Key points

Introduction

The entity of chronic recurrent multifocal osteomyelitis (CRMO) was introduced in 1978, with the description of 9 patients between the ages of 4 and 26 who had inflammatory bone lesions predominantly in the clavicular region and in the metaphyses of tubular bones with associated pustulosis palmoplantaris. Deemed a sterile or aseptic autoinflammatory disorder, based on frequently negative cultures of involved sites, the disease is characterized by multiple foci of osteomyelitis with episodic bone pain. However, CRMO is now considered to be part of the spectrum of disease labeled as synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome.

The term “SAPHO syndrome” was coined in 1987 by Chamot and colleagues, who collected 85 cases with dermatologic findings, including severe acne and palmoplantar pustulosis, coupled with radiographic features of hyperostosis and osteitis. Initially named “syndrome acne-pustulosis-hyperostosis-osteitis,” the “S” was later used to signify “synovitis” when the association with inflammatory arthopathy was identified, placing the syndrome within the spectrum of spondyloarthropathies. However, this categorization remains controversial.

The same French group proposed inclusion and exclusion criteria for the SAPHO syndrome that remain widely used, but no diagnostic criteria are accepted universally ( Box 1 ). Thus, the SAPHO syndrome often is diagnosed by excluding other disease processes, such as infection and malignancy, which may delay the initiation of treatment.

Because the diagnostic label of CRMO focuses only on the osseous manifestations of this disorder, its use no longer is favored. Instead, the acronym SAPHO now is used to describe a broad variety of disorders, including CRMO, that have both osteoarticular and dermatologic manifestations. More than 50 terms have been used to describe these combinations of cutaneous and osseous findings, including sternocostoclavicular hyperostosis, acquired hyperostosis, pustulotic arthroosteitis, and acne-associated spondyloarthropathy. More recently, some have suggested that CRMO and SAPHO syndrome should be classified within the spectrum of autoinflammatory bone diseases, which includes Majeed syndrome and deficiency of interleukin-1 receptor antagonist.

The prevalence of SAPHO syndrome is estimated to be 1 in 10,000 ; however, it may be higher, because this is an underrecognized condition with a variety of clinical presentations. Initial studies revealed no gender predominance ; more recent studies have found there to be a slight, but significant, female preponderance. SAPHO syndrome is most common among children and young adults, but it can occur at any age, with most patients exhibiting a prolonged course that lasts for months to years.

SAPHO syndrome often presents with cutaneous manifestations, which can often be severe and disfiguring. Palmoplantar pustulosis is among the most common cutaneous features of SAPHO syndrome ( Fig. 1 ), with more than one-half of patients developing this condition at some point during their disease course. Other dermatologic diseases seen in patients with the SAPHO syndrome include pustular psoriasis and psoriasis vulgaris. The occurrence of SAPHO syndrome and spondyloarthropathies in the setting of psoriasis supports a pathophysiologic relationship between these diseases. Hidradenitis suppurativa is another dermatologic manifestation that commonly occurs in patients with SAPHO syndrome, the more aggressive lesions of which often are associated with erosive arthropathy. The coexistence of cutaneous signs with osteoarticular symptoms, such as pain in the jaw, anterior chest wall, back, buttocks, and peripheral joints, which frequently are intermittent, typically prompts further investigation with imaging that ultimately leads to a diagnosis of SAPHO syndrome.

Pustulosis palmaris of the left palm (left) and palmoplantar pustulosis of the medial sole of the right foot (right).

( From [Left] Assmann G, Simon P. The SAPHO syndrome – are microbes involved? Best Pract Res Clin Rheumatol 2011;25(3):423–34; and [Right] Zuo RC, Schwartz DM, Lee CC, Anadkat MJ, Cowen EW, Naik HB. Palmoplantar pustules and osteoarticular pain in a 42-year-old woman. J Am Acad Dermatol 2015;72(3):550–3.)

The pathogenesis of SAPHO syndrome is considered to be multifactorial. Some have hypothesized an infectious trigger with a low-virulence pathogen such as Propionibacterium acnes because of the relationship between SAPHO syndrome and acne. Bone biopsies have revealed mostly nonspecific inflammatory changes, with P acnes identified in fewer than 17% of active lesions in several case studies but in as many as 42% of patients in a metaanalysis that included individual case reports and thus was subject to reporting bias. A variety of other bacteria have been identified in biopsies both of bone and skin from patients with SAPHO syndrome, including normal skin flora such as Staphylococcus aureus , but definitive attribution of the cause of SAPHO syndrome to an infectious agent has yet to be established. Similar controversy exists regarding a potential genetic predisposition to developing SAPHO syndrome. HLA-B27 has been proposed as a potential genetic risk factor, given the resemblance between clinical features of SAPHO syndrome and those of spondyloarthropathies. However, the prevalence of HLA-B27 is only approximately 13% among patients with SAPHO syndrome.

Treatment of patients with SAPHO syndrome remains a challenge, because no randomized controlled trials of therapeutic agents have been conducted in patients with this condition. Nonsteroidal antiinflammatory drugs typically are used as initial treatment. Corticosteroids, both oral and intraarticular, can provide patients with temporary symptomatic relief. Patients with positive bacterial cultures have been treated with antibiotics, such as azithromycin, with improvement in symptoms, skin lesions, and MRI evidence of osteitis during treatment; however, this improvement has not persisted after discontinuation of antibiotic therapy. Skin disease can be treated effectively with isotretinoin and phototherapy. Bisphosphonates, such as alendronate and pamidronate, have provided some patients with symptomatic improvement and have resulted in varying degrees of objective radiographic improvement within months to years. Chronic inflammatory arthritis in patients with SAPHO syndrome has improved to varying degrees when treated with disease-modifying antirheumatic drugs, such as methotrexate. Refractory cases have been treated with tumor necrosis factor inhibitors, including adalimumab, etanercept, and infliximab, with promising initial results; however, their long-term efficacy remains unknown. Surgical treatment of osteodestructive lesions should be considered carefully, because these lesions tend to recur and sustained benefit of surgical excision has not yet been established.

Radiographic features of SAPHO syndrome differ based on the stage of disease and the anatomic region affected. Early lesions tend to be osteodestructive, whereas later lesions tend to be osteoproliferative. Chronic inflammation in medullary bone appears as osteitis and chronic inflammation of cortical bone results in hyperostosis. The anterior chest wall, including the costochondral, sternoclavicular, manubriosternal, and costosternal articulations, is involved in 60% to 95% of patients with SAPHO syndrome. The next most commonly involved sites, in approximate order of prevalence, are spine (30%–50% of adult patients), sacroiliac joints, long bones (such as the femur or tibia), and flat bones (such as the mandible or ileum).

Conventional radiographs often fail to detect lesions of SAPHO syndrome early in the course of the disease. A study of conventional radiographic imaging of 19 patients with SAPHO syndrome found that, although all patients eventually developed abnormal radiographs, abnormalities were evident in only 20% at 3 months after the onset of symptoms. In a study of 13 children diagnosed with CRMO, the sensitivity of conventional radiographs to detect structural change within 3 months of symptom onset was only 13% when compared with whole-body MRI. These studies suggest that the majority of edematous osseous lesions associated with SAPHO syndrome are evident on MRI before changes can be detected on conventional radiographs. A high index of clinical suspicion must be maintained when evaluating patients with SAPHO syndrome, because diagnostic findings may not be evident on conventional radiographs early in the course of the disease.

Introduction

The entity of chronic recurrent multifocal osteomyelitis (CRMO) was introduced in 1978, with the description of 9 patients between the ages of 4 and 26 who had inflammatory bone lesions predominantly in the clavicular region and in the metaphyses of tubular bones with associated pustulosis palmoplantaris. Deemed a sterile or aseptic autoinflammatory disorder, based on frequently negative cultures of involved sites, the disease is characterized by multiple foci of osteomyelitis with episodic bone pain. However, CRMO is now considered to be part of the spectrum of disease labeled as synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome.

The term “SAPHO syndrome” was coined in 1987 by Chamot and colleagues, who collected 85 cases with dermatologic findings, including severe acne and palmoplantar pustulosis, coupled with radiographic features of hyperostosis and osteitis. Initially named “syndrome acne-pustulosis-hyperostosis-osteitis,” the “S” was later used to signify “synovitis” when the association with inflammatory arthopathy was identified, placing the syndrome within the spectrum of spondyloarthropathies. However, this categorization remains controversial.

The same French group proposed inclusion and exclusion criteria for the SAPHO syndrome that remain widely used, but no diagnostic criteria are accepted universally ( Box 1 ). Thus, the SAPHO syndrome often is diagnosed by excluding other disease processes, such as infection and malignancy, which may delay the initiation of treatment.

Because the diagnostic label of CRMO focuses only on the osseous manifestations of this disorder, its use no longer is favored. Instead, the acronym SAPHO now is used to describe a broad variety of disorders, including CRMO, that have both osteoarticular and dermatologic manifestations. More than 50 terms have been used to describe these combinations of cutaneous and osseous findings, including sternocostoclavicular hyperostosis, acquired hyperostosis, pustulotic arthroosteitis, and acne-associated spondyloarthropathy. More recently, some have suggested that CRMO and SAPHO syndrome should be classified within the spectrum of autoinflammatory bone diseases, which includes Majeed syndrome and deficiency of interleukin-1 receptor antagonist.

The prevalence of SAPHO syndrome is estimated to be 1 in 10,000 ; however, it may be higher, because this is an underrecognized condition with a variety of clinical presentations. Initial studies revealed no gender predominance ; more recent studies have found there to be a slight, but significant, female preponderance. SAPHO syndrome is most common among children and young adults, but it can occur at any age, with most patients exhibiting a prolonged course that lasts for months to years.

SAPHO syndrome often presents with cutaneous manifestations, which can often be severe and disfiguring. Palmoplantar pustulosis is among the most common cutaneous features of SAPHO syndrome ( Fig. 1 ), with more than one-half of patients developing this condition at some point during their disease course. Other dermatologic diseases seen in patients with the SAPHO syndrome include pustular psoriasis and psoriasis vulgaris. The occurrence of SAPHO syndrome and spondyloarthropathies in the setting of psoriasis supports a pathophysiologic relationship between these diseases. Hidradenitis suppurativa is another dermatologic manifestation that commonly occurs in patients with SAPHO syndrome, the more aggressive lesions of which often are associated with erosive arthropathy. The coexistence of cutaneous signs with osteoarticular symptoms, such as pain in the jaw, anterior chest wall, back, buttocks, and peripheral joints, which frequently are intermittent, typically prompts further investigation with imaging that ultimately leads to a diagnosis of SAPHO syndrome.

Pustulosis palmaris of the left palm (left) and palmoplantar pustulosis of the medial sole of the right foot (right).

( From [Left] Assmann G, Simon P. The SAPHO syndrome – are microbes involved? Best Pract Res Clin Rheumatol 2011;25(3):423–34; and [Right] Zuo RC, Schwartz DM, Lee CC, Anadkat MJ, Cowen EW, Naik HB. Palmoplantar pustules and osteoarticular pain in a 42-year-old woman. J Am Acad Dermatol 2015;72(3):550–3.)

The pathogenesis of SAPHO syndrome is considered to be multifactorial. Some have hypothesized an infectious trigger with a low-virulence pathogen such as Propionibacterium acnes because of the relationship between SAPHO syndrome and acne. Bone biopsies have revealed mostly nonspecific inflammatory changes, with P acnes identified in fewer than 17% of active lesions in several case studies but in as many as 42% of patients in a metaanalysis that included individual case reports and thus was subject to reporting bias. A variety of other bacteria have been identified in biopsies both of bone and skin from patients with SAPHO syndrome, including normal skin flora such as Staphylococcus aureus , but definitive attribution of the cause of SAPHO syndrome to an infectious agent has yet to be established. Similar controversy exists regarding a potential genetic predisposition to developing SAPHO syndrome. HLA-B27 has been proposed as a potential genetic risk factor, given the resemblance between clinical features of SAPHO syndrome and those of spondyloarthropathies. However, the prevalence of HLA-B27 is only approximately 13% among patients with SAPHO syndrome.

Treatment of patients with SAPHO syndrome remains a challenge, because no randomized controlled trials of therapeutic agents have been conducted in patients with this condition. Nonsteroidal antiinflammatory drugs typically are used as initial treatment. Corticosteroids, both oral and intraarticular, can provide patients with temporary symptomatic relief. Patients with positive bacterial cultures have been treated with antibiotics, such as azithromycin, with improvement in symptoms, skin lesions, and MRI evidence of osteitis during treatment; however, this improvement has not persisted after discontinuation of antibiotic therapy. Skin disease can be treated effectively with isotretinoin and phototherapy. Bisphosphonates, such as alendronate and pamidronate, have provided some patients with symptomatic improvement and have resulted in varying degrees of objective radiographic improvement within months to years. Chronic inflammatory arthritis in patients with SAPHO syndrome has improved to varying degrees when treated with disease-modifying antirheumatic drugs, such as methotrexate. Refractory cases have been treated with tumor necrosis factor inhibitors, including adalimumab, etanercept, and infliximab, with promising initial results; however, their long-term efficacy remains unknown. Surgical treatment of osteodestructive lesions should be considered carefully, because these lesions tend to recur and sustained benefit of surgical excision has not yet been established.

Radiographic features of SAPHO syndrome differ based on the stage of disease and the anatomic region affected. Early lesions tend to be osteodestructive, whereas later lesions tend to be osteoproliferative. Chronic inflammation in medullary bone appears as osteitis and chronic inflammation of cortical bone results in hyperostosis. The anterior chest wall, including the costochondral, sternoclavicular, manubriosternal, and costosternal articulations, is involved in 60% to 95% of patients with SAPHO syndrome. The next most commonly involved sites, in approximate order of prevalence, are spine (30%–50% of adult patients), sacroiliac joints, long bones (such as the femur or tibia), and flat bones (such as the mandible or ileum).

Conventional radiographs often fail to detect lesions of SAPHO syndrome early in the course of the disease. A study of conventional radiographic imaging of 19 patients with SAPHO syndrome found that, although all patients eventually developed abnormal radiographs, abnormalities were evident in only 20% at 3 months after the onset of symptoms. In a study of 13 children diagnosed with CRMO, the sensitivity of conventional radiographs to detect structural change within 3 months of symptom onset was only 13% when compared with whole-body MRI. These studies suggest that the majority of edematous osseous lesions associated with SAPHO syndrome are evident on MRI before changes can be detected on conventional radiographs. A high index of clinical suspicion must be maintained when evaluating patients with SAPHO syndrome, because diagnostic findings may not be evident on conventional radiographs early in the course of the disease.

Preimaging planning

Selection of the appropriate imaging studies to evaluate patients with CRMO and SAPHO syndrome depends on the degree of clinical suspicion for the diagnosis. Many of the radiographic findings in CRMO and SAPHO syndrome are similar to those seen in patients with spondyloarthropathies. Thus, as for the patient with spondyloarthritis, useful imaging modalities include conventional radiography, CT scanning, and MRI. Musculoskeletal ultrasound may also be useful to demonstrate entheseal inflammation. Table 1 summarizes the potential benefits and limitations of the various modalities commonly used to image patients with CRMO and SAPHO syndrome.

Table 1

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