Clinical and Experimental Rheumatology 2007; 25: 125-128. BRIEF PAPER Synovitis-acne-pustulosis- ABSTRACT spondylitis, OR 10 (95% CI: 3.3-25, hyperostosis-osteitis Background and objectives. Patients p < 0.0001). with psoriatic arthritis (PsA) as well as Conclusions. Psoriasis/PsA and SAP- syndrome and psoriatic those with synovitis, acne, pustulosis, HO syndrome show a different immuno- arthritis exhibit a different hyperostosis, osteitis (SAPHO) syn- genetic background, however the genet- immunogenetic profi le drome share some common features, and ic basis of SAPHO syndrome remains in fact, for many authors the SAPHO unknown. R. Queiro, P. Moreno, concept fi ts well into the broader concept C. Sarasqueta*, M. Alperi, of PsA. However, some clinical features Introduction J.L. Riestra, J. Ballina are unique to the SAPHO syndrome, and Since 1959 there have been several re- in the other hand, these patients do not ports of patients affected by the com- Rheumatology Department, Hospital show the known association between the bination of cutaneous lesions such as Universitario Central de Asturias (HUCA), HLA-B27 antigen and the spondyloar- acne, palmo-plantar pustulosis (PPP), Oviedo, Spain; *Clinical Epidemiology thropathies. To date, there are no studies hidradenitis suppurativa or pyoderma Unit, Complejo Hospitalario de Donostia, comparing the immunogenetic profi le of gangrenosum, with osteoarticular man- San Sebastián, Spain. these two conditions, so the main objec- ifestations including peripheral syno- Rubén QQueiro,ueiro, PhD;PhD; PuertoPuerto Moreno,Moreno, MD;MD; tive of the present report was to analyse vitis, sacroiliitis, hyperostosis, anterior Cristina Sarasqueta, PhD; Mercedes whether or not both entities may share chest wall swelling or sterile osteitis (1, Alperi, MD; José LuisLuis Riestra,Riestra, PPhD;hD; the same genetic basis. 2). Such heterogeneous conditions were Javier Ballina, PhD. Patients and methods. All patients grouped by French investigators in the Please address correspondence and with SAPHO syndrome (n = 25) seen in mid-1980s under the SAPHO (synovi- reprint requests to: Dr. R. Queiro, a single university hospital from 1985 tis, acne, pustulosis, hyperostosis, os- Staff rheumatologist, HUCA, C/ Celestino Villamil s/n, 33006, to 2005 were recruited and followed teitis) rubric, and since then, the term Oviedo, Spain. up in standardised manner in order to SAPHO has been used as a convenient E-mail: [email protected] study their main characteristics and descriptor in clinical reports and case Received on March 22, 2007; accepted in HLA profi le. The HLA-Cw6, DR and reports worldwide (3). Although both revised form on September 19, 2007. B27 antigen distribution of these cases the SAPHO syndrome acronym and © CCopyrightopyright CLINICAL AND was compared to that of 50 patients with classifi cation criteria were proposed in EXPERIMENTAL RHEUMATOLOGY 22008.008. psoriasis vulgaris, 120 with PsA, and 1987 by Chamot et al., these criteria 170 healthy blood donors. PsA patients have not been validated in comparison Key words: Psoriasis, psoriatic were classifi ed in accordance with their with closely related conditions, partic- arthritis, SAPHO syndrome, predominant pattern observed in the ularly spondyloarthopathies (SpA), al- HLA antigens. last 5 years of disease evolution. Odds though some authors have included the ratios (OR) values were calculated to SAPHO syndrome among the variants measure the strength of the association of psoriatic arthritis (PsA) (3, 4). between HLA antigens and disease, On the other hand, this disease group- while the statistical signifi cance of the ing appears to have a different genetic association was assessed with a two- basis, with neither the HLA DR3/DR4 tailed Fisher’s exact test. P < 0.05 val- association of connective tissue dis- ues were considered signifi cant. eases (CTD)/ rheumatoid arthritis Results. No association was found be- (RA) nor the B27 association of SpA tween HLA-Cw6, B27, or DR antigens, (5). Thus, the SAPHO acronym still re- and SAPHO syndrome. HLA-Cw6 was mains a good term to describe a group strongly associated with psoriasis, of arthritides which share common fea- OR 12 (95% CI: 5.6-26, p < 0.0001) tures, but there is still a need to clearly and PsA, OR 10 (95% CI: 5.4-19.5, elucidate whether this group is a sin- p< 0.0001), however this antigen was gle disease or syndrome, or in contrast, equally distributed among the three whether it could be assigned to the articular categories of PsA. HLA-DR4 spondyloarthropathy group in general, was found under-represented in PsA and to PsA in particular. patients compared to controls, OR 0.4 The present study was undertaken to (95% CI: 0.2-0.7, p = 0.002). HLA- analyse the clinical picture and the DR7 correlated well with psoriatic HLA profi le of a series of patients with oligoarthritis, OR 9.6 (95% CI: 2.9-28, SAPHO syndrome, and in order to com- p< 0.0001), HLA-DR8 was found asso- pare the HLA profi le of these patients to ciated with polyarthritis, OR 6.7 (95% that of PsA patients, analysing if these CI: 2-25, p = 0.002), while HLA-B27 two conditions may show a similar or a Competing interests: none declared. was over-represented in psoriatic different genetic background.

125 BRIEF PAPER SAPHO syndrome and HLA antigens / R. Queiro et al.

Patients and methods group, irrespective of the presence of Table I. Diagnostic criteria for SAPHO All patients from a single teaching hos- peripheral synovitis (n = 42). This lat- syndrome. pital fulfi lling the SAPHO criteria pro- ter defi nition for axial disease in PsA Sterile multifocal chronic osteitis: posed by Chamot et al. (3) (Table I) is not universally accepted but may Involvement of the chest, spine, pelvis or long were recruited and their clinical records represent an appropriate view for clas- bones reviewed for the purposes of the present sifi cation purposes. Distal interphalan- Absence of skin lesions study. Most patients were sent to our geal joint (DIP) disease and “mutilans” Acute or chronic arthritis associated with: department by general practitioners and forms were also recorded, however, Palmoplantar pustulosis dermatologists. All cases were evalu- these forms could be assigned to the Palmoplantar pustular psoriasis Severe acne ated by dermatologists of our hospital in oligoarticular, polyarticular or spondy- Hidradenitis supurativa order to establish an accurate diagnosis litic groups over time. of the cutaneous lesions. All remarkable HLA-Cw6 was investigated by the Sterile mono or polyosteitis associated with: Palmoplantar pustulosis data were collected in a standard man- PCR-SSOP method, while HLA-B27 Palmoplantar pustular psoriasis ner, and this included age at onset, sex, and DR antigens were analysed by clas- Severe acne disease duration, family history, medi- sical serological methods. This HLA Hidradenitis supurativa cal history, physical examination, acute profi le was analysed in the SAPHO Folliculitis phase reactants, cultures and serological group, in those with chronic stable From ref.3 studies to rule out the presence of ha- plaque psoriasis, in PsA patients, and in bitual pathogens causing reactive arthri- 170 healthy blood donors from our gen- tis, type of skin lesions, osteoarticular eral population. The HLA distribution Table II. Demographic, clinical, radiologic, manifestations, form of onset, evolution was then compared between patients and treatment characteristics in a series of and response to treatment. Radiologi- and controls, and between the three 25 patients with SAPHO syndrome. cal study included chest, cervical and groups of diseases. This distribution Variable SAPHO n = 25 lumbar column, pelvis (with sacroiliac was also compared among the three ar- views), as well as projections of all af- ticular categories defi ned for PsA. Age (mean ± SD) 44 ± 8.6 fected joints and bones. When neces- The strength of the association between Gender ratio (female/male) 7/1 Disease duration (mean ± SD) 8.4 ± 6 sary, a CT scan, scintigraphy and/or antigens and disease was evaluated by Synchronous onset (%) 60 MRI was used to evaluate the extension odds ratios (OR), while the statistical Cutaneous fi rst (%) 32 of the joint/bone lesions. The presence signifi cance of the association was as- Osteoarticular fi rst (%) 8 of psoriasis and other extraskeletal man- sessed with a two-tailed Fisher’s exact PPP (%) 80 Pustular psoriasis (%) 12 ifestations associated with the group of test. P < 0.05 values were considered Psoriasis vulgaris (%) 8 SpA was also recorded. Autoimmunity signifi cant. Acne (%) 8 tests included RF, ANA, immunoglobu- All patients were informed about the ob- Hidradenitis suppurativa (%) 4 lins and complement proteins. jectives of the study and informed con- Onychopathy (%) 4 Chest wall involvement (%) 48 In order to test the hypothesis that pa- sent sheets were obtained. The ethical Synovitis (%) 60 tients with SAPHO syndrome may dif- committee of our institution approved Sacroiliitis (%) 20 fer from those suffering psoriasis and the fi nal version of the present study. Discitis (%) 8 PsA, 50 patients with chronic stable Sterile osteitis/osteomyelitis (%) 8 Hyperostosis (%) 40 plaque psoriasis and 120 with PsA were Results NSAIDs use (%) 72 randomly selected from the general da- From 1985 to 2005, 25 patients fulfi lled Antibiotic use (%) 12 tabase of the Dermatology and Rheu- the criteria proposed by Chamot et al. DMARDs use (%) 32 matology departments of our hospital. for the SAPHO syndrome (3). The main Biphosphonate use (%) 12 Anti-TNF alfa use (%) 4 Patients with PsA were divided into clinical, radiological, and demographic Corticosteroid use (%) 20 disease subgroups, as originally cited features, as well as the strategies used by Moll and Wright (6), however as to treat these patients, are shown in See text for a more detailed explanation. PsA patients may change their articular Table II. Most patients were middle- PPP: palmo-plantar pustulosis; DMARDs: Dis- pattern with time, this cohort was divid- aged women (7/1). The main cutane- ease Modifi ying Anti-Rheumatic Drugs. ed in accordance with the predominant ous lesion associated with the SAPHO pattern observed in the last fi ve years concept in this report was PPP (80%). published elsewhere (5). None of our of disease evolution. Thus, patients One patient presented acne conglobata, patients developed uveitis or IBD. with fi ve or more swollen joints were while other had acne fulminans. Only Most patients used NSAIDs as the fi rst included in the polyarticular subgroup one case of hidradenitis suppurativa choice of treatment (72%). Regarding (n = 33), those with four or less in- coexisting with PPP was noted. These the use of Disease Modifying Anti- fl amed joints were diagnosed with oli- three cases needed parenteral antibiot- Rheumatic Drugs (DMARDs), the goarthritis (n = 45), while patients with ics to achieve resolution of the cutane- most used drug was methotrexate in infl ammatory back pain and a grade II ous lesions. The osteoarticular manifes- 20% of the patients, followed by lefl u- or more radiological sacroiliitis were tations seen in this study, as well as its nomide in 8%, and sulphasalazine in included among the spondylitic sub- frequency, were not different from that 4%. Five out of 25 patients needed oral

126 SAPHO syndrome and HLA antigens / R. Queiro et al. BRIEF PAPER

Table III.1. Distribution of HLA antigens in patients and controls. fering from acne arthritis, arthritis of hidradenitis suppurativa, pustulo- HLA Psoriasis n = 50 (%) PsA n = 120 (%) SAPHO n = 25 (%) Controls n = 170 (%) tic arthro-osteitis, chronic recurrent DR1 6 (12) 28 (23) 4 (16) 34 (20) multifocal osteomyelitis, among other DR4 18 (36) 14 (12)* 4 (16) 45 (26) terms (1, 5). In the mid-1980s, French DR7 18 (36) 42 (35) 10 (40) 51 (30) investigators grouped all these entities DR8 4 (8) 18 (15) 0 (0) 14 (8) DR10 3 (6) 7 (6) 2 (8) 2 (1) under the SAPHO acronym, and since DR11 7 (14) 12 (10) 4 (16) 29 (17) then, it has been used as a convenient DR13 10 (20) 24 (20) 6 (24) 46 (27) descriptor in clinical reports worldwide DR14 4 (8) 16 (13) 2 (8) 12 (7) (3). However, there is now a need to DR15 10 (20) 27 (22) 6 (24) 31 (18) clearly elucidate whether this term rep- DR16 5 (10) 2 (2) 2 (8) 8 (5) DR17 14 (28) 28 (23) 2 (8) 41 (24) resents a single disease, a syndrome, or Cw6 27 (54)** 60 (50)*** 5 (20) 31 (18) a nosologic category within the SpA. B27 3 (6) 36 (30)**** 2 (8) 12 (7) We have presented here the clinical, ra- *OR 0.4 (95% CI: 0.2-0.7, p = 0.002); **OR 12 (95% CI: 5.6-26, p < 0.0001); ***OR 10 (95% CI: diologic and genetic data of 25 patients 5-19.5, p < 0.0001); ****OR 2.1 (95% CI: 0.99-4.3, p = 0.05). All comparisons versus controls. with SAPHO syndrome attended at a single university hospital from 1985 Table III.2 Distribution of HLA antigens in psoriatic arthritis articular categories. to 2005. This study may show some bias since most patients showed PPP as HLA Oligoarthritis n = 45 (%) Polyarthritis n = 33 (%) Spondylitis n = 42 (%) the main cutaneous feature of SAPHO concept, and therefore the whole spec- DR1 7 (15) 10 (30) 10 (24) DR4 5 (11) 2 (6) 9 (21) trum of the syndrome was not fully DR7 28 (62)* 5 (15) 9 (21) represented among our patients. Only DR8 4 (9) 13 (39)** 5 (12) one patient had nail involvement, an DR10 2 (4) 3 (9) 2 (5) unexpected fi nding, since many pa- DR11 4 (9) 5 (15) 5 (12) DR13 9 (20) 2 (6) 12 (29) tients with PPP also show psoriatic nail DR14 4 (9) 5 (15) 7 (17) involvement (7). In fact, approximately DR15 12 (27) 7 (21) 9 (21) 25% of PPP cases are associated with DR16 0 (0) 2 (6) 2 (5) classic psoriasis vulgaris, but it is now DR17 14 (31) 7 (21) 9 (21) believed that PPP may not be a form Cw6 24 (53) 13 (39) 21 (50) B27 9 (20) 5 (15) 22 (52)*** of psoriasis (7). This conclusion is de- rived from genetic studies showing no *OR 9.6 (95% CI: 2.9-28, p < 0.0001); **OR 6.7 (95% CI: 2-25, p = 0.002); ***OR 10 (95% CI: 3.3-25, association with HLA-Cw6 or other p < 0.0001). markers on chromosome 6p, which are linked to chronic plaque and gut- corticosteroid, 2 used risedronate, and in those PsA patients belonging to the tate psoriasis (8). In this sense, we one alendronate. One resistant case was spondylitic subgroup in comparison to did not fi nd any correlation between treated with infl iximab. Response to the other PsA subgroups, OR 10 (95% HLA-Cw6 and SAPHO, confi rming therapy was considered good (complete CI: 3.3-25, p<0.0001). HLA-DR4 was the above-mentioned fi ndings. With re- resolution) in 48% of the cases, partial found under-represented in PsA pa- spect to the other skin lesions included (when relapsed) in 40%, whereas 12% tients compared to controls, OR 0.4 under the rubric of SAPHO, we found of patients needed high dose corticoster- (95% CI: 0.2-0.7, p = 0.002). When one case of acne conglobata associated oids, DMARDs, aminobiphosphonates, we compared the HLA-DR distribu- with sterile osteitis of the right ilium; and/or anti-TNF therapy to partially im- tion among the three articular catego- in other case, acne fulminans was as- prove their condition (bad response). ries of PsA, a signifi cant association sociated with acute-onset sterile sacro- HLA-Cw6 was strongly correlated was found between HLA-DR7 and illitis, and in a third case, hidradenitis with psoriasis, OR 12 (95% CI: 5.6- oligoarthritis, OR 9.6 (95% CI: 2.9-28, suppurativa coexisted with PPP and 26, p < 0.0001), and PsA, OR 10 (95% p<0.0001), while HLA-DR8 correlated left ankle synovitis. Contrasting with CI: 5.4-19.5, p < 0.0001), however this with polyarthritis, OR 6.7 (95% CI: our data, hidradenitis suppurativa and antigen was equally distributed among 2-25, p = 0.002). No association was acne are the predominant lesions in the three articular categories defi ned found between HLA-DR antigens and American patients with SAPHO syn- for PsA. There was no difference in SAPHO syndrome. Table III.1 shows drome (5, 9). the distribution of this antigen between the HLA profi le of the three entities, The osteoarticular manifestations of patients with SAPHO syndrome and while Table III.2 represents the HLA the present series included peripheral controls. Only 2 patients with SAPHO distribution among the PsA categories. synovitis, anterior chest wall involve- were HLA-B27 (+), a fi gure similar to ment, sacroiliitis, sterile discitis, chron- the expected frequency for this antigen Discussion ic osteomyelitis, hyperostosis, and in in our normal population (7%). As ex- Under the SAPHO rubric we can fi nd that sense, it did not differ from that pected, HLA-B27 was over-represented patients referred to in the past as suf- published in other larger series (5, 10).

127 BRIEF PAPER SAPHO syndrome and HLA antigens / R. Queiro et al.

In general, response to treatment was infrequent in SAPHO syndrome, and sent one are hampered by the changing good or partially good, though some conversely, typical fi ndings of SAPHO pattern of PsA over time, the hetero-ge- patients needed DMARDs, antibiotics, (anterior chest wall involvement, ostei- neity of the clinical manifestations of high dose corticosteroid, anti-TNF-α tis/osteomyelitis, hyperostosis) are rare the SAPHO syndrome, and the genetic and/or aminobiphosphonates to im- in SpA (5, 10). distance between different studied prove their condition. In fact, 12% of An additional consideration, which populations, therefore the reporting of our patients are still under therapy be- deserves a detailed explanation, is the larger series of SAPHO patients is to cause of a high degree of infl ammation potential relationship between these be encouraged in attempts to defi ne its when tapering their medication, and cases and PsA. As cited above, for genetics, clinical spectrum, response to nearly 40% of this series has presented some investigators SAPHO patients fi t treatment, and pathogenesis. several relapses during the follow up. well into the concept of PsA and they Therefore, SAPHO syndrome seems to are not assumed as separate cases from References be a condition not as benign as initially it (4, 13). However, both groups do not 1. BURNS RE, COLVILLE KM: Acne conglobata thought (5, 10). share the positivity for HLA-Cw6 as with septicemia. Arch Dermatol Syphil 1959; 79: 361-3. As mentioned earlier, the key ques- we could show here. In addition, we 2. VASEY FB: Acne, hidradenitis suppurativa, tion regarding the real nature of the could not fi nd any association between and arthritis. In ESPINOZA L (Ed.) Infections SAPHO syndrome is to know whether HLA-DR antigens and SAPHO, how- in the rheumatic diseases. New York: Grune it represents a single disease/syndrome ever, we found a negative association & Stratton; 1988, p. 357-60. or a nosologic category within the SpA between HLA-DR4 and PsA, a posi- 3. CHAMOT AM, BENHAMOU CL, KAHN MF, BERANECK L, KAPLAN G, PROST A: Syno- (11). There are some features such tive association between HLA-DR7 vitis-acne-pustulosis-hyperostosis-osteitis as the involvement of axial skeleton, and oligoarthritis, and HLA-DR8 with syndrome. Results of a national survey of 85 sacroiliitis, discitis, coexistence with polyarthritis, and, as expected, HLA- cases. Rev Rhum Mal Osteoartic 1987; 54: infl ammatory bowel disease, among B27 antigen correlated well with the 187-96. 4. VEALE D, ROGERS S, FITZGERALD O: Clas- others, which suggest a common path- spondylitic forms of PsA. In support of sifi cation of clinical subsets in psoriatic ar- ogenic mechanism with the SpA group the view that SAPHO and PsA are dif- thritis. Br J Rheumatol 11994;994; 333:3: 1133-8.33-8. (5, 10). Indeed, Maugars et al. found in ferent conditions from an immunoge- 5. KAHN MF, KHAN MA: The SAPHO syn- their series that in most cases enthesis netic perspective, a recent case report drome. Baillieres Clin Rheumatol 1 1994;994; 8 8:: involvement was the fi rst event leading showed the presence of the antigens 333-62. 6. MOLL JMH, WRIGHT V: Psoriatic arthritis. to hyperostosis, so they suggested that A1,24 (9), Cw2, B38 (16), B61 (40), Semin Arthritis Rheum 1973; 3: 55-78. the initial disease targets in SAPHO Bw4, Bw6, and Cw (-), in SAPHO pa- 7. LANGLEY RGB, KRUEGER GG, GRIFFITHS syndrome were enthesis and related tients, an haplotype which have no as- CEM: Psoriasis: epidemiology, clinical fea- tissues. The same group also showed sociation with known diseases (15). tures, and quality of life. Ann Rheum Dis 2005; 64 (Suppl. II): 618-23. that 43% of their patients met criteria In our view, there are unique charac- 8. ASUMALAHTI K, AMEEN M, SUOMELA S et of the ESSG for SpA, but only one of teristics to the SAPHO diseases that al.: Genetic analysis of PSORS1 distinguish- their cases had the HLA-B27 pheno- distinguish them from other disease es guttate psoriasis and palmoplantar pustu- type (12). Following this view, Veale groups and may be common to the losis. J Invest Dermatol 22003;003; 1120:20: 6627-32.27-32. et al. did not fi nd SAPHO syndrome group, thereby defi ning it. Some few 9. STEINHOFF JP, CILURSU A, FALASCA GF, GUZMAN L, REGINATO AJ: A study of musc- as a separate entity in their classifi ca- examples support this view, thus, this uloskeletal manifestations in 12 patients with tion proposal for PsA and they could disease grouping appears to have a dif- SAPHO syndrome. J Clin Rheumatol 2002;2002; confi rm this fi nding in other inception ferent genetic basis, with neither the 8: 13-22. cohort of early PsA (4, 13). HLA-DR3/DR4 association of CTD/ 10. HAYEM G, BOUCHAUD-CHABOT A, BENALI K et al.: SAPHO syndrome: a long-term fol- In spite of this evidence, some ques- RA nor the B27 association of SpA low-up study of 120 cases. Semin Arthritis tions still raise doubts and controversy. (5). Moreover, this syndrome does not Rheum 2000; 29: 332-4. Firstly, it is well known that HLA-B27 show any association with HLA-Cw6, 11. ROSNER I: SAPHO: disease, syndrome, or antigen is the genetic hallmark of the B27, or DR antigens. On the other category? J Clin Rheum 2002; 8: 3. SpA and it is present in nearly 90% hand, the pustulotic nature of its cuta- 12. MAUGARS Y, BERTHELOT JM, DUCLOUX JM, PROST A: SAPHO syndrome: a followup of AS and 50% of PsA patients, but neous lesions also highlights the role study of 19 cases with special emphasis on this marker is not over-represented in of the polymorphonuclear leukocyte enthesis involvement. J Rheumatol 1995;1995; 23:23: SAPHO patients, a fi nding confi rmed in the pathogenesis of this disease cat- 1667-8. by us and others (5, 10, 14). Secondly, egory (11). Additionally, some of its 13. KANE D, STAFFORD L, BRESNIHAN B, FIT- ZGERALD O: A classifi cation study of clini- the HLA-Cw6 antigen is not related to osteoarticular manifestations are char- cal subsets in an inception cohort of early the presence of PPP, but to psoriasis, acterised by the prominence of bony psoriatic peripheral arthritis. DIP or not DIP so there seems to be that the genetic reaction (osteitis, hyperostosis), as a revisited. Rheumatology 2003; 42: 1469-76. basis of both, SAPHO syndrome and favored target tissue, as opposed to the 14. SIMS AM, WORDSWORTH BP, BROWN MA: PsA is quite different. Finally, it is also synovium in RA/CTD and entheses in Genetics susceptibility to ankylosing spondy- litis. Curr Mol Med 2004;2004; 44:: 113-20.3-20. important to take into account that typi- SpA (5, 10). 15. ROZIN AP, NAHIR AM: Is SAPHO syndrome cal x-ray features of SpA, such as bilat- In spite of the above-mentioned data, a target for antibiotic therapy? Clin Rheuma- eral sacroiliitis or syndesmophytes, are genetic association studies like the pre- tol 2007; 26: 817-20.

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