Sebastian Unizony

Rituximab for the Treatment of Igg4-related Disease: Lessons From 10 Consecutive Patients

AbstractPatients with IgG4-related disease (IgG4-RD) typically have elevated serum concentrations of IgG4 and share histopathologic features that are similar across affected organ(s). IgG4-RD patients frequently require prolonged treatment with glucocorticoids and are often unable to taper these medications. Traditional disease-modifying antirheumatic drugs (DMARDs) are generally ineffective. We assessed the clinical and serologic responses to B lymphocyte depletion therapy in 10 consecutive patients with steroid- and DMARD-refractory IgG4-RD.Ten patients with IgG4-RD were treated with rituximab (RTX) (2 infusions of 1000 mg, 15 days apart). Clinical improvement was assessed by monitoring the patient’s ability to taper prednisone to discontinuation and to stop DMARDs; by serial measurements of total IgG and IgG subclasses; and by follow-up radiologic assessments guided by the patient’s particular pattern of organ involvement. We also developed and retrospectively applied the IgG4-RD Disease Activity Index and Flare Tool.Organ involvement included the pancreas, biliary tree, aorta, salivary glands (submandibular and parotid), lacrimal glands, lymph nodes, thyroid gland, and retroperitoneum. Nine of 10 patients demonstrated striking clinical improvement within 1 month of starting RTX. One patient with advanced thyroid fibrosis associated with Riedel thyroiditis and a history of disease in multiple other organ systems did not have improvement in the thyroid gland, but the disease did not progress to involve new organs. All 10 patients were able to discontinue prednisone and DMARDs following RTX therapy. Significant decreases in IgG concentrations were observed for the IgG4 subclass only. Four patients were re-treated with RTX after 6 months because of either symptom recurrence and increasing IgG4 concentration at the time of peripheral B cell reconstitution (n = 2) or because of physician discretion (n = 2). Repeated courses of RTX maintained their effectiveness and resulted in further decreases in IgG4 concentrations. In patients who had an increased IgG4 concentration at the time of presentation, the level of serum IgG4 appeared to be a reliable measure of disease activity.IgG4-RD is an idiopathic, multiorgan inflammatory disease in which diverse organ manifestations are linked by characteristic histopathologic and immunohistochemical features. Treatment with RTX led to prompt clinical and serologic improvement in refractory IgG4-RD in all patients with active inflammation. Serial treatments with RTX may lead to progressive declines in serum IgG4 concentrations and better disease control. Serum IgG4 concentrations may remain low, and clinical disease activity may remain quiescent even after B cell reconstitution in a significant proportion of patients.

Tocilizumab for the treatment of large-vessel vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica.

The interleukin‐6 pathway is up‐regulated in giant cell arteritis (GCA), Takayasu arteritis (TA), and polymyalgia rheumatica (PMR). We retrospectively assessed the outcomes of 10 patients with relapsing/refractory GCA, TA, or PMR treated with tocilizumab (TCZ).

Trial of Tocilizumab in Giant-Cell Arteritis

Background Giant‐cell arteritis commonly relapses when glucocorticoids are tapered, and the prolonged use of glucocorticoids is associated with side effects. The effect of the interleukin‐6 receptor alpha inhibitor tocilizumab on the rates of relapse during glucocorticoid tapering was studied in patients with giant‐cell arteritis. Methods In this 1‐year trial, we randomly assigned 251 patients, in a 2:1:1:1 ratio, to receive subcutaneous tocilizumab (at a dose of 162 mg) weekly or every other week, combined with a 26‐week prednisone taper, or placebo combined with a prednisone taper over a period of either 26 weeks or 52 weeks. The primary outcome was the rate of sustained glucocorticoid‐free remission at week 52 in each tocilizumab group as compared with the rate in the placebo group that underwent the 26‐week prednisone taper. The key secondary outcome was the rate of remission in each tocilizumab group as compared with the placebo group that underwent the 52‐week prednisone taper. Dosing of prednisone and safety were also assessed. Results Sustained remission at week 52 occurred in 56% of the patients treated with tocilizumab weekly and in 53% of those treated with tocilizumab every other week, as compared with 14% of those in the placebo group that underwent the 26‐week prednisone taper and 18% of those in the placebo group that underwent the 52‐week prednisone taper (P<0.001 for the comparisons of either active treatment with placebo). The cumulative median prednisone dose over the 52‐week period was 1862 mg in each tocilizumab group, as compared with 3296 mg in the placebo group that underwent the 26‐week taper (P<0.001 for both comparisons) and 3818 mg in the placebo group that underwent the 52‐week taper (P<0.001 for both comparisons). Serious adverse events occurred in 15% of the patients in the group that received tocilizumab weekly, 14% of those in the group that received tocilizumab every other week, 22% of those in the placebo group that underwent the 26‐week taper, and 25% of those in the placebo group that underwent the 52‐week taper. Anterior ischemic optic neuropathy developed in one patient in the group that received tocilizumab every other week. Conclusions Tocilizumab, received weekly or every other week, combined with a 26‐week prednisone taper was superior to either 26‐week or 52‐week prednisone tapering plus placebo with regard to sustained glucocorticoid‐free remission in patients with giant‐cell arteritis. Longer follow‐up is necessary to determine the durability of remission and safety of tocilizumab. (Funded by F. Hoffmann–La Roche; ClinicalTrials.gov number, NCT01791153.)

Design of the Tocilizumab in Giant Cell Arteritis Trial

Overview. The GiACTA trial is a multicenter, randomized, double-blind, and placebo-controlled study designed to test the ability of tocilizumab (TCZ), an interleukin (IL)-6 receptor antagonist, to maintain disease remission in patients with giant cell arteritis (GCA). Design. Approximately 100 centers will enroll 250 patients with active disease. The trial consists of a 52-week blinded treatment phase followed by 104 weeks of open-label extension. Patients will be randomized into one of four groups. Group A (TCZ 162 mg weekly plus a 6-month prednisone-taper); group B (TCZ 162 mg every other week plus a 6-month prednisone-taper); group C (placebo plus a 6-month prednisone-taper); and group D (placebo plus a 12-month prednisone taper). We hypothesize that patients assigned to TCZ in addition to a 6-month prednisone course are more likely to achieve the primary efficacy endpoint of sustained remission (SR) at 52 weeks compared with those assigned to a 6-month prednisone course alone, thus potentially minimizing the long-term adverse effects of corticosteroids. Conclusion. GiACTA will test the hypothesis that interference with IL-6 signaling exerts a beneficial effect on patients with GCA. The objective of this paper is to describe the design of the trial and address major issues related to its development.

New treatment strategies in large-vessel vasculitis.

Purpose of reviewRecent advancements in the understanding of the pathogenesis of large-vessel vasculitis may broaden our currently limited therapeutic possibilities. This review summarizes the available evidence for new treatment strategies in this spectrum of diseases. Recent findingsInterleukin (IL) 6 appears to be an important mediator of the pathology in large-vessel vasculitis. IL-6 is upregulated in inflamed arteries of patients with giant cell arteritis and Takayasu arteritis, and serum levels of this cytokine mirror disease activity. Encouraging preliminary results have been obtained with the IL-6 receptor (IL-6R) antagonist tocilizumab for the treatment of large-vessel vasculitides, including both giant cell arteritis and Takayasu arteritis, and the aortitis of Cogan syndrome and relapsing polychondritis. A small number of patients with Takayasu arteritis and IgG4-related aortitis have also been successfully treated with the B-cell depleting agent rituximab, and some patients with refractory Takayasu arteritis have responded to the immunomodulator leflunomide. SummaryThe possibility of biologic therapy in large vessel vasculitis has emerged. At this time, better delineation of the immunopathogenic mechanisms of this spectrum of diseases and prospective randomized clinical trials are required to move the field forward and decrease the cumulative glucocorticoid toxicity seen in these disorders.

Clinical outcomes of treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis based on ANCA type

Objective To evaluate whether the classification of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) according to ANCA type (anti-proteinase 3 (PR3) or anti-myeloperoxidase (MPO) antibodies) predicts treatment response. Methods Treatment responses were assessed among patients enrolled in the Rituximab in ANCA-associated Vasculitis trial according to both AAV diagnosis (granulomatosis with polyangiitis (GPA)/microscopic polyangiitis (MPA)) and ANCA type (PR3-AAV/MPO-AAV). Complete remission (CR) was defined as disease activity score of 0 and successful completion of the prednisone taper. Results PR3-AAV patients treated with rituximab (RTX) achieved CR at 6 months more frequently than did those randomised to cyclophosphamide (CYC)/azathioprine (AZA) (65% vs 48%; p=0.04). The OR for CR at 6 months among PR3-AAV patients treated with RTX as opposed to CYC/AZA was 2.11 (95% CI 1.04 to 4.30) in analyses adjusted for age, sex and new-onset versus relapsing disease at baseline. PR3-AAV patients with relapsing disease achieved CR more often following RTX treatment at 6 months (OR 3.57; 95% CI 1.43 to 8.93), 12 months (OR 4.32; 95% CI 1.53 to 12.15) and 18 months (OR 3.06; 95% CI 1.05 to 8.97). No association between treatment and CR was observed in the MPO-AAV patient subset or in groups divided according to AAV diagnosis. Conclusions Patients with PR3-AAV respond better to RTX than to CYC/AZA. An ANCA type-based classification may guide immunosuppression in AAV. Trial registration number NCT00104299; post-results.

Acute fibrinous and organizing pneumonia in systemic lupus erythematosus: A case report and review of the literature

Pulmonary manifestations of systemic lupus erythematosus (SLE) typically include pleuritis, alveolar hemorrhage, and infectious pneumonia due to immunosuppression with less common entities including bronchiolitis, interstitial pneumonia, and pulmonary fibrosis. More rare manifestations include organizing pneumonia (OP) and diffuse alveolar damage (DAD). A similar but distinct entity of acute fibrinous and organizing pneumonia (AFOP), characterized by intra‐alveolar fibrin deposition and associated organizing pneumonia, has been reported in association with connective tissue disorders, but has not been described in association with SLE. Reported herein is a patient with SLE and accompanying antiphospholipid syndrome with recent pulmonary embolism, persistent respiratory symptomology, and persistent radiographic abnormalities who underwent lung biopsy displaying features of AFOP. This case in conjunction with previous literature indicates that AFOP can be a manifestation of connective tissue disease including SLE and may be an underreported variant of medical lung disease due to overlap in histological characteristics with OP and DAD.

Clinical correlations with Porphyromonas gingivalis antibody responses in patients with early rheumatoid arthritis

IntroductionPrior studies have demonstrated an increased frequency of antibodies to Porphyromonas gingivalis (Pg), a leading agent of periodontal disease, in rheumatoid arthritis (RA) patients. However, these patients generally had long-standing disease, and clinical associations with these antibodies were inconsistent. Our goal was to examine Pg antibody responses and their clinical associations in patients with early RA prior to and after disease-modifying antirheumatic drug (DMARD) therapy.MethodsSerum samples from 50 DMARD-naïve RA patients were tested using an enzyme-linked immunosorbent assay with whole-Pg sonicate. For comparison, serum samples were tested from patients with late RA, patients with other connective tissue diseases (CTDs), age-similar healthy hospital personnel and blood bank donors. Pg antibody responses in early RA patients were correlated with standard RA biomarkers, measures of disease activity and function.ResultsAt the time of enrollment, 17 (34%) of the 50 patients with early RA had positive immunoglobulin G (IgG) antibody responses to Pg, as did 13 (30%) of the 43 patients with late RA. RA patients had significantly higher Pg antibody responses than healthy hospital personnel and blood bank donors (P < 0.0001). Additionally, RA patients tended to have higher Pg antibody reactivity than patients with other CTDs (P = 0.1), and CTD patients tended to have higher Pg responses than healthy participants (P = 0.07). Compared with Pg antibody-negative patients, early RA patients with positive Pg responses more often had anti-cyclic citrullinated peptide (anti-CCP) antibody reactivity, their anti-CCP levels were significantly higher (P = 0.03) and the levels of anti-Pg antibodies correlated directly with anti-CCP levels (P < 0.01). Furthermore, at the time of study entry, the Pg-positive antibody group had greater rheumatoid factor values (P = 0.04) and higher inflammatory markers (erythrocyte sedimentation rate, or ESR) (P = 0.05), and they tended to have higher disease activity scores (Disease Activity Score based on 28-joint count (DAS28)-ESR and Clinical Disease Activity Index) and more functional impairment (Health Assessment Questionnaire). In Pg-positive patients, greater disease activity was still apparent after 12 months of DMARD therapy.ConclusionsA subset of early RA patients had positive Pg antibody responses. The responses correlated with anti-CCP antibody reactivity and to a lesser degree with ESR values. There was a trend toward greater disease activity in Pg-positive patients, and this trend remained after 12 months of DMARD therapy. These findings are consistent with a role for Pg in disease pathogenesis in a subset of RA patients.

The Heart in Vasculitis

All primary vasculitides can target the heart, but this complication is more frequent in TAK, PAN, and EGPA. Although pericarditis is seen in virtually all forms of vasculitis, it rarely becomes a significant clinical problem. Myocarditis is more prevalent in EGPA and TAK, and coronary angiitis is most common in TAK, PAN, and BD. In addition, AI is a classic complication of TAK-induced aortitis, and intracavitary cardiac thrombus formation mainly affects patients with BD. Myocarditis, coronary arteritis, and valvular disease can lead to congestive heart failure and represent poor prognostic factors that require aggressive therapy. Imaging and pathology studies have found that subclinical involvement is common (e.g., TAK, PAN, EGPA, GPA, and BD). Management differs depending on the cardiac structure involved and the activity of the disease.Although pericarditis can be treated with NSAIDs, colchicine, or-low dose prednisone, myocarditis and coronary vasculitis require high doses of CS and frequently cytotoxic agents. Valvular lesions, coronary arteriopathy, and ventricular thrombosis often need surgical intervention. In the face of active disease, clinical judgment is important to help weigh the risks and benefits of delaying surgery versus operating in possibly inflamed tissues. As in other rheumatic diseases, risks factors for atherosclerosis (eg, hypertension, dyslipidemia) should be identified and corrected. Finally, heart failure–and ischemia-targeted therapies are important components of the treatment strategy when indicated.

Improved survival in granulomatosis with polyangiitis: A general population-based study.

BACKGROUND Granulomatosis with polyangiitis (GPA) is associated with an increased risk of mortality; however, recent mortality trends in GPA are unknown. We evaluated this issue in a general population context. METHODS Using data collected between 1992 and 2013 by The Health Improvement Network in the United Kingdom, we identified individuals diagnosed as incident cases of GPA and up to 10 non-GPA controls matched on sex, age, year of birth, and year of GPA diagnosis. The cohort was divided into two based on the year of diagnosis (i.e., 1992-2002 and 2003-2013) to evaluate changes in mortality. We calculated hazard ratios for death using a Cox-proportional hazards model and the rate differences using an additive hazard model, while adjusting for potential confounders. RESULTS We identified 465 cases of GPA (mean age: 60 years, 52% male). The early cohort (1992-2002) GPA patients had considerably higher mortality rates than the late cohort (2003-2013) (i.e., 72.0 vs. 35.7 cases per 1000 person-years), as compared with a moderate improvement in the comparison cohorts between the two periods (19.8 vs. 17.0 cases per 1000 person-years). The corresponding absolute mortality rate difference was 52.2 (95% CI: 25.1-79.2) cases and 18.7 (95% CI: 8.3-29.1) cases per 1000 person-years (p for interaction = 0.025). The resulting HRs for mortality were 4.34 (95% CI: 2.72-6.92) and 2.41 (95% CI: 1.74-3.34), respectively (p for interaction = 0.043). CONCLUSION This population-based study suggests that survival of GPA patients has improved considerably over the past 2 decades, affirming the benefits of recent trends in the management of GPA and its complications.