Cytologic and histologic findings of iron pill‐induced injury of the lower respiratory tract

In the airways, iron pill‐induced mucosal injury is uncommon and can lead to necrosis and stricture of the respiratory tracts. The process is characterized by mucosal ulceration with deposition of crystalline iron particles, and the diagnosis is usually made on tissue biopsies. We report a case of iron‐sulfate‐induced mucosal injury in the bronchial washing and biopsy of a patient receiving therapeutic oral iron supplementation with no known aspiration event. Clinically, the patient presented with hemoptysis, and bronchoscopy detected ulcerated main stem bronchus mucosa clinically suspicious for a neoplastic process. Bronchial washings revealed reactive epithelial cells and numerous histiocytes with both intracellular and extracellular refractile brown crystalline material, which was positive on iron stain. The histologic findings on biopsy showed mucosal ulceration with deposits of extracellular crystalline iron particles. These histologic changes are similar to those seen in iron pill‐induced mucosal injury of the upper gastrointestinal tract in patients with “iron pill” gastritis. The cytologic and histologic features of iron pill‐induced airway injury clinically can mimic cancer. The presence of extracellular and intracellular crystalline iron in the airway lumen and/or mucosa with associated varying degrees of ulceration and inflammation confirms the diagnosis. Diagn. Cytopathol. 2013;41:901–903. © 2012 Wiley Periodicals, Inc.     

TACI-Fc gene therapy improves autoimmune sialadenitis but not salivary gland function in non-obese diabetic mice

Oral Diseases (2012) 18 , 365–374 Objective: Patients with Sjögren’s syndrome (SS) show aberrant expression of the B cell‐related mediators, B cell‐activating factor (BAFF), and a proliferation‐inducing ligand (APRIL) in serum and salivary glands (SGs). We studied the biological effect of neutralizing these cytokines by local gene transfer of the common receptor transmembrane activator and CAML interactor (TACI) in an animal model of SS. Material and Methods: A recombinant serotype 2 adeno‐associated virus (rAAV2) encoding TACI‐Fc was constructed, and its efficacy was tested in the SGs of non‐obese diabetic mice. Ten weeks later, SG inflammation was evaluated and serum and SG tissue were analyzed for inflammatory markers including immunoglobulins (Ig) and cytokines. Results: AAV2‐TACI‐Fc gene therapy significantly reduced the number of inflammatory foci in the SG, owing to a decrease in IgD⁺ cells and CD138⁺ cells. Moreover, IgG and IgM levels, but not IgA levels, were reduced in the SG. Overall expression of mainly proinflammatory cytokines tended to be lower in AAV2‐TACI‐Fc‐treated mice. Salivary flow was unaffected. Conclusion: Although local expression of soluble TACI‐Fc reduced inflammation and immunoglobulin levels in the SG, further research will have to prove whether dual blockade of APRIL and BAFF by TACI‐Fc can provide a satisfying treatment for the clinical symptoms of patients.     

Cyclophosphamide for the treatment of systemic lupus erythematosus

Aggressive immunosuppressive therapy with cyclophosphamide has improved the outcome of major organ disease in lupus patients. Controlled trials have shown that pulse cyclophosphamide is the treatment of choice for patients with moderate to severe proliferative nephritis. Long-term follow-up of patients participating in these controlled trials suggests that combining pulse cyclophoshamide with pulse methylprednisolone increases efficacy but not toxicity. Retrospective case series have also shown that pulse cyclophosphamide therapy may be effective for the management of severe or refractory to standard therapy neuropsychiatric, pulmonary, cardiovascular and hematologic disease. Pulse cyclophosphamide is associated with an increased risk for herpes zoster infections in the short term and with sustained amenorrhea in the long-term. Recent studies have also drawn attention to the lack of response (or incomplete response) and flare of lupus after an initial response. In an effort to circumvent these limitations, current investigations explore the therapeutic potential of high-dose, immunoablative cyclophosphamide therapy or low-dose cyclophosphamide in combination with nucleoside analogs or biologic response modifiers.     

Gelatinase expression and activity in the synovium and skin of patients with erosive psoriatic arthritis

OBJECTIVE: Matrix metalloproteinases (MMP), especially the gelatinases (MMP2, MMP9), have been implicated in several features of inflammatory arthritis including angiogenesis and bone erosions. We examined the expression and activity of the gelatinases and their regulators in psoriatic skin and synovium using tissue immunohistochemistry and a sensitive tissue based zymographic technique. METHODS: Lesional and perilesional skin biopsies and synovial samples obtained by closed needle biopsy from 15 patients with erosive psoriatic arthritis (PsA) were analyzed by immunohistochemistry for the expression of the gelatinases and their regulators, tissue inhibitor of metalloproteinase 1 and 2 (TIMP-1, TIMP-2) and membrane type metalloproteinases (MTI-MMP. MT2-MMP), using immunohistochemistry. Synovial tissue from 8 patients with erosive rheumatoid arthritis (RA) was used as a comparison. MMP tissue expression was quantified by 2 blinded independent observers. Immunohistochemical data are reported as the mean percentage positive cells per total nucleated cells in 10 high power fields +/- SD. Functional activity of the gelatinases was measured using a sensitive tissue based zymography technique and corrected for protein content. Zymography data are presented as ng/mg +/- SE. RESULTS: MMP expression was greater in the synovial lining layer (LL) than in the synovial sublining layer (SL) in both PsA and RA tissue for most MMP except collagenase I (MMPI), which was equally distributed between the LL and SL. Expression of MMP or their regulators did not differ between PsA synovial membrane (SM) and RA SM in LL. Moreover, although latent gelatinase A (MMP2) staining in PsA SM was equivalent to RA SM, increased gelatinase A activity was found in PsA SM over RA SM using zymography L82.4 (SD 62.8) vs 10.1 (SD 1.7); p = 0.02]. Compared to PsA SM, lesional skin had lower levels of MT1-MMP (MMP14) (1.4 +/- 1.7 vs 15.7 +/- 8.4; p = 0.009) and MT2-MMP (MMP15) (12.1 +/- 8.7 vs 21.6 +/- 9.9; p = 0.001). CONCLUSION: We characterized the expression and activity of gelatinases in PsA and demonstrate that gelatinase activity in SM of PsA patients with erosive disease is comparable to if not greater than that in RA synovium.     

Current state and future directions of autologous hematopoietic stem cell transplantation in systemic lupus erythematosus

Autologous haematopoietic stem cell transplantation (AHSCT) has been proposed as a treatment modality which may arrest the autoimmune disease process and lead to sustained treatment-free remissions. Since the first consensus statement in 1997, approximately 200 autologous bone marrow or haematopoietic stem cell transplantations (HSCTs) have been reported worldwide for systemic lupus erythematosus (SLE). The current state of AHSCT in SLE was reviewed at a recent meeting of the autoimmune working party of the European Group for Blood and Marrow Transplantation. There was general agreement among experts in this field that in patients with severe SLE refractory to conventional immunosuppressive treatments, AHSCT can achieve sustained clinical remissions (ranging from 50% to 70% disease-free survival at 5 years) associated with qualitative immunological changes not seen with other forms of treatment. However, this clinical benefit is associated with an increase in short-term mortality in most studies. Improving patient selection, long-term follow-up of patients after AHSCT, optimisation of induction and maintenance treatment together with detailed analysis of the immune system are identified as key areas for future research. Optimally, AHSCT should be compared with conventional treatment in randomised controlled trials. Development of stronger transplant registries, defining a core set of clinical data and standardising biological sample collections would make future collaborations and comparison of studies more feasible.     

Long-term effects of combination treatment with fludarabine and low-dose pulse cyclophosphamide in patients with lupus nephritis

OBJECTIVES: To determine the safety and efficacy of a short course of fludarabine combined with cyclophoshamide in lupus nephritis. METHODS: A phase I/II open label pilot study. Thirteen patients with active proliferative lupus nephritis received monthly oral boluses of low-dose cyclophoshamide (0.5 gm/m(2) on day 1) and subcutaneous fludarabine (30 mg/m(2) on days 1-3) for 3-6 cycles. Concomitant prednisone was aggressively tapered from 0.5 mg/kg/day to a low-dose, alternate-day schedule. Patients were followed for at least 24 months after therapy. The primary outcome was the number of patients achieving renal remission defined as stable creatinine, proteinuria <1 gm/day and inactive urine sediment for at least 6 months. RESULTS: The study was terminated early because of bone marrow toxicity. Eleven patients who received at least three cycles were evaluated for efficacy. Ten patients improved markedly with seven patients achieving complete remission and three patients achieving partial remission. There were three serious haematological adverse events during the treatment with one death due to transfusion-associated graft vs host disease. Profound and prolonged CD4 (mean CD4: 98/microl at 7 months and 251/microl at 12 months) and CD20 lymphocytopenia was noted in most patients. Three patients developed Herpes zoster infections. CONCLUSIONS: A short course of low-dose fludarabine and cyclophoshamide can induce long-lasting remissions in patients with proliferative lupus nephritis, but severe myelosuppression limits its widespread use.     

Serological,genetic and clinical associations with increased health‐care resource utilization in inflammatory bowel disease

OBJECTIVE

Inflammatory bowel diseases (IBD) are associated with significant morbidity and economic burden. The variable course of IBD creates a need for predictors of clinical outcomes and health resource utilization (HRU) to guide treatment decisions. We aimed to identify clinical, serological or genetic markers associated with inpatient resource utilization in patients with ulcerative colitis (UC) and Crohn's disease (CD).

METHODS

Patients with IBD with available genetic and serological data who had at least one emergency department visit or hospitalization in a 3‐year period were included. The primary outcome measure was HRU, as measured by the All Patient Refined Diagnosis Related Group classification system. Univariate and multivariate linear and logistic regression models were used to identify the associations with HRU.

RESULTS

Altogether 858 (562 CD and 296 UC) patients were included. Anti‐CBir1 seropositivity (P = 0.002, effect size [ES]: 0.762, 95% confidence interval [CI] 0.512–1.012) and low socioeconomic status (P = 0.005, ES: 1.620 [95% CI 1.091–2.149]) were independently associated with a high HRU. CD diagnosis (P = 0.006, ES: –0.701 [95% CI –0.959 to –0.443]) was independently associated with a low inpatient HRU.

CONCLUSION

In patients with IBD who required at least one emergency department visit or hospitalization, anti‐CBir1 antibody status may be a useful biomarker of HRU when formulating management strategies to reduce disease complications and resource utilization.     

Clinical and radiological outcome of medial patellofemoral ligament reconstruction with a semitendinosus autograft for patella instability

Background: Recurrent patellar instability is a common problem after dislocation. The medial patellofemoral ligament (MPFL) contributes 40–80% of the total medial restraining forces. This study assessed the clinical and radiological outcome after a follow-up of 4 years after linear MPFL reconstruction using an ipsilateral Semitendinosus tendon autograft. Study design and methods: 15 knees in 12 patients were examined with a mean of 47 months after linear reconstruction of the MPFL at a mean age of 30 years. 3 knees underwent previous surgery. 3 patients had mild trochlear dysplasia grade I or II, according to the classification of Dejour. If preoperative tibial tuberosity-trochlear groove distance (TTTG) was more than 15 mm, patients underwent additional medialisation of the tibial tuberosity (n=8) creating a similar postoperative situation for all patients. All patients were available for a postoperative evaluation, which consisted of a subjective questionnaire, the Kujala score, and the recording of potential patellar redislocation and apprehension. Patellar height and tilt was measured on plain radiographs. Postoperative CT scans were performed in patients with an additional tibial tuberosity-transfer. Results: Postoperatively, one patient reported on recurrent bilateral redislocation. Physical examination however revealed no findings. Three knees presented with persistent patellar apprehension. Thirteen knees had improved subjectively after surgery. The mean Kujala score improved significantly from 55.0 to 85.7 points. The patellar tilt decreased significantly from 11.3° to 9.2°. Four knees had patella alta preoperatively, but only two at the latest follow-up visit. Previous surgery or additional trochlear dysplasia had no influence on the clinical outcome. Conclusion: MPFL reconstruction improves clinical symptoms, reduces the patellar tilt substantially, and may correct patella alta. Additional mild trochlear dysplasia did not compromise the outcome; however, this fact needs further attention in a larger study group.