Qingping Yao

Periostitis and hypertrophic pulmonary osteoarthropathy: report of 2 cases and review of the literature.

OBJECTIVES To demonstrate the clinical spectrum of hypertrophic osteoarthropathy (HOA). METHODS We report 2 cases of HOA and performed a computer-assisted search of Medline/PubMed for the medical literature from 1960 to June 2008 using the keywords HOA, periostitis, and clubbing. These were also combined with the text words cancer, rheumatic disease, etiology, pathogenesis, hypothesis, transplant, and treatment. Only the English language literature, with pertinent information, was included. RESULTS Our 2 cases include 1 HOA case with clubbing, in a patient with a right to left shunt from cryptogenic cirrhosis and interstitial lung disease, and 1 HOA case without apparent clubbing, in a patient with chronic lung transplant rejection secondary to tobacco smoking and related emphysema. Review of the literature has shown that HOA is associated with a wide variety of disorders, approximately 80% are found with primary or metastatic pulmonary malignancies. Various rheumatic diseases, such as systemic vasculitis, can also be associated with HOA. With respect to the pathogenesis, vascular endothelial growth factor, platelet-derived growth factor, and platelets may play crucial roles. Therapeutically, bisphosphonates, such as pamidronade or octreotide, may be tried to relieve symptoms in refractory cases. CONCLUSIONS HOA, especially periostitis without clubbing, may go unrecognized. Involvement of vascular endothelial growth factor, platelet-derived growth factor, and platelets in the pathogenesis of HOA has been postulated and supported by recent data. HOA may present as a partial syndrome without clubbing and about 20% of cases have HOA without detectable malignancy. One of our cases represents the first report of the association of HOA with lung transplantation.

A new category of autoinflammatory disease associated with NOD2 gene mutations

IntroductionAutoinflammatory diseases are characterized by seemingly unprovoked episodes of inflammation, without high titers of autoantibodies or antigen-specific T cells, and derive from genetic variants of the innate immune system. This study characterized a cohort of patients with similar phenotypes and nucleotide oligomerization domain 2 (NOD2) gene mutations.MethodsDiagnostically challenging patients with the following clinical and genetic characteristics were prospectively studied between January 2009 and April 2011: periodic fever, dermatitis, polyarthritis, serositis, negative serum autoantibodies and additional positive NOD2 IVS8+158 gene mutation. Genetic testing for gene mutations of NOD2, tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS) and familial Mediterranean fever (FMF) was performed.ResultsAll seven patients with the disease were Caucasians, with four being male. The mean age at disease onset was 40.7 years and disease duration was 3.2 years. These patients characteristically presented with periodic fever, dermatitis and inflammatory polyarthritis. There were gastrointestinal symptoms in three patients, granulomas of the skin and gut in two, and recurrent chest pain in two, with one having pleuritis and pericarditis. Three patients had sicca-like symptoms. Five patients had increased acute phase reactants. All seven patients had negative tests for autoantibodies but carried the NOD2 gene mutation IVS8+158 with four having concurrent R702W mutation.ConclusionsOur cohort may represent a new disease category of autoinflammatory disease with characteristic clinical phenotypes and genotypes. It may somewhat resemble pediatric Blaus syndrome.

Treatment of hypertrophic osteoarthropathy with zoledronic acid: case report and review of the literature.

OBJECTIVES Zoledronic acid (ZA) is rarely used to manage hypertrophic osteoarthropathy (HOA). We report our experience with ZA treatment of a patient with HOA and sarcoidosis who had also undergone lung transplant. We also conducted a literature review of the usefulness of bisphosphonates in HOA. METHODS We performed a PubMed literature search using keywords HOA, periostitis, bisphosphonate, ZA, sarcoidosis, and lung transplant. A PRISMA flow diagram is presented to depict the data collection process, and a case is reported. RESULTS A 62-year-old woman with bilateral lung transplant as a result of severe pulmonary sarcoidosis developed severe limb pain and inflammatory polyarthritis. HOA was diagnosed in the presence of periostitis with the symptoms. Failure of the refractory bone and joint pain to respond to low doses of prednisone, tramadol, or even pamidronate infusion prompted a trial of a single dose of intravenous ZA. Surprisingly, the pain completely resolved without recurrence. A total of 12 cases of HOA treated with bisphosphonates were retrieved from the literature and reviewed. CONCLUSIONS Bisphosphonates are generally effective therapy for HOA-related pain. ZA may be even more efficacious and longer lasting than pamidronate for management of the bone and joint pain associated with HOA irrespective of the underlying disorders.

Dermatitis as a characteristic phenotype of a new autoinflammatory disease associated with NOD2 mutations

OBJECTIVES We sought to characterize a new category of autoinflammatory disease associated with nucleotide-binding oligomerization domain 2 (NOD2) gene mutations. METHODS A total of 22 patients were identified, inclusive of those reported previously. All had autoinflammatory phenotypes and NOD2 gene mutations that were prospectively studied between January 2009 and February 2012. RESULTS All 22 patients were non-Jewish whites (13 women and 9 men). The mean age at diagnosis was 40.1 years (range 17-72), with a mean disease duration of 4.7 years (range 1-13). Three female patients were siblings. Common clinical features were weight loss (13/22), episodic self-limiting fever (13/22), dermatitis (19/22), and inflammatory polyarthritis/polyarthralgia (20/22). Gastrointestinal symptoms occurred in 13 patients, sicca-like symptoms in 9, and recurrent chest pain in 5. All patients carried the NOD2 gene mutations, with the intervening sequence 8(+158) variant in 21 and the R702W variant in 8. LIMITATIONS The NOD2 allelic frequency may need to be examined in a larger population with systemic autoimmune diseases. CONCLUSIONS The characteristic clinical phenotype, notably dermatitis, coupled with certain NOD2 variants constitutes a new autoinflammatory disease entity, which we have named as NOD2-associated autoinflammatory disease.

Systemic lupus erythematosus with sjögren syndrome compared to systemic lupus erythematosus alone: A meta-analysis

ObjectivesThis study aimed to compare the difference of the clinical and laboratory features of the patients between the combined systemic lupus erythematosus (SLE) and Sjögren syndrome (SLE-SS) and SLE only. Materials and MethodsA systematic literature search was performed to identify the articles as to SLE with SS between 1970 and May 2011. The demographics, pertinent clinical, and laboratory data were extracted from 6 publications, and a meta-analysis was performed. The pooled odds ratios and 95% confidence interval were computed for the variability of these parameters between SLE-SS and SLE. ResultsA total of 6 studies were included, consisting of 2489 patients with SLE and 444 with SLE-SS, and the estimated prevalence of the latter was 17.8%. Patients with SLE-SS were older and more often had associated oral ulcers and arthritis. In contrast, proteinuria (odds ratio = 1.77; 95% confidence interval, 1.39–2.25; P < 0.0001) was more common in SLE alone than SLE-SS, and central nervous system involvement tended to be more common. Anti–double-stranded DNA antibodies were equally prevalent in both groups. Anti–SSA/Ro and anti–SSB/La antibodies were more frequent, and anti-Sm and anti-cardiolipin antibodies were less prevalent in SLE-SS than SLE alone. ConclusionsThere are significant variances in certain clinical and laboratory aspects between SLE-SS and SLE. This combined disease of SLE-SS has distinct features with relatively less major internal organ involvement but has more specific autoantibody profile and favorable clinical outcome.

Macrophage activation syndrome complicating adult onset Still’s disease: A single center case series and comparison with literature

OBJECTIVES Macrophage activation syndrome (MAS) is a life-threatening condition that can complicate adult onset Stills disease (AOSD). Due to its rarity, there is no clear consensus concerning treatment recommendations and outcomes. We studied the clinical manifestations and outcomes of a relatively large cohort of patients with MAS and AOSD, and compared the data with the literature reports. METHODS We performed a retrospective review of 7 adult patients with MAS complicating AOSD at the Cleveland Clinic (CCF) over 7 years. All patients underwent bone marrow biopsies. Through MEDLINE and PubMed literature searches, we identified 48 cases of MAS/AOSD. We compared the data of the CCF and literature cohorts. RESULTS We identified 7 patients with MAS complicating AOSD (6 females and 1 males) for our CCF cohort, with 4 cases simultaneously presenting with MAS and AOSD. The mean age at diagnosis of MAS was 41.9 ± 20.2 years and mean follow-up time was 18.6 ± 16.0 months. All patients had fever, arthralgias, and typical rash; 6 had leukocytosis, 4 had sore throat, and 3 had lymphadenopathy. These patients with AOSD also had MAS, with renal insufficiency and disseminated intravascular coagulation in 4, lung involvement in 3, and serositis and shock in 2. There was significant hepatic dysfunction in all patients and 6 had bi-cytopenias. At onset of MAS, all 7 patients had active AOSD. In addition to systemic glucocorticoids, 5 patients received anakinra, with 3 patients receiving combination therapy with cyclosporine. We also identified 48 cases (35 females and 13 males) for the literature cohort with the mean age at diagnosis of MAS of 40.2 ± 16.0 years and mean follow-up time of 17.5 ± 32.3 months. While the 2 cohorts were similar clinically, in the CCF cohort, more patients had renal insufficiency (p < 0.001), higher soluble IL-2 receptor level (p = 0.01), and lower ESR (p = 0.02) as compared with the literature cohort. All of our patients survived with a better outcome than the literature cohort. CONCLUSION MAS can be a serious complication of active AOSD. Our study of a relatively large cohort in conjunction with literature suggests that prompt recognition and treatment with early addition of anakinra, systemic glucocorticoids, and cyclosporine as a triple regimen may improve clinical outcomes.

NOD2-associated autoinflammatory disease: a large cohort study

OBJECTIVE The aims of the study were to characterize the genotype profile of nucleotide-binding oligomerization domain containing 2 (NOD2)-associated autoinflammatory disease (NAID) and to report an extended study of the disease. METHODS A total of 143 adult patients presented with clinical phenotypes suspicious for NAID and all were genotyped for NOD2 sequence variants. The genotype frequencies were compared between our cohort and literature reports. These patients were divided into two groups predicated on the presence or absence of NOD2 variants. RESULTS Of the 143 patients, 67 (47%) carry NOD2 variants; the genotype frequency was significantly higher among our cohort than in the historical healthy controls. Fifty-four of the 67 carriers of NOD2 variants had NAID, which has a genotype profile that is somewhat different from Crohns disease. All NAID patients were non-Jewish whites and 69% were women. The median age at onset was 33.5 years and the median disease duration at diagnosis was 10.7 years. NAID was sporadic in 93% of cases. Patients typically presented with periodic fever, dermatitis and inflammatory arthritis. As compared with the NOD2 variant-negative patients, the skin disease more typically manifested as erythematous patches or plaques on the trunk. Oligopolyarthritis/-arthralgia was common, with characteristic distal lower extremity swelling. Associated NOD2 variants were primarily IVS8(+158) or compound IVS8(+158) and R702W. CONCLUSION This study underscores the NOD2 genotype association with NAID, which is a genetically complex multisystem disorder. It differs phenotypically from Crohns disease with a distinct genotype profile. This disease may be more common than initially thought.

Mucocutaneous Leishmaniasis Masquerading as Wegener Granulomatosis

A 43-year-old Brazilian female presented in 2001 with nasal stuffiness and sinusitis. A biopsy was consistent with limited Wegeners granulomatosis although antineutrophil cytoplasmic antibodies were negative. Her nasal inflammation progressed despite trials of prednisone, methotrexate, and azathioprine. A septal perforation developed and a repeat biopsy showed granulomatous inflammation. In 2006 the patient was referred to Division of Rheumatology, University of California, Los Angeles. The nose was grossly erythematous and a magnetic resonance imaging revealed nasal destruction and sinusitis. Palatine biopsies showed chronic inflammation. Cyclophosphamide at 150 mg/d resulted in markedly improved mucocutaneous lesions. The patient developed a leg and arm rash in 2007. A skin biopsy was positive for Leishmania braziliensis. The cyclophosphamide was discontinued and amphotericin B was initiated with transient benefit. Remission was achieved with pentavalent antimony. Despite multiple nasopharyngeal biopsies, for a 6-year span, mucocutaneous leishmaniasis masqueraded as Wegeners granulomatosis. Cyclophosphamide not only resulted in clinical improvement, due to reduced inflammatory response, but also allowed widespread cutaneous dissemination.

RS3PE: Clinical and Research Development

Remitting seronegative symmetrical synovitis with pitting edema or RS3PE is a rare elderly-onset rheumatic syndrome. Although there are overlapping clinical manifestations between RS3PE, elderly-onset rheumatoid arthritis, and polymyalgia rheumatica, RS3PE has distinct characteristics. RS3PE can be associated with neoplasia and various rheumatic conditions, suggesting that it may be heterogeneous, and is considered as a paraneoplastic rheumatic disease. The pathogenesis of RS3PE may involve vascular endothelial growth factor and infection in RS3PE based upon limited data. Patients with RS3PE without concomitant malignancy respond well to small doses of glucocorticoids and carry good prognosis.

Autoimmune features are associated with chronic antibiotic-refractory pouchitis.

Background:Chronic antibiotic-refractory pouchitis (CARP) occurs more frequently in patients with ileal pouch–anal anastomosis (IPAA) with concomitant autoimmune disorders. The aim of this study was to assess the overlap between dysregulated immune features in patients with IPAA and their association with CARP. Methods:We identified 150 symptomatic patients with IPAA who met inclusion criteria, including measurement of select autoimmune serology. Demographic and clinical variables were compared between patients with and without CARP. Results:Autoimmune thyroid disease was more frequent among patients with CARP. The frequency of primary sclerosing cholangitis (16.7% versus 5.3%; P = 0.04) and serum positivity for microsomal antibody (25% versus 6.1%, P = 0.003) were significantly greater in patients with CARP compared with non-CARP patients, respectively. Increased tissue infiltration by IgG4-expressing plasma cells was detected in 17 of 31 patients (54.8%) in the CARP group as compared with 10/67 (14.9%) in the non-CARP group (P = 0.0001). Forty-seven percent of patients in the CARP group versus 22.8% in the non-CARP group had at least 2 immune features (P = 0.019). Among patients with IgG4 histology, 87% of patients in the CARP group versus 60% in the non-CARP group had at least 1 immune marker (P = 0.004). On multivariate analysis, microsomal antibody expression (odds ratio, 6.8; 95% confidence interval, 1.3–42.6; P = 0.02) and increased IgG4-expressing plasma cells tissue infiltration (odds ratio, 9.6; 95% confidence interval, 3.2–32.6, P = 0.0001) were risk factors for CARP. Conclusions:There is marked overlap of certain immune markers in patients with pouch dysfunction, especially those with CARP. Microsomal antibody expression and elevated IgG4-positive plasma cell infiltration were independent risk factors for CARP.