, perseverance with a regular exercise routine will ultimately be rewarded with relief. With aggressive therapy, many children with early complex regional pain syndrome are quickly able to resume weight bearing.

Psychotherapy, biofeedback, and cognitive behavioral therapy (CBT) may be efficacious in children who do not have rapid resolution with physical therapy, analgesics, and desensitization techniques. One study of 28 children with complex regional pain syndrome showed that cognitive behavioral therapy was more important than the frequency of physical therapy in the treatment of complex regional pain syndrome.44 Other treatments studied include continuous peripheral nerve blocks45 and regional anesthetic and surgical approaches (including sympathetic or somatic nerve blocks, spinal cord stimulation, and surgical sympathectomy).44-49 However, such techniques are rarely necessary in children: In most case reports and series, pediatric patients generally achieve complete resolution of their pain and disability with active physical therapy with or without cognitive behavioral therapy.34,36,39,40,42,43The prognosis in children is generally good,35although relapses may occur at times of stress or following repeat trauma to the limb.

Fibromyalgia is a common but poorly understood chronic pain condition characterized by widespread musculoskeletal aching, fatigue, and sleep disturbance. The prevailing theory of pathogenesis is that it is a dysregulation of pain pathways that lead to central pain sensitization, which is marked by neurohormonal, neurotransmitter, and sleep dysregulation. Fibromyalgia is often unrecognized or misdiagnosed in adults, but the situation is even worse for children, who often have symptoms for years before the diagnosis is made.50,51 In addition, skepticism and controversy over the existence of fibromyalgia continue because of the paucity of objective abnormalities in patients diagnosed with the condition. Despite the absence of characteristic physical, laboratory, radiographic, and pathologic findings, growing evidence supports the consensus that fibromyalgia is not a psychosomatic condition.52-56

Fibromyalgia is most commonly diagnosed in women from ages 20 to 50 and is reported to occur in as many as 2% of the general population.57,58 In children, it is most prevalent in 13- to 15-year-old girls but can occur in younger children; it has been reported in children as young as 5 years old.29,59This pain syndrome was estimated to account for 7.5% of new-patient referrals to the U.S. pediatric rheumatology disease registry, reported in 1998.60In large population-based studies, fibromyalgia or diffuse musculoskeletal pain similar to fibromyalgia is seen in 1.2% to 7.5% of children.61,62

The diagnosis of this syndrome is based on the presence of diffuse aching, pain and stiffness, associated clinical features, and the demonstration of multiple tender points in the absence of other physical findings. The presence of true joint swelling or other physical abnormality mitigates against this diagnosis and should prompt further evaluation for an underlying inflammatory disorder, although one should bear in mind that fibromyalgia and rheumatic diseases not infrequently coexist.77A complete blood count, erythrocyte sedimentation rate, rheumatoid factor test, antinuclear antibody test, muscle enzyme determination, and thyroid function tests are considered in most patients to exclude other conditions. X-rays of affected areas should be normal in fibromyalgia.

The definition of fibromyalgia requires chronic pain as well as stiffness in at least 3 body areas for a minimum of 3 months. The pain is variously described as sharp, dull, constant, intermittent, burning, heavy, or numb. The hallmarks of the physical examination are the absence of abnormal physical findings and the presence of tender points, which are well described and categorized in the literature (see Fig. 207-3). The presence of at least 11 of these tender points is defined by the American College of Rheumatology (ACR) as one of the criteria for fibromyalgia. The 18 tender points are identified by digital palpation over the following anatomic sites. The tender points are found in specific anatomic sites in periarticular structures, including the muscles, ligaments, entheses (tendon insertion sites), bursae, subcutaneous tissues, and bony prominences. The ACR criteria require 11 of 18 tender points (Table 207-2)63; however, the Yunus and Masi criteria, which may be more applicable to children, require only 5 tender points, with other associated symptoms (see Table 207-3).64 Although these points are tender in patients with fibromyalgia, the patient is usually aware of the presence of these points. Patients may have increased pain sensitivity “all over” compared to normal subjects, but the tender points are characteristically more tender than “control” points.

Patients typically complain of stiffness, especially in the morning, which when coupled with complaints of joint pain may cause confusion with arthritis. Patients may also report a subjective feeling of joint swelling, usually a diffuse transient puffiness in the hands and fingers, but objective joint swelling is not present. Nonrestorative sleep (not feeling refreshed when first arising in the morning, even after adequate sleep) is a hallmark of this disorder. A sleep disturbance is common, especially difficulty with falling asleep and staying asleep, but some patients may not recognize their sleep alterations. Instead, the parents or roommate may have noticed frequent “tossing and turning” and awakening during the night. Interestingly, fibromyalgia appears to be associated with restless legs syndrome.5Some patients complain that pain keeps them up at night. Studies show that adults with fibromyalgia have a significant disturbance of alpha wave activity in stage 4 nonrapid eye movement (NREM) sleep.65A study of children with fibromyalgia confirmed that they also have sleep disturbances.66

Additional associations include irritable bowel syndrome, migraine or tension headaches, paresthesias, Raynaud phenomenon, and dizziness attributed to postural orthostatic tachycardia syndrome (POTS) or neurocardiogenic orthostatic hypotension.67-69 Many patients have typical personality traits and behavior patterns, such as anxiety and depression, compulsion, overwork, and perfectionism. Mood disturbances, especially depression, are common. Familial aggregation of fibromyalgia is common in adults70 as well as among children with fibromyalgia.71,72One study found an 8-fold increase in the chances of having a first-degree relative with fibromyalgia among children wih fibromyalgia compared with controls. Specific genetic polymorphisms in genes controlling serotonin, catecholamines, dopamine and other monoamines have been reported to modify the risk of developing fibromyalgia.55,56,73In addition, there are a significant psychosocial, environmental, and family factors that may affect the development of fibromyalgia in children.74-76

Treatment

The physician should establish a supportive and understanding role with the patient and family in order to help guide the patient to recovery. The patient should be encouraged to accept responsibility for management of his or her pain. The management of fibromyalgia includes modalities to relieve pain, moderate but regular aerobic activities, improvement of sleep hygiene, returning to normal activities as much as possible, and emotional support. The first priority is to establish the diagnosis, and to reassure the patient and family that symptoms are not caused by arthritis or another mysterious and/or life-threatening disorder. A positive diagnosis, detailed explanation and establishment of a trusting therapeutic relationship provide the foundation for treatment of fibromyalgia. Just knowing the diagnosis is often a great relief to the patient and the family, who have often been evaluated by multiple doctors that minimized or dismissed the myriad symptoms. An important point is that these patients must come to understand that the aim of treatment is to reduce pain, and most importantly, to allow the return to normal or near-normal activities, but that it may not be possible to completely eliminate the pain and discomfort associated with fibromyalgia.

Various nonmedical approaches to treatment have had variable success.78,79Two approaches that have been studied in detail in adults and have been shown to be efficacious in children are exercise59,80-83 and cognitive behavioral therapy (CBT).84-89 CBT typically involves an 8 to 10 weekly sessions which usually include distraction, relaxation, and coping and stress-reduction techniques, as well as activity pacing, biofeedback, and self-hypnosis. CBT appears to be effective not only in the short term during the sessions, but benefits also appear to be maintained for months afterward. In terms of exercise, a regular physical therapy program should be recommended for muscle stretching and strengthening, and a gradually escalating aerobic exercise program, which may include bicycling, walking, or swimming, should be suggested to recondition the patient. Moreover, aerobic exercise has been demonstrated in patients with fibromyalgia to be efficacious in pain reduction.

Most reviews of existing studies agree that the combination of nonpharmacologic and pharmacologic interventions is most helpful in fibromyalgia in both adults58,87 and children.90In terms of pharmacologic treatments, conventional analgesics such as nonsteroidal anti-inflammatory agents and acetaminophen are often prescribed but are rarely effective. Likewise, other analgesics, including narcotic analgesics, are not beneficial and should not be prescribed, except for possibly tramadol, for which there is some evidence of efficacy.91,92

Treatment with medications that alter neurotransmitter balance, such as antidepressants, has been found to be helpful for some patients. Low doses of a tricyclic antidepressant (TCA) such as amitriptyline at bedtime have been found to be useful,80,87,93,94but the morning drowsiness and increased daytime fatigue that are sometimes a side effect of these medications may limit their usefulness. Other classes of antidepressants, for example, specific selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine95,96 and the more “balanced” serotonin-norepinephrine reuptake inhibitors (SNRIs) such as duloxetine,97,98have proved to be modestly effective in trials of adults with fibromyalgia. One study in adults evaluated the use of a combination of a TCA (amitriptyline) and an SSRI (fluoxetine) and found it to be effective.95Keep in mind that children and adolescents using SSRIs and SNRIs should be monitored carefully because of the possibility of increased depression and suicidality in some patients.Recently, the use of pregabalin, a gamma-aminobutyric acid (GABA) agonist used in the treatment of neuropathic pain, has been found to be modestly effective in clinical trials in adults.99,100

Generalized fatigue is a frequent complaint during many common pediatric infectious illnesses. Additionally, chronic diseases of childhood often are characterized by associated fatigue. The symptoms experienced by children with these conditions typically resolve with treatment of the acute illness or of the underlying chronic disease. In contrast, chronic fatigue syndrome (CFS) is distinguished by prolonged fatigue and associated constitutional symptoms that persist after improvement in the triggering disorder. CFS may be a debilitating illness that significantly impacts activities of daily living and family dynamics. A systematic approach directed at first ruling out identifiable causes of profound fatigue and associated symptoms is essential before arriving at the diagnosis of CFS. Through a careful history and physical exam, and narrowly focused laboratory testing based on clinical presentation, underlying diseases responsible for fatigue may be eliminated. Attention then switches to maximizing the ability to function and initiating an appropriate treatment plan. Although the specific cause of this illness remains to be elucidated and appropriate treatment strategies continue to be controversial, a multidisciplinary, holistic, symptom-based approach can provide the best tools for managing CFS and achieving full recovery.

The symptoms of chronic fatigue syndrome-like illnesses had been described in adults for many years, even prior to the acceptance of specific diagnostic and research criteria.1 However, the recognition that this illness affects children is a relatively recent phenomenon. Bell and colleagues initially described a cluster of pediatric patients who presented during the late 1980s with symptoms consistent with chronic fatigue syndrome and further defined the incidence in a rural community through a retrospective review.2 Over the past several years, several published reports have demonstrated that prolonged fatigue states and chronic fatigue syndrome do indeed occur in the pediatric population, and in fact they may not be rare. Although the etiology of chronic fatigue syndrome remains unknown, reports of clusters of cases imply that environmental triggers, such as infection, may play a role.

Children of all ages may present with chronic fatigue syndrome but evidence suggests that it is more common in the adolescent population than in younger children. The incidence and prevalence of chronic fatigue syndrome in children are somewhat difficult to assess given the absence of specific pediatric criteria, geographical variations, and other variables. Nonetheless, the few available data are fairly consistent: A study in Australian children reported an overall prevalence of 37 per 100,000,3 whereas the retrospective study done by Bell in the United States reported an estimated prevalence of 23/100,000.2 As is the case in adults, pediatric chronic fatigue syndrome seems to be more common in girls, with an overall female to male ratio of 2:1, although some studies have failed to demonstrate such a female predominance.2 In addition, children in higher socioeconomic groups appear be affected more frequently.4

As in adults, the specific mechanisms through which children develop chronic fatigue syndrome remain unknown. Many theories have been proposed regarding the etiology of chronic fatigue syndrome. These have included immune dysfunction,5,6 dysregulation of the hypophyseal-pituitary axis,7 chronic infection and alterations in the autonomic nervous system9 or in the metabolic response to stress. However, to date, there is no convincing evidence for a single genetic or environmental cause. Most specialists agree that the manifestations of chronic fatigue syndrome are likely multifactorial, with both physiological and psychological factors playing a role in development of the condition. Similarly, specific genetic influences on the development of chronic fatigue syndrome remain unknown, though the observation that chronic fatigue syndrome and related disorders appear to be more common within certain families suggests a possible heritable factor. The development of more sophisticated methods of genetic analysis may provide insight into the influence of inheritance on chronic fatigue syndrome.10

As long as specific pediatric criteria for chronic fatigue syndrome have not been established, the adult diagnostic criteria established by the Centers for Disease Control and Prevention (CDC) in 1988 and modified in 1994 must serve as a framework upon which to establish a likely diagnosis in children.1 Per current revised CDC criteria, following a careful exclusion of identifiable causes, diagnosis may be made if the patient meets both of the following criteria:

1. 1. Clinically evaluated, unexplained persistent or relapsing chronic fatigue that is of new or definite onset, is not the result of ongoing exertion, is not substantially relieved by rest, and results in substantial reduction in previous levels of occupational, educational, social, or personal activities.

   2. The concurrent occurrence of four or more of the following symptoms: substantial impairment in short-term memory or concentration; sore throat; tender lymph nodes; muscle pain; multijoint pain without swelling or redness; headaches of a new pattern, type, or severity; unrefreshing sleep; postexertional malaise lasting more than 24 hours.

These clinical criteria for identifying patients with possible chronic fatigue syndrome represent common pediatric symptoms that may be seen in a broad swath of childhood illnesses. For example, sore throat and tender lymph nodes may be present during acute viral infection or in the setting of streptococcal pharyngitis. Myalgias and arthralgias may be suggestive of acute infection, primary muscle disease, benign hypermobility syndrome, or chronic inflammatory diseases. Headaches and alteration in memory may occur secondary to infections, inflammatory diseases, mass lesions, or new-onset headache disorder. Additionally, the primary symptom of prolonged fatigue may be present secondary to altered sleep as a result of obstructive sleep apnea, or due to chronic diseases including anemia, rheumatologic conditions, malignancy, chronic infection, and hypothyroidism. Given these considerations, the potential differential diagnosis for a child presenting with fatigue and associated constitutional symptoms is broad. In addition to carefully reviewing the medical condition of children with suspected chronic fatigue syndrome, a thoughtful psychosocial assessment is essential for ruling out psychiatric illness, social factors such as disruption of family dynamics, or other stressors that may present with somatic symptoms.

Because many pediatric diseases can manifest with symptoms similar to those of chronic fatigue syndrome (CFS), this illness remains a diagnosis of exclusion. The first step in evaluating a pediatric patient for possible CFS is to obtain a detailed history (both medical and psychosocial) directed at diagnosing recognizable diseases that require a specific treatment plan. Additionally, performing laboratory studies in order to evaluate basic parameters, as well as focused laboratory testing based on information gathered via history and physical exam, is prudent. The Centers for Disease Control and Prevention (CDC) has recommended that adults undergoing consideration for possible CFS have basic laboratory testing as summarized in Table 208-1. These tests should also be considered in children presenting with possible CFS. Further laboratory testing, imaging, or other studies should be conducted in a focused manner based upon the history and physical exam. Although the currently accepted CDC diagnostic criteria for adults require fatigue greater than 6 months for the diagnosis of CFS, the pediatric literature suggests that this diagnosis may be more appropriately made earlier in children. A general algorithm for assessment of children with possible CFS is presented in Figure 208-1.

The treatment of children with chronic fatigue syndrome should be directed toward relief of the specific primary symptoms manifested by the individual patient. Therapy should be multidisciplinary, focused on maintaining ability to function in activities such as school, sports, and social interactions. Medical therapy primarily consists of appropriate analgesics such as acetaminophen or nonsteroidal anti-inflammatory medications to treat musculoskeletal pain or symptoms such as headache. Evidence suggests that some patients with CFS also are affected by the postural orthostatic tachycardia syndrome (POTS).11 Patients with primary symptoms such as lightheadedness or dizziness with change in body position may feel better with medications such as fludrocortisone, alpha-agonists, or beta-blockers, and these are often helpful in children with POTS-like symptoms complicating chronic fatigue syndrome, too.

A significant percentage of children with significant prolonged fatigue may experience comorbid depression, anxiety, or other psychiatric illnesses, either as a preexisting condition or as a reaction to illness. Antidepressants, anxiolytics, or other psychotropic medications, may be indicated in these individuals at least in the short term to potentiate other interventions. Additionally, among the complex components of chronic fatigue syndrome, there is often a significant psychosocial contribution. Not surprisingly, therefore, cognitive behavioral therapy (CBT) typically has a salubrious effect. In a study of adults, CBT was more effective in restoring psychological well-being and exercise tolerance than either a conventional medical therapy or a program of education and support.12 Studies in adolescents with chronic fatigue syndrome have also suggested that CBT is an important component of treatment promoting improved ability to function and long-term outcome.13

The specific recommendations for physical exercise in children with chronic fatigue syndrome (CFS) remain controversial. Additionally, studies in adults have been somewhat conflicting in determining whether aerobic capacity is impaired in patients with CFS.14 Nonetheless, a program of graded aerobic exercise consisting of a 1:3 ratio of exercise time to rest is currently recommended by the CDC. Overly vigorous exercise may lead to increased post-exertional malaise with recurrent cycles of relapse (the so-called over training syndrome). This presents a particular problem in the management of the child and adolescent with CFS, because it is often difficult for children to self-regulate their activities. Conversely, children with CFS often feel worse in the short term after exercising, so in order to avoid either excessive or inadequate exertion, careful oversight of exercise programs is important. Regular aerobic exercise may also help children adjust the disrupted sleep patterns that typify CFS. Therapeutic goals should include restoring normal sleep–wake cycles through appropriate sleep hygiene characterized by consistent bedtime and elimination of napping.

Because symptoms of chronic fatigue syndrome may persist for prolonged periods of time, it is essential to also focus on maintaining the ability of the child to function, particularly in the school environment. The practitioner should advocate for appropriate educational accommodations while promoting the affected child’s school attendance. An individualized educational plan often facilitates active school participation, augmented by supportive services such as tutoring as needed. In a study by Lim et al, adolescents with chronic fatigue syndrome were treated using a 4-week in-patient program incorporating gradual reintroduction of physical activity, psychological therapy, and reintroduction into the school environment. Although 66% of patients were not attending school prior to the program, 78% were able to attend school full time at long-term followup. No control group was reported, but these data still support the idea that multidisciplinary treatment may be effective in promoting the ability of individuals to cope with symptoms of chronic fatigue syndrome.15

The prognosis for children and adolescents with chronic fatigue syndrome appears to be more favorable than that of adults. Krilov et al. reported that on long-term follow-up, approximately 95% of patients were somewhat improved, whereas 43% noted complete resolution of symptoms.16 Additionally, in a 13-year follow up of the patient population originally described by Bell et al., approximately 80% of patients reported improvement with 37% reporting that the illness had completely resolved.17 This is not to say that the condition may be taken lightly, or that good outcomes may be assumed without expert management. As with many pediatric conditions, however, the combination of early aggressive therapy with a child’s natural resilience does allow caregivers to be optimistic when explaining expectations for children with chronic fatigue syndrome.

Autoinflammatory syndromes, formerly known as periodic fever syndromes, are defined as recurrent attacks of often unprovoked systemic inflammation that are related to a lack of adequate regulation of the innate immune system.1-3 Unlike autoimmune diseases, these conditions are not generally marked by autoantibodies or autoreactive T cells. Many of these syndromes have a genetic etiology3,4 (eTable 209.1) involving the excessive production and activity of interleukin (IL)-1β.5 The conditions are no longer known as periodic fever syndromes, 6-8 because most are not truly periodic nor is fever a necessary feature.

As understanding of the pathogenesis of autoinflammatory syndromes increases, so does the spectrum of conditions that may be included within this category. Thus, systemic juvenile idiopathic arthritis, genetic inflammatory granulomatous diseases (early onset sarcoidosis and Blau syndrome) and Behçet disease (eTable 209.2) are now considered to be autoinflammatory disorders, although this chapter will be limited to conditions that do not fall into other diagnostic categories.

These syndromes should be suspected in patients, mainly young children, with recurrent fever unexplained by infections and/or with episodic symptoms in various systems, especially the skin, gastrointestinal tract, joints, and eyes. A complete history and physical examination are crucial, and often careful determination of the organ systems involved, age of onset, length of attacks, intervals between attacks, and triggering events will allow the correct diagnosis to be suspected before genetic tests are performed (Tables 209-1 and 209-2). It is very useful to examine patients during an attack or if not possible, to ask parents to record attacks carefully in a diary and send pictures of relevant physical findings.

Autoinflammatory syndromes also should be considered in patients with unexplained elevations of acute phase reactants, even in the absence of symptoms. It is also useful to measure markers of inflammation during and between attacks, as in some syndromes attacks are only the “tip of the inflammatory iceberg” and patients consistently have increased inflammatory indices. These patients are at higher risk of developing amyloid A (AA) amyloidosis, the major adverse outcome of the autoinflammatory syndromes (eTable 209.2). A family history often reveals relatives with similar symptoms, including unexplained cases of renal failure or amyloidosis. Specific autoinflammatory syndromes often show a predilection for certain ethnic groups.

Familial Mediterranean fever (FMF), first described in 1945, is the most common inherited autoinflammatory syndrome.9 It is an autosomal recessive disorder that results in recurrent attacks of fever, serositis, arthritis, and rash. Late complications of untreated FMF include the development of renal AA amyloidosis leading to the nephrotic syndrome and renal failure. The highest prevalence of FMF is in Sephardic Jews, Armenians, Arabs, and Turks. Because of the availability of genetic diagnosis, FMF is now recognized more frequently among Ashkenazi Jews, Greeks, and Italians as well.10,11 A national study in Turkey found a prevalence of 0.093%.12The prevalence of FMF among Sephardic Jews varies from 1:100 to 1:2000 (carrier rate of 1:5 to 1:45) and 1:87 to 1:1000 (carrier rate 1:7 to 1:32) among Armenians.13,14

Pathophysiology and Genetics

The familial Mediterranean fever gene (MEFV) has been localized to the short arm of chromosome 16.15-17 The product of this gene is a 781 amino acid protein termed pyrin (marenostrin in Europe). There may be a phenotype–genotype correlation with more severe disease and amyloidosis occurring in patients with the M694V, M694I, and M680I mutations.18 However, not all patients have homozygous or compound heterozygous pyrin mutations. In various series, between 30% to 70% of patients diagnosed with definitive familial Mediterranean fever by clinical criteria lack one or even both mutations, especially patients from Western Europe or the United States.19-21 In some families transmission of the condition appears to be autosomal dominant.22Mutations or polymorphisms in genes other than pyrin may impact the development of familial Mediterranean fever or the severity of the disease, including the development of amyloidosis.18,23

The pyrin protein consists of three main domains, the N-terminal 92 amino acid pyrin domain, the B-box, and the C-terminal B30.2 domain. Most mutations occur in exon 10 of the MEFV gene encoding the B30.2 domain.4 The pyrin protein plays a role in apoptosis and regulation of the innate immune response, mainly via the pyrin domain. Pyrin directly interacts with and binds to caspase 1 and inhibits the conversion of pro IL-1β to IL-1β.24,25 Mutations in the B30.2 region of pyrin, particularly those mutations considered more severe (positions 680 and 694) interfere in this binding process, thus contributing to increased levels of IL-1β and inflammation. Increased levels of IL-1β and inflammation with and without stimulation by exogenous stimuli have been demonstrated in mouse models and in people with pyrin mutations.4

Clinical Features

Clinical signs of familial Mediterranean fever develop by age 10 in 80% of patients and by age 20 in 90%.8,27,28 A typical attack of familial Mediterranean fever results in a 12- to 72-hour attack of fever, serositis, and monoarthritis of the knee or ankle, often accompanied by an erysipelaslike rash over the involved joint. Severe abdominal pain that may mimic peritonitis or appendicitis accompanies fever in nearly 90% of patients. Other symptoms related to serositis include pleuritis (30–45% of patients), pericarditis, and scrotal swelling. Acute arthritis is seen in 50% to 75% of patients and is characterized by massive neutrophilic effusions. It usually resolves within one week, though in 5% to 10% of cases the arthritis takes a chronic course, especially in the hip and sacroiliac joints.

Since the discovery of the genetic cause of familial Mediterranean fever, additional presentations of the condition have been recognized. These include recurrent abdominal pain of childhood, recurrent arthritis without fever, prolonged febrile myalgia, and exercise-induced myalgia.7,8 Less commonly, vasculitis may be a manifestation of an MEFV mutation, especially Henoch-Schonlein purpura or polyarteritis nodosa.28-30 For unclear reasons, the course of polyarteritis nodosa related to FMF is usually more benign than the idiopathic form. Children with frequent attacks and a chronic increase of inflammatory indices often have growth abnormalities and short stature. Splenomegaly is also common.

Amyloidosis

Prior to the discovery of colchicine as an effective therapy for familial Mediterranean fever by Goldfinger in 1972,31 amyloidosis was the major cause of morbidity and mortality. Amyloidosis usually presents with proteinuria and progresses to the nephrotic syndrome and renal failure within 3 to 5 years. Rarely familial Mediterranean fever can present with amyloidosis (“type II phenotype”). Later manifestations include signs of gastrointestinal involvement such as abdominal pain, diarrhea, malabsorption, and weight loss, as well as cardiomyopathy, macroglossia, joint stiffness, bleeding disorders, and peripheral neuropathies.

Risk factors for the development of amyloidosis include the particular genotype, especially patients homozygous for 694 and 680 mutations, family history of amyloidosis, geography of the patient (less amyloidosis in the United States), male gender, serum amyloid A genotype (there is an odds ratio of 7 for patients with an α/α genotype), and poor compliance with colchicine therapy.8,32

Amyloidosis should be suspected when regular screening urinanlysis demonstrates proteinuria. Renal biopsy then confirms the diagnosis, though less invasive diagnostic methods such as subcutaneous abdominal fat aspiration, rectal biopsy, and nuclear 123I labeled scan for serum amyloid P-component may be considered.33,34 The latter method can also be used to monitor the total body load of amyloid.34 Treatment once amyloidosis has developed is generally limited to minimizing its progression by controlling inflammation. A novel agent to decrease or inhibit fibril formation by blocking polymerization of serum amyloid A, eprodisate disodium, has recently been shown to slow the decrease in creatinine clearance, though very few patients actually have a marked improvement in their amyloidosis.35

Diagnosis

Diagnostic criteria for familial Mediterranean fever were described in 1997 based on the clinical pattern, ethnicity, family history, and response to colchicine.36 Laboratory tests are nonspecific and reflect elevated acute phase reactants. Elevations in the erythrocyte sedimentation rate, C-reactive protein, leukocyte count, fibrinogen, and serum amyloid A are usually present during attacks and frequently also between attacks. Serum amyloid A levels may be useful in monitoring treatment efficacy.37 The diagnosis should not rely only on genetic testing because at least 30% of familial Mediterranean fever patients are either heterozygote for the MEFV gene or do not show any mutations when tested in commercial laboratories.19-21 Questions regarding the testing of relatives of patients with genetically proven familial Mediterranean fever, and concerning the management of asymptomatic patients with homozygote genetic mutations, remain controversial.

Treatment

Treatment with colchicine (1–2 mg/day) is effective in preventing amyloidosis in nearly all patients and in preventing attacks in 60% to 70% of patients.31,38-42 However, 20% to 30% of patients are only partially responsive to maximal tolerated doses of colchicine, whereas 5% of patients are totally unresponsive and continue to have frequent attacks. Unresponsive patients may include those with more severe genetic mutations or patients with modifying genes that may inhibit the activity of colchicine, such as polymorphisms in MDR-1 P-glycoprotein pump transporter genes that result in lower intracellular concentration of colchicine.43 Good compliance is crucial; in some patients missing even one dose of colchicine can precipitate an attack.

Colchicine is generally well tolerated. The most common adverse effects include abdominal pain and diarrhea, especially in those receiving higher doses of colchicine and in patients with lactose intolerance.8,42 These effects are usually transient and respond to gradual dose changes, dividing the daily dose, lactose avoidance, and antidiarrheal and antibloating agents. Other rare adverse effects include myalgia/myositis, peripheral neuropathy, and bone marrow suppression. Colchicine dose not affect growth or development. Currently, there are no safe and effective alternatives for those who fail or do not tolerate colchicine. Corticosteroids are effective only for prolonged febrile myalgia and familial Mediterranean fever–related vasculitis.28

Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), an autosomal recessive disease, was first described in 1984 in 6 Dutch patients.44 The mean age of onset is 6 months, with greater than 70% of patients having the first episode prior to 12 months of age.45 The disease is seen mainly in the Netherlands and Western Europe.

Pathophysiology and Genetics

HIDS is actually a metabolic disease caused by mutations in the MVK gene on the long arm of chromosome 12, encoding mevalonate kinase.46,47 The vast majority of patients have mutations in the V377I (founder gene) and I268T positions.48 Mutations result in an unstable enzyme that is less active than the wild type, particularly when patients are febrile. Hence attacks are often precipitated by infection and by vaccines that are pyrogenic.49 The cause of the fever and other symptoms is not clear, but it appears that a deficiency of geranylgeranyl and other isoprenoid substrates, rather than excessive mevalonate, is responsible for effecting inflammation.50 One theory is that this deficiency affects IL-1β processing through effects on R-type GTPase, dependent on prenylation. Total absence of MVK results in mevalonic aciduria, a syndrome characterized by severe neurologic sequelae in addition to febrile episodes (see Chapter 137).

Clinical Features

Attacks typically occur every 3 to 6 weeks and last for 3 to 7 days. Besides fever, patients develop a maculopapular, often mobiliform, rash, abdominal pain with vomiting and diarrhea, cervical lymphadenopathy, arthralgia or arthritis, and oral and genital ulceration (Fig. 209-1). Amyloidosis is a rare complication of HIDS (<3%).51

Diagnosis and Treatment

Acute phase reactants are elevated during attacks. IgD levels are usually elevated above 100 IU/ml, and IgA is elevated in 80% to 90% of patients. Mevalonate kinase activity is decreased and urinary mevalonic acid is elevated, mainly during attacks.52 Homozygous genetic mutations are present in 75% of patients.53 However, HIDS may be seen in patients without genetic mutations when tested commercially (termed “variant HIDS”). If clinical suspicion is high, serum IgD and either MVK genetic testing or urinary mevalonic acid should be obtained.8 False-positive causes of increased IgD levels (usually not to the degree in HIDS) include other autoinflammatory diseases, HIV, diabetes mellitus, smoking, and pregnancy. In patients younger than age 3, normal IgD levels may represent a false-negative test.

NSAIDs have some symptomatic benefit. Colchicine, thalidomide, and corticosteroids are ineffective. Simvastatin may reduce the number of febrile days but has no effect on the frequency of attacks.54 Case reports also suggest occasional benefit from montelukast, etanercept, and anakinra.55,56 Regardless of treatment, attacks usually decrease in severity and frequency over time.8

First described in 1982 as familial Hibernian fever, the gene mutation for the autosomal dominant disorder tumor-necrosis factor receptor associated periodic syndrome (TRAPS) was discovered in 1999.57,58 TRAPS is the most common autosomal dominant autoinflammatory disorder. Although initially described in patients of Irish or Scottish descent, TRAPS is found in all ethnic groups. TRAPS presents in 75% of cases during the first decade of life (median age 3), but it can present at any age. There is a slight male predominance (3:2).

Pathophysiology and Genetics

The TRAPS gene (TNFRSF1A) has been localized to the short arm of chromosome 12.58 The product of this gene is the 55 kDa TNF cell membrane receptor. There is a phenotype-genotype correlation with more severe disease and amyloidosis occurring in patients with cysteine residue mutations that alter protein structure.8 Milder mutations of low penetrance, including R92Q and P46L are frequently seen in normal controls (up to 9% of the population).4 These mutations may not be pathogenic by themselves but may contribute to other still unclear causes of increased inflammation. Decreased shedding of mutated membrane-bound TNF receptors was thought to explain the unopposed serum TNF effects observed in TRAPS.59

However, it is now clear that not all mutations result in defective shedding. The pathogenesis of TRAPS may involve defects in TNF induced apoptosis and stimulation of intracellular inflammatory pathways. This also may result in a decrease in the concentration of surface receptors.

Clinical Features

Attacks typically last 1 to 6 weeks, and occur 2 to 6 times per year, commonly triggered by exercise.60-63 They are marked by fever as well as serositis (abdominal, chest and testicular pain), conjunctivitis, arthralgia and myalgia. Two unique features are periorbital edema and a painful, distally migrating, erythematous rash (Fig. 209-1B). This rash represents a mononuclear perivascular infiltrate of the subcutaneous fascia and occasionally panniculitis. Patients with certain mutations, particularly R92Q, may develop a shorter and milder attack, with involvement of the pharynx and oral ulcerations. Less common manifestations include recurrent pericarditis and central and focal neurologic abnormalities. Amyloidosis develops in 14% to 25% of patients, particularly those with cysteine mutations and a family history of amyloid (Fig. 209-1B).8

Diagnosis and Treatment

Unlike other autoinflammatory diseases in which genetic abnormalities are only supportive of the diagnosis, the identification of TRAPS is based on finding a genetic mutation in the TNFRSF1A gene. Amyloidosis develops in 14% to 25% of patients, particularly those with cysteine mutations and a family history of amyloid.8

Nonsteroidal anti-inflammatory drugs (NSAIDs) may be effective for mild attacks. Corticosteroids are often beneficial for severe attacks, but escalating doses are often required as the efficacy tends to decrease over time. Colchicine is not effective.

In view of the role of defective shedding of the TNF receptor in the pathogenesis of TRAPS, researchers hypothesized that etanercept, a soluble TNF fusion protein receptor developed for the treatment of inflammatory arthritis, would be beneficial. Initial case reports supported this hypothesis.63,64 However, follow-up indicates that etanercept is not effective in all patients, and in others it loses effectiveness over time. Anti-IL-1 medications such as anakinra may be effective in such cases.65 In general, aggressive therapy with the TNF receptor binding antagonist etanercept or anti-IL-1 agents such as anakinra should be reserved for patients with severe disease or those at increased risk of developing amyloidosis.

Three autosomal dominant syndromes that constitute the cryopyrin-associated periodic syndromes (CAPS). All are caused by single base mutations on the CIAS1/NALP3 gene located on the long arm of chromosome 1 encoding the protein cryopyrin.66,67 Some mutations are specific to one of the syndromes and some mutations overlap among all three syndromes (eTable 209.1).65,66 Often, especially in patients with neonatal-onset multisystem inflammatory disease, no mutations are found. Thus, as with other autoinflammatory syndromes, it is clear that other factors influence the development and severity of CAPS.68

The cryopyrin protein contains an N-terminal pyrin domain and has an important role in regulation of the assembly of the inflammasome (Fig. 198-1). This is a group of proteins that, once assembled, activates caspase-1, leading to cleavage of pro-IL-1β to active IL-1β. Mutations of cryopyrin protein probably increase the rate of spontaneous inflammasome assembly.68,69 Cryopyrin is present mainly in neutrophil cells and chondrocytes, explaining the target organs of these diseases.

The three diseases that compose CAPS are considered variants of the same process, varying by severity of symptoms, systems involved and outcome.68,70 All respond dramatically to anti-IL-1 therapy.

Familial Cold Autoinflammatory Syndrome (FCAS)

Familial cold urticaria familial cold autoinflammatory syndrome (FCAS), the mildest of the CAPS, was first described in 1940 and the genetic mutation discovered in 2001.71 Most FCAS patients are located in the United States. Almost all patients have a genetic mutation in the CIAS1/NALP3 gene. FCAS often starts at birth and is apparent in 95% of the patients by 6 months.

Typically, the attack starts 2 to 3 hours after generalized cold exposure (as opposed to the direct contact that triggers cold-induced urticaria). Patients develop an urticarial like rash that starts on the extremities and spreads to the trunk, low-grade fever, arthralgia, conjunctivitis, nausea, extreme thirst, sweating and headaches. The attack peaks at 6 to 8 hours and lasts up to 24 hours. The frequency of attacks is variable, but they may occur with debilitating regularity. The rash is not true urticaria (mast cells), rather there is a perivascular polymorphonuclear cellular infiltrate in the dermis. Amyloidosis is a rare complication of FCAS (2–4%).

NSAIDs and antihistamine therapies are not effective. Corticosteroids may alleviate symptoms but the magnitude and frequency of effective doses may result in significant adverse effects. Anti-IL-1 agents are very effective in alleviating symptoms. In a recent controlled trial, rilonacept a fusion protein soluble IL-1 receptor, has been shown to be effective.72,73

Muckle-Wells Syndrome (MWS)

Muckle-Wells syndrome (MWS), the CAPS of intermediate severity, was described in 1962 and the genetic mutation was found together with that of FCAS in 2001.66,74 MWS starts later in life than FCAS and can appear at any age. Most cases are in Europe. Genetic mutations in the CIAS1/NALP3 gene are found in 65% to 75% of patients.

Attacks are usually not triggered by cold exposure. A typical attack includes fever, rash, arthralgia, arthritis, myalgia, headaches, conjunctivitis, episcleritis and uveitis. Attacks are more persistent than those of FCAS, lasting up to 3 days. Fifty to seventy percent of patients develop sensorineural hearing loss that typically starts in adolescence. Amyloidosis develops in 25% of patients with MWS.74,75 MWS also responds dramatically to anti- IL-1 therapy.75,76

Neonatal-Onset Multisystem Inflammatory Disease (NOMID)

Neonatal-onset multisystem inflammatory disease (NOMID), in Europe called chronic infantile neurologic, cutaneous, articular syndrome (CINCA), is the most severe of the CAPS. It was first described in 1981, and the association with the CIAS1/NALP3 gene was reported in 2002.67,77 However, only about 50% to 60% of patients have mutations in this gene.

The onset of NOMID is at or within several weeks of birth.69,78,79 Up to half of affected infants are born prematurely. Patients present with an urticaria like rash and fever, often occurring daily. They also have symptoms related to chronic aseptic meningitis such as headaches, irritability and vomiting. Late neurologic complications include hydrocephalus, developmental delay, mental retardation, and hearing loss. Ocular findings include conjunctivitis, uveitis, and papillitis of the optic nerve, resulting in visual loss. By about age 2, 50% of patients have developed a severe arthropathy, consistently mainly of cartilage growth abnormalities leading to severe pain, metaphyseal and epiphyseal overgrowth, ossification irregularities, deformities, and disabilities. There is little synovial inflammation in NOMID. Patients have typical morphological changes including short stature, frontal bossing, macrocephaly, saddle nose, short, thick extremities with clubbing of fingers, and wrinkled skin. About 20% die by age 20 and others develop amyloidosis.

NSAIDs, antihistamines, corticosteroids, colchicine, methotrexate, and other immunosuppressive medications are marginally effective and do not change the disease course. One case report showed that etanercept was effective, mainly for the arthropathy.80 Anakinra, a recombinant IL-1 receptor antagonist, is dramatically effective in treating the rash, fever, and meningitis of NOMID, with normalization of acute phase reactants and a steroid-sparing effect.81-83 However, existing joint damage and mental retardation are not reversible. Early recognition and treatment are crucial in preventing long-term damage and disability.

Pyogenic sterile arthritis, pyoderma gangrenosum, acne syndrome PAPA was first described in 1997 and has been reported mainly in Europe.84 PAPA usually presents in the first decade of life, but can become manifest at any age. It is the result of mutations on the long arm of chromosome 15 in the PSTPIP1 gene encoding the CD2 antigen-binding protein.85 This cytoskeleton protein also binds to pyrin, thereby enabling its function.86 Similar to FMF, mutations in PSTPIP1 may affect IL-1 activity. The protein also inhibits apoptosis.

Clinical Manifestations84

Attacks are often triggered by minor trauma, resulting in fever, and massive neutrophilic joint effusion primarily affecting large joints. Patients also may develop pyoderma gangrenosum, severe acne (mainly during adolescence) and diabetes mellitus.

Treatment and Outcome

Intra-articular corticosteroid injections and surgical drainage do not affect outcome. Case reports suggest that anti-TNF agents and anakinra may be effective.87,88

If incompletely controlled, PAPA results in progressive destructive arthritis, skin scarring from acne, and significant depression from the severe sequellae of the disease. Longevity often depends on whether diabetes develops.

Periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) is probably the most common periodic fever syndrome in childhood and was initially described in 1987.89 The etiology in unknown. Although no specific genetic mutations have been found, familial cases of PFAPA are known and many Middle Eastern patients have heterozygous FMF mutations.

Clinical Features

The onset of PFAPA is usually in early childhood (<5 years).90-92 This is the only autoinflammatory syndrome that is truly periodic with attacks occurring usually every 21 to 28 days and fever lasting 5 to 7 days. Patients usually report a prodrome of feeling unwell several hours before the start of an attack. Pharyngitis and cervical adenopathy are present in 80% to 100% of patients and aphthous stomatitis in 60% to 70%. Patients also frequently have abdominal pain, nausea/vomiting, arthralgia, and headaches.

Diagnosis and Treatment

Diagnostic criteria have been defined for children with typical clinical features. In addition, patients must be completely asymptomatic between attacks, exhibit normal growth and development, and not have cyclic neutropenia.90 Other autoinflammatory syndromes, particularly TRAPS or HIDS, need to be considered in patients with atypical features or in those who are not completely well between attacks. Patients have increased acute phase reactants during attacks, which normalize between attacks. Some patients have a mild increase in IgD and some have heterozygous mutations of other autoinflammatory genes, especially MEFV.91

A single dose of prednisone (0.6–2 mg/kg) at the onset of symptoms usually aborts that attack,90-92 though it may also decrease the intervals between attacks. Cimetidine is effective as a prophylactic agent in about 33% of patients (40 mg/kg/day, in 2 divided doses),90,93 although it usually does not abort attacks. Recent reports suggest that tonsillectomy is curative in nearly all patients.94,95

The natural course of PFAPA in untreated patients is benign. The frequency and severity of attacks diminish over time, and PFAPA usually resolves fully during the second decade of life.90,91,95 Amyloidosis is not a complication of PFAPA.

Chronic recurrent multifocal osteomyelitis (CRMO) was first described in 1972.96 The disease is usually sporadic and the etiology unknown. The median age of onset is 10 years. Several related autoinflammatory bone disorders have been found to have a genetic etiology.97 A rare autosomal recessive disorder of CRMO with congenital dyserythropoietic anemia (Majeed syndrome) is associated with mutations in the LPIN2 gene.98,99 Cherubism, an autosomal dominant chronic inflammatory disease of excessive bone degradation of the upper and lower jaws followed by development of fibrous tissue masses, is associated with mutations in the SH3BP2 and possibly PTPN11 genes.100 A mouse model of CRMO with mutations in the PISPIP2 gene has been described.101

Patients with CRMO develop recurrent episodes of bone pain and fever. Bone lesions include osteolytic lesions surrounded by sclerotic bone, especially in the metaphysis of long bone. Any bone may be involved, particularly the clavicle and ribs, and asymptomatic lesions may be demonstrable on technetium bone scan. Bacterial cultures of biopsies are negative. Other associated clinical findings may include synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO syndrome), isolated palmoplantar pustolosis, psoriasis, sacroiliitis, inflammatory bowel disease, and pyoderma gangrenosum.102

The natural history of CRMO is waxing and waning symptoms, often with spontaneous remissions and healing of lesions followed by relapses. In the past patients were thought to have a good long-term prognosis, but recent studies have found chronic disease in about 50% of patients. Without treatment, chronic bone deformities, leg length inequality, and disability are common.103,104

Antibiotics are usually not effective. Some patients respond to NSAIDs. Others may benefit from corticosteroids, methotrexate, sulfasalazine, azithromycin, interferon, infliximab, or bisphosphanates, especially pamidronate. No markers predicting the optimal agent for an individual patient have been reported.

Schnitzler syndrome, first described in 1972, is characterized by a chronic urticarial eruption with a monoclonal IgM gammopathy.105,106 Other findings include intermittent fever, joint, and/or bone pain with radiologic evidence of osteosclerosis, lymphadenopathy, hepatosplenomegaly, and elevated acute phase reactants. The etiology is still unknown. The disease pursues a chronic course, without remission. Traditional NSAID, colchicine, dapsone, and antihistamine therapy is usually not effective. Late evolution to a lymphoproliferative malignancy, often Walderstom macroglobulinemia, occurs in at least 15% of patients. Amyloidosis has been reported in some cases. Recently, one patient was reported to respond dramatically to anakinra.107

There are rare cases of FMF+TRAPS, HIDS+TRAPS, and CAPS+TRAPS.108,109 Often these patients have the R92Q TNFRSF1A and E148Q MEFV mutations. These overlap cases may express more severe manifestations of autoinflammatory disease with “mixed” characteristics.

Autoinflammatory gene mutations also may play a role in the severity and clinical presentations of other diseases including Behçet disease, inflammatory bowel disease, juvenile idiopathic arthritis, and palindromic arthritis.110-113 Most recently, reports have suggested that these gene mutations may affect the outcome of septic shock and may increase the risk of secondary amyloidosis and the development of atherosclerotic plaque.114,115