Non-bacterial Osteitis Syndromes: CRMO, SAPHO, Majeed, and DIRA

OVERVIEW: What every practitioner needs to know

The spectrum of non-bacterial osteitis syndromes (NBO) includes several clinically distinguishable syndromes:

– Chronic recurrent multifocal osteomyelitis (CRMO)

– Synovitis, acne, pustulosis, hyperostosis syndrome (SAPHO)

– Chronic recurrent multifocal osteomyelits and congenital dyserythropoietic anemia (Majeed syndrome)

– Deficiency of the IL-1 receptor antagonist (DIRA)

Are you sure your patient has a non-bacterial osteitis syndrome? What are the typical findings for this disease?

CRMO and SAPHO represent the spectrum of autoinflammatory bone disease in which non-infectious osteitis is the unifying feature collectively termed non-bacterial osteitis (NBO). The systemic autoinflammatory diseases include NBO and the periodic fever syndromes. All are considered defects of innate immunity characterized by recurrent attacks of spontaneous inflammation in the absence of autoimmunity or infection.

The most common clinical findings in the NBO syndromes (including CRMO and SAPHO) include recurrent episodes of bone pain with or without fever due to discrete inflammatory lesions in one or more bones of the axial or peripheral skeleton. X-rays and magnetic resonance imaging (MRIs) of affected areas show irregular radiolucent foci with sclerosis in different stages of healing. Bone scans show uptake of Technetium-99 in active lesions. The bone lesions are indistinguishable from infectious osteomyelitis on imaging. Bone biopsy histology shows nonspecific inflammation with neutrophilic infiltrate early and mixed inflammatory cells, sclerosis and new bone formation in older lesions. Cultures of bone aspirates or biopsies are sterile. The boney lesions are refractory to antimicrobial therapy.

Other associated findings in the NBO syndromes frequently include comorbid autoinflammatory or autoimmune diseases commonly involving the skin, bowel, and/or joints. The diseases generally follow an unpredictable disease course with periodic waxing and waning of symptoms over a few years to up to 10 years.

NBO is a diagnosis of exclusion. As such it is critical to rule out infection, malignancy, or systemic autoimmune disorders other than arthritis or inflammatory bowel disease to make a diagnosis of NBO. Skin and bone biopsies, particularly if only a single osteolytic focus is present, should be used to exclude other causes and confirm diagnosis of NBO. (See Table I)

Table I.

Suspect diagnosis if ≥2 majorOR1 major and ≥3 minor criteria are present:
Major Criteria*	Minor Criteria*
Radiologically-proven osteolytic/sclerotic bone lesions	Normal CBC
Multifocal bone lesions	Otherwise good health
Palmoplantar pustulosis or psoriasis (neutrophilic dermatoses)	Elevated ESR & CRP
Sterile bone biopsy with inflammation & sclerosis on histology	Symptoms >6 mo
	Hyperostosis
	Comorbid autoimmune/autoinflammatory disease other than neutrophilic dermatoses
	1^st or 2^nd degree relative with autoimmune or autoinflammatory disease

*compiled from classifications proposed by El-Shanti H & Ferguson P, Clin Orthop Relat Res 462:11, 2007 and Hospach T et al, J Pediatr 169:1105, 2010.

Inheritance of non-bacterial osteitis

The spectrum of NBO includes both monogenic and complex inherited syndromes, as well sporadic cases in which underlying gene defect(s) have not yet been identified.

Autosomal recessive:

– Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome)

– Deficiency of the IL-1 receptor antagonist (DIRA)

Sporadic or unidentified gene defect(s):

– Chronic recurrent multifocal osteomyelitis (CRMO)

– Synovitis, acne, pustulosis, hyperostosis syndrome (SAPHO)

CRMO

There is a striking overlap of symptoms and comorbidities between CRMO and SAPHO. CRMO may represent the pediatric presentation of SAPHO.

The classic clinical presentation of CRMO is episodic bone pain with low grade fever. The bone pain is usually has an insidious onset, is well localized, and aching in character. Patients may be afebrile. On exam there is tenderness to palpation, with swelling and warmth overlying the involved bone. Objective signs of arthritis may involve one or more joints. The skin findings include psoriasis, palmoplantar pustulosis and cystic acne with scarring. The disease course will be characterized by frequent exacerbations and remissions. The average age of onset is 10 years, with a range of 4-55 years. The mean time from onset of symptoms to diagnosis is18 months.

Bone involvement in CRMO is characterized by an average of 2-18 bone lesions, usually in an asymmetric distribution, and often localized to bone sites typically seen in acute hematogenous (infectious) osteomyelitis in children. 10% of patients have a unifocal lesion, requiring bone biopsy for definitive diagnosis to rule out infectious osteomyelitis.

On laboratory testing, mild or moderate elevations of ESR (15-65 mm/h) and CRP (5-40 mg/l) are found during flares in 60% patients. White blood cell counts are normal or only mildly elevated (5-15,000 x 10⁹/l). RF is negative and ANA is also usually negative unless the patient has concomitant autoimmune thyroiditis. 10% of patients are positive for HLA-B27.

Comorbid conditions found in CRMO include other autoinflammatory or autoimmune disorders involving skin, joints or bowel:

Neutrophilic dermatoses in 20-80% patients:

psoriasis

palmoplantar pustulosis

acne fulminans or conglobata

neutrophilic eccrine hidradenitis

Sweet syndrome [acute febrile neutrophilic dermatosis]

pyoderma gangrenosum
Enthesitis, spondyloarthropathy, psoriatic arthritis in 10-35% patients.
Inflammatory bowel disease (Crohn’s disease or ulcerative colitis) within 1-5 yr in 10-25% patients.

The wide range in frequency of the associated diseases is probably due to discordance in the timing of the NBO and the onset of skin, bone and bowel manifestations, and confusion resulting from the clinical overlap between CRMO and SAPHO.

40-50% of 1^st or 2^nd degree relatives have chronic autoimmune or autoinflammatory disease.

SAPHO

As noted above there is significant overlap in clinical symptoms, laboratory findings and comorbidities between SAPHO and CRMO.

Features that distinguish SAPHO from CRMO are the finding of skin manifestations in more than 85% of patients, an older age at presentation, and predilection for different bones.

The classic presentation of SAPHO is with bone pain due to chronic recurrent osteitis and concomitant severe skin disease without fever. The most common site of involvement in SAPHO (unlike CRMO) is anterior chest wall pain (see below). Bone involvement usually includes 1-8 bone lesions in asymmetric distribution. Tenderness to palpation, swelling and warmth overlying involved bone is noted on exam. The osteitis is unifocal in 40-50% patients, and often requires diagnostic bone biopsy to rule out infection.

Severe scarring acne, psoriasis or palmoplantar pustulosis is commonly present on examination. SAPHO may present as acute or chronic arthritis with skin manifestations, especially psoriasis. The average age of onset is 30 years with a range of 12-65 years.

The most common sites of skeletal osteolytic foci are:

– Anterior chest wall/sternocostoclavicular joint: 60%

– Spine: 35%

– Long bones: 25%

– Clavicle: 20-25%

– Knee/ankle/wrist: 11%

– Sacroiliac joint: 6%

Laboratory findings include mildly elevated ESR (10-65 mm/h) and CRP (10-40 mg/l) during flares of osteitis and skin inflammation. The CBC shows either a normal or mildly elevated white blood cell count (5-15,000 x 10⁹/l). RF and ANA are negative except when there is concomitant autoimmune thyroiditis. Four to 15% of patients are HLA-B27 positive.

Comorbid conditions include the onset of skin manifestation either with or even before the development of bone lesions in up to 85%. The typical skin finding is a neutrophilic dermatosis such as:

Palmoplantar pustulosis: 40-50%.
Acne conglobata or fulminans: >25%.
Psoriasis vulgaris: 20-55%.
30-35% of patients have two concomitant skin manifestations.
Sweet syndrome and pyoderma gangrenosum is less common.
Crohn’s disease or ulcerative colitis in 10%, usually presents 0.5-5 yr after onset of bone pain.
RF-negative peripheral arthritis or psoriatic arthritis in 30%, spondyloarthropathy in 20-25%.

Majeed Syndrome

Majeed Syndrome is an autosomal recessively inherited NBO with a more severe phenotype than either CRMO and SAPHO. The onset of symptoms is usually later in infancy or within the first 2 years of life. A predilection for small bone involvement, the fever pattern, the course of the disease and the association with a dyserythropoietic anemia, all help distinguish Majeed Syndrome from DIRA, CRMO and SAPHO.

Symptoms of Majeed Syndrome include the distinctive clinical course that includes flares of bone pain and fever >38.5°C for 3-4 days, recurring every 2-4 weeks. Severe joint and bone pain begins abruptly and there is tenderness to palpation with warmth and soft tissue swelling over involved bones and joints. Chronic multifocal osteomyelitis in the metaphyses of long bones and osteolytic foci in small joints of hands and feet are distinctive features. A dyserythropoietic anemia may develop in first year of life. Hepatomegaly and transient neonatal cholestatic jaundice occur in some patients.

Laboratory findings include a hypochromic microcytic anemia with reticulocytosis, transient neutropenia after birth but subsequent mild leukocytosis (10-20,000 x 10⁹/l), an elevated ESR (often >60 mm/h) and CRP (>20 mg/l). RF and ANA are negative.

Comorbid conditions:

– Congenital dyserythropoietic anemia; mild to transfusion dependent in severity

– Transient neutrophilic dermatosis, usually Sweet syndrome

– Psoriasis common in obligate carriers and first degree relatives

– Pyoderma gangrenosum and cystic acne not seen

DIRA

DIRA is an autosomal recessively inherited NBO due to deficiency of IL-1 receptor antagonist (IL-1Ra) that presents in the perinatal period. The very early age of onset, severity of disease, association with Sweet syndrome rather than other neutrophilic dermatoses, and unusual radiologic findings distinguish it from CRMO and SAPHO. The lack of anemia, an earlier presentation and unusual radiologic findings distinguish DIRA from Majeed syndrome.

Symptoms of DIRA usually appear in the first 2-3 weeks of life. The infants appear ill and exhibit signs of systemic inflammation without fever. The patients have irritability and pain on palpation of long bones, joint swelling and a pustular rash that can vary in appearance. Other clinical features include significant osteopenia with associated fractures, hepatosplenomegaly, CNS vasculopathy, venous thromboses, pneumonitis or pulmonary hemosiderosis resulting in respiratory distress, and oral mucosal lesions.

Bone involvement includes multifocal osteolytic lesions and periosteal elevation along the metaphysis of multiple long bones. Involvement of the spine and skull is also seen and may lead to vertebral collapse and secondary cervical spine fusion. Heterotopic ossification may occur around hip and proximal femur. Epiphyseal ballooning of anterior ribs occurs in nearly 100% infants.

Laboratory findings include:

– ESR 40-80 mm/h, CRP >15-75 mg/l

– Significant leukocytosis, often >20-40,000 x 109/l

– No associated autoantibodies or RF

What other diseases/conditions share some of these symptoms?

Bacterial osteomyelitis, arthritis or discitis

Brucellosis, tuberculosis, actinomycosis, cat-scratch fever

Chronic granulomatous disease

HLA B27-associated juvenile spondyloarthropathy or sacroilitis

Juvenile psoriatic arthritis

Gout

Malignant bone tumors: Osteosarcoma, Ewing’s sarcoma, Rhabdomyosarcoma, Eosinophilic granuloma, Langerhans cell histiocytosis

Benign bone tumors: osteoid osteoma, osteoblastoma

Leukemia, lymphoma, neuroblastoma, metastases

Other systemic autoinflammatory syndromes: Pyogenic sterile arthritis, pyodema gangrenosum, and acne (PAPA) syndrome, Neonatal onset multisystem inflammatory disorder (NOMID), Cherubism

Retinoid therapy

Hypophosphatasia

Caffey’s disease (infantile cortical hyperostosis)

What caused this disease to develop at this time?

No specific disease triggers have been identified although skin colonization with Proprionibacterium acnes may exacerbate symptoms.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Initial screening tests:

– CBC, differential during fever and when symptom-free

– ESR, CRP during fever and when symptom-free

– Complete metabolic panel, calcium, phosphorus, magnesium

– Uric acid, LD

– Quantitative immunoglobulins

– Blood, urine cultures

– PPD

Additional screening tests as needed:

– Brucella, Bartonella serologies

– NBT (nitroblue-tetrazolium test) or DHR (dihydrorhodamine)

– ANA panel, RF, ANCA

– HLA typing for B27, B51

– Joint fluid analysis for cell count, crystals and culture

– Bone marrow aspirate and biopsy

Confirmatory studies:

– Skin biopsy for histology

– Bone biopsy for histology, stains and cultures

Interpretation of results:

– Marked leukocytosis with left shift, ESR >80 and CRP >80 suggest an infectious process, which may be confirmed by pan-cultures, serologies or bone biopsy.

– Positive PPD and presence of osteitis requires bone biopsy to rule out tuberculosis discitis or osteomyelitis.

– Elevated uric acid or LD may suggest leukemia or lymphoma requiring bone marrow biopsy for exclusion.

– Low alkaline phosphatase suggests Caffey’s disease.

– Hypogammaglobulinemia in association with osteitis may suggest infectious process secondary to primary immunodeficiency.

– Abnormally low NBT or DHR is suggestive of chronic granulomatous disease and osteomyelitis secondary to a catalase-positive organism.

– Positive HLA-B27, biopsy-proven neutrophilic dermatosis, normal CBC other than mild leukocytosis, mildly elevated ESR and CRP, and negative ANA and RF suggest NBO.

Summary:

NBO is a diagnosis of exclusion.

One must rule out infection, malignancy, or systemic autoimmune disorders (other than arthritis or inflammatory bowel disease) to make a diagnosis of NBO.

Skin and bone biopsies, particularly if only a single osteolytic focus, should be used to exclude other causes and confirm diagnosis of NBO.

Would imaging studies be helpful? If so, which ones?

Chest radiograph (x-ray) for infection, inflammatory lung disease, adenopathy or mass.

Bone x-rays as initial screen for bone pain.

Technetium-99 bone scan for skeletal localization of NBO versus tumor, infection or orthopedic abnormality.

Magnetic resonance imaging (MRI) with and without contrast of specific joints and bones for characterization of osteolytic lesion and differentiation from malignant or benign tumors, arthritis, other bony abnormalities.

Bone computed tomography (CT) for differentiating bone tumors, stress fractures, osteomyelitis.

Chest, abdomen, pelvis CT as part of evaluation for lymphadenopathy, inflammatory conditions, or tumor.

Confirming the diagnosis

Prolonged or recurrent bone pain with or without fever:

– CBC, ESR, CRP, CMP, uric acid, LD, blood cultures

– PPD

– Bone x-rays, MRI, bone scan and +/- CT.

(See Table II)

Table II.

Results	Action
Positive blood cultures	Treat infection
PPD reactive and CXR negative	Bone biopsy for histology/microbiology
If WBC >20,000, ESR >80, CRP >50	Proceed with infectious work-up and consider bone biopsy
If elevated uric acid, LD, cytopenias	Proceed with malignancy work-up
If ESR<80, CRP <50, WBC <20,000 AND multiple osteolytic foci in different bones	Bone biopsy unnecessary; treat as NBO
If ESR<80, CRP <50, WBC <20,000 AND single osteolytic focus	Bone biopsy for histology/microbiology to confirm NBO

If you are able to confirm that the patient has a non-bacterial osteitis syndrome, what treatment should be initiated?

Therapies that should be initiated immediately: (See Table III)

Table III.

CRMO	NSAIDS: choose naproxen 10 mg/kg b.i.d.; celecoxib 50-100 mg b.i.d., indomethacin 1 mg/kg b.i.d., OR meloxicam 7.5-15 mg dailyOmeprazole 10-20 mg daily OR lansoprazole 15-30 mg daily
SAPHO	NSAIDS: choose naproxen 10 mg/kg b.i.d., celecoxib 50-100 mg b.i.d., indomethacin 1 mg/kg b.i.d., OR meloxicam 7.5-15 mg daily Omeprazole 10-20 mg daily OR lansoprazole 15-30 mg daily
Majeed syndrome	NSAIDS: choose naproxen 10 mg/kg b.i.d.; celecoxib 50-100 mg b.i.d., indomethacin 1 mg/kg b.i.d., OR meloxicam 7.5-15 mg dailyOmeprazole 10-20 mg daily OR lansoprazole 15-30 mg dailyconsider prednisone 0.5-2 mg/kg/day for severe symptoms; taper and discontinue OR Methylprednisolone 30 mg/kg IV q.24 hr times 1-3, then prednisone
DIRA	Anakinra 1-2 mg/kg (max 100 mg) SQ dailyconsider prednisone 0.5-2 mg/kg/day for severe symptoms; taper and discontinue OR Methylprednisolone 30 mg/kg IV q.24 hr times 1-3, then prednisone

Longer term treatment (See Table IV)

Table IV.

CRMO	NSAIDS: choose naproxen 10 mg/kg b.i.d.; celecoxib 50-100 mg b.i.d., indomethacin 1 mg/kg b.i.d., OR meloxicam 7.5-15 mg dailyOmeprazole 10-20 mg daily OR lansoprazole 15-30 mg dailyconsider prednisone 0.5-2 mg/kg/day for severe symptoms; taper and discontinue ORMethylprednisolone 30 mg/kg IV q.24 hr times 1-3, then prednisoneconsider methotrexate 0.5-1 mg/kg (max 25 mg) p.o./SQ q.wk OR Sulfasalazine 30-50 mg/kg daily (max 2 gm)consider pamidronate 1 mg/kg (max 30 mg) IV times 1-3 days q.12 wk for 0.5-3 yr AND/OREtanercept 0.4 mg/kg (max 25 mg) SQ b.i.w.-t.i.w. OR 0.8 mg/kg (max 75 mg) SQ q.wk ORInfliximab 5-7.5 mg/kg IV q.4-8 wk ORAdalimumab 20 mg SQ q.1-2 wk (if >4 y & <30 kg) OR 40 mg SQ q.wk (if >30 kg)
SAPHO	NSAIDS: choose naproxen 10 mg/kg b.i.d.; celecoxib 50-100 mg b.i.d., indomethacin 1 mg/kg b.i.d. OR meloxicam 7.5-15 mg daily Omeprazole 10-20 mg daily OR lansoprazole 15-30 mg daily Prednisone 0.5-2 mg/kg/day for severe symptoms; taper and discontinue ORMethylprednisolone 30 mg/kg IV q.24 hr times 1-3, then prednisoneconsider methotrexate 0.5-1 mg/kg (max 25 mg) p.o./SQ q.wk ORSulfasalazine 30-50 mg/kg daily (max 2 gm)consider pamidronate 1 mg/kg IV (max 30 mg) IV times 1-3 days q.12 wk for 0.5-3 yr AND/OREtanercept 0.4 mg/kg (max 25 mg) SQ b.i.w.-t.i.w. OR 0.8 mg/kg (max 75 mg) SQ q.wk ORInfliximab 5-7.5 mg/kg IV q.4-8 wk ORAdalimumab 20 mg SQ q.1-2 wk (if >4 y & <30 kg) OR 40 mg SQ q.wk (if >30 kg)
Majeed syndrome	NSAIDS: choose naproxen 10 mg/kg b.i.d.; celecoxib 50-100 mg b.i.d., indomethacin 1 mg/kg b.i.d. OR meloxicam 7.5-15 mg daily Omeprazole 10-20 mg daily OR lansoprazole 15-30 mg dailyconsider prednisone 0.5-2 mg/kg/day for severe symptoms; taper and discontinue ORMethylprednisolone 30 mg/kg IV q.24 hr times 1-3, then prednisoneconsider methotrexate 0.5-1 mg/kg p.o./SQ q. wk ORPamidronate 1 mg/kg (max 30 mg) IV times 1-3 days q.12 wk for 0.5-3 yr AND/OREtanercept 0.4 mg/kg (max 25 mg) SQ b.i.w.-t.i.w. OR 0.8 mg/kg (max 75 mg) SQ q.wk ORInfliximab 5-7.5 mg/kg IV q.4-8 wk ORAdalimumab 20 mg SQ q.1-2 wk (if >4 y & <30 kg) OR 40 mg SQ q.wk (if >30 kg)
DIRA	Anakinra 1-2 mg/kg (max 100 mg) SQ daily

Alternative treatments if standard therapy fails: (See Table V)

Table V.

CRMO	Anakinra 2 mg/kg (100 mg) SQ dailySurgical resection of NBO
SAPHO	Anakinra 2 mg/kg SQ dailyIsotretinoin 1 mg/kg/day times 5 moSurgical resection of NBO
Majeed syndrome	Anakinra 2 mg/kg (100 mg) SQ daily

Multiple options for treatment: (See Table VI)

Table VI.

Doxycycline 2.2 mg/kg (max 100 mg) daily ORAzithromycin 1-5 mg/kg t.i.w. ORIsotretinoin 1 mg/kg/day times 5 mo	Common treatments for acne; benefit for SAPHO/NBO unclear. Significant adverse effects for isotretinoin but more efficacious for acne than antibiotics.
Methotrexate 0.5-1 mg/kg p.o./SQ q. wk ORSulfasalazine 30-50 mg/kg daily (max 2 gm)	Both may improve bone pain, but no data to support one option over another. Methotrexate is used for treatment of arthritis, IBD, and neutrophilic dermatoses versus sulfasalazine which is used to treat mild arthritis and IBD, not skin manifestations.
Pamidronate 1 mg/kg (max 30 mg) IV times 1-3 days q.12 wk for 0.5-3 yr AND/OREtanercept 0.4 mg/kg (max 25 mg) SQ b.i.w.-t.i.w. OR 0.8 mg/kg (max 75 mg) SQ q.wk ORInfliximab 5-7.5 mg/kg IV q.4-8 wk ORAdalimumab 20 mg SQ q.1-2 wk (if >4 y & <30 kg) OR 40 mg SQ q.wk (if >30 kg)	All TNF inhibitors improve bone pain, neutrophilic dermatoses and arthritis, but etanercept should not be used if IBD present since may trigger flare. Likely benefit for NBO: Infliximab ≥ adalimumab > etanercept, although risk of adverse reaction is inversely correlated with possible benefit.Choice of pamidronate versus TNF inhibitors in NBO patients refractory to NSAIDS, should be based at least in part on manifestations. TNF inhibitors decrease inflammation, associated pain, fever, acute phase reactants, as well as IBD, neutrophilic dermatoses and possibly early osteolytic lesions with predominantly neutrophilic infiltrates. Pamidronate may help bone pain as part of bone remodeling of chronic bone lesions and associated collapse.

What are the adverse effects associated with each treatment option?

Table VII. Adverse effects associated with NBO treatments

Table VII.

NSAIDS	Gastritis, gastric ulcer, gastroesophageal reflux, rash, edema, liver/renal toxicity (uncommon in children)
Corticosteroids	Infection, weight gain, muscle atrophy, adrenocortical insufficiency, osteopenia, growth delay, avascular necrosis, emotional lability, acne, hypertension, diabetes
Methotrexate	Nausea, emesis, fatigue, oral stomatitis, liver toxicity, birth defects
Etanercept(TNF inhibitor)	Infection, injection site reaction, CNS demyelinating disorder, positive ANA, malignancy (very low risk)
Infliximab(anti-TNF mAb)	Infection (risk > etanercept), allergic reaction, anaphylaxis, nausea, diarrhea, abdominal pain, fatigue, elevated LFTs, serum sickness, positive ANA, CNS demyelinating disease, heart failure, cytopenias, future malignancy (risk > etanercept)
Adalimumab(anti-TNF mAb)	Infection (risk > etanercept), injection site pain, elevated LFTs, positive ANA, CNS demyelinating disease, heart failure, cytopenias, future malignancy (risk > etanercept)
Anakinra(IL-1 receptor antagonist)	Infection, severe injection site reaction/pain, future malignancy
Pamidronate	Mandibular osteonecrosis, muscle pain, renal toxicity, cytopenias, hypocalcemia, anaphylaxis
Sulfasalazine	Abdominal pain, GI upset, elevated LFTs, erythema multiforme, Stevens-Johnson syndrome, rash, renal/lung toxicity, cytopenias, infertility
Isotretinoin	Dry skin/mucus membranes, pseudotumor cerebri, liver toxicity, hypertriglyceridemia, osteopenia, rash, psychosis, depression, birth defects

What are the possible outcomes of non-bacterial osteitis syndromes?

What will you tell the family about prognosis?

CRMO

Duration of disease: 1-20 yr; mean: 3-6 yr.

Disease course: Frequent exacerbations and remissions to be expected.

Clinical outcome generally good.

However, 25-60% patients have persistent bone pain and osteitis 5-15 yr after disease onset:

>20% with physical sequelae, including leg length discrepancy, bony overgrowth, generalized growth retardation, vertebral compression fractures, disability.

50% with psychological sequelae.

Response to treatment unpredictable, but >60% patients respond well to NSAIDS alone.

Younger age and numerous bone lesions at onset of symptoms may predict poor response to NSAIDS and persistent disease.
SAPHO

Disease duration: 2-20 yr; average 4-5 yr.

Disease course:

Complete remission after single attack in 10%.

Relapsing/remitting features in 35-40%.

Chronic symptoms with partial remissions in 50%.

Response to treatment unpredictable and may be less responsive to NSAIDS than CRMO.

Female sex, anterior chest wall involvement, peripheral arthritis, chronic skin manifestations, and elevated acute phase reactants may predict chronic course.
Majeed Syndrome:

Striking flares of bone pain and fever >38.5°C for 3-4 days every 2-4 wk.

Disease course: Chronic illness with rare brief remissions.

Treatment empirical, but increasing evidence for use of biologics to remit symptoms.

Overall poor quality of life, shortened lifespan and significant morbidities: ‘

Severe growth failure.

Absent or delayed pubertal development.

Progressive upper and lower extremity joint flexion contractures affecting mobility and normal functioning.

Osteoporosis.
DIRA:

Chronic illness with death <10 yr of age in untreated patients.

Treatment with anakinra rapidly resolves all signs of disease, including fever and NBO, confirming critical role of IL-1 in inflammation, osteoclast activation and bone loss.

What will you tell the family about risks/benefits of the available treatment options?

Table VIII. Risks and benefits of various treatments for NBO Syndromes

Table VIII.

Drug	Indication	Risks	Benefits
NSAIDS	Arthritis, pain, fever	Adverse effects	Reduce fever, pain
Corticosteroids	Fever, arthritis, severe rash, IBD	Adverse effects	Relieve fever, rash, arthritis, bone pain, GI inflammation; decrease acute phase reactants
Etanercept	Arthritis, fever and rash	Adverse effects; flares IBD or rash	Controls fever, arthritis; decreases acute phase reactants, may improve osteitis
Infliximab	Arthritis, IBD, inflammation not controlled by etanercept, chronic uveitis	Adverse effects; flares psoriasis (rare)	Controls fever, arthritis, IBD, rash, uveitis; improves acute phase reactants
Adalimumab	Arthritis, IBD, inflammation not controlled by etanercept, chronic uveitis	Adverse effects; flares psoriasis (rare)	Controls fever, arthritis, IBD, rash, uveitis; improves acute phase reactants
Anakinra	Treatment of DIRA; fever, arthritis	Adverse effects; fails to remit DIRA (symptoms recur off treatment)	Controls DIRA symptoms, fever, arthritis, rash; improves acute phase reactants
Pamidronate	Osteoporosis, compression fractures, hypercalcemia	Adverse effects	May improve bone pain; treat osteoporosis, compression fractures
Methotrexate	Arthritis, IBD, psoriasis, uveitis	Adverse effects	Improves arthritis, IBD, psoriasis, uveitis
Sulfasalazine	Mild arthritis, mild IBD	Adverse effects	May improve arthritis, GI symptoms
Isotretinoin	Severe acne	Adverse effects	Controls acne; may improve bone pain

What causes this disease and how frequent is it?

Detailed epidemiology:

CRMO

Most common NBO in children.

Prevalence: 1-2:10⁶.

No ethnic or racial predilection.

SAPHO

Prevalence: 1:10⁵.

No ethnic or racial predilection.

Majeed Syndrome

Incidence: extremely rare.

Described in seven individuals from three consanguineous Arab families.

Unique mutation identified in each affected family.

Prevalence of mutation: 1:35,000 in Jordan.

DIRA

Incidence: extremely rare.

Described in nine patients from Newfoundland, the Netherlands, Lebanon, and Puerto Rico.

Apparent founder effect with mutation frequency of 0.4% in Newfoundland and 2.6% in Puerto Rico.

What’s known about the genetics?

CRMO

Etiology is currently unknown.

Mostly sporadic disease and likely multifactorial.

Studies of concordance in monozygotic twins and families with more than one affected sibling and normal parents suggest an autosomal recessive inheritance as well, although underlying gene defects have not been identified.

No association between NOD2/CARD15
mutations in Crohn’s disease and CRMO.

Murine model of CRMO is due to a mutation in the pstpip2 gene and the human homolog, PSTPIP2, is structurally related to PSTPIP1
, mutations in which cause PAPA syndrome.

A recently identified susceptibility locus for NBO on chromosome 18q21.3-22 includes PSTPIP2.

SAPHO

Mostly sporadic and likely multifactorial similar to CRMO.

Recent analysis of 38 patients found no association with PSTPIP2
, NOD2 and LPIN2 genetic variants.

Majeed Syndrome

Due to homozygous mutations in the gene LPIN2 encoding the protein lipin-2, whose functions have not been fully elucidated.

Original descriptions identified three disease-causing mutations: S734L, C181X, and R776SfsX66.

DIRA

Due to homozygous mutations in the IL1RN gene that are unique to country of origin: N52KfsX25, E77X, Q54X.

Also results from a homozygous 175-kb deletion of the IL1RN
locus encoding the IL-1 receptor antagonist (IL-1Ra) and five IL-1 family members in one patient.

How do these pathogens/genes/exposures cause the disease?

CRMO

Unknown for sporadic form, but single gene defects encoding proteins critical to inflammation may contribute to pathogenesis.

One such protein, PSTPIP2, associates with actin and may play a role in inhibition of monocyte/macrophage function during inflammation.

Loss-of-function mutations in PSTPIP2
sustain inflammatory responses and cause CRMO in mice.

Although a candidate gene in families with possible autosomal recessive inheritance, loss-of-function mutations in PSTPIP2
have not been identified.
SAPHO

Unknown, but may be due to mutations in same gene(s) responsible for CRMO.
Majeed Syndrome

Lipin-2 plays a role in lipid metabolism and may be involved in apoptosis of neutrophils as one mechanism to curtail normal inflammatory responses.

Loss-of-function mutations in lipin-2 interfere with normal cell death pathways and result in persistent inflammation and increased production of proinflammatory cytokines.
DIRA

Absence of the negative regulator, IL-1Ra, leads to unopposed IL-1 signaling through the IL-1 receptor.

Sustained IL-1 signaling increases production of IL-1, provoking inflammation.

Other clinical manifestations that might help with diagnosis and management

Management of NBO is geared towards control of comorbidities as well as bone inflammation.

Treatment regimens vary considerably for the spectrum of NBO as a result, interfering with assessments of efficacy.

What complications might you expect from the disease or treatment of the disease?

Disease complications include bone thinning and collapse, stress fractures, kyphoscoliosis, limitations in range of motion of affected joints, deformities, and decreased ability to do activities of daily living.

Treatment complications include exacerbation of osteitis, skin manifestations and occult inflammatory bowel disease, organ toxicity, osteoporosis, growth failure, infections and future malignancy.

Are additional laboratory studies available; even some that are not widely available?

Genotyping for PAPA and Majeed syndromes.

How can non-bacterial osteitis syndromes be prevented?

No known prevention.

Genetic counseling critical for Majeed syndrome and DIRA.

Prenatal diagnosis requires identification of disease-causing mutation.

What is the evidence?

El-Shanti, H, Ferguson, PJ. “Chronic Recurrent Multifocal Osteomyelitis”. Lin Orthop Relat Res. vol. 462. 2007. pp. 11

Ferguson, PJ, El-Shanti, HI. “Autoinflammatory bone disorders”. Curr Opin Rheumatol. vol. 19. 2007. pp. 492

Wipff, J, Adamsbaum, C, Kahan, A, Job-Deslandre, C. “Chronic recurrent multifocal osteomyelitis”. Joint Bone Spine. 2011.

Salles, M, Olive, A, Perez-Andres, R, Holgado, S, Matep, L, Riera, E, Tena, X. “The SAPHO syndrome: a clinical and imaging study”. Clin Rheumatol. vol. 30. 2011. pp. 245

Henderson, C, Goldbach-Mansky. “Monogenic autoinflammatory diseases: new insights into clinical aspects and pathogenesis”. Curr Opin Rheumatol. vol. 22. 2010. pp. 567

Colina, M, Govoni, M, Orzincolo, C, Trotta, F. “Clinical and Radiological Evolution of Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis Syndrome: A Single Center Study of 71 Subjects”. Arthritis Rheum. vol. 61. 2009. pp. 813

Tlougan, BE, Podjasek, JO, O’Haver, J, Cordova, KB, Nguyen, XH, Tee, R. “Chronic recurrent Multifocal Osteomyelitis (CRMO) and Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis (SAPHO) Syndrome with Associated Neutrophilic Dermatoses: A Report of Seven Cases and Review of the Literature”. Pediatr Dermatol. vol. 26. 2009. pp. 97

Ferguson, PJ, Chen, S, Tayeh, MK, Ochoa, L, Leal, SM, Pelet, A. “Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome)”. J Med Genet. vol. 42. 2005. pp. 551

Al-Mosawi, ZS, Al-Saad, KK, Ijadi-Maghsoodi, R, El-Shanti, HI, Ferguson, PJ. “A Splice Site Mutation Confirms the Role of LPIN2 in Majeed Syndrome”. Arthritis Rheum. vol. 56. 2007. pp. 960

Reddy, S, Ja, S, Geoffrey, R, Lorier, R, Suchi, M, Broeckel, U. “An Autoinflammatory Disease Due to Homozygous Deletion of the IL1RN Locus”. N Enngl J Med. vol. 360. 2009. pp. 2438

Hurtado-Nedelec, M, Chollet-Martin, S, Chapeton, D, Hugot, J-P, Hayem, G, Gerard, B. “Genetic Susceptibility Factors in a Cohort of 38 Patients with SAPHO Syndrome: A Study of PSTPIP2, NOD2, and LPIN2 Genes”. J Rheumatol. vol. 37. 2010. pp. 401

Aksentijevich, I, Masters, SL, Ferguson, PJ, Dancey, P, Frenkel, J, van Royen-Kerkhoff, A. “An Autoinflammatory Disease with Deficiency of the Interleukin-1-Receptor Antagonist”. N Engl J Med. vol. 360. 2009. pp. 2426

Bodar, EJ, Drenth, JPH, van der Meer, JWM, Simon, A. “Dysregulation of innate immunity: hereditary periodic fever syndromes”. Brit J Haematol. vol. 144. 2009. pp. 279

Masters, SL, Simon, A, Aksentijevich, I, Kastner, DL. “Horror Autoinflammaticus: The Molecular Pathophysiology of Autoinflammatory Disease”. Ann Rev Immunol. vol. 27. 2009. pp. 621

Catalano-Pons, C, Comte, A, Wipff, J, Quartier, P, Faye, A, Gendrel, D. “Clinical outcome in children with chronic recurrent multifocal osteomyelitis”. Rheumatol. vol. 47. 2008. pp. 1397

Eleftheriou, D, Gerschman, T, Sebire, N, Woo, P, Pilkington, CA, Brogan, PA. “Biologic therapy in refractory chronic non-bacterial osteomyelitis of childhood”. Rheumatol. vol. 49. 2010. pp. 505

Galadari, H, Bishop, AG, Venna, SS, Sultan, E, Do, D, Zeltser, R. J Am Acad Dermatol. vol. 61. 2009. pp. 123

Gikas, PD, Islam, L, Aston, W, Tirabosco, R, Saifuddn, A, Briggs, TWR. “Nonbacterial osteitis: a clinical, histopathological, and imaging study with a proposal for protocol-based management of patients with this diagnosis”. J Orthop Sci. vol. 14. 2009. pp. 505

Hospach, T, Langendoerfer, M, von Kalle, T, Maier, J, Dannecker, GE. “Spinal involvement in chronic recurrent multifocal osteomyelitis (CRMO) in childhood and effect of pamidronate”. Eur J Pediatr. vol. 169. 2010. pp. 1105

Ben Abdelghani, K, Dran, DG, Gottenberg, JE, Morel, J, Sibilia, J, Combe, B. “Tumor necrosis factor-alpha blockers in SAPHO syndrome”. J Rheumatol. vol. 37. 2010. pp. 1699

Glaser, RL, Goldbach-Mansky, R. “The Spectrum of Monogenic Autoinflammatory Syndromes: Understanding Disease Mechanisms and Use of Targeted Therapies”. Curr Allergy Asthma Rep. vol. 8. 2008. pp. 288

Ongoing controversies regarding etiology, diagnosis, treatment

Long term treatment with biologics given uncertain future risks, particularly of malignancy, organ toxicity, infections.

Consensus diagnosis and medical management of CRMO and SAPHO.

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