Abraham Gedalia

Etanercept in children with polyarticular juvenile rheumatoid arthritis

BACKGROUND We evaluated the safety and efficacy of etanercept, a soluble tumor necrosis factor receptor (p75):Fc fusion protein, in children with polyarticular juvenile rheumatoid arthritis who did not tolerate or had an inadequate response to methotrexate. METHODS Patients 4 to 17 years old received 0.4 mg of etanercept per kilogram of body weight subcutaneously twice weekly for up to three months in the initial, open-label part of a multicenter trial. Those who responded to treatment then entered a double-blind study and were randomly assigned to receive either placebo or etanercept for four months or until a flare of the disease occurred. A response was defined as an improvement of 30 percent or more in at least three of six indicators of disease activity, with no more than one indicator worsening by more than 30 percent. RESULTS At the end of the open-label study, 51 of the 69 patients (74 percent) had had responses to etanercept treatment. In the double-blind study, 21 of the 26 patients who received placebo (81 percent) withdrew because of disease flare, as compared with 7 of the 25 patients who received etanercept (28 percent) (P=0.003). The median time to disease flare with placebo was 28 days, as compared with more than 116 days with etanercept (P<0.001). In the double-blind study, there were no significant differences between the two treatment groups in the frequency of adverse events. CONCLUSIONS Treatment with etanercept leads to significant improvement in patients with active polyarticular juvenile rheumatoid arthritis. Etanercept is well tolerated by pediatric patients.

Childhood sarcoidosis: A rare but fascinating disorder

Childhood sarcoidosis is a rare multisystemic granulomatous disorder of unknown etiology. In the pediatric series reported from the southeastern United States, sarcoidosis had a higher incidence among African Americans. Most reported childhood cases have occurred in patients aged 13–15 years. Macrophages bearing an increased expression of major histocompatibility class (MHC) II molecules most likely initiate the inflammatory response of sarcoidosis by presenting an unidentified antigen to CD4+ Th (helper-inducer) lymphocytes. A persistent, poorly degradable antigen driven cell-mediated immune response leads to a cytokine cascade, to granuloma formation, and eventually to fibrosis. Frequently observed immunologic features include depression of cutaneous delayed-type hypersensitivity and a heightened helper T cell type 1 (Th1) immune response at sites of disease. Circulating immune complexes, along with signs of B cell hyperactivity, may also be found. The clinical presentation can vary greatly depending upon the organs involved and age of the patient. Two distinct forms of sarcoidosis exist in children. Older children usually present with a multisystem disease similar to the adult manifestations, with frequent hilar lymphadenopathy and pulmonary infiltrations. Early-onset sarcoidosis is a unique form of the disease characterized by the triad of rash, uveitis, and arthritis in children presenting before four years of age. The diagnosis of sarcoidosis is confirmed by demonstrating a typical noncaseating granuloma on a biopsy specimen. Other granulmatous diseases should be reasonably excluded. The current therapy of choice for sarcoidosis in children with multisystem involvement is oral corticosteroids. Methotrexate given orally in low doses has been effective, safe and steroid sparing in some patients. Alternative immunosuppressive agents, such as azathioprine, cyclophosphamide, chlorambucil, and cyclosporine, have been tried in adult cases of sarcoidosis with questionable efficacy. The high toxicity profile of these agents, including an increased risk of lymphoproliferative disorders and carcinomas, has limited their use to patients with severe disease refractory to other agents. Successful steroid sparing treatment with mycophenolate mofetil was described in an adolescent with renal-limited sarcoidosis complicated by renal failure. Novel treatment strategies for sarcoidosis have been developed including the use of TNF-alpha inhibitors, such as infliximab. The long-term course and prognosis is not well established in childhood sarcoidosis, but it appears to be poorer in early-onset disease.

Pathophysiology and clinical spectrum of infections in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an inflammatory and multisystemic autoimmune disorder characterized by an uncontrolled autoreactivity of B and T lymphocytes leading to the production of autoantibodies against self-directed antigens and tissue destruction. Environmental factors, such as infections, which are an important cause of morbidity and mortality, are potential triggers of the disease. This article discusses bacterial, viral, and opportunistic microorganism infections in SLE, and the role of immunosuppressive therapy and immunodeficiencies in the disease.

Sarcoidosis: A Pediatric Perspective

Childhood sarcoidosis is a rare multisystemic granulomatous disease of unknown etiology. The clinical presentation can vary greatly depending upon the organs involved. Two distinct forms of sarcoidosis exist in children. Older children usually present with a multisystem disease similar to the adult manifestation, with frequent hilar lymphadenopathy and pulmonary infiltration. Early-onset childhood sarcoidosis is a unique form of the disease characterized by the triad of rash, uveitis, and arthritis in patients presenting before age 4 years. The diagnosis of sarcoidosis is confirmed by demonstrating a typical noncaseating granuloma on a biopsy specimen. The current therapy of choice for childhood sarcoidosis with multisystem involvement is corticosteroids. Methotrexate given orally in low doses is effective and safe and has steroid-sparing properties.

Low-dose Methotrexate in the Treatment of Severe Juvenile Rheumatoid Arthritis and Sarcoid Iritis

OBJECTIVE To assess the efficacy of low-dose oral methotrexate (MTX) therapy for children with severe iritis. METHODS MTX in a weekly dose of 7.25 to 12.5 mg/m2 was administered orally to four patients (two with juvenile rheumatoid arthritis [JRA] and two with sarcoidosis) with severe iritis not adequately controlled by topical and systemic corticosteroid therapy. The treatment was initiated with half of the total dose and increased every 2 weeks until the final dose was reached. Iritis was graded from 0 to +4 according to the density of cells in the anterior chamber of the eye. RESULTS There were three girls and one boy with a mean age of 10.5 years. Two patients were African American and two were Caucasian. The mean age at onset of iritis was 6 years. The mean duration of MTX therapy was 28.8 months. Significant improvement was noted in two of the four patients in ocular inflammation, demonstrated by reduction of cell density from +4 to +1. Two patients had a mild improvement of the iritis. However, corticosteroids were significantly reduced in all patients. One patient was completely off steroids within 30 months of MTX therapy. In the remaining three cases, the steroid dose was successfully tapered from 0.82 mg/kg/d to 0.15 mg/kg/d (mean doses) within a mean duration of 20 months. No side effects were observed with MTX therapy. CONCLUSION Low-dose MTX therapy was effective and safe, and displayed steroid-sparing properties in four children with severe iritis.

SEPTIC ARTHRITIS IN CHILDREN

Because of its seriousness, septic arthritis should be considered early in the differential diagnosis of any child presenting with joint inflammation. Physicians who care for children should be aware of the early signs and symptoms of septic arthritis and be aggressive about establishing the diagnosis so that treatment is not delayed. Early orthopedic consultation and a low threshold for performing arthrocentesis are prudent. Prolonged and appropriate antimicrobial therapy is warranted to achieve optimal results.

Antinuclear antibody (ANA) and ANA profile tests in children with autoimmune disorders: a retrospective study.

Abstract: The study objective was to determine the clinical value of positive antinuclear antibody (ANA) and ANA profile tests in children with autoimmune disorders. A retrospective chart review was carried out of all patients under 18 years of age with a positive ANA test (HEp-2 cell substrate, titre ≥1:40) and ANA profile (ELISA) referred to the paediatric rheumatology service at the authors” institution between 1992 and 1996. Of 245 children with a positive ANA test, 134 (55%) had an autoimmune disease, including juvenile rheumatoid arthritis (n = 49), systemic lupus erythematosus (SLE) (n = 40) and others (n = 45). The remaining 111 patients did not have identifiable autoimmune diseases. Patients with autoimmune disorders had significantly higher ANA titres of ≥1:160 (χ2= 16, P<0.0001). In addition, of the 245 patients with a positive ANA test, 86 had an ANA profile performed; this was positive in 32 and negative in 54. All 32 patients with a positive ANA profile (100%) had an autoimmune disorder, compared to 22 ( 41%) of 54 with a negative ANA profile who had autoimmune disorders. Of 22 SLE patients with a positive ANA profile, 16 (73%) had positive anti-dsDNA and 15 (68%) had positive anti-Sm and positive anti-RNP. A positive ANA profile correlated strongly with an ANA titre ≥1:640 (χ2= 5.7 , P<0.02). The study demonstrated that only 55% of children with a positive ANA test had a definitive diagnosis of autoimmune disorder. These children tend to have higher ANA titres of ≥1:160. However, a positive ANA profile was strongly correlated with an ANA titre ≥1:640 and highly indicative of an autoimmune disorder (100%). We suggest that in order to reduce cost, an ANA profile should not be performed on all patients with positive ANA, but reserved for those with an ANA titre of ≥1:640 and/or those with a high clinical index of suspicion for autoimmune disorder, especially SLE.

Case Report: Steroid Sparing Effect of Intravenous Gamma Globulin in a Child With Necrotizing Vasculitis

This article reports the case of a boy aged 2 years 6 months, who had fever, arthritis, and necrotizing cutaneous vasculitis. Evaluation revealed no evidence of direct infectious causes. However, high anti-streptolysin and streptozyme titers during the acute phase support the possibility that streptococcal infection played an important role in the pathogenesis of this disease. The patients condition improved significantly with the administration of prednisone. However, several attempts to diminish the prednisone dose resulted in relapses. Subsequently, the prednisone was successfully tapered and discontinued after intravenous gamma globulin administration. It is recommended that intravenous gamma globulin should be considered before immunosuppressive therapy in the treatment of necrotizing vasculitis.

Membranous nephropathy associated with childhood sarcoidosis

Abstract Sarcoidosis is a chronic multisytemic granulomatous disease of unknown etiology. It is relatively rare in children. Renal involvement in sarcoidosis is described less commonly than other organ involvement such as pulmonary, eye, musculoskeletal, and skin. We report a 13-year-old girl with sarcoidosis and nephrotic syndrome. Renal biopsy showed findings of membranous nephropathy. She received intravenous pulse methylprednisolone and oral cyclophosphamide with resolution of the symptoms of fever and edema, and improvement of the proteinuria. Her condition is stable with no progression of her renal disease. To the best of our knowledge, this is the first report of membranous nephropathy associated with childhood sarcoidosis.

Kawasaki disease: pathophysiology, clinical manifestations, and management.

Kawasaki Disease, a systemic vasculitis of unknown origin with specific predilection for the coronary arteries, is the most common cause of childhood-acquired heart disease in western countries. Despite its world-wide incidence, the pathophysiology of this enigmatic disease is still under investigation. Diagnosis is made on a clinical basis, with supportive laboratory evidence and imaging. Once identified, timely initiation of treatment is imperative in order to quell the inflammatory response and decrease the incidence of long-term sequelae, specifically coronary artery aneurysms. Finally, longitudinal follow-up should be implemented based on risk stratification and individualized to each patient.