Synovitis,acne,pustulosis,hyperostosis,and osteitis (SAPHO) syndrome with remarkably elevated serum IgG4

Introduction

Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is a rare inflammatory disorder first reported by Chamot et al. ¹ in 1987. The etiology of SAPHO syndrome remains unclear and has been reported to be a combination of genetic, infectious, and immunological factors. ² Notably, immune system dysfunction is observed with altered humoral immune response. ² Immunoglobulin G4 (IgG4) is a subclass of immunoglobulin which has been recently recognized to be related to a collection of diseases. ³ Serum IgG4 level has been reported to be increased in IgG4-related systemic disease (IgG4-RSD), allergic disorders, idiopathic membranous nephropathy, rheumatoid arthritis (RA), and a variety of pulmonary disorders.^3–6 We present the first case report of SAPHO syndrome with remarkable elevation of serum IgG4 level. This report indicates a spectrum of diseases with serum IgG4 elevation broader than previously reported. Moreover, it also provides information on the underlying abnormal immune response in SAPHO syndrome.

Materials and methods

Clinical case

The patient was a 45-year-old male, and he had been undergoing pain of the anterior chest wall since 2011. He noticed arthralgia of right elbow and pain in the buttock and upper thigh in 2013. Nonsteroidal anti-inflammatory drugs (NSAIDs) had been prescribed empirically, but the above symptoms continued to exacerbate.

On admission, physical examination revealed deformity and tenderness of the right elbow with limited range of movement (Figure 1(a)). Patrick’s test was positive on both sides. No skin lesion was observed, nor was proptosis, swelling of parotid or submandibular glands, or enlarged superficial lymph nodes. He denied any history of fever, rashes, diarrhea, bloody stools, or abdominal pain. He also had no history of allergic rhinitis, asthma, parasitic infections, renal disorders, or pulmonary diseases.

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Figure 1.

(a) Deformity of the right elbow. (b) Whole body bone scintigraphy revealed the classic “bull’s head” sign in the anterior chest wall. (c)–(d) Computed tomography images of the anterior chest wall revealed cortical bone erosions in bilateral sternoclavicular and sternocostal joints, accompanied by osteosclerosis in the adjacent cancellous bone. (e) Coronal T2-weighted magnetic resonance image of the right elbow showed joint effusion, as well as hyperintense in the olecranon of ulna, which was suggestive of bone marrow edema.

Blood analysis indicated elevated hyper-sensitivity C reactive protein (hs-CRP), 19.4 mg/L; erythrocyte sedimentation rate (ESR), 48 mm/h; and immunoglobulin G (IgG), 19.0 g/L (7.0–17.0 g/L). Further analysis of serum IgG subclass showed remarkably increased IgG4 at 3480 mg/L (80–1400 mg/L), as well as the proportion of IgG4 to the total IgG, 15.6% (1%–4%). Rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP) antibody, antinuclear antibody (ANA), and human leukocyte antigen B27 (HLA-B27) were all negative. Complete blood count, liver function test, serum creatinine, and blood glucose were all within the normal range.

Whole body bone scintigraphy using ⁹⁹Tc^m-MDP showed increased tracer uptake in the right elbow, bilateral sacroiliac joints, and the anterior chest wall, which represented a typical “bull’s head” sign (Figure 1(b)). Computed tomography (CT) images of anterior chest wall revealed cortical bone erosions in bilateral sternoclavicular and sternocostal joints, accompanied by osteosclerosis in the adjacent cancellous bone (Figure 1(c) and (d)). Coronal T2-weighted magnetic resonance image of the right elbow showed joint effusion, as well as hyperintense in the olecranon of ulna, which was suggestive of bone marrow edema (Figure 1(e)). Sacroiliac CT scan suggested mild degenerative change. The diagnosis of SAPHO syndrome was made.

Celecoxib (0.2 g/day) and leflunomide (20 mg/day) was given orally for 2 months. The arthralgia of right elbow remitted completely, and the buttock pain was also partly relieved. The ESR and hs-CRP were decreased to normal. The level of IgG4 declined to 2580 mg/L while the total IgG also declined to 12.73 g/L. However, the symptoms relapsed 1 year later, and the serum IgG4 increased back up to 3220 mg/L, so did the proportion of IgG4 to the total IgG, 17.7%. An analysis of serum cytokines was performed, which indicated a significant elevation of serum interleukin 6 (IL-6) at 56.5 pg/mL (<5.9 pg/mL). The serum IL-8 and IL-10 levels were normal. Interestingly, the serum IL-6 level seemed to be paralleled to the serum hs-CRP and IgG4 level despite of the limited data (Supplementary Figure 1). The patient still had regular follow-up visits in our hospital.

A written informed consent was obtained from the patient before publication.

Discussion

SAPHO syndrome is diagnosed according to the presence of at least one of the four following features: osteoarticular manifestations in severe acne, osteoarticular manifestations in palmoplantar pustulosis, hyperostosis with or without dermatosis, and recurrent multifocal chronic osteomyelitis (CRMO). ⁷ Although no skin lesion was observed in this case, the hyperostosis of anterior chest wall, in addition to the typical “bull head” sign, supported the diagnosis of SAPHO syndrome. Exclusion criteria ⁸ were also met.

Notably, the skin lesions and osteoarticular manifestations are not always paralleled in terms of time in SAPHO syndrome. According to accredited literature, the time interval of the presence of the two could be as long as 38 years. ² Moreover, while the axial skeletons are mostly involved in SAPHO syndrome, in 36% of the cases peripheral joints are involved, ² and 5%–10% of patients have long bones involvement, ⁸ as was shown in this case. What is intriguing is that the serum IgG4 level was significantly elevated in our patient.

Contrary to the previous report that serum IgG levels were normal in patients with SAPHO syndrome, ⁹ we found increased serum IgG in our patient, which led us to perform an IgG subclass analysis. With the existing knowledge, this is the first report of SAPHO syndrome with remarkably elevated serum IgG4 level. IgG4 is a subclass of immunoglobulin G whose biological function remains unclear. Recently, it has been discovered to be related a spectrum of diseases, with the new concept of IgG4-related systemic disease (IgG4-RSD) being proposed. ³ Yet, in the case of our patient, there was no clinical evidence supporting such diagnosis, given that he did not present with swelling of tear or salivary glands, enlarged superficial lymph nodes, or symptoms relating to pancreatitis.

The production of IgG4 is thought to be part of the Th2 immune response relying on the cytokine IL-4/IL-13. ⁵ Alternatively, cytokines produced by Treg, such as IL-10, also stimulate the production of IgG4. ⁵ However, it is perplexing that the Th2 axis is not found to be activated in SAPHO syndrome, ¹⁰ and IL-10 was discovered to be decreased. ⁹

What might be of suggestive value was the significant elevation of serum IL-6 level. Although not reported previously to be elevated in SAPHO syndrome, serum IL-6 was found significantly higher in patients with ankylosing spondylitis. ¹¹ We find the following arguments that might be suggestive of possible relevance between increased serum IL-6 and IgG4 level through literature reviews: (1) In some patients with multicentric Castleman’s disease (MCD), both serum IL-6 and IgG4 levels were elevated. Histologically, abundant IgG4-positive cells infiltration was observed. The pathological findings alone could not be differentiated from IgG4-RD.^12,13 (2) Generally, in diseases called “hyper-IL-6 syndrome,” serum IgG4 levels were also found to be increased, so were the IgG4-positive cells in lesion tissues shown by immunohistochemistry. Such diseases included MCD, RA and other autoimmune diseases.^14–17 (3) In vitro, IL-6 may stimulate the production of IgG4 by enhancing the differentiation of committed B cells.^18,19 Therefore, according to all the arguments above, we propose a hypothesis that there might be a causal relationship between the increased serum IL-6 level and the elevation of serum IgG4 level in this patient with SAPHO syndrome. Also, the SAPHO syndrome could potentially be categorized as a type of hyper-IL-6 syndrome.

The serum IgG4 level has been reported to be increased in a series of conditions, including IgG4-RSD, allergic disorders, allergen immunotherapy, idiopathic membranous nephropathy, RA, MCD, Churg-Strauss syndrome, sarcoidosis, and a variety of pulmonary disorders including leiomyosarcoma, Loeffler’s syndrome, periarteritis nodosa and mycosis fungoides.^3–6 This report argues that there might be remarkable elevation of serum IgG4 in SAPHO syndrome—a rare inflammatory disorder. Although the mechanism of its production and its crosstalk with SAPHO syndrome remains unknown, yet it might be related to the elevation of serum IL-6.