The Effects of Adalimumab in Behçet Disease Patients on Clinical Manifestations and on Pro-Inflammatory Cytokines Milieu: Long-Term Follow-Up.

BACKGROUND: Behçet's disease is a multi-systemic chronic relapsing inflammatory disease, classified among the vasculitides. The heterogeneity of clinical manifestations challenges the disease management. OBJECTIVES: To assess efficacy and safety of adalimumab in patients with active persistent Behçet's arthritis who did not respond to disease-modifying anti-rheumatic drugs and to assess the impact of treatment on the cytokine milieu. METHODS: Our cohort comprised 10 patients with active arthritis who received adalimumab in a 24-week investigator-initiated prospective open-label study. Patients who relapsed within 12 weeks following adalimumab discontinuation could enter a 3-year extension study. The patients underwent a comprehensive assessment including questionnaires and measurement of inflammatory cytokines, adalimumab serum levels, and anti-drug antibodies. RESULTS: A significant improvement was observed in arthritis, disease activity visual analogue scales, Behçet's disease current activity form, and interleukin-6 (IL-6) levels, but not in health assessment questionnaire and functional assessment of chronic illness therapy fatigue scale questionnaire. Resolution of oral and urogenital ulcers was achieved in all patients. Significant reduction of pain was reported by 40% of patients. The disease relapsed in 9 of 10 patients, within 2-6 weeks following adalimumab discontinuation. Of the 7 patients who continued the study, arthritis was resolved in 5. Two patients with high neutralizing antidrug antibodies titer relapsed. CONCLUSIONS: Adalimumab treatment achieved a significant improvement in arthritis, mucocutaneous manifestations, and IL-6 levels in all study patients but only 40% reported significant pain reduction. The arthritis relapsed in 90% of patients following adalimumab discontinuation and long-term treatment was required.

[THE INPUT OF MEASURING INFLIXIMAB LEVELS AND LEVELS OF ANTIBODIES TO INFLIXIMAB IN THE MANAGEMENT OF PATIENTS WITH RHEUMATIC DISEASES].

BACKGROUND: High levels of infliximab (IFX) directed antibodies (IFX-Ab) may result in significant reduction in IFX concentration and loss of drug efficacy. OBJECTIVES: To assess the input of measuring serum IFX levels and levels of IFX-Ab in the management of rheumatic diseases. METHODS: Serum levels of IFX and anti-IFX-Ab were measured by ELISA (IFX-Abs were also identified by anti-human lambda chain Ab) and correlated to patients (responders and nonresponders) disease activity scores. RESULTS: A total of 144 tests for IFX were performed in 91 patients (mean age 50.2 years and disease duration 9.9 years). Among responders (57 patients) levels (mean, median) of IFX were significantly higher than in non-responders (34 patients) (4.2 mcg/ml (2.3) versus 1.1 mcg/ml (0.45)); levels of IFX-Ab in responders were significantly lower than in non-responders (4.59 mcg/ml (1.0) versus 13.1 (6.1)). High IFX-Ab levels predicted IFX discontinuation in 8.8% of responders and 55.9% among non-responders. In non-responders with low IFX levels and low IFX-Ab, the shortening of re-treatment intervals lead to significant improvement. In about 28% of patients, results of blood tests influenced treatment decisions. CONCLUSIONS: Assessment of immunogenicity of anti-TNF monoclonal antibodies proved useful information for guiding the therapy in rheumatic diseases with suboptimal clinical response. Patients with low IFX levels and low levels of IFXAb may benefit from increasing the drug dose or decreasing of re-treatment intervals. In patients with negligible serum levels of IFX and high levels of IFX-Ab, the therapy should be switched to another biological agent, probably with a different mechanism of action.

Safety of Corticosteroid Treatment in Rheumatologic Patients With Markers of Hepatitis B Viral Infection: Pilot Evaluation Study.

BACKGROUND: Immunosuppressive agents may induce hepatitis B flares. The minimal corticosteroid dose and duration of therapy leading to HBV reactivation is unknown. OBJECTIVE: To assess whether short-term corticosteroid therapy for rheumatologic diseases induces HBV reactivation. METHODS: The records of all HBsAg or HBcore antibodies positive, anti-HBs negative patients who were hospitalized in the rheumatology department during 2001-2014 and treated with corticosteroids were reviewed. Alanine aminotransferase (ALT), HBV serology, and serum HBV DNA at baseline and 1-3 months after discharge were recorded. RESULTS: Complete data were found for 23 patients who were hospitalized 73 times for 7 days of treatment with IV corticosteroids. Eighteen patients were HBsAg positive. The mean methylprednisolone dose was 33.9 ± 24 mg/d. The concomitant therapy included DMARDs (15), low-dose corticosteroids (8), and biologicals (10). Serum HBV DNA was detected at baseline in seven patients. Three HBsAg-positive patients treated with cyclophosphamide had HBV hepatitis flare-up with elevated ALT. Two HBsAg-positive patients had reappearance of HBV DNA in serum after treatment with azathioprine and infliximab, respectively, but the ALT levels remained normal. Lamivudine therapy reduced the serum HBV DNA and improved ALT levels in all patients. Corticosteroid therapy by itself did not trigger exacerbation of HBV hepatitis. No HBV reactivation occurred in lamivudine-treated patients after recurrent exposure to biologicals or cyclophosphamide. CONCLUSIONS: Short episodes of corticosteroids seem to be safe in HBV carriers, even in the presence of DMARDs, but lamivudine prophylaxis should be considered for patients exposed to biologicals or cyclophosphamide. Larger prospective trials are needed to establish guidelines.

Long-term follow-up of patients with scleroderma interstitial lung disease treated with intravenous cyclophosphamide pulse therapy: a single-center experience.

BACKGROUND: Scleroderma lung disease (ILD-SSc) is treated mainly with cyclophosphamide (CYC). The effectiveness of CYC was judged after 12-24 months in most reports. OBJECTIVES: To analyze the effect of monthly intravenous CYC on pulmonary function tests including forced vital capacity (FVC) and diffusing lung capacity (DLCO), as well as Rodnan skin score (mRSS), during long-term follow-up. METHODS: We retrospectively collected the data on 26 ILD-SSc patients who began CYC treatments before 2007. Changes in FVC, DLCO and mRSS before treatment, and at 1,4 and 7 years after completion of at least six monthly intravenous CYC treatments for ILD-SSc were analyzed. RESULTS: Mean cumulative CYC dose was 8.91 ± 3.25 G. More than 30% reduction in FVC (0%, 8%, and 31% of patients), DLCO (15%, 23%, 31%), and mRSS (31%, 54%, 62%) at years 1, 4 and 7 was registered. During the years 0-4 and 4-7, annual changes in FVC, DLCO and mRSS were 3.2 vs. 0.42% (P < 0.040), 4.6 vs. 0.89% (P < 0.001), and 1.8 vs. 0.2 (P = 0.002). The greatest annual FVC and DLCO reduction over the first 4 years correlated with mortality (P = 0.022). There were no differences in the main variables regarding doses of CYC (< 6 G and > 6 G). CONCLUSIONS: In patients with ILD-SSc, CYC stabilized the reduction of FVC during treatment, but this effect was not persistent. The vascular characteristic of ILD-SSc (DLCO) was not affected by CYC treatment. CYC rapidly improved the mRSS. This effect could be achieved with at least 6 G of CYC. Higher rates of annual reduction in FVC and DLCO in the first 4 years indicate the narrow window of opportunity and raise the question regarding ongoing immunosuppression following CYC infusions.

Rituximab: rescue therapy in life-threatening complications or refractory autoimmune diseases: a single center experience.

Rituximab (RTX) is a chimeric anti-CD20 antibody, approved for rheumatoid arthritis (RA) patients who failed anti-Tumor Necrosis Factor therapy. It has been used occasionally for life-threatening autoimmune diseases (AID). We report our center experience in the use of RTX in life-threatening complications or refractory AID. Clinical charts of patients treated with RTX at our center were reviewed, cases treated for life-threatening complications or refractory AID were analyzed. Acute damage to vital organs such as lung, heart, kidney, nervous system with severe functional impairment were defined as life-threatening complications; treatment failure with high-dose corticosteroids, cyclophosphamide, IVIG, plasmapheresis was defined as refractory autoimmune disease. During the years 2003-2009, 117 patients were treated with RTX, most of them for RA. Nine patients (6 females, mean age 51.5 years, mean disease duration 6.3 years) answered the criteria. The indications were as follows: pulmonary hemorrhage (1 patient with cryoglobulinemic vasculitis, 1 with systemic sclerosis, 1 with ANCA-associated vasculitis), catastrophic anti-phospholipid syndrome (2 SLE patients), non-bacterial endocarditis and pulmonary hypertension (1 patient with mixed connective tissue disease), vasculitis and feet necrosis (1 patient with systemic lupus erythematosus), severe lupus demyelinative neuropathy and acute renal failure (1 patient), and severe rheumatoid lung disease with recurrent empyema and pneumothorax (1 patient). B cell depletion was achieved in all patients. The median time since starting of complications to RTX administration was 3 weeks (range 2-15 weeks). Complete remission (suppression of the hazardous situation and return to previous stable state) was seen in 7 out of 9 patients. Partial remission (significant improvement) was achieved in the remained. The median time to response was 3 weeks (range 1-8 weeks), mean follow-up 47.2 months (range 6-60 months). A rapid tapering off of steroids was achieved in all patients. Two patients relapsed and were successfully retreated with RTX: the patient with severe RA lung relapsed after 3 years, one of the patients with ANCA-associated pulmonary alveolar hemorrhage relapsed after 10 months. There were no side effects during RTX infusion. Two episodes of serious infections were registered: fatal Gram-negative sepsis 6 months after RTX treatment, and septic discitis 4 months after receiving RTX. RTX serves as a safe, efficient, and prompt rescue therapy in certain life-threatening conditions and resistant to aggressive immunosuppression AID. RTX when administrated at an earlier stage, prevented irreversible vital organ damage, and allowed rapid steroid tapering off in already severe immunodepressed patients.

Depletion of B lymphocytes in rheumatoid arthritis patients modifies IL-8-anti-IL-8 autoantibody network.

Cytokines and chemokines are key regulatory molecules involved in rheumatoid arthritis (RA). B-cell depletion therapy improves RA clinically but its mechanism is not completely understood. One possible mechanism for this therapy is the modification of the proinflammatory cytokine homeostasis of RA. We show here that the levels of the proinflammatory chemokine IL-8 in serum samples from RA patients unexpectedly increased by up to 100-fold 8 weeks after the administration of rituximab, despite clinical improvement. We also show that RA patients produced anti-IL-8 autoantibodies and that their levels dropped after RTX treatment. Moreover, we identified antibody-IL-8 immune complexes in the synovial fluid and serum of RA patients, and found that the amount of these complexes decreased after the administration of RTX. Our results indicate that B-cell depletion therapy modifies the cytokine-autoantibody network by reducing the levels of anti-cytokine autoantibodies and, consequentially, the formation of antibody-cytokine immune complexes.

Cutting balloons versus conventional long balloons for PCI of long coronary lesions.

BACKGROUND: PCI for long coronary lesions remains a challenge because of high incidence of early complications and late restenosis. Cutting balloon angioplasty may result in reduced procedural complications and late restenosis than angioplasty with conventional long balloons (LBA) due to minimized injury to the culprit arteries. OBJECTIVE: To compare the immediate and one-year outcomes of CBA and LBA for long coronary lesions. METHODS: 169 consecutive patients were retrospectively identified who underwent CBA or LBA for de novo lesions 20 mm in length and 2.5 mm in diameter. The primary endpoint was immediate procedural outcomes and angiographic restenosis at one year. RESULTS: CBA was performed in 54 patients (56 lesions) and LBA in 115 patients (151 lesions). Baseline characteristics were similar in both groups with a mean lesion length of 34.89+/-11.19 mm, and vessel diameter of 3.03+/-0.54 mm. CBA resulted in reduced incidence of side branch loss (23.2% versus 41.7%, P=0.022) which was associated with less peri-procedural infarction (OR: 11.39 (95% CI: 1.34-96.53), P=0.026). It also caused less dissection (23.2% versus 38.4%, P=0.048) leading to a trend of less provisional focal stenting (32.1% versus 41.1%, P=0.264). The rate of angiographic restenosis and clinically driven target lesion revascularization at one year (follow-up 91.1%) was similar (25% versus 21.2%, and 20.4% versus 20%, for CBA versus LBA, both P=NS). The mean event-free survival was also similar (10.15+/-0.45 months for CBA versus 9.50+/-0.39 months for LBA, P=NS). CONCLUSION: CBA demonstrated better immediate results and equivalent late results than LBA, and therefore, it may be considered a reasonable firstline approach for PCI of long coronary lesions.

Provisional stenting for multivessel PCI.

BACKGROUND: Bare stents reduce acute complications and repeat revascularization following percutaneous coronary intervention (PCI), but are costly and may lead to in-stent restenosis. It remains unclear whether stents should be universally implanted or whether provisional stenting mainly to suboptimal balloon dilatation results is an acceptable approach for multivessel PCI. OBJECTIVE: To compare the long-term clinical restenosis and target lesion revascularization (TLR) of stented and non-stented coronary artery lesions in patients who had multivessel PCI. METHODS: We performed retrospective analysis of matched data from 129 consecutive patients who underwent multivessel PCI (at least optimal balloon angioplasty to one coronary artery segment and balloon angioplasty plus stenting to another coronary artery in the same patient, all lesions are de novo native coronary artery lesions with vessel diameter >/=2.5 mm). The study endpoint was restenosis and repeat revascularization at one-year follow-up. RESULTS: Baseline characteristics were similar in both groups. Low in-hospital MACE (3.1%). Acute myocardial infarction, emergency revascularization via either PCI or CABG was detected and angiographic success was achieved in 99.3% of lesions in both groups. The rate of clinically driven angiographic restenosis and TLR at one-year (follow-up 100%) was similar (17.1% versus 18.6%, P=0.871, and 13.9% versus 16.3%, P=0.728, for optimal balloon angioplasty versus provisional stenting. CONCLUSIONS: The main findings from this study are that long-term angiographic restenosis and TLR was comparable for optimal balloon angioplasty and provisional stenting, suggesting that provisional stenting is an acceptable approach for multivessel PCI.

Beneficial autoimmunity to proinflammatory mediators restrains the consequences of self-destructive immunity.

Therapies that neutralize the function of TNF-alpha suppress rheumatoid arthritis (RA) but not osteoarthritis (OA). We show that patients suffering from RA but not OA have significant levels of autoantibodies directed to TNF-alpha. Thus, the immune system can selectively generate autoimmunity to proinflammatory mediators when such a response is beneficial for the host. A well-defined model of RA was used to elaborate the contribution of beneficial autoimmunity to the regulation of disease. We show that during the disease autoantibody production is elicited against few inflammatory, but not regulatory, mediators. Selective amplification of these beneficial antibodies by targeted DNA vaccines provided protective immunity. Epitope mapping revealed that anti-TNF-alpha immunity is highly restricted and excretes no crossreactivity to other known gene products. Its selective exclusion substantially exacerbated the disease. Administration of anti-TNF-alpha antibodies could then override this aggravation. This substantiates the significance of beneficial autoimmunity in restraining self-destructive immunity.