Josef Hermann

Anti-tumor necrosis factor-alpha therapy with infliximab as an alternative to corticosteroids in the treatment of human leukocyte antigen B27-associated acute anterior uveitis.

OBJECTIVE To evaluate the potentials of infliximab, a mouse-human chimeric immunoglobulin G1 monoclonal antibody that binds both the soluble form and the membrane-bound precursor of tumor necrosis factor-alpha (TNF-alpha), thus inhibiting a broad range of biologic activities of TNF-alpha, in the therapy of patients with acute HLA B27-associated anterior uveitis. DESIGN Prospective noncomparative case series. PARTICIPANTS Seven consecutive patients with acute onset of HLA B27-associated anterior uveitis, with at least three anterior chamber cells. INTERVENTION Infliximab IV (Centocor, Malvern, PA) at a dosage of 10 mg/kg body weight was used as the only anti-inflammatory drug. MAIN OUTCOME MEASURES Anterior chamber cells and flare were evaluated before infliximab treatment and at defined time points after treatment. C-reactive protein (CRP) levels were assessed in all patients before IV delivery of infliximab and were re-evaluated after 1 week. RESULTS Patients were observed for a mean period of 17 +/- 0.8 months. Seven patients received a single infliximab infusion of 10 mg/kg body weight. One patient received a second infusion 3 weeks after the first because of a uveitis flare-up. The median duration (+/- standard deviation) of uveitis was 8 +/- 12 days. All patients responded to infliximab with immediate improvement of clinical symptoms and a rapid decrease in anterior chamber cells. Total resolution of the uveitis was achieved with infliximab as the sole anti-inflammatory drug in all but one patient, who also showed systemic inflammatory activity, as indicated by a threefold increase in the serum CRP level. A relapse was seen in four patients after a median period of 5 +/- 6.4 months. CONCLUSION Infliximab proved to be a powerful therapeutic agent in acute HLA B27-associated uveitis and may therefore be a future alternative or supplement to steroid treatment. Larger controlled studies on the efficacy and dosage of infliximab in different forms of anterior uveitis will nonetheless be needed to evaluate the effectiveness of anti-TNF-alpha treatment in acute, as well as chronic, uveitis.

Improvement of insulin sensitivity in insulin resistant subjects during prolonged treatment with the anti‐TNF‐α antibody infliximab

Sir, Insulin resistance (IR) is an important component in the pathophysiology of type-II diabetes, hypertension, hyperlipidaemia and finally cardiovascular disease with both genetic and environmental factors contributing to its development. Tumour necrosis factor alpha (TNFα ), a proinflammatory cytokine, may play a prominent role in obesity associated IR as well as β -cell dysfunction [1]. Elevated expression of TNFα in obese insulin resistant rodents and humans was observed along with the indication of elevated plasma TNFα in some studies. TNFα has tissue specific effects on glucose homeostasis and is known to impair insulin receptor signalling experimentally. Furthermore, cytokines that activate (NF)-kB (a nuclear transcription factor closely involved into regulation of cellular inflammatory response), such as TNFα , are thought to be a common denominator for β cell apoptosis in type 1 and type 2 diabetes [2]. In addition, it has been suggested that TNFα is a powerful regulator of adipose tissue [3]. Neutralizing TNFα in obese fa/fa-rats has shown increased insulin sensitivity [4]. So far, in humans two studies failed to demonstrate an effect of acute administration of either a chimeric anti-TNFα antibody [5] or a recombinant soluble human TNFα receptor [6] on insulin sensitivity in obese or type-II diabetic subjects. Prolonged administration of anti–TNFα antibody is used in the treatment of chronic inflammatory diseases such as rheumatic diseases [7] or Crohn’s disease [8]. Here we report observational findings of chronic treatment with infliximab (a chimeric anti-TNFα antibody) on insulin sensitivity as assessed by the homeostasis model assessment (HOMA: fasting plasma glucose (mmol L − 1 ) × fasting serum insulin (mU L − 1 ) divided by 225 [9]), in such patients. Our index case, a 31 years old male with a body-mass-index (BMI) of 31·2 kg m − 2 was diagnosed with type-II diabetes in November 1999 with an HbA 1c of 9·2%. The patient lost weight within 8 months to a BMI of 22·4 kg m − 2 and was treated with insulin (approx. 28 IU per day). As a result stable, good glycaemic control (fasting blood glucose: 6·05 mmol L − 1 ) in the absence of hypoglycaemia could be reached and maintained till 2001. In January 2001 treatment with infliximab (5 mg kg − 1 ) every 8 weeks, was started due to refractory psoriatic arthritis. At this time point he exhibited an unexpectedly severe insulin resistance with a HOMA of 36·98 despite maintenance of normal body weight (In healthy subjects the median HOMA is about 1·4 whereas only 10% of them exhibit a HOMA between 4·5 and 20). After 4–5 months, the patient noticed a decline in insulin requirements and the occurrence of hypoglycaemia. In October 2001, after a severe hypoglycaemic episode, the patient stopped insulin treatment. In July 2002, still on infliximab treatment glucose status was reevaluated. Fasting plasma glucose was 5·17 mmol L − 1 and 2-h after challenge with 75 g glucose 10·56 mmol L − 1 were observed indicating the presence of impaired glucose tolerance instead of insulin requiring diabetes. The respective serum insulin was 32·8 mU L − 1 and 96·4 mU L − 1 , HbA1c was 5·4%. Today the patient is still without insulin therapy. This observation prompted us to evaluate insulin sensitivity retrospectively, using the HOMA, in samples stored from patients treated with infliximab after obtaining informed consent (Fig. 1). Interestingly, with exception of our lean index patient, only the most obese patients (patients 3 and 5), available for analysis (Table 1), showed a pronounced insulin resistance at baseline and improved substantially. In contrast, the other patients (patients 2 and 4) with a lower BMI were insulin sensitive at baseline and did not change during infliximab Division of Rheumatology (B. Yazdani-Biuki, H. P. Brezinschek, J. Hermann, T. Mueller, W. Graninger), Diabetes and Metabolism Clinic (H. Stelzl, T. C. Wascher), and Division of Oncology ( P. Krippl), Department of Internal Medicine, Medical University Graz, Austria.

Important immunoregulatory role of interleukin-11 in the inflammatory process in rheumatoid arthritis

OBJECTIVE To investigate the possible immunoregulatory role of interleukin-11 (IL-11) in rheumatoid arthritis (RA). METHODS IL-11 protein was assayed in RA tissue, and the effect of exogenous IL-11 on neutralization of endogenous IL-11 was investigated with respect to tumor necrosis factor alpha (TNFalpha), matrix metalloproteinase (MMP), and tissue inhibitor of metalloproteinases (TIMP) production. RESULTS IL-11 was found in RA synovial membranes, synovial fluids, and blood sera. Blockade of endogenous IL-11 resulted in a 2-fold increase in TNFalpha levels, which increased to 22-fold if endogenous IL-10 was also blocked. Addition of exogenous IL-11 inhibited spontaneous TNFalpha production in RA synovium only in the presence of soluble IL-11 receptor. However, exogenous IL-11 directly inhibited spontaneous MMP-1 and MMP-3 production, and up-regulated TIMP-1 in RA synovial tissue. CONCLUSION IL-11 has important endogenous immunoregulatory effects in RA synovium, which suggests that exogenous IL-11 may have therapeutic activity in RA.

Disparity between ultrasound and clinical findings in psoriatic arthritis

Objective To investigate the association between psoriatic arthritis (PsA)-specific clinical composite scores and ultrasound-verified pathology as well as comparison of clinical and ultrasound definitions of remission. Methods We performed a prospective study on 70 consecutive PsA patients. Clinical assessments included components of Disease Activity Index for Psoriatic Arthritis (DAPSA) and the Composite Psoriatic Disease Activity Index (CPDAI). Minimal disease activity (MDA) and the following remission criteria were applied: CPDAI joint, entheses and dactylitis domains (CPDAI-JED)=0, DAPSA≤3.3, Booleans remission definition and physician-judged remission (rem-phys). B-mode and power Doppler (PD-) ultrasound findings were semiquantitatively scored at 68 joints (evaluating synovia, peritendinous tissue, tendons and bony changes) and 14 entheses. Ultrasound remission and minimal ultrasound disease activity (MUDA) were defined as PD-score=0 and PD-score ≤1, respectively, at joints, peritendinous tissue, tendons and entheses. Results DAPSA but not CPDAI correlated with B-mode and PD-synovitis. Ultrasound signs of enthesitis, dactylitis, tenosynovitis and perisynovitis were not linked with clinical composites. Clinical remission or MDA was observed in 15.7% to 47.1% of PsA patients. Ultrasound remission and MUDA were present in 4.3% and 20.0% of patients, respectively. Joint and tendon-related PD-scores were higher in patients with active versus inactive disease according to CPDAI-JED, DAPSA, Booleans and rem-phys, whereas no difference was observed regarding enthesitis and perisynovitis. DAPSA≤3.3 (OR 3.9, p=0.049) and Booleans definition (OR 4.6, p=0.03) were more useful to predict MUDA than other remission criteria. Conclusions PsA-specific composite scores partially reflect ultrasound findings. DAPSA and Booleans remission definitions better identify MUDA patients than other clinical criteria.

Psoriatic Arthritis and Rheumatoid Arthritis: Findings in Contrast-Enhanced MRI

OBJECTIVE Our objective was to define typical MRI findings of the wrist and the hand in patients with psoriatic arthritis (PsA) and rheumatoid arthritis (RA). MATERIALS AND METHODS Eighteen PsA and 21 RA patients with arthralgia of the wrist or hand joints underwent gadolinium-enhanced MRI of the wrist and hand. Two experienced radiologists interpreted abnormalities in consensus with respect to periarticular soft-tissue swelling, synovitis with or without effusion, periostitis, bone edema, bone erosions, bone cysts, and tenosynovitis. The distribution of the abnormalities also was evaluated. RESULTS Erosions were statistically more frequent in patients with RA (p < 0.05). Periostitis was statistically seen more frequently in patients with PsA (p < 0.05). No statistically significant difference was found in the frequency of synovitis, bone marrow edema, bone cysts, and tenosynovitis between the two groups (p > 0.05). The radiocarpal joint, the midcarpal joints, the carpometacarpal joints, and the metacarpophalangeal joints were significantly affected more frequently in patients with RA than in patients with PsA (p < 0.05), whereas the proximal interphalangeal joints were significantly more frequently affected in patients with PsA (p < 0.05). CONCLUSION Periostitis and synovitis of the proximal interphalangeal joints are typical MRI findings in patients with PsA, whereas synovitis with erosions of the wrist, the midcarpal joints, the carpometacarpal joints, and the metacarpophalangeal joints are typical findings in patients with RA.

Ultrasound for diagnosis of carpal tunnel syndrome: comparison of different methods to determine median nerve volume and value of power Doppler sonography

Objective To compare ultrasound measurement of median nerve cross-sectional area (CSA) at different anatomical landmarks and to assess the value of power Doppler signals within the median nerve for diagnosis of carpal tunnel syndrome (CTS). Methods A prospective study of 135 consecutive patients with suspected CTS undergoing two visits within 3 months. A final diagnosis of CTS was established by clinical and electrophysiological findings. CSA was sonographically measured at five different levels at forearm and wrist; and CSA wrist to forearm ratios or differences were calculated. Intraneural power Doppler signals were semiquantitatively graded. Diagnostic values of different ultrasound methods were compared by receiver operating characteristic curves using SPSS. Results CTS was diagnosed in 111 (45.5%) wrists; 84 (34.4%) had no CTS and 49 (20.1%) were possible CTS cases. Diagnostic values were comparable for all sonographic methods to determine median nerve swelling, with area under the curves ranging from 0.75 to 0.85. Thresholds of 9.8 and 13.8 mm2 for the largest CSA of the median nerve yielded a sensitivity of 92% and a specificity of 92%. A power Doppler score of 2 or greater had a specificity of 90% for the diagnosis of CTS. Sonographic median nerve volumetry revealed a good reliability with an intraclass correlation coefficient of 0.90 (95% CI 0.79 to 0.95). Conclusions Sonographic assessment of median nerve swelling and vascularity allows for a reliable diagnosis of CTS. Determination of CSA at its maximal shape offers an easily reproducible tool for CTS classification in daily clinical practice.

Relapse of Diabetes After Interruption of Chronic Administration of Anti–Tumor Necrosis Factor-α Antibody Infliximab: A case observation

Tumor necrosis factor-α (TNF-α), a proinflammatory cytokine, plays a prominent role in obesity-associated insulin resistance and β-cell dysfunction (1) and, therefore, in the development of diabetes. An association between obesity and elevated TNF-α levels and, furthermore, the substantial decline of TNF-α levels with the simultaneous restoration of insulin sensitivity during weight loss was reported by Dandona et al. (2). Recently, we found evidence that prolonged administration of anti–TNF-α antibody is able to improve insulin sensitivity in …

Clinical interpretation of antineutrophil cytoplasmic antibodies: parvovirus B19 infection as a pitfall

Background: While antibodies directed against proteinase 3 (PR3-ANCA) and myeloperoxidase (MPO-ANCA) have a high specificity for the diagnosis of systemic vasculitis, they may also be found as an epiphenomenon of acute viral infection. Objective: To investigate whether positive ANCA test results may be a common feature of acute parvovirus B19 infection. Methods: Sera were analysed from 1242 patients from a rheumatology outpatient clinic for reactivity with parvovirus B19 and EBV antibodies. They were tested for the presence of PR3-ANCA and MPO-ANCA, along with sera known to contain IgM antibodies to these viruses obtained from among 41 366 samples submitted for virological screening. Results: ANCA were found in 10% (5/50) of the sera positive for IgM antibodies to parvovirus and in 3/51 sera containing IgM antibodies to EBV. Three of six patients with arthritis and concomitant parvovirus infection were found positive for PR3-ANCA and two were found positive for MPO-ANCA. All six patients tested negative for ANCA after six months of follow up. Conclusions: PR3-ANCA and MPO-ANCA may occur transiently in patients with acute B19 infection or infectious mononucleosis, highlighting the importance of repeated antibody tests in oligosymptomatic clinical conditions in which systemic autoimmune disease is suspected.

Cell-type specific response of peripheral blood lymphocytes to methotrexate in the treatment of rheumatoid arthritis

The mode of action of methotrexate in the treatment of rheumatoid arthritis is still questionable. Although in vitro results suggest an immunosuppressive effect of methotrexate, several clinical studies have failed to confirm these effects in patients treated with oral low-dose methotrexate. With respect to the highly variable bioavailability of methotrexate, we investigated the effects of an intravenous administration of 15 mg methotrexate per week on peripheral blood lymphocyte subsets in eight patients with rheumatoid arthritis. Methotrexate after 12 weeks significantly (P<0.01) reduced total peripheral blood lymphocytes and led to a pronounced redistribution of lymphocyte subsets with a preferred reductive effect on B-lymphocytes (P<0.005) and T-lymphocytes (P<0.05). Natural killer cells and killer cell-like T cells, on the other hand, were unaffected by the treatment. Our results suggest a cell-type specific effect of intravenously administered low-dose methotrexate on peripheral blood lymphocytes. This effect, in our opinion, may contribute to the mode of action of methotrexate as an immunosuppressive drug in the treatment of rheumatoid arthritis.

Rituximab for systemic sclerosis: arrest of pulmonary disease progression in five cases Results of a lower dosage and shorter interval regimen

Systemic sclerosis (SSc) can be a devastating disease with lethal complications such as interstitial lung disease (ILD). Therapeutic strategies include cyclophosphamide but patients are frequently refractory even to this aggressive immunosuppressant. Lafyatis et al published a 6-month open observational study of 15 patients with diffuse scleroderma receiving one course of rituximab (2 × 1 g within 2 weeks) (1, 2). They found no significant clinical improvement in the extent of thickened skin and no significant benefit in pulmonary functional tests. Daoussis et al published a 1-year randomized controlled trial, in which eight scleroderma patients improved on skin fibrosis and pulmonary function (2, 3). This success was prolonged in an open 2-year observation of patients receiving four weekly pulses of 375 mg/m2 rituximab after 6, 12, and 18 months (2, 4). We report here a significant benefit with a different dosing regimen in a small open series of scleroderma patients with ILD. Five consecutive patients with anti-topoisomerase I (Scl-70)-positive diffuse scleroderma and ILD failed to respond to conventional therapy with intravenous cyclophosphamide. Demographic data and patients’ characteristics are shown in a Table (attached as supplementary material). All five patients received 500 mg rituximab on day 0 and day 14 every 3 months for a period of 1 year. Changes in the modified Rodnan skin score (mRSS) and diffusion lung capacity of carbon monoxide (DLCO) are shown in Figure 1. Figure 1. Changes in (A) the modified Rodnan skin score (mRSS), (B) the diffusing capacity of the lung for carbon monoxide (DLCO), and (C) forced vital capacity (FVC) measurements in all five scleroderma patients (SP, BM, EB, BC, and ZS) treated with rituximab ... In three patients descriptive quantitation of the extent of lung fibrosis by our radiologist (AL) was available. This decreased substantially as shown in Figure 2 (attached as supplementary material). Moreover, in all five patients digital ulcerations healed and the severity of Raynaud’s phenomenon and vascular pain decreased. The number of capillary bleeds and megacapillaries decreased as shown by capillary microscopy. The B-lymphocyte count decreased, as expected, in all patients after rituximab treatment, while there was no change in the concentration of serum immunoglobulins, autoantibody titres, or C-reactive protein (CRP) levels (5). Our clinical experience matches the observations that rituximab may be a promising drug to control the progression of lung involvement in SSc (1–7). The issue of dosing of rituximab in scleroderma needs to be examined in longitudinal and controlled studies. In rheumatoid arthritis, a meta-analysis showed no significant difference in outcome regarding the used dosage of rituximab (2). The common single application of glucocorticoids prior to rituximab infusion does not seem to be of relevance for our patient outcomes because similar amounts of glucocorticoids had also been administered during previous cyclophosphamide treatment in all five cases. In summary, we demonstrate in an uncontrolled series of five patients that rituximab was able to improve skin thickness and lung function in severe progressive SSc refractory to immunosuppressive therapy with cyclophosphamide. It seems appropriate to test the effect of dosage, co-medication, and the time course of rituximab application in controlled and longitudinal studies.