Letters to the Editor: Refractory SAPHO syndrome with positive Th17-related pathway immunohistochemistry staining

Abstract

A 34-year-old female was presented with left clavicle mass, recurrent ostalgia, and vesiculo-pustular rash in hands and feet. During 9 years of disease duration, she received first- and second-line therapies, however, with poor respond to non-steroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs. Upon arrival, the physical examination revealed right clavicle swollen with severe tenderness and poor lumbar motility. Laboratory evaluation revealed elevated inflammatory indicators and imaging examinations revealed multiple bone erosion and sclerosis. The immunohistochemical staining of the bone biopsy presented the elevation of the Th17-related cytokines interleukin (IL)-6, IL-17, and IL-23, and negative expression of tumor necrosis factor (TNF)-β and receptor activator NK-κB ligand (RANKL). The immunohistochemical staining of target tissue revealed possible physiologic pathway and potential treatment target. Th17-related pathway might function as the central pathway of pathophysiologic process in SAPHO syndrome.

SAPHO syndrome is a rare disease characterized by synovitis, acne, pustulosis, hyperostosis, and osteitis. ¹ SAPHO syndrome was once classified as one subtype of seronegative spondyloarthropathy. While the osteitis plays a key role in the pathological process of the disease, the current studies prefer that SAPHO syndrome is a kind of autoinflammatory disease. Several pro-inflammatory cytokines such as tumor necrosis factor (TNF)α, interleukin (IL)-6, IL-8, and IL-18 were found to be involved in the pathogenesis of SAPHO, recently Th17 cells and its pathways were discovered to be the key pathway in the disease.^2–4

Treatment for SAPHO syndrome includes non-steroidal anti-inflammatory drugs (NSAIDs) as first-line regimen and glucocorticoid, disease-modifying antirheumatic drugs (DMARs), immuno-biologicals, and bisphosphonates as second-line regimen, while some of the patients do not respond well to the routine therapies. There, we described a patient with refractory SAPHO syndrome who did not respond to the routine medical therapy. By immunohistochemical staining of bone lesion, we figured out the potential key pathway for pathophysiologic process and treatment.

We reported a 34-year-old Chinese female with left clavicle mass and ostalgia with consent to participate in the study. She first noted a progressing bean-size mass with mild tenderness in left clavicle 9 years ago. After 1 year, she received left claviculectomy and pathological diagnosed with osteofibrous dysplasia. She reported a complete relief of pain in her clavicle until new ostalgia arised in right clavicle 5 years ago, which could be only partially relieved by zoledronate. She developed pain in left hip and left lower extremity as well as vesiculo-pustular rash in hands and feet 3 years ago which could be improved by NSAIDs occasionally. After that, she experienced several recurrence of such ostalgia with poor respond to NSAIDs. She presented to Peking Union Medical College Hospital with severe recurrence of both clavicles and right hip pain 2 years ago. Physical examination found right clavicle swollen with severe tenderness and poor lumbar motility with 1 cm of Schober’s test and 50 cm of finger-floor distance.

Laboratory evaluation revealed elevated erythrocyte sedimentation rate (58 mm/h) and C-reactive protein (18.2 mg/L). Her rheumatoid factor (RF), anti-nuclear antibody (ANA), anti-extractable nuclear antibody (ENA), and human leukocyte antigen (HLA)-B27 were negative.

As for imaging examinations, bone scintigraphy demonstrated increased tracer uptake in bilateral sternocostal joints and sternoclavicular joints, as well as in multiple ribs and vertebral bodies (Figure 1(a)). Computed tomography (CT) of lumbar spine revealed vertebral cortical erosion, sclerosis in cancellous bone, and syndesmophytes in L3 S1, accompanied by narrowing of adjacent disk spaces (Figure 1(b)). Furthermore, magnetic resonance (MR) images obtained with various sequences of lumbar spine provided additional information of abnormal signal intensity L3 S1 (Figure 1(b)), corresponding to bone marrow edema, fatty deposition, and sclerosis, suggesting its inflammatory process. Lumbar vertebra lesion biopsy was done and showed bone trabecular degenerative changes and fibrous tissue hyperplasia, with plasma cell infiltration, suggesting chronic osteomyelitis.

Figure 1.

(a) Bone scintigraphy, (b) computed tomography (CT), and (c–e) magnetic resonance (MR) images of lumbar spine in this patient.

Bone scintigraphy (Figure 1(a)) demonstrated increased tracer uptake in bilateral sternocostal joints and sternoclavicular joints, as well as in multiple ribs and vertebral bodies. CT of lumbar spine (Figure 1(b)) revealed vertebral cortical erosion, sclerosis in cancellous bone, and syndesmophytes in L3 S1, accompanied by narrowing of adjacent disk spaces. Furthermore, T2-weighted (Figure 1(c)), T1-weighted (Figure 1(d)), and fat-saturated T2-weighted (Figure 1(e)) MR images of lumbar spine provided additional information of abnormal signal intensity L3 S1, corresponding to bone marrow edema, fatty deposition, and sclerosis.

According to the diagnostic criteria raised by Nguyen, ¹ the diagnosis of SAPHO syndrome was made. Methotrexate and salicylazosulfapyridine were administered due to the elevated inflammatory indicators and the poor respond to NSAIDs. However, the above treatment only brought a partial remission of the clinical symptoms and the down-trending of serum indices for 6 months. Then bisphosphonates were administrated once without satisfied improvement. Several recurrences appeared during the follow-up time when Chinese herbs (glucosides of paeony), leflunomide, and etanercept were tried but could only relief the symptoms for 2–4 weeks.

In order to better understand the reason why she presented a refractory SAPHO syndrome, we detected the TNF-β, IL-1β, IL-6, IL-17, IL-23, and receptor activator NK-κB ligand (RANKL) expression in her former clavicle and vertebral biopsy by immunohistochemistry staining. The results showed positive IL-6 (Figure 2(a)), IL-17 (Figure 2(b)), IL-23 (Figure 2(c)), and IL-1β (Figure 2(d)) expression and negative RANKL (Figure 2(e)) and TNF-β (Figure 2(f)).

Figure 2.

Clavicle biopsy immunohistochemistry staining. Numerous plasma and lymphocytes infiltrated between the bone marrow of the clavicle biopsy specimen. A positive IHC staining of the inflammation cells presented in the cytoplasm for (a) IL-6, (b) IL-17, (c) IL-23, and (d) IL-1β expression and negative staining of (e) RANKL and (f) TNF-β.

As a disease with characteristics of auto-inflammatory disease, the treatment for SAPHO syndrome refers to seronegative spondyloarthropathy. Until now, there have been no treatment guidelines for SAPHO syndrome. NSAIDs are the first-line treatment, mainly focused on relieving symptoms. Other second-line medication is usually empirical and multimodal, such as glucocorticoid and DMARDs. However, immune-biological agents were reported as a new therapy in recent 10 years, such as TNF blockers, IL-1 blocker, and Ustekinumab.^5–7 Since hyperostosis and osteitis are the key manifestation of SAPHO syndrome, bisphosphonates are also one of an alternatives in SAPHO syndrome with severe bone involvement.

In this case, the diagnosis of SAPHO syndrome was based on the clinical manifestation, laboratory and radiological results, as well as pathological findings. However, the treatment brought great challenges to the physicians. Since most first- and second-line medications were inefficacious, we are wondering the key pathophysiologic process in this case. The immunohistochemical staining revealed negative expression of TNF-β and RANKL, indicating that TNF-β and RANKL-osteoprotegerin (OPG) pathway did not play an important role in the development of SAPHO syndrome in this case. That may explain why the patient did not respond to the TNF blockers and bisphosphonates.

However, we noted the elevation of IL-6, IL-17, and IL-23, which are the Th17-related cytokines in this case. Evidences showed that Th17 cells increased in the peripheral blood of patients with SAPHO syndrome compared to patients with psoriatic arthritis or health people, and there was an activation of Th17 axis, but not of Th1 and Th2 in SAPHO patients. ² So, the elevation of IL-6, IL-17, and IL-23 may indicate the Th17-related pathway function as the central pathway of pathophysiologic process in this case, and that might be the reason why former medication was ineffective.

As far as we know, it is the first case report of the elevation of Th17-related cytokines in target tissue by immunohistochemical staining. This might be a new method to seek to theoretical foundation for the choice of treatment for SAPHO syndrome. We suggested that the critical process in SAPHO syndrome might be the Th17 activation, which leads to the secretion of IL-17 and elevation of RANKL, ending in the abnormality of bone metabolism and the clinical manifestation in SAPHO syndrome.