The SAPHO Syndrome

SPONDYLARTHOPATHIES

The SAPHO Syndrome Minhchau Thi Nguyen, MD,* Andrea Borchers, PhD,* Carlo Selmi, MD,*,† Stanley M. Naguwa, MD,* Gurtej Cheema, MD,* and M. Eric Gershwin, MD*

Objective: To review the epidemiology, presentation, diagnosis, treatment, pathogenesis, and genetics of the syndrome known under the acronym of SAPHO for Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis to heighten awareness of this entity. Methods: We conducted a Medline search using SAPHO syndrome, chronic recurrent multifocal osteitis/osteomyelitis, and related terms as keywords and extracted further relevant articles from the retrieved references. Results: The SAHPO acronym identifies a syndrome encompassing a variety of osteoarticular disorders that are frequently accompanied by dermatoses characterized by neutrophilic pseudoabscesses, but can also occur in isolation. SAPHO syndrome is rare, although probably underrecognized because its diagnosis may be challenging because of the wide variability in its musculoskeletal and cutaneous manifestations. This is especially true when atypical sites are involved and when specific skin lesions are absent. There are no standardized treatment protocols available. Current treatments are empirical and have the objective of providing relief from the at times debilitating pain associated with SAPHO syndrome. They include nonsteroidal anti-inflammatory drugs and analgesics as first-line agents. Systemic corticosteroids, disease-modifying anti-rheumatic drugs, biologicals targeting tumor necrosis factor alpha and interleukin-1, and bisphosphonates have all been beneficial in some patients, but ineffective in others. This suggests that the pathogenesis of SAPHO syndrome is multifactorial, but this aspect remains poorly explored, although bacteria and immunological dysfunction are hypothesized to play a role. Conclusions: The early recognition, diagnosis, and prompt treatment of SAPHO syndrome can prevent the unnecessary use of long-term antibiotics or invasive procedures, while rapidly alleviating pain in a majority of affected patients. © 2012 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 42:254-265 Keywords: synovitis, acne, pustulosis, hyperostosis, osteitis

S

tarting in the 1960s, there have been reports of an association between cutaneous manifestations, in particular palmoplantar pustulosis (PPP), pustular psoriasis, hidradenitis suppurativa, and severe acne (fulminans or conglobata), with certain osteoarticular manifestations like peripheral synovitis or aseptic osteitis affecting the anterior chest wall and other skeletal sites. Since then, more than 50 designations have been used to

*Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis. †Clinical Immunology, IRCCS Istituto Clinico Humanitas, Milan, Italy. Address reprint requests to M. Eric Gershwin, MD, Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616. E-mail: megershwin@ ucdavis.edu.

254

describe these combinations, the more common ones being pustulotic arthro-osteitis, sternocostoclavicular hyperostosis, acne-associated spondyloarthropathy, acquired hyperostosis syndrome, or chronic recurrent multifocal osteomyelitis. A group of French researchers, suspecting that these disorders might share common characteristics, conducted a national investigation of such cases (1). Their results indicated that a specific type of bone involvement, namely inflammatory osteitis with hyperostosis, constituted a common denominator and exhibited the same characteristics whether accompanied by dermatologic manifestations or not. These bone lesions are mainly localized in the anterior chest wall, but may involve any skeletal segment (2). As a unifying concept, the French researchers proposed to group these disorders under the acronym SAPHO (originally Syndrome Acne

0049-0172/12/$-see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semarthrit.2012.05.006

M.T. Nguyen et al.

Pustulosis Hyperostosis Osteitis, the “S” being changed to Synovitis the following year) (1,3). Even though pustular dermatoses originally appeared to be the unifying element, their presence is not absolutely required because (1) the typical osteoarticular manifestations are identical in the absence or presence of cutaneous involvement and (2) it has since become more fully appreciated that dermatologic manifestations can occur years before bone lesions and may have been forgotten, but can also develop long after the osteoarticular lesions. Note that the original description of the SAPHO syndrome and the inclusion criteria proposed for this entity specifically include cases of chronic recurrent multifocal osteomyelitis (CRMO) (1,3). This condition was first described by Giedion et al. in 1972 (4) under the name of subacute and chronic symmetrical osteomyelitis, and most frequently affects children, but has been reported in adults (5-8), whereas typical manifestations of SAPHO syndrome have been described in children (9). There still is some debate over whether CRMO represents the pediatric form of SAPHO or constitutes a separate entity. However, CRMO exhibits all the essential features of the SAPHO syndrome, including osteitis; hyperostosis; and the association with skin disorders such as PPP, severe acne, pyoderma gangrenosum, and, in rare cases, Sweet syndrome—although in a lower proportion of cases (⬃30% compared to 50% to 85% in adults). In addition, CRMO-like SAPHO syndrome is associated with inflammatory bowel disease (IBD) (10-13). However, CRMO most frequently affects the metaphyses of tubular bones, whereas other forms of SAPHO syndrome most often involve the axial skeleton, particularly the anterior chest wall. CRMO can affect the sternocostoclavicular region, but this generally manifests as hyperostosis of the medial end of the clavicle and, unlike in adults, spares other elements of this region, including the sternoclavicular joint (14). Nonetheless, in the following, CRMO is considered a subtype of the SAPHO syndrome that affects children much more frequently than adults. SAPHO syndrome is generally considered to be a rare condition, possibly due to being underdiagnosed. A prevalence estimate of ⬍1/10,000 is frequently mentioned, although it is unclear what this is derived from because there are no actual data. Based on long years of experience with SAPHO, a German rheumatologist and SAPHO expert estimates its prevalence to lie somewhere between that of systemic lupus erythematosus and scleroderma and provides a figure of 0.04% (ie, 40/100,000) (15). In the original collection of French SAPHO cases overall, the gender distribution was approximately equal (1). Since then, the majority of cohorts comprising more than 20 patients were characterized by a female preponderance, including various patient groups from France, Italy, and Japan (16-20), as had already been noted in an earlier description of pustulotic arthro-osteitis (21). An exception is a Spanish cohort, for which equal numbers of men and women were reported (22). The SAPHO syndrome

255

may present at any age but is most commonly seen in children and young to middle-aged adults (16,17). CLINICAL PRESENTATION The osteoarticular involvement is generally insidious in onset, but eventually patients will present with pain that is frequently dramatic and incapacitating and may be exacerbated by movement or application of pressure. Soft tissue swelling, often with redness and heat, and limitation of motion at the affected skeletal site(s) are other presenting signs. Morning stiffness is quite frequently reported ranging in severity from mild to lasting several hours, and in cases of long bone involvement, a limp may be evident. Of note, quite a few cases of CRMO were preceded by trauma (23-26). Systemic manifestations are uncommon; however, fever is sometimes reported and modest elevations of erythrocyte sedimentation rate or C reactive protein are common. In adults, the most commonly affected skeletal site is the anterior chest wall (65% to 90%, Table 1), followed by the spine (in ⬃30%), with the thoracic spine being most frequently affected, followed by the lumbar and then the cervical spine (2,27). Sacroiliitis is seen in up to 13% to 52% of patients with SAPHO syndrome (2,27). The appendicular skeleton is not a frequent localization in adults with SAPHO syndrome, with 5% to 10% of them showing involvement of the long bones, and 1% to 10% of patients experiencing mandibular lesions. In contrast, long bones represent the most frequent site of involvement in children, where the distal and proximal tibia are most commonly affected, followed by the proximal and distal femur (10,14,23,28). Lesions of spine, clavicle, pelvis, and other sites are reported with highly variable frequencies. In both adults and children, there can be arthritis of the articulations adjacent to bone lesions, ie, the anterior chest wall and sacroiliac joints in adults, the ankles and knees in children (10,23,28). Synovitis in peripheral joints distant from the sites of bone involvement is seen in ⬃30% of adults, but more rarely in children (10). Skin manifestations may be evident at the time of presentation with osteoarticular symptoms, but may have occurred years earlier or may develop later. In an early description of 53 cases, skin involvement occurred within an interval of 2 years before or after the onset of rheumatological symptoms in 70% of cases (21), but delays of up to nearly 4 decades have been reported (16,21,29). In the largest cohorts described to date, skin involvement preceded musculoskeletal symptoms in 40% to 68% of patients, occurred simultaneously in ⬍30% of patients, and manifested later in 32% to 60% of cases (16,17,22). At least 15% of adults and more than 70% of children may never experience skin lesions, whereas others may exhibit 2 or even 3 different ones. The cutaneous lesions are neutrophilic dermatoses. The most common one is PPP, representing 50% to 75% of all dermatologic manifestations (Table 1) and affecting close to 60% of patients with

256

The SAPHO syndrome

Table 1 Frequency of Clinical Manifestations in SAPHO Patients Reference Country n Age at diagnosis (mean, range) Male/female Years of study Follow-up (yr) Anterior chest wall involvement (%) Inflammatory back pain (%) Spinal (%) Sacroiliitis (%) Long bones/peripheral (%) Mandible (%) Peripheral arthritis (%) Cutaneous manifestations (N/%) Of those (in %) PPP overall Severe acne overall Psoriasis vulgaris overall PPP, isolated PPP ⫹ psoriasis vulgaris PPP ⫹ severe acne PPP ⫹ hidradenitis suppurativa Psoriasis vulgaris, isolated Severe acne, isolated Severe acne ⫹ hidradenitis suppurativa Other manifestations Inflammatory bowel disease (n/%) Of those Crohn’s disease Of those ulcerative colitis HLA-B27 (%)

(18)

(24)

France 120 37.7 (5-67) 50/70 1974-1997 Mean 4.9 (range 1-23) 63 NA 33 40 5.8 10.8 33 110 (84)

France 52 42 (15-73) 26/26 1984-2007 NA

⬎58b 29.7

52 39 33

73 13

Italy 71 45.5 (35.7-54.0)a 23/48 1990-2008 0 70 24 34

27

33 63

c

37.6 20.8 7.9c 11.9 21.8

9 (7.5) 6/9 (67%) 3/9 (33%) 13

(19)

2 (4) 2/2 (100%) 0 18

40 (56) 65 25 7.5 50 0 12 2 8 23 5

2 (3) 2/2 (100%) 0 4

NA, not available; PPP, palmoplantar pustulosis. aMedian and interquartile range. bCannot be determined exactly from the data provided because some patients with SA had both PPP and PV, and only data for SA plus PPP and/or PV were reported. cThis figure is for the combination of severe acne with PPP and/or psoriasis vulgaris.

extended follow-up (16,17). Of note, many pathologists feel that PPP cannot be distinguished unequivocally from pustular psoriasis, and it has become customary to subsume both entities under pustulosis or PPP. There is still some debate over whether psoriasis vulgaris should be included among the dermatologic manifestations of SAPHO. Although it may represent up to one third of all skin involvement, it is frequently seen in combination with PPP or severe acne and occurs in isolation in only 5% to 10% of cases. Severe acne, ie, acne conglobata and fulminans, affects approximately one fourth of patients with SAPHO syndrome, with men clearly predominating (1,16). Hidranetitis suppurativa (also called acne inversa) is considered to be a severe form of acne by some and to represent a distinct entity that resembles acne by others. It mainly affects women, yet men predominate among the cases of SAPHO syndrome that have been reported in association with hidradenitis suppurativa (30-32). African Americans appear to be particularly susceptible.

Other rare cutaneous manifestations of the SAPHO syndrome include pyoderma gangrenosum and Sweet’s syndrome (17,33-35). Skin involvement is not as frequent in children compared to adults. RADIOLOGY Radiography Two of the osteoarticular manifestations of SAPHO syndrome are hyperostosis and osteitis, which are chronic inflammatory reactions involving the cortical and medullary bone. In the initial stages of the disease, radiographs of affected areas are often normal. Early lesions are often purely osteolytic with or without a sclerotic margin, typically accompanied by an endosteal or periosteal reaction (14). With disease progression, these lesions become mixed lytic/sclerotic or entirely sclerotic (14). Chronic lesions are predominantly sclerotic, with cortical thicken-

M.T. Nguyen et al.

ing accompanied by narrowing of the medullary canal and enlargement of trabeculae. Anterior Chest Wall Anterior chest wall lesions can involve any component of the sternocostoclavicular region. Lesions usually develop in 3 stages: stage 1 is localized to the area of the costoclavicular ligament and may manifest as a primary enthesopathy; in stage 2, an arthropathy of the sternoclavicular joint develops with osteolytic and osteosclerotic changes of the medial end of the clavicle and adjacent structure, such as sternum, first rib, and costal cartilage; and stage 3 marks the progression of osteosclerosis, hyperostosis, and hypertrophy of these and other surrounding structures (2,27). Adjacent joints may develop arthritis or ankylosis. In contrast to adults, only the clavicle is involved in children, whereas the sternoclavicular joint, sternum, and ribs are rarely affected. Ossification of the costoclavicular ligament and first costal cartilage with bony masses extending to the region between clavicle and first rib and ankylosis of the sternoclavicular joint has been described in adults, particularly in Japanese patients (36,37), but not in children. Axial Skeleton Spinal involvement is usually segmental, most commonly affecting a single vertebra, although occasionally up to 4 adjacent vertebrae, but an individual patient may have up to 5 such lesions (2,27,38). Manifestations in the axial skeleton can take a variety of forms and can occur in various combinations. They include osteosclerosis of one or more vertebral bodies with development of hyperostosis; osteolytic lesions with variable degree of vertebral collapse; spondylitis with or without discitis, in the latter case resembling infectious spondylodiscitis; paravertebral ossifications; and sacroiliitis (2,27). Paravertebral ossifications in SAPHO syndrome most commonly are nonmarginal and asymmetrical syndesmophytes similar to, but not identical with, the syndesmophytes seen in psoriasis (2,27). Note, however, that others consider them to be enthesophytes rather than true syndesmophytes (17). In chronic cases, florid hyperostosis may result in massive bony bridging, which can evolve into ankylosis of the adjacent disk spaces and associated kyphosis. Once ankylosis is complete, hyperostosis has been observed to resolve (17). The sacroiliitis of SAPHO syndrome is more frequently unilateral than seen in ankylosing spondylitis and is characterized by sclerosis and hyperostosis primarily on the iliac side of the joint. Appendicular Skeleton The long bones are infrequently involved in adult patients, but represent the most common site of involvement in children. In the early stages, they typically show osteolysis in the metaphysis adjacent to the growth plate

257

(2,14). The extent of periosteal reaction depends on the size of the involved bone, generally being more pronounced in small-diameter bones (14). The lesions heal with sclerosis and progressive hyperostosis. The disorder originally called diffuse sclerosing osteomyelitis of the mandible is now recognized to represent a form of SAPHO syndrome, whether occurring in isolation or in conjunction with bone lesions at other sites. It is seen in up to 10% of patients, usually affects the corpus and ramus, while the temporomandibular joint is often spared, and is frequently accompanied by painful swelling of the overlying soft tissue (2,27,39). Mandibular lesions are characterized by diffuse unilateral sclerosis, often associated with pronounced periosteal reaction. Other Imaging Modalities Whole-body scintigraphy is useful because it not only shows increased tracer uptake in the affected bone but frequently reveals clinically silent lesions. High tracer uptake in the sternocostoclavicular region yields the socalled “bull’s head sign,” with the manubrium sterni representing the upper skull and the inflamed sternoclavicular joint with the adjacent claviculae forming the horns (40). This configuration is virtually pathognomonic for SAPHO syndrome, but is not entirely sensitive, although it may even be present in SAPHO patients who do not report symptoms of the anterior chest wall (41). Whole-body magnetic resonance imaging (MRI) has the same sensitivity as whole-body scintigraphy, but the added advantage of avoiding radiation exposure, which becomes particularly important when repeated imaging is necessary during follow-up. Conventional MRI is not only considerably more sensitive than radiography, but also can show marrow edema as well as adjacent soft tissue inflammation. It is particularly helpful in examining vertebral bodies and can be used to monitor disease progression because chronic sclerotic bone lesions exhibit low signal intensity in both T1- and T2-weighted images, whereas active lesions appear hypointense on T1- and hyperintense on T2-weighted images. Computed tomography, especially multi-slice computed tomography with secondary reconstructions, is best suited for a detailed depiction of the osteoarticular lesions and is the imaging modality of choice for the sternoclavicular region, which is difficult to visualize by conventional radiographs due to the superimposition of ribs, spine, and mediastinum. HISTOLOGY The histologic characteristics of the bone lesions change over the course of the disease. In the early stages, there is acute inflammation with a predominantly neutrophilic infiltrate, and both bone resorption and prominent periosteal bone formation have been described (5,42,43). In biopsy specimens from children with CRMO, multinucleated giant cells, granulomatous foci, and necrotic bone fragments have been observed (5,44). Subsequently, the

258

The SAPHO syndrome

Table 2 Inclusion and Exclusion Features of the SAPHO Syndrome (3) Inclusion features

Sometimes reported

Exclusion features

Osteo-articular manifestations of acne conglobata, acne fulminans, or hidradenitis suppurativa Osteo-articular manifestations of PPP Hyperostosis (of the anterior chest wall, limbs or spine) with or without dermatosis CRMO involving the axial or peripheral skeleton with or without dermatosis Possible association with psoriasis vulgaris Possible association with an inflammatory enterocolopathy Features of ankylosing spondylitis Presence of low-virulence bacterial infections Septic osteomyelitis Infectious chest wall arthritis Infections PPP Palmo-plantar keratodermia DISH except for fortuitous association Osteoarticular manifestations of retinoid therapy

The presence of 1 of the 4 inclusion features is sufficient for a patient to be included in the SAPHO syndrome.

infiltrate consists of scattered lymphocytes, plasma cells, histiocytes, and only a few polymorphonuclear cells (5,42,43). Memory T lymphocytes of the CD8⫹ subset constitute the major cell type (45). In the late stages, the infiltrate is sparse or absent and enlarged sclerotic trabeculae as well as marrow fibrosis are observed. There are

increased numbers of osteoblasts and occasionally osteoclasts as well (5,42,43). DIAGNOSIS Because the signs and symptoms of SAPHO syndrome are nonspecific and the osteoarticular manifestations cover a broad spectrum, the diagnosis is one of exclusion. There are no validated diagnostic criteria, but many physicians apply the inclusion and exclusion criteria formulated by Benhamou et al. (3) (Table 2). The presence of only 1 of the 4 inclusion criteria is sufficient to arrive at a diagnosis of SAPHO syndrome. Separate diagnostic criteria have been proposed for nonbacterial osteitis, which includes CRMO (Table 3) (11). The diagnosis is relatively straightforward in patients with typical localizations of pain (eg, the anterior chest wall), the corresponding radiographic findings, and characteristic skin lesions. It is much more challenging when atypical sites are involved or skin manifestations are absent, and it becomes impossible in patients with single skeletal lesions that lack signs of hyperostosis. A detailed history, inquiring specifically about previous cutaneous and skeletal involvement, may provide diagnostic clues. Whole-body scintigraphy or MRI may reveal additional clinically silent sites of osteoarticular involvement. The bone lesions of SAPHO may not be distinguishable from infectious osteomyelitis or bone neoplasms, which must be excluded through a biopsy yielding the appropriate histologic findings and negative bacterial cultures. The main differential diagnoses of SAPHO syndrome include infectious osteomyelitis, osteosarcoma, Ewing sarcoma, bony metastasis, eosinophilic granuloma, Paget’s disease, infectious spondylodiscitis, sternoclavicular osteoarthritis, condensing osteitis of the clavicle, and osteonecrosis of the medial clavicular epiphysis (13,46). In children, juvenile idiopathic arthritis constitutes another differential diagnosis. For example, in a French CRMO cohort, initial diagnoses were infec-

Table 3 Proposed Major and Minor Diagnostic Criteria of NBO (8) Major Diagnostic Criteria (1) (2) (3) (4)

Radiologically proven osteolytic/-sclerotic bone lesion Multifocal bone lesions PPP or psoriasis Sterile bone biopsy with signs of inflammation and/ or fibrosis, sclerosis

Minor Diagnostic Criteria (A) Normal blood count and good general state of health (B) CRP and ESR mildly to moderately elevated (C) Observation time longer than 6 mo (D) Hyperostosis (E) Associated with other autoimmune diseases apart from PPP or psoriasis (F) Grade I or II relatives with autoimmune or autoinflammatory disease, or with NBO

Two major or 1 major and 3 minor criteria must be fulfilled for a diagnosis of NBO. As a reminder, CRMO is a subtype of NBO, requiring either multifocal bone lesions or a single lesion associated with PPP or psoriasis and a chronic (⬎6 mo) relapsing-remitting disease course (8). Multifocality and chronicity are not required for inclusion in SAPHO syndrome. In addition, the proposed diagnostic criteria of NBO include only PPP or psoriasis, even though severe acne, pyoderma gangrenosum, and other dermatologic manifestations have been described in children with CRMO (5,6). In contrast, the proposed inclusion criteria for SAPHO syndrome include severe acne and hidradenitis suppurativa in addition to PPP. The status of psoriasis vulgaris in SAPHO is still a matter of debate, with the criteria proposed by Benhamou et al. (3) listing this condition only as “sometimes reported.” An association with another autoimmune disease in the patients themselves or in first- or second-degree relatives features only in the proposed criteria for NBO, but not those for SAPHO syndrome.

M.T. Nguyen et al.

tious osteomyelitis in 6 of 14 patients, bone tumor in 2, and juvenile idiopathic arthritis in 2 (47). Chest pain due to anterior chest wall involvement may be mistaken for an acute cardiac event (17). TREATMENT Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and Analgesics Due to the rarity of the SAPHO syndrome, no randomized controlled clinical trials have been conducted to evaluate the efficacy of individual therapeutic modalities. Consequently, treatment is not evidence-based, but derived from observations in published case reports and small case series, along with expert judgment. Therapy is aimed at symptom relief and mainly includes NSAIDs and analgesics as first-line agents. However, at least one half of all SAPHO patients do not experience sufficient pain relief and protection from disease exacerbations with such conservative therapy (1,17). Because of the similarity between the osteitis of SAPHO syndrome and particularly of CRMO with infectious osteomyelitis, numerous patients have been treated with antimicrobial agents, even if bacterial cultures prepared from their biopsy yielded negative results. The vast majority of patients did not derive any benefit from such therapy. However, there have been a few reports of positive responses (eg, in 4/20 patients in a large French cohort (16), and 2/9 patients in a group of Italian patients) (17). Propionibacterium acne is a low-virulence pathogen suspected of playing a role in SAPHO syndrome (48). In 14 German patients whose biopsy was positive for P. acne and another 13 patients who had not undergone a biopsy, a 16-week course of antimicrobial therapy was associated with a significant decrease in disease activity of both the osteitis and the dermatologic lesions (49). However, disease activity returned to baseline levels within 3 months following discontinuation of therapy. Corticosteroids and Disease-Modifying Anti-Rheumatic Drugs (DMARDs) In patients refractory to NSAIDs and analgesics, corticosteroids can be quite effective, particularly when given as intra-articular injections (1,16,25,50). However, some patients experience only partial or no relief or require doses high enough to induce Cushing syndrome (51-53) and relapse after treatment withdrawal has been observed (47). As steroid-sparing agents or in refractory cases, the use of DMARDs, particularly methotrexate, sulfasalazine, or azathioprine, has been reported to be beneficial in some patients, although ineffective in others (11,16,54). Biologicals Treatment with biologicals that antagonize tumor necrosis factor (TNF) has shown promising results in cases of SAPHO syndrome refractory to NSAIDs, corticoste-

259

roids, and DMARDs, including several children (54-61). The most frequently used TNF antagonist is infliximab, but a few patients treated with etanercept or adalimumab have also been described. The most common dosage schedules are summarized in Table 4, but higher doses— achieved either by increasing the individual dose or by shortening the dosage intervals— have been found necessary in some patients. The response is generally rapid, with dramatic improvement even after the first dose, but more gradual improvement can also occur. Remission of bone pain has been reported in the majority of patients, but generally requires continued therapy. However, there are also reports of patients who did not benefit from TNF␣ blockade (62). Follow-up has been short in most cases reported to date. Only a limited number of patients underwent repeat imaging studies. In some of these, there was evidence of continued subclinical disease activity with persistence of existing lesions or even development of new, clinically silent lesions, even though pain had subsided completely under TNF blockade (59). The skin lesions initially improve, and complete remission of acne and PPP has been described in some patients, but recurrence, particularly of PPP, was observed in several cases (54,63). As has been noted in other indications of TNF blockade, individual patients show differential clinical responses and adverse event profiles to the 3 types of TNF antagonists; therefore, switching of a patient to different antagonists can be beneficial. Even though there are indications that TNF antagonists are somewhat less effective than in other rheumatic diseases, their use should be considered in patients whose SAPHO syndrome is refractory to other therapeutic regimens. Of note, it has been reported that SAPHO syndrome (with PPP and spondylitis) developed during infliximab therapy of a patient with Crohn’s disease (64). Up to 10% of SAPHO patients develop IBD, most frequently Crohn’s disease and mainly after the onset of SAPHO symptoms (8,10-12,16,17,22). Nonetheless, the development of SAPHO syndrome during infliximab treatment is unexpected in view of the successful treatment of this syndrome with infliximab. Note, however, that the paradoxical induction of diseases that are often successfully treated with TNF blockade is a well-known phenomenon (65). In particular, the development of psoriasis has been observed in patients with various rheumatic diseases undergoing treatment with biologicals and has also been reported in patients with SAPHO syndrome (54). However, this is the first—and so far only— case of SAPHO syndrome arising during treatment with infliximab (64). Bisphosphonates Bisphosphonates inhibit bone resorption and have some anti-inflammatory properties. Several small case series and case reports indicate that open-label use of intravenous bisphosphonates results in marked pain relief and even sustained remission in a considerable portion of

(21) Not associated Not done Deficiency of the IL-1RA (DIRA) IL-1RA IL1RN

PSTPIP2

Papa

Proline serine threonine phosphatase interacting protein 1 Proline serine threonine phosphatase interacting protein 2

Two mouse models with nonsynonymous homozygous mutations

Aseptic multifocal osteomyelitis, periostitis, pustulosis

38 SAPHO Not done

(8) No mutations 10 CRMO

(8) No mutations 10 CRMO

(21)

PSTPIP1 (CD2BP1)

Results

Not associated 38 SAPHO

Anemia due to congenital erythropoiesis abnormalities; transient neutrophilic dermatosis Pyogenic Arthritis, Pyoderma gangrenosum, Acne Features of CRMO

Disease Manifestations Disease

Majeed syndrome

Encoded Protein

Lipin 2

Gene LPIN2

References

The SAPHO syndrome

Number of SAPHO/CRMO Patients Examined

Table 4 Gene Mutations Leading to Human Genetic Auto-Inflammatory Disorders with Features of SAPHO and the Results of Genetic Analyses in SAPHO/CRMO Patients

260

patients refractory to NSAIDs, corticosteroids, and DMARDS (51,62,66-68), including 2 small series of children (69,70). Many other patients experience at least partial improvement, but a number of treatment failures have also been reported (54,62,67). Pamidronate has been the most frequently used bisphosphonate, but there are case reports of good results with other types of bisphosphonates (71-74). The dosage schedules for pamidronate have been highly variable, ranging from a single infusion of 30 mg (43) to infusions on days 1, 7, 14, 28, and 56 (68), but single infusions of 60 mg repeated as needed or 60 mg on 3 consecutive days with or without re-treatment are most common (Table 4). The response can be very rapid, but in most patients several courses of bisphosphonates are required to achieve a lasting response. Markers of bone remodeling, in particular increased levels of serum cross laps at the beginning of therapy and a marked decrease during therapy, may be prognostic of a good clinical response to pamidronate (67). Interestingly, flares of cutaneous involvement have also been reported to diminish or even subside after bisphosphonate therapy (62), but this is not a consistent finding (66). Adverse effects of intravenous bisphosphonates in patients with SAPHO syndrome consist mostly of fever and flue-like symptoms particularly during or after the first infusion, but have included renal dysfunction in other patient groups. Therefore, it is of particular interest that the use of an oral bisphosphonate also demonstrated effectiveness in a patient with SAPHO syndrome (75). Note that repeated bone scans do not necessarily show decreased technetium uptake (62,68), although such cases have been reported (76). Surgery Numerous patients with SAPHO syndrome have undergone surgical procedures such as saucerization, decortication, and partial or complete resection of the affected bone. Although this was reported to be beneficial in isolated cases (36,48,77,78), it is generally not recommended because there is a high recurrence rate (36,48,50,78). Resections may be necessary, however, in cases of severe functional limitations and important esthetic concerns, as can occur when the mandible is affected (39). DISEASE COURSE AND PROGNOSIS The course of the disease in individual patients is highly variable. In a recently described cohort, 13% of patients had monophasic disease and 35% experienced a relapsing-remitting course for up to a few years, but eventually reached remission. The disease took a chronic course with exacerbations separated by brief periods of improvement in the remaining 52% of patients (17). Predictors of a chronic disease course in this study were female gender and the presence at disease onset of anterior chest wall involvement, peripheral arthritis, dermatologic lesions,

M.T. Nguyen et al.

and high levels of acute phase reactants. In partial contrast, 71% of patients in a French cohort experienced self-limited disease, whereas the disease became chronic in the remainder (22). Involvement of additional sites during the course of the disease is a frequent observation (16,17,79). Note that the intervals between flares are highly variable, even in individual patients, and can range from a few weeks to several months, sometimes even years. In some cases, exacerbations of bone and skin lesions occur almost synchronously (24,25), whereas no temporal correlation between rheumatologic and dermatologic symptoms is seen in others (16,17). The prognosis is generally considered to be relatively good. Disabling complications are rare (16,17), and even patients with chronic disease were found to experience gradual improvement (79). Nonetheless, the peripheral arthritis in SAPHO syndrome may become erosive in a minority of patients (16,17). When the inflammation spreads from the affected bones and joints into the adjacent tissue, soft tissue swelling can result in venous obstruction and thrombosis. Most frequently, this manifests as thoracic outlet syndrome, subclavian vein obstruction, and superior vena cava syndrome (16,27,77). Such soft tissue lesions may be mistaken for a mediastinal tumor and result in unnecessary biopsy or even mutilating surgical procedures unless there is awareness that this can represent a manifestation of SAPHO syndrome (77). In addition, approximately 8% to 10% of patients have or develop inflammatory bowel disease, with Crohn’s disease being 3 to 4 times more frequent than ulcerative colitis (Table 1) (8,1012,16,17,22). The disease course in children is similarly characterized by periods of exacerbations and remissions with an increasing number of lesions over time (10), but CRMO is generally considered to be a relatively benign and selflimiting disease without major sequelae. Indeed, healing of lesions with sclerosis and normalization of the bone structure over a period of 0.5 to 5 years after remission have been described in children with CRMO (24). Nonetheless, the disease remained active in ⬃60% of patients 3 to 5 years after diagnosis (28,47). Even a median of 13 years after diagnosis, one fourth of CRMO patients were found to experience chronic pain due to active disease (10). Others reported a high frequency of pathologic fractures (49%) and vertebral fractures derived from pathologic fractures (44%) in patients with CRMO (11). In addition, CRMO patients may suffer from permanent bone deformities and limb length abnormalities and even generalized growth failure (28,80). Educational outcomes and career choices may also be affected by CRMO (28). PATHOGENESIS The pathogenesis of SAPHO syndrome remains unknown and the mechanisms linking osteoarticular and skin lesions are enigmatic. The highly variable response to

261

each and every treatment modality used to date suggests that a multitude of pathways is involved. Several hypotheses have been proposed. One is that bone and skin lesions arise in response to persistent infection with low-virulence pathogens. Among the microorganisms cultured from bone biopsies of some patients with SAPHO syndrome, P. acne has been most frequently identified (48,49,81). Note, however, that in a vast majority of patients, cultures are negative, even when tested with polymerase chain reaction employing universal primers for eubacterial and mycobacterial genes (45,47), and antibiotics are generally ineffective, even if a few cases with a good clinical response to antimicrobial agents have been described (16,17). It has also been hypothesized that SAPHO syndrome represents an autoimmune process triggered by a bacterial or viral pathogen via molecular mimicry. None of these hypotheses explain why skin lesions precede bone lesion in some patients and follow them in others or why years or decades can pass between cutaneous and osteoarticular manifestations. There have been several systematic investigations of autoantibodies in patients with the SAPHO syndrome (17,18,82). The results were always negative for rheumatoid factor, anti-citrullinated peptide, and extractable nuclear antigens with 1 exception (18). Antinuclear antibodies (ANA) were negative in all patients of 1 cohort (82) and were not detected at presentation, but developed in 2 of 71 patients during follow-up (17). In the third investigation, however, ANA at titers of 1/160 were detected in 14 of 90 (16%) patients, yet 10 of these patients never took medications associated with the induction of ANA (18). ANA at titers ⱖ1/80 were found in almost 37% of this cohort. Similarly, 33% of patients with nonbacterial osteitis including CRMO were reported to have ANA titers ⬎1:120 (11). Their specificity could not be determined. Antithyroid globulin and antithyroid peroxidases were detected in 2% to 3% of patients in 2 studies (18,82), but these antibodies were present in 23% and 21% of the patients in another cohort, and 6 patients had overt hyperthyroidism (17). Genetics Considering that there are far less than 1000 published cases of SAPHO syndrome, the number of familial cases that have been described is quite substantial. These concern monozygotic twins (83-85), sibling pairs (19,50,86,87) and trios (19,88,89), a mother– daughter pair (90), and several other cases in which the relationship is not specified (17). In several instances, the affected siblings shared numerous human leukocyte antigens (HLA) phenotypes (87,88,91). In addition, a family has been described in which the patient and her grandmother had SAPHO, the mother had recurrent pustulosis, severe acne, and intermittent multifocal bone pain that had not been evaluated, and several other family members had severe acne and various other skin diseases (92). Of note,

262

neutrophils from both the primary patient and her mother exhibited a defect in the internal oxidative burst of neutrophils in response to a variety of stimuli (92). This is noteworthy because neutrophilic pseudoabscesses are characteristic of the dermatoses associated with SAPHO syndrome, and the early infiltrate in bone lesions is also dominated by neutrophils. Among 89 cases of nonbacterial osteitis, including CRMO, 6% of the families contained more than 1 affected member, including father and son, father and 2 of his daughters, monozygotic twin sisters, and 2 other pairs of sisters (11). In addition, almost 40% of the patients had a family history of autoimmune diseases (11). Similarly, among 45 CRMO patients, 47% of first- or second-degree relatives reportedly had 1 or more chronic inflammatory disorder(s), including psoriasis, IBD, arthritis, and severe acne (93). Several other SAPHO cases with a family history of psoriasis (almost always without psoriatic arthritis) have been reported (12,17,24,47,69,94,95), whereas a family history of ankylosing spondylitis seems to be rare (47). Although the familial clustering of SAPHO cases appears to be more limited than seen in the spondyloarthropathies, particularly psoriatic arthritis, it nonetheless suggests a genetic component in the pathogenesis of the syndrome. Some of the early studies indicated that the frequency of HLA-B27 was increased in patients with SAPHO syndrome compared to the general population (1,13), although possession of this antigen was nowhere near as frequent as seen in ankylosing spondylitis (where ⱖ85% are positive). Recent studies have reported frequencies between 4% in Italy and 18% in France (17) (Table 1). Whether this constitutes an excess is difficult to determine because no phenotype frequencies for the general population are provided in these studies. Generally, between 2% and 9% of most populations of European descent are HLA-B27 carriers, but the frequency can range from 0 to ⱖ20 worldwide. In an analysis of 25 SAPHO and 120 psoriatic arthritis patients, SAPHO showed no association with HLA-B27, HLA-Cw6, or HLA-DR antigens, whereas HLA-Cw6 was associated with psoriasis and psoriatic arthritis and HLA-B27 was associated with psoriatic spondylitis (96). Insights into possible genetic associations may also come from 2 mouse models with nonsynonymous homozygous mutations in the PSTPIP2 gene, encoding the proline serine threonine phosphatase interacting protein 2, spontaneously developing features of CRMO. In addition, the SAPHO syndrome shares some features with several human genetic auto-inflammatory diseases with autosomal-recessive inheritance, including the Majeed syndrome, PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne) syndrome, and deficiency of interleukin-1-receptor antagonist (80,93). The Majeed syndrome consists of CRMO, anemia due to congenital erythropoiesis abnormalities, and transient neutrophilic dermatoses. It is due to a homozygous mutation of the LPIN2 gene

The SAPHO syndrome

(encoding lipin 2) (97). The PAPA syndrome is caused by mutations in PSTPIP1. However, an analysis of genetic susceptibility factors in patients with SAPHO syndrome did not identify an association of SAPHO syndrome with LPIN2 (19). There also was no association with PSTPIP2 or with NOD2/CARD15, a gene implicated in Crohn’s disease, which is a complication in up to 10% of patients with SAPHO. No mutations in either PSTPIP1 or PSTPIP2 were detected in 10 patients with CRMO (11). Deficiency of interleukin-1 receptor antagonist (IL-1Ra) production due to homozygous mutations in the IL1RN gene results in an autosomal-recessive auto-inflammatory disease characterized by aseptic multifocal osteomyelitis, periostitis, and pustulosis (98). Affected patients can be rescued by administration of anakinra, the recombinant human IL-1RA. Whether SAPHO syndrome is associated with genetic variants of IL-1RA or related genes has not been investigated to date. However, when 6 SAPHO patients whose disease was refractory to a variety of treatment modalities were treated with anakinra, 5 of them experienced considerable pain relief and a reduction in disease activity, but a complete lack of efficacy was observed in the sixth patient (99). Treatment with anakinra of a child with CRMO who exhibited significantly elevated levels of plasma IL-1RA (implying activation of the IL-1 pathway) initially resulted in symptom resolution and improvement of disease activity, but efficacy was lost after a year (61). The only significant genetic association reported for the SAPHO syndrome to date is with the T309G allele and the GG genotype of the Mdm2-gene, which were not associated with psoriasis and psoriatic arthritis (100). An association with the p53 single nucleotide polymorphism G72C just failed to reach statistical significance in that study. The tumor suppressor protein p53 plays an important role in cell cycle regulation and apoptosis of damaged cells and also regulates the transcription factor NF-␬B, which is central to a variety of proinflammatory pathways. Mdm2, in turn, is the most important negative regulator of p53. Both of the alleles with increased frequencies in patients with SAPHO syndrome have been associated with ineffective p53 responses, but it remains to be elucidated which p53 functions are involved in the development of this syndrome. Intense expression of TNF␣ mRNA and protein has been reported in bone biopsy specimens of a few patients with SAPHO syndrome (52). In addition, activation of the IL-1 pathway as evidenced by elevated levels of plasma IL-1RA was reported in another patient (61). The clinical response of SAPHO patients to treatment with TNF or IL-1 blockade (anakinra) further suggests that these inflammatory cytokines play an important role in the pathogenesis of the SAPHO syndrome. Therefore, the inhibitory effects of p53/Mdm2 axis on NF-␬B-induced proinflammatory pathways may be particularly relevant. SAPHO syndrome shares a variety of features with the seronegative spondyloarthropathies (SpAs), including

M.T. Nguyen et al.

sacroiliitis, enthesitis, paravertebral ossifications, and ankylosis. The association with IBD and psoriasis is another characteristic common to both SAPHO syndrome and SpAs. In addition, pustular psoriasis and PPP are difficult to distinguish histologically and clinically and may represent the same entity. On the other hand, carriage of HLAB27 is classically linked with the SpAs, particularly with ankylosing spondylitis, where the prevalence of this antigen exceeds 85% (101,102). Nevertheless, HLA-B27 is at best only moderately overrepresented in patients with SAPHO syndrome. A better comprehension of the nosologic relation between SAPHO syndrome and the seronegative SpAs may eventually provide insights into the pathogenesis of SAPHO syndrome. Currently, however, such an understanding not only remains elusive but also would not be very useful because the pathogenetic mechanisms of the SpAs also remain largely unknown. A variety of mechanisms have been proposed for ankylosing spondylitis, but essentially all of them involve HLA-B27 (103). Reactive arthritis is caused by infectious organisms, the presence of which would exclude a diagnosis of SAPHO syndrome. It, too, is strongly associated with HLA-B27. SAPHO syndrome encompasses a broad spectrum of hyperostotic and osteitic lesions associated with dermatologic manifestations. It is believed to share some characteristics with spondyloarthropathies and other autoimmune diseases (104), but more likely is in the autoinflammatory part of the spectrum of immunologic diseases (105). Recognition of SAPHO syndrome is important to avoid unnecessary invasive procedures and prolonged antibiotic treatment of osteoarticular lesions. However, the course of the disease is benign and the longterm functional prognosis is good if promptly diagnosed and treated (106). REFERENCES 1. Chamot AM, Benhamou CL, Kahn MF, Beraneck L, Kaplan G, Prost A. Le syndrome acné pustulose hyperostose ostéite. Résultats d’une enquête nationale; 85 observations. [Acne-pustulosishyperostosis-osteitis syndrome. Results of a national survey. 85 cases.] Rev Rhum Mal Osteoartic 1987;54:187-96. 2. Earwaker JW, Cotten A. SAPHO: Syndrome or concept? Imaging findings. Skeletal Radiol 2003;32:311-27. 3. Benhamou CL, Chamot AM, Kahn MF. Synovitis-acne-pustulosis hyperostosis-osteomyelitis syndrome (SAPHO). A new syndrome among the spondyloarthropathies? Clin Exp Rheumatol 1988;6:109-12. 4. Giedion A, Holthusen W, Masel LF, Vischer D. [Subacute and chronic “symmetrical” osteomyelitis] (article in multiple languages). Ann Radiol (Paris) 1972;15:329-42. 5. Björkstén B, Boquist L. Histopathological aspects of chronic recurrent multifocal osteomyelitis. J Bone Joint Surg Br 1980; 62:376-80. 6. Schilling F. [Chronic recurrent multifocal osteomyelitis (CRMO)]. Rofo 1998;168:115-27. 7. Vittecoq O, Said LA, Michot C, Mejjad O, Thomine JM, Mitrofanoff P, et al. Evolution of chronic recurrent multifocal osteitis toward spondylarthropathy over the long term. Arthritis Rheum 2000;43:109-19.

263 8. Bognar M, Blake W, Agudelo C. Chronic recurrent multifocal osteomyelitis associated with Crohn’s disease. Am J Med Sci 1998;315:133-5. 9. Tlougan BE, Podjasek JO, O’Haver J, Cordova KB, Nguyen XH, Tee R, et al. Chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome with associated neutrophilic dermatoses: A report of seven cases and review of the literature. Pediatr Dermatol 2009;26:497-505. 10. Huber AM, Lam PY, Duffy CM, Yeung RS, Ditchfield M, Laxer D, et al. Chronic recurrent multifocal osteomyelitis: Clinical outcomes after more than five years of follow-up. J Pediatr 2002; 141:198-203. 11. Jansson A, Renner ED, Ramser J, Mayer A, Haban M, Meindl A, et al. Classification of non-bacterial osteitis: Retrospective study of clinical, immunological and genetic aspects in 89 patients. Rheumatology (Oxford) 2007;46:154-60. 12. Schilling F, Märker-Hermann E. Die chronisch rekurrierende multifokale osteomyelitis in Assoziation mit chronisch entzündlichen Darmerkrankungen: Die enteropathische CRMO. [Chronic recurrent multifocal osteomyelitis in association with chronic inflammatory bowel disease: entheropathic CRMO.] Z Rheumatol 2003;62:527-38. 13. Kahn MF, Khan MA. The SAPHO syndrome. Baillieres Clin Rheumatol 1994;8:333-62. 14. Khanna G, Sato TS, Ferguson P. Imaging of chronic recurrent multifocal osteomyelitis. RadioGraphics 2009;29:1159-77. 15. Schilling F. SAPHO Syndrom. Available at wwworphanetnet, accessed March 1, 2012. 16. Hayem G, Bouchaud-Chabot A, Benali K, Roux S, Palazzo E, Silbermann-Hoffman O, et al. SAPHO syndrome: A long-term follow-up study of 120 cases. Semin Arthritis Rheum 1999;29: 159-71. 17. Colina M, Govoni M, Orzincolo C, Trotta F. Clinical and radiologic evolution of synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome: A single center study of a cohort of 71 subjects. Arthritis Rheum 2009;61:813-21. 18. Grosjean C, Hurtado-Nedelec M, Nicaise-Roland P, FerreyraDillon R, Bollet C, Quintin E, et al. Prevalence of autoantibodies in SAPHO syndrome: A single-center study of 90 patients. J Rheumatol 2010;37:639-43. 19. Hurtado-Nedelec M, Chollet-Martin S, Chapeton D, Hugot JP, Hayem G, Gérard B. Genetic susceptibility factors in a cohort of 38 patients with SAPHO syndrome: A study of PSTPIP2, NOD2, and LPIN2 genes. J Rheumatol 2010;37:401-9. 20. Suei Y, Taguchi A, Tanimoto K. Diagnostic points and possible origin of osteomyelitis in synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome: A radiographic study of 77 mandibular osteomyelitis cases. Rheumatology (Oxford) 2003; 42:1398-403. 21. Sonozaki H, Mitsui H, Miyanaga Y, Okitsu K, Igarashi M, Hayashi Y, et al. Clinical features of 53 cases with pustulotic arthro-osteitis. Ann Rheum Dis 1981;40:547-53. 22. Sallés M, Olivé A, Perez-Andres R, Holgado S, Mateo L, Riera E, et al. The SAPHO syndrome: A clinical and imaging study. Clin Rheumatol 2011;30:245-9. 23. Beretta-Piccoli BC, Sauvain MJ, Gal I, Schibler A, Saurenmann T, Kressebuch H, et al. Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome in childhood: A report of ten cases and review of the literature. Eur J Pediatr 2000;159:594-601. 24. Jurik AG, Helmig O, Ternowitz T, Møller BN. Chronic recurrent multifocal osteomyelitis: A follow-up study. J Pediatr Orthop 1988;8:49-58. 25. Björkstén B, Gustavson KH, Eriksson B, Lindholm A, Nordström S. Chronic recurrent multifocal osteomyelitis and pustulosis palmoplantaris. J Pediatr 1978;93:227-31. 26. Sofman MS, Prose NS. Dermatoses associated with sterile lytic bone lesions. J Am Acad Dermatol 1990;23:494-8.

264 27. Depasquale R, Kumar N, Lalam RK, Tins BJ, Tyrrell PN, Singh J, et al. SAPHO: What radiologists should know. Clin Radiol 2012;67:195-206. 28. Catalano-Pons C, Comte A, Wipff J, Quartier P, Faye A, Gendrel D, et al. Clinical outcome in children with chronic recurrent multifocal osteomyelitis. Rheumatology (Oxford) 2008;47: 1397-9. 29. Kahn MF, Bouvier M, Palazzo E, Tebib JG, Colson F. Sternoclavicular pustulotic osteitis (SAPHO). 20-Year interval between skin and bone lesions. J Rheumatol 1991;18:1104-8. 30. Rosner IA, Burg CG, Wisnieski JJ, Schacter BZ, Richter DE. The clinical spectrum of the arthropathy associated with hidradenitis suppurativa and acne conglobata. J Rheumatol 1993;20: 684-7. 31. Bhalla R, Sequeira W. Arthritis associated with hidradenitis suppurativa. Ann Rheum Dis 1994;53:64-6. 32. Steinhoff JP, Cilursu A, Falasca GF, Guzman L, Reginato AJ. A study of musculoskeletal manifestations in 12 patients with SAPHO syndrome. J Clin Rheumatol 2002;8:13-22. 33. Kahn MF, Chamot AM. SAPHO syndrome. Rheum Dis Clin North Am 1992;18:225-46. 34. Yamasaki O, Iwatsuki K, Kaneko F. A case of SAPHO syndrome with pyoderma gangrenosum and inflammatory bowel disease masquerading as Behçet’s disease. Adv Exp Med Biol 2003;528: 339-41. 35. Conway R, Ryan A, Khan K. A case of SAPHO syndrome presenting as isolated iliitis and spondylitis. J Rheumatol 2011;38: 1810-1. 36. Sonozaki H, Azuma A, Okai K, Nakamura K, Fukuoka S, Tateishi A, et al. Clinical features of 22 cases with “inter-sterno-costoclavicular ossification.” A new rheumatic syndrome. Arch Orthop Traumat Surg 1979;95:13-22. 37. Colhoun EN, Hayward C, Evans KT. Inter-sterno-costo-clavicular ossification. Clin Radiol 1987;38:33-8. 38. Laredo JD, Vuillemin-Bodaghi V, Boutry N, Cotten A, ParlierCuau C. SAPHO syndrome: MR appearance of vertebral involvement. Radiology 2007;242:825-31. 39. Zemann W, Pau M, Feichtinger M, Ferra-Matschy B, Kaercher H. SAPHO syndrome with affection of the mandible: Diagnosis, treatment, and review of literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;111:190-5. 40. Freyschmidt J, Sternberg A. The bullhead sign: Scintigraphic pattern of sternocostoclavicular hyperostosis and pustulotic arthroosteitis. Eur Radiol 1998;8:807-12. 41. Davies AM, Marino AJ, Evans N, Grimer RJ, Deshmukh N, Mangham DC. SAPHO syndrome: 20-year follow-up. Skeletal Radiol 1999;28:159-62. 42. Reith JD, Bauer TW, Schils JP. Osseous manifestations of SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome. Am J Surg Pathol 1996;20:1368-77. 43. Van Doornum S, Barraclough D, McColl G, Wicks I. SAPHO: Rare or just not recognized? Semin Arthritis Rheum 2000;30: 70-7. 44. Yu L, Kasser JR, O’Rourke E, Kozakewich H. Chronic recurrent multifocal osteomyelitis. Association with vertebra plana. J Bone Joint Surg Am 1989;71:105-12. 45. Girschick HJ, Huppertz HI, Harmsen D, Krauspe R, MüllerHermelink HK, Papadopoulos T. Chronic recurrent multifocal osteomyelitis in children: Diagnostic value of histopathology and microbial testing. Hum Pathol 1999;30:59-65. 46. Boutin RD, Resnick D. The SAPHO syndrome: An evolving concept for unifying several idiopathic disorders of bone and skin. AJR Am J Roentgenol 1998;170:585-91. 47. Job-Deslandre C, Krebs S, Kahan A. Chronic recurrent multifocal osteomyelitis: Five-year outcomes in 14 pediatric cases. Joint Bone Spine 2001;68:245-51.

The SAPHO syndrome 48. Edlund E, Johnsson U, Lidgren L, Pettersson H, Sturfelt G, Svensson B, et al. Palmoplantar pustulosis and sternocostoclavicular arthro-osteitis. Ann Rheum Dis 1988;47:809-15. 49. Assmann G, Kueck O, Kirchhoff T, Rosenthal H, Voswinkel J, Pfreundschuh M, et al. Efficacy of antibiotic therapy for SAPHO syndrome is lost after its discontinuation: An interventional study. Arthritis Res Ther 2009;11:R140. 50. Eyrich GK, Harder C, Sailer HF, Langenegger T, Bruder E, Michel BA. Primary chronic osteomyelitis associated with synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO syndrome). J Oral Pathol Med 1999;28:456-64. 51. Guignard S, Job-Deslandre C, Sayag-Boukris V, Kahan A. Pamidronate treatment in SAPHO syndrome. Joint Bone Spine 2002;69:392-6. 52. Wagner AD, Andresen J, Jendro MC, Hülsemann JL, Zeidler H. Sustained response to tumor necrosis factor alpha-blocking agents in two patients with SAPHO syndrome. Arthritis Rheum 2002;46:1965-8. 53. Wolber C, David-Jelinek K, Udvardi A, Artacker G, VolcPlatzer B, Kurz H. Sacroileitis im rahmen eines SAPHO Syndroms—Promptes ansprechen auf etanercept [Successful therapy of sacroiliitis in SAPHO syndrome by etanercept]. Wien Med Wochenschr 2011;161:204-8. 54. Ben Abdelghani K, Dran DG, Gottenberg JE, Morel J, Sibilia J, Combe B. Tumor necrosis factor-alpha blockers in SAPHO syndrome. J Rheumatol 2010;37:1699-704. 55. De Souza A, Solomon GE, Strober BE. SAPHO syndrome associated with hidradenitis suppurativa successfully treated with infliximab and methotrexate. Bull NYU Hosp Jt Dis 2011;69: 185-7. 56. Castellví I, Bonet M, Narváez JA, Molina-Hinojosa JC. Successful treatment of SAPHO syndrome with adalimumab: A case report. Clin Rheumatol 2010;29:1205-7. 57. Vilar-Alejo J, Dehesa L, de la Rosa-del Rey P, Novoa-Medina J, Valerón Almazán P, Santana Medina N, et al. SAPHO syndrome with unusual cutaneous manifestations treated successfully with etanercept. Acta Derm Venereol 2010;90:531-2. 58. Arias-Santiago S, Sanchez-Cano D, Callejas-Rubio JL, Fernández-Pugnaire MA, Ortego-Centeno N. Adalimumab treatment for SAPHO syndrome. Acta Derm Venereol 2010;90:301-2. 59. Fruehauf J, Cierny-Modre B, Caelen Lel S, Schwarz T, Weinke R, Aberer E. Response to infliximab in SAPHO syndrome. BMJ Case Rep, 2009; 2009. 60. Marangoni RG, Halpern AS. Chronic recurrent multifocal osteomyelitis primarily affecting the spine treated with anti-TNF therapy. Spine (Phila Pa 1976) 2010;35:E253-6. 61. Eleftheriou D, Gerschman T, Sebire N, Woo P, Pilkington CA, Brogan PA. Biologic therapy in refractory chronic non-bacterial osteomyelitis of childhood. Rheumatology (Oxford) 2010;49: 1505-12. 62. Amital H, Applbaum YH, Aamar S, Daniel N, Rubinow A. SAPHO syndrome treated with pamidronate: An open-label study of 10 patients. Rheumatology (Oxford) 2004;43:658-61. 63. Massara A, Cavazzini PL, Trotta F. In SAPHO syndrome antiTNF-alpha therapy may induce persistent amelioration of osteoarticular complaints, but may exacerbate cutaneous manifestations. Rheumatology (Oxford) 2006;45:730-3. 64. Van Den Eynde M, Lecluyse K, Chioccioli C, Brouckaert M, Caussin E, Lammens P. Maladie de Crohn et syndrome SAPHO, au cours d’un traitement à l’infliximab: Cas clinique et revue de la littérature [Crohn’s disease and the SAPHO syndrome during treatment with infliximab: a case report and review of literature]. Gastroenterol Clin Biol 2007;31:607-10. 65. Borchers AT, Leibushor N, Cheema GS, Naguwa SM, Gershwin ME. Immune-mediated adverse effects of biologicals used in the treatment of rheumatic diseases. J Autoimmun 2011;37: 273-88.

M.T. Nguyen et al. 66. Colina M, La Corte R, Trotta F. Sustained remission of SAPHO syndrome with pamidronate: A follow-up of fourteen cases and a review of the literature. Clin Exp Rheumatol 2009;27:112-5. 67. Solau-Gervais E, Soubrier M, Gerot I, Grange L, Puechal X, Sordet C, et al. The usefulness of bone remodelling markers in predicting the efficacy of pamidronate treatment in SAPHO syndrome. Rheumatology (Oxford) 2006;45:339-42. 68. Valls-Roc M, Sanmarti M, Salles M, Holgado S, Olive A. SAPHO syndrome and pamidronate revisited. Rheumatology (Oxford) 2005;44:137; Author reply 137-8. 69. Kerrison C, Davidson JE, Cleary AG, Beresford MW. Pamidronate in the treatment of childhood SAPHO syndrome. Rheumatology (Oxford) 2004;43:1246-51. 70. Miettunen PM, Wei X, Kaura D, Reslan WA, Aguirre AN, Kellner JD. Dramatic pain relief and resolution of bone inflammation following pamidronate in 9 pediatric patients with persistent chronic recurrent multifocal osteomyelitis (CRMO). Pediatr Rheumatol Online J 2009;7:2. 71. Kopterides P, Pikazis D, Koufos C. Successful treatment of SAPHO syndrome with zoledronic acid. Arthritis Rheum 2004;50:2970-3. 72. Just A, Adams S, Brinkmeier T, Barsegian V, Lorenzen J, Schilling F, et al. Successful treatment of primary chronic osteomyelitis in SAPHO syndrome with bisphosphonates. J Dtsch Dermatol Ges 2008;6:657-60. 73. Soyfoo MS, Gangji V, Margaux J. Successful treatment of SAPHO syndrome with ibandronate. J Clin Rheumatol 2010;16:253. 74. Fioravanti A, Cantarini L, Burroni L, Mazzei MA, Volterrani L, Galeazzi M. Efficacy of alendronate in the treatment of the SAPHO syndrome. J Clin Rheumatol 2008;14:183-4. 75. Ichikawa J, Sato E, Haro H, Ando T, Maekawa S, Hamada Y. Successful treatment of SAPHO syndrome with an oral bisphosphonate. Rheumatol Int 2009;29:713-5. 76. Galadari H, Bishop AG, Venna SS, Sultan E, Do D, Zeltser R. Synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome treated with a combination of isotretinoin and pamidronate. J Am Acad Dermatol 2009;61:123-5. 77. van Holsbeeck M, Martel W, Dequeker J, Favril A, Gielen J, Verschakelen J, et al. Soft tissue involvement, mediastinal pseudotumor, and venous thrombosis in pustulotic arthro-osteitis. A study of eight new cases. Skeletal Radiol 1989;18:1-8. 78. Yanamoto S, Kawasaki G, Yoshitomi I, Mizuno A. Diffuse chronic sclerosing osteomyelitis of the mandible with synovitis, acne, pustulosis, hyperostosis, and osteitis: Report of a long-term follow-up case. J Oral Maxillofac Surg 2010;68:212-7. 79. Maugars Y, Berthelot JM, Ducloux JM, Prost A. SAPHO syndrome: A followup study of 19 cases with special emphasis on enthesis involvement. J Rheumatol 1995;22:2135-41. 80. Wipff J, Adamsbaum C, Kahan A, Job-Deslandre C. Chronic recurrent multifocal osteomyelitis. Joint Bone Spine 2011;78: 555-60. 81. Govoni M, Colina M, Massara A, Trotta F. SAPHO syndrome and infections. Autoimmun Rev 2009;8:256-9. 82. Hurtado-Nedelec M, Chollet-Martin S, Nicaise-Roland P, Grootenboer-Mignot S, Ruimy R, Meyer O, et al. Characterization of the immune response in the synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome. Rheumatology (Oxford) 2008;47:1160-7. 83. Golla A, Jansson A, Ramser J, Hellebrand H, Zahn R, Meitinger T, et al. Chronic recurrent multifocal osteomyelitis (CRMO): Evidence for a susceptibility gene located on chromosome 18q21.3-18q22. Eur J Hum Genet 2002;10:217-21. 84. Gonzalez T, Gantes M, Bustabad S, Diaz-Flores L. Acne fulminans associated with arthritis in monozygotic twins. J Rheumatol 1985;12:389-91. 85. Darley CR, Currey HL, Baker H. Acne fulminans with arthritis in identical twins treated with isotretinoin. J R Soc Med 1984;77:328-30. 86. Festen JJ, Kuipers FC, Schaars AH. Multifocal recurrent periostitis responsive to colchicine. Scand J Rheumatol 1985;14:8-14.

265 87. Kurc D, De Saint-Père R, Madoule P, Laoussadi S, Caquet R. [Chronic osteitis and arthritis of palmoplantar pustulosis. A familial form of B-27 negative spondylarthropathy]. Rev Med Interne 1987;8:79-84. 88. Dumolard A, Gaudin P, Juvin R, Bost M, Peoc’h M, Phelip X. SAPHO syndrome or psoriatic arthritis? A familial case study. Rheumatol Oxf Engl 1999;38:463-7. 89. Ben Becher S, Essaddam H, Nahali N, Ben Hamadi F, Mouelhi MH, Hammou A, et al. Recurrent multifocal periostosis in children. Report of a familial form]. Ann Paediatr (Paris) 1991;38:345-9. 90. Riffat G, Alexandre C, Pallot-Prades B, Prallet B, Cartry O, Chappard D. A propos d’une observation familiale de SAHPO. Rhumatologie 1991;43:159-63. 91. Eyrich GK, Langenegger T, Bruder E, Sailer HF, Michel BA. Diffuse chronic sclerosing osteomyelitis and the synovitis, acne, pustolosis, hyperostosis, osteitis (SAPHO) syndrome in two sisters. Int J Oral Maxillofac Surg 2000;29:49-53. 92. Ferguson PJ, Lokuta MA, El-Shanti HI, Muhle L, Bing X, Huttenlocher A. Neutrophil dysfunction in a family with a SAPHO syndrome-like phenotype. Arthritis Rheum 2008;58:3264-9. 93. Ferguson PJ, El-Shanti HI. Autoinflammatory bone disorders. Curr Opin Rheumatol 2007;19:492-8. 94. Schilling F, Kessler S, Das S-S. Klinisch-rheumatologische und radiologische Differenzierung und Klassifizierung eines Krankengutes von 86 fällen [SAPHO syndrome: clinico-rheumatologic and radiologic differentiation and classification of a patient sample of 86 cases]. Z Rheumatol 2000;59:1-28. 95. Olivieri I, Padula A, Ciancio G, Salvarani C, Niccoli L, Cantini F. Successful treatment of SAPHO syndrome with infliximab: Report of two cases. Ann Rheum Dis 2002;61:375-6. 96. Queiro R, Moreno P, Sarasqueta C, Alperi M, Riestra JL, Ballina J. Synovitis-acne-pustulosis-hyperostosis-osteitis syndrome and psoriatic arthritis exhibit a different immunogenetic profile. Clin Exp Rheumatol 2008;26:125-8. 97. Ferguson PJ, Chen S, Tayeh MK, Ochoa L, Leal SM, Pelet A, et al. Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome). J Med Genet 2005;42:551-7. 98. Aksentijevich I, Masters SL, Ferguson PJ, Dancey P, Frenkel J, van Royen-Kerkhoff A, et al. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med 2009;360:2426-37. 99. Wendling D, Prati C, Aubin F. Anakinra treatment of SAPHO syndrome: Short-term results of an open study. Ann Rheum Dis 2012;71(6):1098-100. 100. Assmann G, Wagner AD, Monika M, Pfoehler C, Pfreundschuh M, Tilgen W, et al. Single-nucleotide polymorphisms p53 G72C and Mdm2 T309G in patients with psoriasis, psoriatic arthritis, and SAPHO syndrome. Rheumatol Int 2010;30:1273-6. 101. Chatzikyriakidou A, Voulgari PV, Drosos AA. What is the role of HLA-B27 in spondyloarthropathies? Autoimmun Rev 2011; 10:464-8. 102. Ehrenfeld M. Geoepidemiology: The environment and spondyloarthropathies. Autoimmun Rev 2010;9:A325-9. 103. Mansour M, Cheema GS, Naguwa SM, Greenspan A, Borchers AT, Keen CL, et al. Ankylosing spondylitis: A contemporary perspective on diagnosis and treatment. Semin Arthritis Rheum 2007;36:210-23. 104. Youinou P, Pers JO, Gershwin ME, Shoenfeld Y. Geo-epidemiology and autoimmunity. J Autoimmun 2010;34:J163-7. 105. McGonagle D, McDermott MF. A proposed classification of the immunological diseases. PLoS Med 2006;3:e297. 106. Cotten A, Flipo RM, Mentre A, Delaporte E, Duquesnoy B, Chastanet P. SAPHO syndrome. RadioGraphics 1995;15:114754.