Manuel Ramos-Casals

Morbidity and mortality in systemic lupus erythematosus during a 10-year period. A comparison of early and late manifestations in a cohort of 1,000 patients.

In the present study, we assessed the frequency and characteristics of the main causes of morbidity and mortality in systemic lupus erythematosus (SLE) during a 10-year period and compared the frequency of early manifestations with those that appeared later in the evolution of the disease. In 1990, we started a multicenter study of 1,000 patients from 7 European countries. All had medical histories documented and underwent medical interview and routine general physical examination when entered in the study, and all were followed prospectively by the same physicians during the ensuing 10 years (1990–2000).A total of 481 (48.1%) patients presented 1 or more episodes of arthritis at any time during the 10 years, 311 (31.1%) patients had malar rash, 279 (27.9%) active nephropathy, 194 (19.4%) neurologic involvement, 166 (16.6%) fever, 163 (16.3%) Raynaud phenomenon, 160 (16.0%) serositis (pleuritis and/or pericarditis), 134 (13.4%) thrombocytopenia, and 92 (9.2%) thrombosis. When the prevalences of the clinical manifestations during the initial 5 years of follow-up (1990–1995) were compared with those during the ensuing 5 years (1995–2000), most manifestations were found to be more frequent during the initial 5 years. Of the 1,000 patients, 360 (36%) presented infections, 169 (16.9%) hypertension, 121 (12.1%) osteoporosis, and 81 (8.1%) cytopenia due to immunosuppressive agents. Twenty-three (2.3%) patients developed malignancies; the most frequent primary localizations were the uterus and the breast.Sixty-eight (6.8%) patients died, and the most frequent causes of death were similarly divided between active SLE (26.5%), thromboses (26.5%), and infections (25%). A survival probability of 92% at 10 years was found. A lower survival probability was detected in those patients who presented at the beginning of the study with nephropathy (88% versus 94% in patients without nephropathy, p = 0.045). When the causes of death during the initial 5 years of follow-up (1990–1995) were compared with those during the ensuing 5 years (1995–2000), active SLE and infections (28.9% each) appeared to be the most common causes during the initial 5 years, while thromboses (26.1%) became the most common cause of death during the last 5 years.In conclusion, most of the SLE inflammatory manifestations appear to be less common after a long-term evolution of the disease, probably reflecting the effect of therapy as well as the progressive remission of the disease in many patients. Meanwhile, a more prominent role of thrombotic events is becoming evident, affecting both morbidity and mortality in SLE.

Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases.

Tumor necrosis factor (TNF)-targeted therapies are increasingly used for a rapidly expanding number of rheumatic and autoimmune diseases. With this use and longer follow-up periods of treatment, there are a growing number of reports of the development of autoimmune processes related to anti-TNF agents. We have analyzed the clinical characteristics, outcomes, and patterns of association with the different anti-TNF agents used in all reports of autoimmune diseases developing after TNF-targeted therapy found through a MEDLINE search of articles published between January 1990 and December 2006. We identified 233 cases of autoimmune diseases (vasculitis in 113, lupus in 92, interstitial lung diseases in 24, and other diseases in 4) secondary to TNF-targeted therapies in 226 patients. The anti-TNF agents were administered for rheumatoid arthritis (RA) in 187 (83%) patients, Crohn disease in 17, ankylosing spondylitis in 7, psoriatic arthritis in 6, juvenile RA in 5, and other diseases in 3. The anti-TNF agents administered were infliximab in 105 patients, etanercept in 96, adalimumab in 21, and other anti-TNF agents in 3. We found 92 reported cases of lupus following anti-TNF therapy (infliximab in 40 cases, etanercept in 37, and adalimumab in 15). Nearly half the cases fulfilled 4 or more classification criteria for systemic lupus erythematosus (SLE), which fell to one-third after discarding preexisting lupus-like features. One hundred thirteen patients developed vasculitis after receiving anti-TNF agents (etanercept in 59 cases, infliximab in 47, adalimumab in 5, and other agents in 2). Leukocytoclastic vasculitis was the most frequent type of vasculitis, and purpura was the most frequent cutaneous lesion. A significant finding was that one-quarter of patients with vasculitis related to anti-TNF agents had extracutaneous involvement. Twenty-four cases of interstitial lung disease associated with the use of anti-TNF agents were reported. In these patients, 2 specific characteristics should be highlighted: the poor prognosis in spite of cessation of anti-TNF therapy, and the possible adjuvant role of concomitant methotrexate. In conclusion, the use of anti-TNF agents has been associated with an increasing number of cases of autoimmune diseases, principally cutaneous vasculitis, lupus-like syndrome, SLE, and interstitial lung disease. Abbreviations: ANA = antinuclear antibodies, ANCA = antineutrophil cytoplasmic antibodies, aPL = antiphospholipid antibodies, CNS = central nervous system, ILD = interstitial lung disease, RA = rheumatoid arthritis, SLE = systemic lupus erythematosus, TNF = tumor necrosis factor.

Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review

Background: Antimalarial drugs (AMs), chloroquine (CQ) and hydroxychloroquine (HCQ), are frequently withdrawn in patients with lupus with either severe or remitting disease. However, additional effects beyond immunomodulation have been recently described. The aim of the present work was to analyse all the published evidence of the beneficial and adverse effects of AM therapy in systemic lupus erythematosus (SLE). Methods: A systematic review of the English literature between 1982 and 2007 was conducted using the MEDLINE and EMBASE databases. Randomised controlled trials (RCTs) and observational studies were selected. Case reports were excluded except for toxicity reports. The GRADE system was used to analyse the quality of the evidence. Results: A total of 95 articles were included in the systematic review. High levels of evidence were found that AMs prevent lupus flares and increase long-term survival of patients with SLE; moderate evidence of protection against irreversible organ damage, thrombosis and bone mass loss. Toxicity related to AMs is infrequent, mild and usually reversible, with HCQ having a safer profile. In pregnant women, high levels of evidence were found that AMs, particularly HCQ, decrease lupus activity without harming the baby. By contrast, evidence supporting an effect on severe lupus activity, lipid levels and subclinical atherosclerosis was weak. Individual papers suggest effects in preventing the evolution from SLE-like to full-blown SLE, influencing vitamin D levels and protecting patients with lupus against cancer. Conclusions: Given the broad spectrum of beneficial effects and the safety profile, HCQ should be given to most patients with SLE during the whole course of the disease, irrespective of its severity, and be continued during pregnancy.

Catastrophic antiphospholipid syndrome: clues to the pathogenesis from a series of 80 patients.

The antiphospholipid syndrome (APS), originally defined as the combination of venous or arterial thrombotic events, recurrent fetal loss, and, frequently, a moderate thrombocytopenia in association with antiphospholipid antibodies (aPL), was subsequently greatly expanded to include diverse conditions, for example, heart valve lesions, adrenal insufficiency, and pulmonary syndromes such as acute respiratory distress syndrome (ARDS), “capillaritis,” and pulmonary alveolar hemorrhage, among others (16, 17). It was then realized that several “microangiopathic syndromes” also existed, as opposed to large vessel occlusive disease. Single organs, such as the kidneys, heart, skin, and brain, have been affected by this “thrombotic microangiopathy” in the context of the “classic” or “simple” APS. The temporal occurrence of thrombotic events in patients with this classic APS usually extends over months or years. In 1992, the existence of a new “subset” was described in which multiple vascular occlusive events, usually affecting small vessels supplying organs and presenting over a short period of time, were the outstanding features. This subset was termed the “catastrophic” APS. Although large vessel occlusions were also present, their prevalence did not in any way approach that in patients with the classic APS. The occlusions occurred over days to several weeks, and more than 50% of patients usually succumbed despite seemingly adequate therapy, including anticoagulation, steroids, etc. (6). In 1998, a comprehensive review article with the clinical and laboratory description of 50 such patients was published (8). In the present paper we describe the clinical and serologic features of the largest series of patients with catastrophic APS hitherto reported, including 30 new cases from interested physicians in many different countries, as well as a comprehensive literature review of 50 additional recently published case reports with this syndrome. This new series, comprising a total of 80 patients, enables us to analyze further and clarify not only the clinical importance of this syndrome, but also its pathogenesis. 0025-7974/01/8006-0355/0 MEDICINE® 80: 355-77, 2001 Vol. 80, No. 6 Copyright

Primary Sjögren syndrome: clinical and immunologic disease patterns in a cohort of 400 patients.

IntroductionSjogren syndrome (SS) is a systemic autoimmune disease that mainly affects the exocrine glands and usually presents as persistent dryness of the mouth and eyes due to functional impairment of the salivary and lacrimal glands (12). In the absence of an associated systemic autoimmune

Primary Sjögren syndrome in Spain: clinical and immunologic expression in 1010 patients.

We conducted the current study to characterize the clinical presentation of primary Sjögren syndrome (SS) in a large cohort of Spanish patients and to determine whether epidemiologic, clinical, and analytical features modulate disease expression. Patients were from the GEMESS Study group, which was formed in 2005 and included 12 Spanish reference centers. By March 2007, the database included 1010 consecutive patients, recruited since 1994, both incident and prevalent cases. The cohort included 937 women and 73 men (ratio, 13:1), with a mean age of 53 years at diagnosis and 59 years at inclusion in the registry. Multivariate analysis showed that male patients had a lower frequency of thyroiditis, Raynaud phenomenon, and antinuclear antibodies. Young-onset patients had a low degree of sicca involvement (xerostomia and parotid enlargement) and a high frequency of immunologic markers (anti-Ro/SS-A and low C4 levels). Patients with disease duration of more than 10 years had a higher prevalence of xerophthalmia, parotid enlargement, lung involvement, and peripheral neuropathy in comparison with incident cases. The subset of patients with anti-Ro/La antibodies had the highest prevalence of most systemic, hematologic, and immunologic alterations (higher frequency of Raynaud phenomenon, altered parotid scintigraphy, positive salivary gland biopsy, peripheral neuropathy, thrombocytopenia, and rheumatoid factor). Hypocomplementemia was associated with a higher frequency of vasculitis and lymphoma, and cryoglobulins with a higher frequency of parotid enlargement, vasculitis, and leukopenia. Epidemiologic, clinical, and analytical features have a significant impact on the clinical presentation of primary SS, influencing the results of the main diagnostic tests, the prevalence and diversity of extraglandular involvement, and the frequency of the main immunologic markers. Primary SS should be considered as a systemic autoimmune disease that can express in many guises beyond sicca involvement. Abbreviations: ANA = antinuclear antibodies, CNS = central nervous system, RF = rheumatoid factor, SS = Sjögren syndrome.

Rituximab in systemic lupus erythematosusA systematic review of off-label use in 188 cases

The complexity of the therapeutic approach in systemic lupus erythematosus (SLE) is increased by the large number of patients who do not respond to the first-line therapies and by relapses after initial clinical remission. In these patients, second-line drugs are often prescribed according to individual clinical decisions. The emergence of biological therapies has increased the therapeutic armamentarium available in these complex situations, but their use is limited by the lack of licensing. Available data on the use of rituximab in SLE rely on a large number of case reports and some observational studies. We analyzed current evidence on the therapeutic use of rituximab in adult SLE patients by a systematic review of reports included in the PubMed database between 2002 and 2007. A total of 188 SLE patients treated with rituximab were identified; 171 (91%) patients showed a significant improvement in one or more of the systemic SLE manifestations. There were 103 patients with lupus nephritis, with an overall rate of therapeutic response of renal involvement of 91%. Adverse events were reported in 44 (23%) patients; the most frequent were infections (19%). Although it is not yet possible to make definite recommendations, the global analysis of all cases reported to date support the off-label use of rituximab in severe, refractory SLE cases, whereas its use as a first-line therapy or in patients with a predominantly mild form of the disease is not advised.

Treatment of Primary Sjögren Syndrome: A Systematic Review

CONTEXT A variety of topical and systemic drugs are available to treat primary Sjögren syndrome, although no evidence-based therapeutic guidelines are currently available. OBJECTIVE To summarize evidence on primary Sjögren syndrome drug therapy from randomized controlled trials. DATA SOURCES We searched MEDLINE and EMBASE for articles on drug therapy for primary Sjögren syndrome published between January 1, 1986, and April 30, 2010. STUDY SELECTION Controlled trials of topical and systemic drugs including adult patients with primary Sjögren syndrome were selected as the primary information source. RESULTS The search strategy yielded 37 trials. A placebo-controlled trial found significant improvement in the Schirmer and corneal staining scores, blurred vision, and artificial tear use in patients treated with topical ocular 0.05% cyclosporine. Three placebo-controlled trials found that pilocarpine was associated with improvements in dry mouth (61%-70% vs 24%-31% in the placebo group) and dry eye (42%-53% vs 26%). Two placebo-controlled trials found that cevimeline was associated with improvement in dry mouth (66%-76% vs 35%-37% in the placebo group) and dry eye (39%-72% vs 24%-30%). Small trials (<20 patients) found no significant improvement in sicca outcomes for oral prednisone or hydroxychloroquine and limited benefits for immunosuppressive agents (azathioprine and cyclosporine). A large trial found limited benefits for oral interferon alfa-2a. Two placebo-controlled trials of infliximab and etanercept did not achieve the primary outcome (a composite visual analog scale measuring joint pain, fatigue, and dryness); neither did 2 small trials (<30 patients) testing rituximab, although significant results were observed in some secondary outcomes and improvement compared with baseline. CONCLUSIONS In primary Sjögren syndrome, evidence from controlled trials suggests benefits for pilocarpine and cevimeline for sicca features and topical cyclosporine for moderate or severe dry eye. Anti-tumor necrosis factor agents have not shown clinical efficacy, and larger controlled trials are needed to establish the efficacy of rituximab.

Adult haemophagocytic syndrome

Haemophagocytic syndromes (haemophagocytic lymphohistiocytosis) have a wide range of causes, symptoms, and outcomes, but all lead to a hyperinflammatory response and organ damage--mainly reported in paediatric patients, but reports of adult presentation are increasing. Analysis of the genetic and molecular pathophysiology of these syndromes have improved the understanding of the crosstalk between lymphocytes and histiocytes and their regulatoty mechanisms. Clinical presentations with a broad differential diagnosis, and often life-threatening outcome, complicate the management, which might include supportive intensive care, immunosuppressive and biological treatments, or haemopoietic stem cell transplantation. Insufficient knowledge of these syndromes could contribute to poor prognosis. Early diagnosis is essential to initiate appropriate treatment and improve the quality of life and survival of patients with this challenging disorder.

Autoimmune diseases induced by TNF-targeted therapies

Anti-TNF agents are increasingly being used for a rapidly expanding number of rheumatic and systemic autoimmune diseases. As a result of this use, and of the longer follow-up periods of treatment, there are a growing number of reports of the development of autoimmune processes related to anti-TNF agents. The clinical characteristics, outcomes, and patterns of association with the different anti-TNF agents used in all reports of autoimmune diseases developing after TNF-targeted therapy, were analyzed through a baseline Medline search of articles published between January 1990 and May 2008 (www.biogeas.org). A total of 379 cases of autoimmune diseases secondary to TNF-targeted therapies were identified. The anti-TNF agents were administered for rheumatoid arthritis in more than 80% of cases. The use of anti-TNF agents has been associated with an increasing number of cases of autoimmune diseases, principally cutaneous vasculitis, lupus-like syndrome, systemic lupus erythematosus and interstitial lung disease. Other autoimmune diseases associated with TNF-targeted therapies have been recently described, e.g. sarcoidosis, antiphospholipid syndrome-related features, and autoimmune hepatitis or uveitis. Large, prospective, postmarketing studies are required to evaluate the risk of developing autoimmune diseases in patients receiving TNF-targeted therapies.