Poster Presentation 29th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting 2019

Skeletal Sarcoidosis – A novel therapy for skeletal sarcoid lesions

Sarcoidosis is a multi-system, infiltrative and inflammatory disease of unknown aetiology characterised by the presence of non-caseating granulomas. Systemic sarcoidosis can present with diverse features; ranging from the insidious onset of mild fatigue or subtle respiratory symptoms, to a multi-organ involvement which may be fulminant. Osseous sarcoid lesions are estimated to occur in between 2-13% of cases (1) however are often asymptomatic with systemic disease treatment taking priority (2).

We describe a case of systemic sarcoidosis heralded by extensive skeletal manifestations which were poorly controlled with corticosteroids or azathioprine yet subsequently showed marked clinical and radiological response to Zoledronic acid. (Figure 1) Lytic lesions on imaging appear to resolve over the time course of 14 months.

CASE
42 female presented with a 20-year history of recurrent migraine headaches which had increased in frequency and severity, with new right-sided sensorineural hearing loss. Constitutional systemic symptoms of weight gain, neck pain and dry cough. Initial biochemical testing normal (normocalcaemic, normal PTH, 25-OH vitamin D 56) except mildly elevated serum ACE. Bone turnover markers were within normal limits. A lumbar puncture was performed was unremarkable(normal cell count, protein, glucose and ACE).

The patient proceeded to MRI Brain due to persistent headache with sensorineural hearing loss. An MRI of the brain and cervical spine demonstrated enhancing lytic lesions in the left parietal bone and left basiclivus.

A CT Neck/Chest/Abdomen/Pelvis was ordered on the presumption of malignancy. Multiple lytic lesions involving the patients skull, axial spine, humerus and pelvis were demonstrated. CT of the chest also revealed a reticulonodular infiltrate with a peribronchovascular distribution in both lungs suggesting the diagnosis of sarcoidosis, although notably without the marked hilar lymphadenopathy. 

An FDG-PET (Pictures to follow) was performed which confirmed multiple areas of increased tracer uptake in cervical fat and muscle, lower cervical lymph nodes and lung parenchyma. There was some uptake in hilar nodes as well as multiple bones including the skull base and cervical spine and axial skeleton.

Pathology
The diagnosis of systemic sarcoidosis was confirmed following 2 biopsies of prominent supraclavicular lymph node which demonstrated “a mixed population of lymphocytes, plasma cells, macrophages, epitheloid histocytes and multinucleated giant cells. No caseous or necrotising inflammation is seen nor is there atypia or evidence of malignancy. The features are suggestive of a granulomatous inflammatory process such as sarcoidosis.”

Biopsy of a pelvic lytic in the right iliac crest confirmed the diagnosis (Fig 4). At this time the patient had only mildly elevated serum ACE levels. 
“Biopsy contains fibrosis and inflammation involving bone and adjacent skeletal muscle. The inflammation includes multinucleate giant cells as well as lymphocytes. No suppuration or caseation is seen nor is there evidence of vasculitis. A small amount of haemopoietic marrow is involved by the inflammatory process. No atypical cellular infiltrate is present. This is a fibrosing granulomatous inflammatory process. No microorganisms are found on the MethAg, PUTT or PAS stains. The overall features are consistent with sarcoidosis. No features of IgG4 disease on either the H + E or immunoperoxidase stained slides” (Further staining of pre-treatment bone biopsy to follow)

Progress
A therapeutic trial of high-dose glucocorticoids was trialed however the patient was unable to tolerate this due to palpitations and marked psychomotor agitation. Respiratory symptoms (cough and dyspnoea) were managed with inhaled glucocorticoids. A trial of an alternative immunosuppressant (Azathioprine) was hindered by the development of acute hepatitis. As symptomology (headache, neck pain) appear to correlate with boney lesions, and other systemic manifestations appeared well controlled, a trial of Zolendronic acid was given. Over the course of 14 months, marked resolution of skeletal lesions (previously appearing and aggressive) on serial imaging studies. 

Discussion
Despite increasing diagnosis (via MRI and FDG-PET (5))) of osseous sarcoid, the osteolytic lesions associated with the disease remain rare, and treatment of other systemic manifestations (respiratory, cutaneous, neurological and other) often takes precedence. To our knowledge, this is the first case of skeletal sarcoid managed with IV Zolendronic acid. Genetic factors, epidemiology of sarcoidosis and hypotheses behind the healing of extensive skeletal lesions, with comparison to other disease processes (lytic lesions of multiple myeloma) will be reviewed in detail.

Key points 

• Sarcoidosis is an inflammatory systemic disease that varies in clinical presentation and the aetiology remains unclear
• Zoledronic acid (IV) may serve as an option in patients with bony sarcoid with systemic disease may be under control or have symptomatic boney lesions
• Marked radiological improvement in skeletal lesions to osteclast-inhibiting agents (in this case IV Zolendronic) acid may lead to further understanding of the pathogenesis of this multi-system inflammatory disease
• Skeletal physiology, patient and disease factors leading to response will be reviewed in detail