Oral alendronate in pediatric chronic recurrent multifocal osteomyelitis

Chronic recurrent multifocal osteomyelitis (CRMO) primarily affects children and adolescents, and is characterized by episodic sterile osteomyelitis over several years. No definitive treatment is available. Non‐steroidal anti‐inflammatory drugs (NSAID) are common first‐line agents, but provide limited improvement in bone pain and do not affect disease duration. Several agents are utilized in the case of non‐response to NSAID, including corticosteroids, methotrexate, and tumor necrosis factor‐blocking agents. Bisphosphonates are increasingly being used. Most case series involve cyclic i.v. pamidronate, but this restricts the social lives of children and their families. Although oral medication has advantages over cyclic i.v. infusion because it does not require repeated hospital admissions, there have been no reports on treatment with oral bisphosphonates, such as alendronate, in pediatric CRMO patients. This case report describes the use of oral bisphosphonate as an alternative treatment in CRMO patients in whom standard therapy has failed.     

Die chronisch rezidivierende multifokale Osteomyelitis (CRMO) Übersicht und erste Befunde einer genetisch-rheumatologischen Studie

Chronic recurrent multifocal osteomyelitis (CRMO) is a nonbacterial osteomyelitis and most commonly occurs during childhood. Associations with palmoplantar pustulosis (PPP) have been reported in about 20%. Since the etiology of the disease is unknown it is suspected to be an autoimmune osteomyelitis. Own studies [27] demonstrate evidence for a genetic basis of CRMO for the first time. The clinical features, diagnostic procedures and therapeutic options are demonstrated.     

The syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. Report of a new family and a review

A new autosomal recessive syndrome of chronic recurrent multifocal osteomyelitis (CRMO) and congenital dyserythropoietic anaemia (CDA) with microcytosis has recently been described in four children (two sibships) of one consangineous Arab family. In this report, we describe the clinical features and course of the syndrome of CRMO and CDA in two additional patients (one sibship) from another consanguineous Arab family and review the literature. The two patients (brother and sister), the products of a consanguineous marriage, developed the syndrome at an early age of 3 weeks and 2 months respectively. The diagnosis of CRMO was confirmed by radiological and technetium isotope bone scans. Bone marrow studies confirmed the diagnosis of CDA. Peripheral blood films showed hypochromia and microcytosis. The sites involved by CRMO were periarticular, mainly around the elbow, knee, wrist and small joints of the hand. The brother is now 21 years old and the sister 3.5 years old and CRMO is still active with frequent relapses. The brother developed flexion deformities at the age of 13 years. Both patients failed to thrive; weight and height were below the 5th percentile. CONCLUSION: This is the second report of the syndrome of chronic recurrent multifocal osteomyelitis and microcytic congenital dyserythropoietic anaemia, confirming it as a clinical entity, inherited as an autosomal recessive trait. The disease is characterised by an early onset, long clinical course of remissions and relapses, and seems to be different from the sporadic form of chronic recurrent multifocal osteomyelitis.     

Chronic recurrent multifocal osteomyelitis: clinical outcomes after more than five years of follow-up

OBJECTIVE: To determine the clinical outcomes of children with chronic recurrent multifocal osteomyelitis (CRMO). STUDY DESIGN: Inception cohorts of children with CRMO were established at two tertiary pediatric centers. Outcome data were obtained through review of hospital charts, interview and examination of patients, and completion of questionnaires by patients. RESULTS: Of 45 eligible subjects, 23 (51%) were assessed. Median time since diagnosis was 13 years (range, 6-25). At evaluation, 6 (26%) had active disease; 18 (78%) had Health Assessment Questionnaire scores of 0 (no/minimal physical disability), and 5 had scores >0. Some impairment was seen in all domains of measurement of quality-of-life test, especially those concerning nonphysical aspects of health. Six (26%) subjects continued to have pain as a result of CRMO. Associated medical problems included arthritis in 6, sacroiliitis in 3, psoriasis in 5, recurrent pustular rashes in 2, and inflammatory bowel disease in 3. CONCLUSIONS: Long-term clinical outcomes for children with CRMO appear to be generally good, with most subjects having no evidence of disease activity or sequelae. However, a number of subjects had persistent disease and, therefore, remain at risk of physical and psychologic complications. Further research is required to identify patients at risk for persistent disease, and to determine therapies that may prevent morbidity.     

Infliximab is effective in acute but not chronic childhood ulcerative colitis

PURPOSE: The authors report their experience with infliximab in pediatric patients with ulcerative colitis (UC). METHODS: Fourteen patients were reviewed. Group 1 included five patients with newly diagnosed, fulminant colitis refractory to 7 to 10 days of intravenous steroids. Group 2 included four patients with ulcerative colitis in remission off steroid therapy who experienced relapse and were hospitalized with fulminant colitis refractory to intravenous steroids for 7 to 10 days. Group 3 included five patients chronically dependent on steroids with colitis refractory to medical management. All patients were treated on an open-label basis with infliximab infusions of 5 mg/kg/dose at 0, 2, and 6 weeks and every 6 to 8 weeks thereafter. Follow-up was maintained for at least 6 weeks. Clinical status was scored with the Lichtiger Colitis Activity Index (LCAI) at each visit. LCAI >or=10 was considered treatment failure. We defined success as LCAI or=11 before infliximab treatment. All group 1 patients experienced response to infliximab. All but one (75%) patient in group 2 had a response. Only one (20%) group 3 patient had a response to infliximab. CONCLUSION: Infliximab was an effective agent in the treatment of acute UC in our patients. Long-term steroid use and emergency colectomy were avoided. Infliximab was less effective in patients who were dependent on steroids.     

Pyoderma gangrenosum in a six-month-old boy

Pyoderma gangrenosum (PG) is an uncommon, chronic ulcerative condition of the skin that was first described in 1930. It can occur in any age group, but only 4% of the patients are infants or children. An underlying systemic disease is present in approximately 50% of the patients with PG. The most common associations include inflammatory bowel disease, arthritis, lymphoproliferative disorders and chronic recurrent multifocal osteomyelitis (CRMO). PG has been reported in association with CRMO in only a few children whose ages were between 18 months and 12 years. We report a six-month-old boy who was diagnosed as CRMO based on his clinical examination and histological findings. This is the youngest case reported in the literature (under 12 months of age) with PG associated with CRMO.     

Extensive Coronary Aneurysms With Thrombosis in Resistant Kawasaki Disease

Giant coronary artery aneurysms that occur in 0.5 to 1% of patients with Kawasaki disease can be fatal if associated with thrombosis. Some patients may show persistent inflammation and fever despite treatment with repeated doses of intravenous immunoglobulin (IVIG), steroids, and aspirin. This report describes an infant boy with resistant Kawasaki disease who presented with extensive coronary artery involvement and coronary thrombosis. His inflammation was not controlled with multiple doses of IVIG, parenteral and oral steroids, or high-dose aspirin, and he finally needed infliximab, a monoclonal antibody against tumor necrosis factor alpha. The progression of coronary thrombosis was arrested by the platelet glycoprotein 2b/3a receptor blocker, abciximab, during the acute phase of the disease.     

Spinal involvement in chronic recurrent multifocal osteomyelitis (CRMO) in childhood and effect of pamidronate

There are only a few studies that address the frequency and type of spinal involvement in patients with chronic recurrent multifocal osteomyelitis (CRMO) as well as the outcome of these patients treated with pamidronate (PAM). We performed a retrospective study on patients with CRMO and analyzed clinical and pain assessments as well as regional and whole body MRI findings and compared with posttreatment findings. Of 102 children and adolescents with CRMO, 27 (26%) had involvement of the spine. Vertebral deformities were seen in 14 of these 27 patients, scoliosis or kyphosis in 6. After routine whole body MRI, 19 complained of back pain, whereas eight were asymptomatic with spinal lesions detected incidentally. A total of 72 spinal lesions were detected, thoracic vertebrae being the most commonly affected. Seven patients were treated with PAM; all of whom had vertebral deformities and ongoing back pain. Pain resolution was achieved within 3 months of PAM treatment in every case. One patient subsequently developed a pain amplification syndrome. Repeat MRI performed at a mean interval of 13 months revealed partial or complete resolution of vertebral hyperintensities in every patient. Improvement of vertebral height was seen in a total of three vertebrae in two patients. Severe side effects were not observed. In conclusion, we demonstrated that spinal involvement and associated vertebral deformities with or without kyphoscoliosis are not rare in CRMO, and PAM appears to be an effective and safe treatment for this condition. Although controlled studies are urgently needed, the use of PAM for refractory CRMO with extended spinal involvement (vertebral deformities, kyphosis, and scoliosis) should be considered, especially after failing of conventional therapy.     

Recurrent osteitis and Coxiella burnetii: the relation to chronic recurrent multifocal osteomyelitis]

Chronic recurrent multifocal osteomyelitis (CRMO) is a disorder of suspected--but unproved-infectious etiology. OBSERVATION: A girl presented with a typical CRMO involving successively the left fibula, radius, humerus and the right carpus. A Coxiella burnetii infection was indicated during the first attack. Two recurrences occurred in spite of suitable antibiotic treatment and with negative infectious investigation. Two months after stopping antibiotic treatment, a new recurrence associated with antibodies increase and positive bone culture occurred. CONCLUSION: Coxiella burnetii can initiate a CRMO. The mechanism involved is probably a delayed hypersensitivity. CRMO would therefore be the first type of reactive osteitis.     

Chronic recurrent multifocal osteomyelitis with MR correlation: A case report

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare disorder of unknown etiology. The main characteristics on plain X-rays are a lytic destruction in the metaphyseal region of the long bones followed by progressive sclerosis. The symmetrical pattern and the frequent involvement of the sternoclavicular joints and vertebrae are typical. An association with palmoplantar pustulosis has also been described. Laboratory findings are nonspecific. Although MRI is not necessary to make the diagnosis of chronic osteomyelitis, it is useful in assessing the extent and the evolution of the lesions. CRMO of the tibial and fibular bones is described in a 14-year-old girl, who suffered from pain and soft tissue swelling in both ankles. Initial plain X-rays and laboratory findings were normal. After relapsing clinically, progressive sclerosis of both fibular bones occurred. Lytic lesions in the left tibia and both fibular bones were visible. Scintigraphic examination showed pathologic tracer accumulation in both legs. The diagnosis of CRMO was suggested based on CT and MRI findings. CRMO was confirmed after curettage and bone biopsy. Histopathological findings were consistent with active chronic osteomyelitis.     

A prospective study of the efficacy and tolerance of a chimeric antibody to tumor necrosis factors (remicade) in severe pediatric crohn disease

OBJECTIVES: To evaluate the efficacy and toxicity of infliximab in children with severe Crohn disease (CD), the authors prospectively monitored 21 children aged 15 +/- 2 years with severe CD who they treated with infliximab (5 mg/kg) on days 0, 15, and 45. One patient received only one injection. Eighteen patients were corticosteroid dependent, and 6 were receiving parenteral nutrition. Three patients were corticoid resistant (1 mg/kg/d >15 days). Sixteen had perianal disease. RESULTS: The Harvey-Bradshaw index (HB) decreased from 8 +/- 3 on day 0 to 1 +/- 2 on day 45 (P = 0.001). The inflammation factors decreased (P = 0.001), and albumin increased (P = 0.002). Nineteen children were in complete remission (HB < 4) on day 45, and 2 had improved (HB = -6 points). Tumor necrosis factor-alpha (TNFalpha) in the stools (n = 16) decreased (P = 0.04). All perianal fistulas (n = 12) were closed by day 90. Fourteen of 21 patients had stopped taking steroids at 3 months, and all had stopped parenteral nutrition. Growth velocity was significantly greater after infliximab administration (Z score, +0.5) than before (-0.45; P = 0.004). Nineteen of 21 patients had relapsed (90%) at 1 year despite continued immunosuppressors. Seven had surgery because of an uncontrolled relapse ( 5), stenosis ( 1), or fistula ( 1). Six patients developed antinuclear antibodies (1/40-1/640e), and two had anti-DNA antibodies. Epstein-Barr virus (EBV) polymerase chain reaction (PCR) values increased (>100-fold) in eight patients. One child developed an anaphylactic reaction to the medication, and one had a catheter-related sepsis. CONCLUSION: Infliximab produces spectacular results for children with severe CD and is well tolerated. However, its effect is transitory for many (90%), with frequent relapses despite continued immunosuppressors. Long-term management with infliximab should be tested despite its worrying side effects.     

Infliximab treatment for refractory Kawasaki syndrome

OBJECTIVE: To evaluate the use of tumor necrosis factor (TNF)-alpha blockade for treatment of patients with Kawasaki syndrome (KS) who fail to become afebrile or who experience persistent arthritis after treatment with intravenous gamma globulin (IVIG) and high-dose aspirin. STUDY DESIGN: Cases were retrospectively collected from clinicians throughout the United States who had used infliximab, a chimeric murine/human immunoglobulin (Ig)G1 monoclonal antibody that binds specifically to human TNF-alpha-1, for patients with KS who had either persistent arthritis or persistent or recrudescent fever > or =48 hours following infusion of 2 g/kg of IVIG. RESULTS: Response to therapy with cessation of fever occurred in 13 of 16 patients. C-reactive protein (CRP) level was elevated in all but one patient before infliximab infusion, and the level was lower following infusion in all 10 patients in whom it was re-measured within 48 hours of treatment. There were no infusion reactions to infliximab and no complications attributed to infliximab administration in any of the patients. CONCLUSION: The success of TNF-alpha blockade in this small series of patients suggests a central role of TNF-alpha in KS pathogenesis. Controlled, randomized clinical trials are warranted to determine the role of anti-TNF-alpha therapy in KS.     

Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease

Hepatosplenic T cell lymphoma (HSTCL) are rare cancers ( approximately 100 published cases worldwide) and comprise 5% of peripheral T cell lymphomas. As of October 5, 2006, the FDA's Adverse Event Reporting System has received 8 cases of HSTCL in young patients using infliximab, a tumor necrosis factor-alpha blocking agent, to treat inflammatory bowel disease (6 of the 8 cases had a fatal outcome). All 8 patients were receiving concomitant immunosuppressant therapy (eg, azathioprine, prednisone). It has not been established that infliximab had an exclusive or primary role in the pathogenesis of these HSTCL cases; however, it appears that patients using this product may be at greater risk for developing this rare lymphoma.     

Chronic recurrent multifocal osteomyelitis and tumoral calcinosis--is there an association?

BACKGROUND: Idiopathic tumorous calcinosis is a rare benign disease of the periarticular tissue near large joints. Deposits of hydroxyapatite in single or multiple pseudocysts lead to consecutive pain or complaints by attaching the surrounding tissues. The etiology of this disease is not definitively clear. CASE REPORT: We describe the case of an 11-year-old turkish girl with a well known chronic recurrent multifocal osteomyelitis (CRMO) and hyperphosphataemia. Furthermore, she developed a tumorous calcinosis around the left hip, which recurred after surgery, and around the ankle joint. CONCLUSIONS: CRMO and tumorous calcinosis can be associated diseases. The development of tumorous calcinosis in patients with CRMO and hyperphosphataemia should be excluded.     

Chronic recurrent multifocal osteomyelitis of the mandible. A case report]

Chronic recurrent multifocal osteomyelitis (CRMO) is a disorder rarely localized to the lower jaw. CASE REPORT: A fourteen-year-old boy complained of a swollen of his lower jaw. After a CT Scan, a bone biopsy was performed and yielded S. oralis against which an adapted intravenous antibiotherapy was administered without efficacy. The absence of malignant process and the revelation of an other focus of fixation at the Tc bone scan localized on humerus called to mind the diagnosis of CRMO. CONCLUSION: The diagnosis of this disease is difficult and based on a number of concording arguments:clinical and radiological signs of osteomyelitis, multifocal presentation, recurrent relapses and remissions, inaction of antibiotics, elimination of the other differential diagnosis, in particular the infectious osteitis.     

Dramatic pain relief and resolution of bone inflammation following pamidronate in 9 pediatric patients with persistent chronic recurrent multifocal osteomyelitis (CRMO)

Background  

Chronic recurrent multifocal osteomyelitis (CRMO) is an inflammatory, non-infectious osteopathy that affects predominantly patients ≤ 18 years of age. There is no uniformly effective treatment. Our objective is to describe clinical, magnetic resonance imaging (MRI), and bone resorption response to intravenous pamidronate in pediatric CRMO.     

Chronic recurrent multifocal osteomyelitis – report of eight patients

The authors undertook a retrospective review of the clinical records and radiologic findings of eight children with chronic, recurrent multifocal osteomyelitis (CRMO). This disease is a recognized clinicopathologic entity with typical radiographic findings, mostly in the metaphyses of the long bones. The diagnosis is one of exclusion without pathognomonic findings. The patients were treated with non-steroidal anti-inflammatory drugs. There was no evidence of altered bone growth or abnormal joint development. It is concluded that CRMO is a distinct clinical entity that is different from acute or subacute bacterial osteomyelitis. Recognition of this condition is important to avoid treatment with antibiotics and repeated operations. Accepted: 8 April 1998     

Changing pattern of osteomyelitis in infants and children

A retrospective analysis of 332 children with osteomyelitis (OM), managed from 1966 to 1996, was undertaken to evaluate etiology, clinical course and treatment results. In 64% of all patients positive bacterial cultures were obtained, Staphylococcus aureus, streptococci, pneumococci, and Haemophilus influenzae were the most frequently cultured pathogens. In two-thirds of the cases long bones (femur, tibia, humerus) were affected. Osteoarthritis or suppurative arthritis was evident in 27%; 32 of 170 (19%) re-evaluated patients had moderate or severe sequelae. Risk factors for an unfavorable course were the onset of disease in early infancy, suppurative arthritis, and an affected epiphysis. Suppurative arthritis, in particular, needs early evacuation to prevent sequelae. In recent years we observed an increasing number of patients presenting with atypical forms of OM. Since 1989 10 patients were considered to have chronic recurrent multifocal OM (CRMO). In 6 of them the clavicle was involved; their ages ranged from 3 to 14 years. The erythrocyte sedimentation rate was elevated (median 48, range 9–110 mm), while other inflammatory parameters like C-reactive protein (median 9, range <5–85 mg/l) or leucocyte count were slightly elevated or normal. Histopathology was stage-dependent, with a predominance of lymphoplasmacellular infiltration. A nonbacterial origin of CRMO is probable but not proven. Histopathology is not suitable for differentiation between bacterial and nonbacterial forms of bone inflammation. Accepted: 5 January 1999     

Chronic recurrent osteomyelitis with clavicular involvement in children: diagnostic value of different imaging techniques and therapy with non-steroidal anti-inflammatory drugs

Chronic recurrent, uni- or multifocal osteomyelitis (CRMO), an inflammatory disorder of unknown origin, involves mk:/night/arul/4310946m.3dultiple osseous sites and may affect the clavicle. We report on 6 children with clavicular involvement out of 11 children suffering from CRMO. The major clinical symptoms were local swelling and pain. Five children had hyperostosis of the clavicle and synovitis of adjacent joints. Histology showed chronic osteomyelitis with a predominance of lymphocytes in the inflammatory infiltrates. Cultures of biopsy tissue specimens were sterile. The patients were followed for at least 3.5 years. Three patients had up to six relapses. The most effective diagnostic tools to define CRMO were standard X-ray and bone scan in combination with biopsy and cultures. In our patients CT and MRI were misleading as they suggested the presence of malignancy. However, the sensitivity of MRI to detect involvement of bone, adjacent joints and soft tissues were better in comparison to X-ray or bone scan. Non-steroidal anti-inflammatory drugs were effective in reducing pain, swelling and limitation of motion. Reconstructive surgery was not indicated in any case. The long-term outcome of growth and function of affected bones was excellent. Conclusion Diagnosis of chronic osteomyelitis of the clavicle should be made by history and physical examination and be confirmed by standard X-ray, bone scan and open biopsy. In contrast MRI and CT can provide data on the involvement of adjacent joints, soft tissue and muscles especially in the early process of disease, but do not add information relevant to the patient's management. Treatment with non-steroidal anti-inflammatory drugs is rapidly beneficial in most patients. Received: 24 January 1997 / Accepted: 26 May 1997