**1. Introduction**

92 Rheumatoid Arthritis – Treatment

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> Synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome is a rare disorder characterized by osteoarticular and dermatological manifestations. The denotation was first proposed by Chamot et al. in 1987 after investigation of 85 cases (Chamot et al., 1987). The most common site of SAPHO syndrome is the upper anterior chest wall, characterized by predominantly osteosclerotic lesions and hyperostosis. The axial skeleton and peripheral bones can be involved. Peripheral synovitis is also common. Skin manifestations include palmoplantar pustulosis (PPP), severe acne and various patterns of psoriasis.

> The pathogenesis of SAPHO syndrome has not been determined. Most of the reported series to date are anecdotal, small or uncontrolled, thus a variety of therapeutic approaches exist. Treatment remains empirical with several drugs including non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, antibiotics, disease modifying anti-rheumatic drugs (DMARDs) and/or bisphosphonates (BPs), but results are inconsistent and usually variable. Recently, some successful experiences with anti-tumor necrosis factor-alpha (TNF-α) agents for refractory cases have been reported (Asmussen, 2003; Ben Abdelghani et al., 2010; Castellvi et al., 2010; Deutschmann et al., 2005; Iqbal & Kolodney, 2005; Kyriazis et al., 2004; Massara et al., 2006; Moll et al., 2008; Olivieri et al., 2002; Sabugo et al., 2008; Wagner et al., 2002; Widmer et al., 2003). The therapeutic strategy was largely originated from that for spondyloarthropathies, because accumulated arguments indicate that SAPHO syndrome can be classified with the inflammatory spondyloarthropathies (Takigawa et al., 2008) and treatment with anti-TNF-α agents is now well established in spondyloarthropathies or rheumatoid arthritis (RA). Chronic proliferative synovitis is one of the most important

Expression of Tumor Necrosis Factor-Alpha (TNF-TNF-Converting Enzyme and

Matrix Metalloproteinase-3 in SAPHO Syndrome Synovium - A Rare Case Accompanied by … 95

Fig. 1. Clinical findings of fingers (a), toes (b), and radiographs of bilateral fingers (c) and toes (d) in a patient with SAPHO syndrome accompanied by acrodrmatitis continua of Hallopeau. Erythema, pustules and onychodystrophy are present on all fingers and toes, which are compatible with the dermatological features of acrodermatitis continua of Hallopeau (a, b). Characteristic osteolysis of acrodermatitis continua of Hallopeau are

observed in phalanges of fingers (c) and toes (d).

pathological features in RA, and proliferated synovium is a major source of proinflammatory cytokines and proteinases. TNF-α is a key cytokine, which triggers the inflammatory cascade and stimulates the production of matrix degradable proteinases such as matrix metalloproteinases (MMPs) (Okada, 2005). TNF-α converting enzyme (TACE) processes a membrane form of TNF-α to a soluble form (Moss et al., 1997), and the binding of the latter form to TNF receptors triggers pathological events in RA (Christodoulou & Choi, 2006; Horiuchi et al., 2010; Ohta et al., 2001). Although synovitis is one of the major manifestations of SAPHO syndrome, detailed information on the pathological features is still lacking.

In this chapter, we describe a patient with SAPHO syndrome accompanied by marked knee synovitis and acrodermatitis continua of Hallopeau (ACH) as a skin manifestation. ACH is a rare acropustular eruption, characterized by sterlile pustules, paronychia and atrophic skin changes, onychodystrophy and osteolysis of the distal phalanges of the fingers and toes (Ryan et al., 2009). ACH is considered to be a localized subtype of pustular psoriasis (Yerushalmi et al., 2000) and our report is a first case of ACH as a skin manifestation of SAPHO syndrome. We focused on synovitis, analyzed synovial tissues histopathologically and demonstrated the expression of TNF-α, TACE and MMP-3 in SAPHO syndrome synovium. We also concisely review cases treated with anti-TNF-α agents in the literature and discuss the therapeutic strategy for SAPHO syndrome.

### **2. Case report**

A 76-year-old Japanese man first presented to a neighborhood university hospital in 1993 with subungal pustules, erythema and onychodystrophy on all fingers and toes. A diagnosis of ACH was histologically confirmed at the time. He had been treated with topical corticosteroid and vitamin D3. In January 2006, he presented to our department for the first time with persistent swelling and pain in his left knee. Physical examination showed marked patellar ballottement with local heat. A knee puncture yielded 60mL of yellow cloudy joint fluid, but cultures for bacteria were negative. For other osteoarticular symptoms, moderate lower back and buttock pain existed but no other joint pain, costa-sterno-clavicular joint included, was found**.** At the time, dermatological symptoms of ACH still remained on all fingers and toes (Figure 1a, b). Laboratory tests showed almost within normal value including indices of inflammation (erythrocyte sedimentation rate 10mm/hour, C-reactive protein level 0.19mg/dL [normal <0.30mg/dL]) and rheumatoid factor was negative. Radiographic study revealed characteristic osteolysis in phalanges of fingers and toes (Figure 1c, d). Magnetic resonance imaging revealed knee synovitis and bone marrow edema at the second lumbar vertebral body (Figure 2), compatible with sterile osteitis.

We made a diagnosis of SAPHO syndrome because the presence of ACH (a variant of pustular psoriasis), knee synovitis, and osteitis of the vertebral body were sufficient to the criteria. The patient was treated with NSAIDs for osteoarticular symptoms and topical treatment for skin lesions.

In October 2007, arthroscopic surgery was performed for knee synovitis. Intra-operative findings showed marked proliferation of villous contoured synovial tissues with rich blood circulation (Figure 3a). Continuous paraffin sections of biopsied synovial tissues were used for histopathological analyses, and standard microscopic study showed hyperplastic synovitis with lymphocytes infiltration and many blood vessels similar to RA (Figure 3b, c, d). Immunohistochemistry revealed the expression of TNF-α (Figure 3e), TACE (Figure 3f)

pathological features in RA, and proliferated synovium is a major source of proinflammatory cytokines and proteinases. TNF-α is a key cytokine, which triggers the inflammatory cascade and stimulates the production of matrix degradable proteinases such as matrix metalloproteinases (MMPs) (Okada, 2005). TNF-α converting enzyme (TACE) processes a membrane form of TNF-α to a soluble form (Moss et al., 1997), and the binding of the latter form to TNF receptors triggers pathological events in RA (Christodoulou & Choi, 2006; Horiuchi et al., 2010; Ohta et al., 2001). Although synovitis is one of the major manifestations of SAPHO syndrome, detailed information on the pathological features is

In this chapter, we describe a patient with SAPHO syndrome accompanied by marked knee synovitis and acrodermatitis continua of Hallopeau (ACH) as a skin manifestation. ACH is a rare acropustular eruption, characterized by sterlile pustules, paronychia and atrophic skin changes, onychodystrophy and osteolysis of the distal phalanges of the fingers and toes (Ryan et al., 2009). ACH is considered to be a localized subtype of pustular psoriasis (Yerushalmi et al., 2000) and our report is a first case of ACH as a skin manifestation of SAPHO syndrome. We focused on synovitis, analyzed synovial tissues histopathologically and demonstrated the expression of TNF-α, TACE and MMP-3 in SAPHO syndrome synovium. We also concisely review cases treated with anti-TNF-α agents in the literature

A 76-year-old Japanese man first presented to a neighborhood university hospital in 1993 with subungal pustules, erythema and onychodystrophy on all fingers and toes. A diagnosis of ACH was histologically confirmed at the time. He had been treated with topical corticosteroid and vitamin D3. In January 2006, he presented to our department for the first time with persistent swelling and pain in his left knee. Physical examination showed marked patellar ballottement with local heat. A knee puncture yielded 60mL of yellow cloudy joint fluid, but cultures for bacteria were negative. For other osteoarticular symptoms, moderate lower back and buttock pain existed but no other joint pain, costa-sterno-clavicular joint included, was found**.** At the time, dermatological symptoms of ACH still remained on all fingers and toes (Figure 1a, b). Laboratory tests showed almost within normal value including indices of inflammation (erythrocyte sedimentation rate 10mm/hour, C-reactive protein level 0.19mg/dL [normal <0.30mg/dL]) and rheumatoid factor was negative. Radiographic study revealed characteristic osteolysis in phalanges of fingers and toes (Figure 1c, d). Magnetic resonance imaging revealed knee synovitis and bone marrow edema at the second lumbar

We made a diagnosis of SAPHO syndrome because the presence of ACH (a variant of pustular psoriasis), knee synovitis, and osteitis of the vertebral body were sufficient to the criteria. The patient was treated with NSAIDs for osteoarticular symptoms and topical

In October 2007, arthroscopic surgery was performed for knee synovitis. Intra-operative findings showed marked proliferation of villous contoured synovial tissues with rich blood circulation (Figure 3a). Continuous paraffin sections of biopsied synovial tissues were used for histopathological analyses, and standard microscopic study showed hyperplastic synovitis with lymphocytes infiltration and many blood vessels similar to RA (Figure 3b, c, d). Immunohistochemistry revealed the expression of TNF-α (Figure 3e), TACE (Figure 3f)

and discuss the therapeutic strategy for SAPHO syndrome.

vertebral body (Figure 2), compatible with sterile osteitis.

still lacking.

**2. Case report** 

treatment for skin lesions.

Fig. 1. Clinical findings of fingers (a), toes (b), and radiographs of bilateral fingers (c) and toes (d) in a patient with SAPHO syndrome accompanied by acrodrmatitis continua of Hallopeau. Erythema, pustules and onychodystrophy are present on all fingers and toes, which are compatible with the dermatological features of acrodermatitis continua of Hallopeau (a, b). Characteristic osteolysis of acrodermatitis continua of Hallopeau are observed in phalanges of fingers (c) and toes (d).

Expression of Tumor Necrosis Factor-Alpha (TNF-TNF-Converting Enzyme and

Fig. 3. Macro- and microscopic findings of knee synovitis in a patient with SAPHO syndrome accompanied by acrodrmatitis continua of Hallopeau. Arthroscopy reveals RA like villous contoured synovial tissues with rich blood circulation (a). Continuous paraffin sections (b-h) were stained with hematoxylin and eosin (b-d) or immunostained with antibodies against TNF-α (e), TACE (f), MMP-3 (g), or CD68 (h). Note that hyperplastic synovitis with lymphocytes infiltration, rich blood vessels similar to RA (b, c, d), and TNF-α,

TACE and MMP-3 are expressed in synovial lining cells (e-g).

Matrix Metalloproteinase-3 in SAPHO Syndrome Synovium - A Rare Case Accompanied by … 97

Fig. 2. Radiographic study (a, b) and magnetic resornance imaging (c, d, e) of lumber spine in a patient with SAPHO syndrome accompanied by acrodrmatitis continua of Hallopeau. Bone marrow edema at the second lumbar vertebral body (arrow) is compatible with sterile osteitis.

and MMP-3 (Figure 3g) in synovial cells of the lining layer. TNF-α and TACE were expressed dominantly in CD68 positive synovial cells of the lining and sublining layer, whereas MMP-3 was expressed dominantly in CD68 negative synovial cells of the lining layer (Figure 3e-h). Primary antibodies used for these analyses were polyclonal antibodies for TNF-α (654250; Calbiochem, Germany), TACE (sc-25782; Santa Cruz Biotechnology, USA), monoclonal antibodies for MMP-3 (55-2A2; Daiichi Fine Chemical Co., Japan) and CD68 (M0814; DakoCytomation, Denmark). After arthroscopic synovectomy, his knee symptoms immediately diminished. In 2008, additional administration of alendronate (35

Fig. 2. Radiographic study (a, b) and magnetic resornance imaging (c, d, e) of lumber spine in a patient with SAPHO syndrome accompanied by acrodrmatitis continua of Hallopeau. Bone marrow edema at the second lumbar vertebral body (arrow) is compatible with sterile osteitis. and MMP-3 (Figure 3g) in synovial cells of the lining layer. TNF-α and TACE were expressed dominantly in CD68 positive synovial cells of the lining and sublining layer, whereas MMP-3 was expressed dominantly in CD68 negative synovial cells of the lining layer (Figure 3e-h). Primary antibodies used for these analyses were polyclonal antibodies for TNF-α (654250; Calbiochem, Germany), TACE (sc-25782; Santa Cruz Biotechnology, USA), monoclonal antibodies for MMP-3 (55-2A2; Daiichi Fine Chemical Co., Japan) and CD68 (M0814; DakoCytomation, Denmark). After arthroscopic synovectomy, his knee symptoms immediately diminished. In 2008, additional administration of alendronate (35

Fig. 3. Macro- and microscopic findings of knee synovitis in a patient with SAPHO syndrome accompanied by acrodrmatitis continua of Hallopeau. Arthroscopy reveals RA like villous contoured synovial tissues with rich blood circulation (a). Continuous paraffin sections (b-h) were stained with hematoxylin and eosin (b-d) or immunostained with antibodies against TNF-α (e), TACE (f), MMP-3 (g), or CD68 (h). Note that hyperplastic synovitis with lymphocytes infiltration, rich blood vessels similar to RA (b, c, d), and TNF-α, TACE and MMP-3 are expressed in synovial lining cells (e-g).

Expression of Tumor Necrosis Factor-Alpha (TNF-TNF-Converting Enzyme and

SNSA (Takigawa et al., 2008).

et al., 2000; Moreland et al., 1999).

Matrix Metalloproteinase-3 in SAPHO Syndrome Synovium - A Rare Case Accompanied by … 99

4.7% and 0.3% of Japanese 990 SNSA patients showed PPP and SAPHO syndrome, respectively (Hukuda et al., 2001). Takigawa et al. reported that 23% of 13 SAPHO syndrome patients met the criteria of SNSA regardless of whether ESSG or Amor criteria were used (Takigawa et al, 2008). In their series, if PPP is added as a skin lesion to the criteria of spondyloarthropathy, 100% and 92% of their cases would fullfill the diagnostic criteria of ESSG and Amor, respectively. Sonozaki proposed pustulotic arthro-osteitis is one subtype of SNSA (Sonozaki et al., 1981). Thus Takigawa et al. proposed that SAPHO syndrome, especially spinal lesions related to PPP, should be recognized as a subtype of

The treatment of SAPHO syndrome remains empirical. In practice, NSAIDs are applied for osteoarticular symptoms and topical treatment for skin lesions. This first-line treatment is effective in two-thirds of cases (Hayem et al., 1999). In cases not respond to the first-line treatment, the second-line treatment, including glucocorticoids, BPs, and DMARDs such as methotrexate and sulfasalazine, is considered, but results are usually inconsistent and insufficient (Hayem et al., 1999). Recently some successful experiences with anti-TNF-α agents for recalcitrant cases of SAPHO syndrome have been reported (Asmussen, 2003; Ben Abdelghani et al., 2010; Castellvi et al., 2010; Deutschmann et al., 2005; Iqbal & Kolodney, 2005; Kyriazis et al., 2004; Massara et al., 2006; Moll et al., 2008; Olivieri et al., 2002; Sabugo et al., 2008; Wagner et al., 2002; Widmer et al., 2003). This therapeutic strategy was largely originated from that for spondyloarthropathies in which the efficacy and safety of anti-TNF-α therapy is well established (Davis et al., 2003; Mease

TNF-α is a proinflammatory cytokine found in increased concentrations in the joints and skin of patients with RA, pasoriatic arthritis and psoriasis, and plays crucial roles in the pathogenesis of these chronic inflammatory disease (Bradley, 2008; Ettehadi et al., 1994; Feldmann & Maini, 2001; Partsch et al., 1997; Tutrone et al., 2001). In RA synovium, TNF-α is produced abundantly and contribute to the pathogenesis by inducing the production of other proinflammatory cytokines, chemokines, and MMPs (Brennan et al., 1995; Ivashkiv, 1996; MacNaul et al., 1990). TNF-α is generated as a proform called transmembrane TNF-α that is consist of 233 amino acid residues (26kDa) and expressed on TNF-α-producing cells as a homotrimer (Kriegler et al., 1988; Luettiq et al., 1989; Pennica et al., 1984). This transmembrane TNF-α is cleaved between alanine76-valine77 bond by TACE, resulting in the release of soluble TNF-α that is consist of 157 amino acid residues (17kDa). Soluble TNFα is a homotrimer of 17-kDa cleaved monomers and transmembrane TNF-α also exists as a homotrimer of 26-kDa uncleaved monomers (Tang et al., 1996). Both soluble and transmembrane TNF-α mediate pleiotrophic effects (apoptosis, cell proliferation and cytokine production) through binding to type 1 and type 2 TNF receptors (TNF-R1 and TNF-R2), but transmembrane TNF-α is supposed to mediate its biological activities mainly through TNF-R2 (Bazzoni & Beutler, 1996; Black et al., 1997; Grell et al., 1995; Moss et al., 1997; Vandenabeele et al., 1995). The remaining of cytoplasmic domain of transmembrane TNF-α after cleavage with TACE migrated back into the nucleus of the transmembrane TNF-α-expressing cells and is supposed to mediate cytokine production (Domonkos et al., 2001). It is very interesting that transmembrane TNF-α transmits signals both as a ligand and as a receptor. Differential clinical efficacies of anti-TNF-α agents may be explained by their different action on transmembrane TNF-α-expressing cells (Horiuchi et al., 2010).

mg/week) was started. In the four year follow-up period, there has been no recurrence of knee synovitis, no exacerbation of dermatological symptoms of ACH, and the patient has had only mild low back pain which have responded to NSAIDs and alendronate.
