SAPHO syndrome is a disorder characterized by S ynovitis, A cne, P ustulosis, H yperostosis, and O steitis. As the osteoarticular and skin manifestations often do not occur simultaneously and there are no validated diagnostic criteria, the diagnosis can be difficult. Clinical and imaging investigation is necessary to establish the many differential diagnoses of SAPHO syndrome. The etiopathogenesis involves infectious (probably Propionibacterium acnes ), immunologic, and genetic factors. Treatment is based on information gathered from case reports and small series, and is related to specific skin or articular symptoms.
Key points
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SAPHO syndrome is a disorder characterized by S ynovitis, A cne, P ustulosis, H yperostosis, and O steitis.
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As the osteoarticular and skin manifestations often do not occur simultaneously and there are no validated diagnostic criteria, the diagnosis can be difficult.
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Clinical and imaging investigation is necessary to establish the many differential diagnoses of SAPHO syndrome.
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The etiopathogenesis involves infectious (probably Propionibacterium acnes ), immunologic, and genetic factors.
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Treatment is based on information gathered from case reports and small series, and is related to specific skin or articular symptoms.
Introduction
In 1987 a group of French researchers, after conducting a national investigation, proposed the acronym SAPHO syndrome to encompass a group of clinical and radiographic entities constituted by specific skin, bone, and joint manifestations. The meaning of this acronym was initially S yndrome A cne P ustulosis H yperostosis O steitis, and the “S” was changed to S ynovitis in the following year. Twenty-five years after its inception, the complete syndrome described by the acronym is not common; moreover, the dermatologic manifestations are not frequently concomitant with the joint symptoms, with its distinct clinical and radiographic manifestations occurring in isolation in a significant number of patients. In the twenty-first century, with the development of new perspectives on treatment, interest in the SAPHO syndrome has increased significantly.
Introduction
In 1987 a group of French researchers, after conducting a national investigation, proposed the acronym SAPHO syndrome to encompass a group of clinical and radiographic entities constituted by specific skin, bone, and joint manifestations. The meaning of this acronym was initially S yndrome A cne P ustulosis H yperostosis O steitis, and the “S” was changed to S ynovitis in the following year. Twenty-five years after its inception, the complete syndrome described by the acronym is not common; moreover, the dermatologic manifestations are not frequently concomitant with the joint symptoms, with its distinct clinical and radiographic manifestations occurring in isolation in a significant number of patients. In the twenty-first century, with the development of new perspectives on treatment, interest in the SAPHO syndrome has increased significantly.
Epidemiology
SAPHO is a rare disorder that affects predominantly children and adults. It is not common in individuals older than 60 years. The high variability in the clinical and imaging presentation depends on the stage of the lesions and the imaging method.
There is no predilection for gender, except for the male predominance in patients with severe acne. The estimated prevalence is 1 in 10,000 and the largest series are European. There are also descriptions from China and Australia. It is not frequent in United States, Canada, and Latin America. SAPHO is most severe in African Americans with hidradenitis suppurativa, and presents with heterogeneous musculoskeletal and cutaneous manifestations, including erosive polyarthritis or oligoarthritis with nonspecific mild inflammatory fluid.
In a French study analyzing 120 patients with SAPHO syndrome, of whom 102 were followed up prospectively, 9 patients had the diagnosis of inflammatory bowel disease, and no severe or disabling complications were noted. Except for a significant association of palmoplantar pustulosis or psoriasis vulgaris with axial osteitis ( P = .07), the dermatologic presentation had no significant influence on rheumatic symptoms.
An Italian study analyzed 71 patients with SAPHO syndrome who had a minimum follow-up of 2 years. Six patients were diagnosed as having Crohn disease and 14 had never had cutaneous involvement. After a median disease duration of 10 years, 13% presented a limited (<6 months) disease course, 35% had a relapsing-remitting course, and 52% had an acute painful phase and a chronic course.
A retrospective study in a single center in Spain reported 52 patients with SAPHO syndrome between 1984 and 2007 (26 men, mean age at diagnosis 42 ± 12 years), with articular involvement preceding cutaneous involvement in 59.6% of patients. Anterior chest wall pain was the most frequent manifestation (73%), followed by peripheral arthritis (32%) and pain in the sacroiliac joints (26.9%); skin manifestations were referred by 63.5% and human leukocyte antigen (HLA) B27 was positive in 8% of the patients.
Clinical picture
It is important for the rheumatologist, dermatologist, and clinician to understand the distinct signs and symptoms that constitute the core manifestations of the SAPHO syndrome, as they are predominantly nonspecific and overlap with many other diseases.
Osteoarticular Manifestations
The most common musculoskeletal manifestations of SAPHO syndrome include erosive or nonerosive oligoarthritis affecting knees, ankles, metacarpal phalangeal and metatarsal phalangeal joints; enthesitis; sclerosis of the sacroiliac joints; and osteitis of the anterior chest wall (sternum, clavicle, ribs), axial skeleton, and pelvis. The affected bones are painful; the painful swelling of the anterior chest wall is caused by hyperostosis and osteitis.
The characteristic synovitis affecting peripheral joints is referred by around one-third of patients. The peripheral arthritis is frequently insidious at onset, associated with morning stiffness. The joints are swollen and painful, and it is suggested that the articular involvement is an extension of the adjacent osteitis, especially when affecting sternocostal, sternoclavicular, sacroiliac, and hip joints. Enthesitis can represent an initial symptom of SAPHO syndrome in some patients. Inflammatory enthesopathies can cause ossification, contributing to the formation of bone bridges. The mandible is affected in approximately 10% of cases. The lesions are radiolucent and well defined with evidence of osteitis and sclerosis, causing edema and pain without suppuration and/or joint limitation. Chronic recurrent multifocal osteomyelitis (CRMO) usually manifests as recurrent flares of bone pain and inflammation without fever. Kahn and Khan consider that the presence of CRMO, even in the absence of cutaneous manifestations, is sufficient to establish the diagnosis of SAPHO. Nowadays, CRMO is considered the pediatric equivalent of SAPHO syndrome, and recent data suggest its inclusion as an autoinflammatory disease. The articular involvement is frequently intermittent, with exacerbations and remissions, and there is no correlation with cutaneous activity of the disease. In the follow-up of at least 2 years of 71 patients with SAPHO syndrome, the presence of peripheral synovitis was associated with a chronic disease course ( P = .0036).
Skin Manifestations
The characteristic skin manifestations are severe acne (conglobata or fulminans) ( Fig. 1 ) and pustulosis palmoplantaris (PPP) ( Fig. 2 ). Severe acne can affect around one-fourth of patients, and PPP 50% to 75% of patients. The largest cohorts of SAPHO syndrome have shown that the skin involvement preceded musculoskeletal symptoms in 40% to 68%, occurred simultaneously in 30%, and was a late manifestation in 32% to 60% of patients. At least 15% of adults and more than 70% of children may never experience skin manifestations.
Other Manifestations
Rare and uncommon manifestations of SAPHO syndrome are muscular weakness and generalized seizures due to central nervous system involvement ; venous thrombosis ; and bilateral optic canal involvement with retrobulbar pain, decreased vision, and a protruding appearance of the left eye. SAPHO has also been described as a widespread bony metastatic disease of unknown origin.
Is SAPHO a Spondyloarthritis?
Although SAPHO syndrome can share clinical and radiologic features with spondyloarthritis (SpA), including sacroiliitis, enthesitis, paravertebral ossifications, and ankylosis, and many times is associated with psoriasis and inflammatory bowel disease, its consideration as a variant of the SpA is controversial and not definitely established. A genetic study analyzing the HLA profile in 25 patients with SAPHO syndrome in a comparison with 50 patients with psoriasis vulgaris, 150 with psoriatic arthritis, and 170 healthy blood donors, found a different genetic background in the patients with SAPHO syndrome compared with the group with psoriasis and psoriatic arthritis.
Imaging
There is a great variability in imaging, which depends on the stage of the lesion and the imaging method. Special attention should be given to examination of the spine, which can facilitate an early diagnosis and prevent inadequate biopsies and unnecessary surgery.
Radiography
Two important osteoarticular manifestations are hyperostosis and osteitis, which are chronic inflammatory reactions involving the cortical and medullary bone. Radiographs of the affected areas are frequently normal at the initial stages of the disease. Early lesions are often purely osteolytic, with or without a sclerotic margin. With disease progression these lesions become lytic/sclerotic or entirely sclerotic. Chronic lesions are predominantly sclerotic. The anterior chest wall can involve any component of the sternoclavicular region; adjacent joints may develop arthritis or ankylosis. In contrast to adults, only the clavicle is involved in children. Mandibular lesions are characterized by diffuse sclerosis of the affected area, often associated with pronounced periosteal reaction.
Spinal involvement has a variety of forms, including vertebral hyperostosis; osteolytic lesions with vertebral collapse; spondylitis with or without discitis; paravertebral ossifications and further syndesmophytes; and sacroiliitis.
Ultrasonography
Ultrasonography can be indicated to investigate the presence and the characteristics of enthesitic manifestations. Queiro and colleagues analyzed the ultrasonographic findings in 210 entheses of SAPHO patients and 420 entheses in a control group, and found significant statistical prevalence of ultrasonographic alterations in the SAPHO group (15%) compared with controls (4.8%: P <.01); the most frequently affected entheses were patellar and Achilles tendon, and no control patient presented signs of enthesitis or perienthesitis on power Doppler.
Bone Scintigraphy
Bone scintigraphy can be useful because it not only shows increased uptake in the affected joints, but also frequently reveals clinically silent lesions. The sternoclavicular joint can present the characteristic “bullhead sign,” with the manubrium sterni representing the upper skull and the inflamed sternoclavicular joint with the adjacent claviculae forming the horns.
Computed Tomography
Computed tomography (CT) is important for the investigation of the sternoclavicular region, which is frequently difficult to be visualized by conventional radiography because of the superimposition of ribs, spine, and mediastinum. CT examination can show cortical bone erosions, joint-space narrowing, ligament ossification, subchondral sclerosis, and periosteal bone formation. 18 F-Fluorodeoxyglucose positron emission tomography (PET)/CT can help differentiate SAPHO syndrome from suspected metastatic bone disease in patients who present several sites of bone involvement but no primary malignancy.
Magnetic Resonance Imaging
Nowadays, magnetic resonance imaging (MRI) is the most sensitive technique in the evaluation of soft-tissue swelling, intra-articular effusion, and synovial reaction in SAPHO syndrome. MRI can also show vertebral corner erosion lesions early in the diagnosis of SAPHO syndrome in patients with spinal symptoms.
When bone tumors are considered in the differential diagnosis of SAPHO syndrome, a bone biopsy guided by CT or MRI can be performed to confirm the diagnosis.
Diagnosis
The frequent atypical or incomplete presentation, and the clinical mimicry with other diseases such as osteomyelitis, can delay the diagnosis of SAPHO syndrome. Unfortunately, there are no validated criteria for the diagnosis of SAPHO syndrome, and most patients do not fulfill the diagnosis of complete SAPHO. In 1988, Benhamou and colleagues proposed a group of inclusion and exclusion criteria ( Box 1 ) that are still used by many physicians. In 2003, Khan proposed new classification criteria for SAPHO syndrome at the ACR 67th Annual Scientific Meeting (cited in Ref. but not published) ( Box 2 ).
Inclusion Criteria a
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Osteoarticular manifestations of acne conglobata, acne fulminans, or hidradenitis suppurativa
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Osteoarticular manifestations of PPP
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Hyperostosis (of the anterior chest wall, limbs, or spine) with or without dermatosis
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CRMO involving the axial or peripheral skeleton with or without dermatosis
Sometimes Reported
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Possible association with psoriasis vulgaris
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Possible association with inflammatory enterocolopathy
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Features of ankylosing spondylitis
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Presence of low-virulence bacterial infections
Exclusion Criteria
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Septic osteomyelitis
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Infectious chest wall arthritis
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Infectious PPP
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Palmoplantar keratoderma
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Diffuse idiopathic skeletal hyperostosis, except for fortuitous association
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Osteoarticular manifestations of retinoid therapy
a The presence of 1 of the 4 inclusion features is sufficient for a diagnosis of SAPHO syndrome.
Inclusion
Bone ± joint involvement associated with PPP and psoriasis vulgaris
Bone ± joint involvement associated with severe acne
Isolated a sterile hyperostosis/osteitis (adults)
Chronic recurrent multifocal osteomyelitis (children)
Bone ± joint involvement associated with chronic bowel diseases
Exclusion
Infectious osteitis
Tumoral conditions of the bone
Noninflammatory condensing lesions of the bone
a Exception: growth of Propionibacterium acnes .
Differential diagnosis
The differential diagnosis among these different syndromes will help to avoid inappropriate diagnostic procedures and treatment. Briefly discussed here are the main syndromes that are considered important in the differential diagnosis of SAPHO syndrome ( Box 3 ).
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Acne-associated syndrome
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PAPA (Pyogenic sterile Arthritis, Pyoderma gangrenosum, and Acne) syndrome
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PASH (Pyoderma gangrenosum, Acne, and Suppurative Hidradenitis) syndrome
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Arthritis associated with hidradenitis suppurativa (also called acne inversa)
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Follicular occlusion triad, in particular with acne conglobata
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Behçet disease
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Minocycline-induced autoimmume syndromes
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Isotretinoin side effect
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Pustular psoriasis
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Sneddon-Wilkinson disease
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Pustulotic arthro-osteitis
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Acquired hyperostosis syndrome (AHS)
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Chronic recurrent multifocal osteomyelitis (CRMO)
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Diffuse sclerosing osteomyelitis of the mandible (DSOM)
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Majeed syndrome
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Nonbacterial osteitis (NBO)
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Tuberculous spondylitis
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Secondary syphilis
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Primary bone tumors
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Metastatic tumors
S ynovitis . The peripheral involvement in the patients with the diagnosis of SAPHO syndrome and related diseases is completely nonspecific.
A cne. The association of the characteristic acne conglobata or acne fulminans with arthritis has appeared in the literature since 1961. In fact, there are many different acne-associated syndromes, revised by Chen and colleagues. SAPHO syndrome and 2 other diseases (PAPA and PASH) highlight the attributes of inflammation for the formation of acne. PAPA ( P yogenic sterile A rthritis, P yoderma gangrenosum, and A cne) syndrome is an autosomal dominant disease that shares several features with SAPHO syndrome. Recently, the PASH ( P yoderma gangrenosum, A cne, and S uppurative H idradenitis) syndrome has been proposed, which is similar to PAPA with acute and recurrent acne conglobata, but without aseptic abscesses. Although uncommon, there are descriptions of arthritis associated with hidradenitis suppurativa (also called acne inversa) ( Fig. 3 ); these patients have predominantly peripheral arthritis, with rare and frequently asymptomatic axial involvement. When acne conglobata is associated with hidradenitis suppurativa and dissecting cellulitis, it is called the follicular occlusion triad. Acneiform skin lesions, more frequently papulopustular, can be observed in patients with Behçet disease with arthritis. A concern related to acne conglobata is the side effects of minocycline, a drug frequently used for the treatment of acne. There are specific minocycline-induced autoimmume syndromes, characterized by serum sickness, drug-induced lupus, autoimmune hepatitis, and vasculitis. Another drug used in the treatment of acne, isotretinoin, also can cause musculoskeletal or mucocutaneous symptoms in 2% to 5% of treated patients.
P ustulosis . The characteristic PPP is a common cutaneous manifestation of SAPHO syndrome, affecting around 65% of patients. PPP cannot be distinguished from pustular psoriasis in many cases. Although psoriasis vulgaris can affect one-third of patients with SAPHO syndrome, its presence is almost always associated with PPP or severe acne, which is the reason why it is not considered as a skin manifestation of SAPHO syndrome. Subcorneal pustular dermatosis (Sneddon-Wilkinson syndrome) is considered a variant of pustular psoriasis. Pustulotic arthro-osteitis is a disorder characterized by PPP and osteoarticular inflammation, affecting predominantly the anterior chest wall, spine, pelvis, sacroiliac joint, and long bones.
H yperostosis. Hyperostosis is a chronic inflammatory reaction involving the cortical and medullary bones. It affects more frequently the axial skeleton, particularly the anterior chest wall and sternoclavicular joints. The chronic hyperostosis of the spine may result in bony bridges that can evolve to ankylosis. AHS is a chronic inflammatory hyperostosis that affects the sternoclavicular joint in 80% of cases, also presenting skin manifestations (PPP, pustular psoriasis, or severe acne) in 20% to 60% of patients.
O steitis. In 1972, CRMO was described as a chronic inflammatory process in children and young adults. DSOM was initially considered a disease restricted to temporomandibular joints, but many researchers have observed that many patients also presented with PPP, cutaneous psoriasis, and/or osteitis in various different locations. Majeed syndrome is characterized by CRMO of early onset and lifelong course, associated with congenital dyserythropoietic anemia that presents with hypochromic microcytic anemia during the first year of life and ranges to transfusion-dependent, with transient inflammatory dermatosis often manifest as Sweet syndrome (neutrophilic skin infiltration). NBO is characterized by sterile bone lesions with nonspecific histopathologic features of inflammation; only when it is chronic and recurrent can it be considered CRMO. Sterile bone inflammation in children demands various differential diagnoses, including genetic mutations and autoinflammatory diseases. Tuberculous spondylitis, secondary syphilis, primary bone tumors, and metastatic tumors also represent differentials of SAPHO syndrome. An example of osteitis observed on MRI is shown in Fig. 4 .
