Stress in a Case of SAPHO Syndrome

Yonit Wohl, MD; R. Bergman, MD; E. Sprecher, MD, PhD; Sarah Brenner, MD

In this article, we describe a case of seemingly article, we report the case of a second patient—a stress-induced SAPHO (synovitis, , pustulo- man with SAPHO skin and bone manifestations sis, , ) syndrome in a man apparently triggered partly or entirely by stress. who exhibited the central features of palmo- plantar psoriasis and anterior chest involvement. Case Report We also review the etiology, pathogenesis, and A 45-year-old man of Yemenite origin presented to treatment of SAPHO syndrome and emphasize our outpatient clinic with a 2-month history of a the important differences between this syndrome palmoplantar pustular eruption and was hospital- and . ized. Previous ambulatory treatment (topical steroids, tar preparations, acitretin tablets) was n 1987, Chamot and Benhamou1 coined the stopped after one week because of hyperlipidemia. acronym SAPHO (synovitis, acne, pustulosis, Shoulder and anterior chest pain also developed at I hyperostosis, osteitis) to designate a clinicora- that time. diologic entity with a combination of skin, bone, Ischemic heart disease was ruled out, and non- and joint manifestations. Since Sonozaki2 first steroidal anti-inflammatory drugs (NSAIDs) were reported on SAPHO in 1981, the syndrome (under begun (diclofenac suppositories, ibuprofen tablets). a variety of names) has been the subject of an The patient’s medical history included 40 pack-years increasing number of articles. The fundamental of heavy smoking. There was no family history of component of SAPHO syndrome is inflammatory psoriasis. The patient described having been forced to osteitis, mainly on the anterior chest wall. The leave his job and being under severe emotional stress syndrome also may affect the axial skeleton (spine during the 3 months preceding his rash outbreak. and sacroiliac joints) and peripheral joints and Results of the physical examination were normal even flat bones such as the ilium and mandible. except for tenderness on palpation of the sternum Skin diseases are prominent in two thirds of and on elevation of the right arm, symmetrical dis- patients with SAPHO syndrome. These diseases tribution of thick erythematous plaques with adher- include, in decreasing frequency, pustulosis palmaris ent white scales and small pustules merging into et plantaris, , , lakes of pus on the palms and soles (Figure 1), a sin- suppurativa, and various patterns of gle erythematous scaled lesion on the scalp, and fine psoriasis. The skeletal and cutaneous manifestations pitting on several fingernails. Erythrocyte sedimen- of SAPHO syndrome are usually expressed simulta- tation rate was elevated (40 mm/h); blood count neously but can occur as much as 2 decades apart. and blood chemistry results were normal, except for Minor skin disease does not exclude the diagnosis of a finding of hypertriglyceridemia (305 mg/dL). Pus SAPHO syndrome. culture results were negative for bacteria, viruses, To our knowledge, we were the first to report a and fungi; results of blood and urine cultures were case of SAPHO syndrome related to stress.3,4 The normal. Results were negative from serologic patient was a young woman with classically present- workups for collagen vascular diseases, human ing palmoplantar pustular psoriasis, acne, and sterno- immunodeficiency virus, and human leukocyte clavicular joint involvement.3,4 In the present antigen (HLA) typing for B27. Results of a histo- logic examination of an early pustular lesion showed Accepted for publication May 31, 2002. psoriasiform epidermal hyperplasia with alternating Drs. Wohl and Brenner are from the Department of Dermatology, parakeratosis and orthokeratosis (Figures 2 and 3), Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, subcorneal infiltration of polymorphonuclear lym- Tel Aviv University, Israel. Drs. Bergman and Sprecher are from the phocytes, widened dermal papillae, and an increased Department of Dermatology, Rambam Medical Center, Haifa, Israel. Reprints: Sarah Brenner, MD, Department of Dermatology, Tel Aviv number of tortuous capillaries. Sourasky Medical Center, 6 Weizmann St, Tel Aviv 64239, Israel Results of radiographs of the chest, cervical and (e-mail: [email protected]). lumbar spine, and sacroiliac and acetabular joints

VOLUME 71, JANUARY 2003 63 SAPHO Syndrome

A B

Figure 1. Pustular eruption on the palm (A) and sole (B) of a 45-year-old man.

were normal. A technetium-labeled bone scan image cal osteitis and past or current history of skin lesions showed increased uptake in the sternal body and with histologic evidence of neutrophil-rich aseptic lateral third of the sternocostal joints (Figure 4). infiltrations.5 This syndrome primarily affects young SAPHO syndrome was diagnosed on the basis of adults but can occur and have the same manifesta- the clinical and histologic skin findings, as well as tions in children.6 In most series, females are the finding of multifocal osteitis on the bone scan. affected more than males are; among patients with The patient was treated with a topical steroid, tar, acne, the reverse is true. and salicylic acid preparations and improved grad- In SAPHO syndrome, the main histologic ually. NSAID treatment was discontinued. The inflammatory process is osteitis. Radiologic findings recommendation from a psychiatric consultation for osteitis are diverse, because manifestations did not include anxiolytic or antidepressant treat- change with lesion progression. Early lesions, in ment. New crops of pustules appeared on the palms which polymorphonuclear cells dominate, can go and soles after the patient spent a weekend at undetected on plain radiographs; only a technetium- home. A regular regimen of topical psoralen and labeled bone scan image shows positive results at phototherapy was started, the patient began a new this stage. Later in the course of the disease, the job, and the eruption gradually cleared. inflammatory infiltrate consists mainly of mono- cytes and fibroblasts, and bone remodeling and Comment bone marrow fibrosis have occurred; at this stage, SAPHO syndrome includes a broad array of clinical sclerosis and hyperostosis are found on clinical and patterns characterized by pseudoinfectious multifo- radiologic examination.7

64 CUTIS® SAPHO Syndrome

Figure 2. Results of a punch biopsy of a pustular lesion Figure 3. Subcorneal infiltration of polymorphonuclear were positive for psoriasiform epidermal hyperplasia with lymphocytes (H&E, original magnification 400). alternating parakeratosis and orthokeratosis and showed an increase in the number of tortuous capillaries in the dermal papillae (H&E, original magnification 100). by associations with psoriasis, sacroiliitis, inflam- matory bowel disease, and increased prevalence of HLA B27 in as much as 30% of subjects in differ- Our patient presented with pustulosis palmaris et ent Western studies. plantaris and anterior chest multifocal osteitis— Some of the skeletal components of SAPHO features compatible with SAPHO criteria. We made syndrome closely resemble psoriatic arthritis; dis- the diagnosis early in the course of the disease, in tinguishing these 2 entities is mandatory because the acute stage of osteitis, when only the bone scan they differ in the pathologic process underlying image showed activity in the affected foci. bone changes and, more important, in natural his- Although the etiology and pathogenesis of tory.10 The main pathologic process in psoriatic SAPHO syndrome remain unclear, they seem to arthritis is enthesopathy, which causes erosive mainly involve the immune system, with complex skeletal lesions and mutilation. In SAPHO interactions occurring among superantigens, syndrome, osteitis is chronic but not mutilating. cytokines, and growth factors. Kahn and Kahn5 The high prevalence of the HLA B27 haplotype in suggested the presence of a specific gene associated both entities, however, may unite them in a single with psoriasis-related conditions. Propionibacterium pathogenic spectrum. acnes, a common skin saprophyte, was isolated Our patient had 3 factors known to induce or from some open bone biopsies in one study, but exacerbate SAPHO syndrome: heavy smoking other specimens were sterile.8 Hayen et al9 specu- (which correlates with developing pustulosis palmaris lated that SAPHO syndrome is a form of seronega- et plantaris), NSAID use, and severe stress. The tive —a suggestion supported patient’s circumstances suggested that emotional

VOLUME 71, JANUARY 2003 65 SAPHO Syndrome

Figure 4. Bone scan image shows increased radioactive uptake in the sternal body and lateral third of the sterno- costal joints. stress was the major inducer of his skin disease and -endorphin in stress induction of flares in psoriasis. other components of the clinical picture. The role This peptide is believed to regulate expression of of stress in the development and progression of cytokeratin 16 in epidermal cultures of psoriatic various dermatoses is well known, particularly in skin—a known marker of hyperproliferative states, psoriasis.11-13 Stress seems to induce an enhanced mainly psoriasis.15 Although the connection autonomic response and changes in pituitary– between stress and psoriasis is well documented, the adrenal activity, which result in immunomodulation relation between stress and SAPHO syndrome has of natural killer cell activity. Stress also perturbs not yet been firmly established. epidermal permeability barrier homeostasis in vitro, If nonorthopedic physicians are to take advan- which links this mechanism with development of tage of the relatively favorable prognosis for psoriasis.14 Still more evidence for the effect of SAPHO syndrome and are to avoid unnecessary stress is provided by involvement of peptide invasive diagnostic tests (eg, bone biopsies) that

66 CUTIS® SAPHO Syndrome

add to patient stress, they need to know how to 6. Benedetta C, Sauvain M, Gal I, et al. Synovitis, acne, recognize this disease. For patients with SAPHO pustulosis, hyperostosis, osteitis (SAPHO) syndrome in syndrome, dermatologists need to be able to offer childhood: a report of ten cases and review of the litera- treatment that is optimal for pain associated with ture. Eur J Pediatr. 2000;159:594-601. rheumatic disease and that does not exacerbate 7. Van Doornum S, Barraclough D, McColl G, et al. skin disease. SAPHO: rare or just not recognized? Semin Arthritis Treatment of our patient’s case posed a few prob- Rheum. 2000;30:70-77. lems. NSAIDs were discontinued, and smoking was 8. Edlund E, Johnsson U. Palmoplantar pustulosis and discouraged. Retinoids, considered for controlling sternoclavicular arthroosteitis. Ann Rheumatol Dis. the skin disease, were ruled out because they cause 1988;47:809-815. hyperostosis and could have further impaired the 9. Hayen G, Bouchaud-Chabot A, Benali K, et al. SAPHO patient’s serum lipid profile. A regular regimen of syndrome: a long term follow up study of 120 cases. topical psoralen and phototherapy, combined with Semin Arthritis Rheum. 1999;29:159-171. topical steroid treatment, soon cleared the eruption 10. Maugars Y, Berthelot JM, Ducloux JM, et al. SAPHO but only slightly relieved the patient’s chest pain. syndrome: a follow-up study of 19 cases with special Both the eruption and the chest pain improved fur- emphasis on enthesis involvement. J Rheumatol. ther when the patient began a new job. 1995;22:2135-2141. Our patient’s case underscores the stress compo- 11. Al’Abadie MS, Kent GG, Gawkrodger DJ. The relation- nent of the pathogenesis of SAPHO syndrome. ship between stress and the onset and exacerbation of Stress should be addressed in each case of this non- psoriasis and other skin conditions. Br J Dermatol. fatal but debilitating syndrome. 1994;130:199-203. 12. Gupta MA, Gupta AK. The Psoriasis Life Stress REFERENCES Inventory: a preliminary index of psoriasis related 1. Chamot AM, Benhamou CL. Le syndrome synovite, stress. Acta Derm Venereol. 1995;75:240-243. acne, pustolose, hyperostose, osteite (SAPHO): resultats 13. Schmid-Ott G, Jacobs R. Stress-induced endocrine and d’une enquete nationale. Rev Rheum Mal Osteoartritic. immunological changes in psoriasis patients and healthy 1987;54:187-196. controls: a preliminary study. Psychother Psychosom. 2. Sonozaki H, Mitsui H, Miyanaga Y, et al. Clinical fea- 1998;67:37-42. tures of 53 cases with pustulotic arthro-osteitis. Ann 14. Garg A, Chren MM. Psychological stress perturbs epi- Rheum Dis. 1981;40:547-553. dermal permeability barrier homeostasis: implications for 3. Orion E, Brenner S. Stress induced SAPHO syndrome. J the pathogenesis of stress associated skin disorders. Arch Eur Acad Dermatol Venereol. 1999;12:43-46. Dermatol. 2001;137:53-59. 4. Brandsen RE, Brenner S, Dekel S, et al. SAPHO syn- 15. Bigliardi M, Bigliardi P, Eberle A, et al. Beta endorphin drome. Dermatology. 1993;186:176-180. stimulates cytokeratin 16 expression and downregulates 5. Kahn MF, Kahn MA. The SAPHO syndrome. Baillieres opiate receptor expression in human epidermis. J Invest Clin Rheumatol. 1994;8:333-362. Dermatol. 2000;114:527-532.

VOLUME 71, JANUARY 2003 67