Yousuf Karim

Anti-dsDNA, anti-Sm antibodies, and the lupus anticoagulant: significant factors associated with lupus nephritis

Background: Lupus nephritis (LN) is a common manifestation in patients with systemic lupus erythematosus (SLE). Autoantibodies and ethnicity have been associated with LN, but the results are controversial. Objective: To study the immunological and demographic factors associated with the development of LN. Patients and methods: A retrospective case-control study of 127 patients with biopsy-proven LN, and 206 randomly selected patients with SLE without nephritis as controls was designed. All patients had attended our lupus unit during the past 12 years. Standard methods were used for laboratory testing. Results: Patients with LN were significantly younger than the controls at the time of SLE diagnosis (mean (SD) 25.6 (8.8) years v 33.7 (12.5) years; p<0.0001). The proportion of patients of black ethnic origin was significantly higher in the group with nephritis (p=0.02). There were no differences in sex distribution or duration of follow up. A higher proportion of anti-dsDNA, anti-RNP, anti-Sm, and lupus anticoagulant (LA) was seen in the group with nephritis (p=0.002; p=0.005; p=0.0001; p=0.01, respectively). In univariate, but not in multivariate, analysis male sex and absence of anti-dsDNA were associated with earlier onset of renal disease (p=0.03; p=0.008). In multivariate analysis the only factors associated with nephritis were younger age at diagnosis of SLE, black race, presence of anti-dsDNA, anti-Sm, and LA. No demographic or immunological associations were seen with WHO histological classes. Conclusions: Young, black patients with anti-dsDNA, anti-Sm antibodies, and positive LA, appear to have a higher risk of renal involvement. These patients should be carefully monitored for the development of LN.

Mycophenolate mofetil and systemic lupus erythematosus: an overview

Mycophenolate mofetil (MMF) is an immunosuppressive agent used in transplantation, with evidence of superior protection against acute transplant rejection compared to azathioprine-containing regimens. Subsequently MMF has been used in a variety of autoimmune conditions. The major experience in systemic lupus erythematosus (SLE) has focused on proliferative lupus nephritis. Following its success in the treatment of lupus nephritis, MMF is now being used to control other SLE manifestations such as, lupus disease activity, haematological manifestations and resistant skin lupus. In this review, we discuss our own experience and the literature report about the use of MMF in SLE.

The relationship between pro-resorptive inflammatory cytokines and the effect of high dose vitamin D supplementation on their circulating concentrations

Inflammatory/pro-resorptive cytokines and chemokines form part of a complex inter-dependent network and may be influenced by vitamin D. We investigated their inter-relationship and the effect of a loading dose of vitamin D. We measured plasma concentrations of an array of cytokines including tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), IL-6, IL-17, IL-8, granulocyte macrophage colony stimulating factor (GM-CSF), and the chemokine monocyte chemoattractant protein-1 (MCP-1). Cytokines, 25 (OH) vitamin D, 1,25 (OH)2 vitamin D, the Wnt inhibitor, DKK1 concentrations and bone turnover markers were measured at baseline and 3 months following a bolus dose (300,000 IU) of vitamin D2 in 39 subjects with vitamin D insufficiency. We observed strong correlations between TNF-α with GM-CSF (r=0.628, p<0.001), IL-17 (r=0.7, p<0.001) and MCP-1 (r=0.5, p=0.001), between IL-1β with IL-17 (r=0.45, p=0.004) and between the 2 chemokines, IL-8 and MCP-1 (r=0.45, p=0.004). A positive correlation was seen between DKK1 and IL-1β (r=0.35, p=-0.029). Following vitamin D loading at 3 months, the relationships between some of the cytokines changed (TNF-α and MCP-1: r=0.38, p=0.017, IL-1β and IL-17: r=0.3, p=0.06). 1,25 (OH)2 vitamin D increased markedly following supplementation. Significant correlations were seen between 25 (OH) vitamin D (r=0.4 p=0.016) and 1,25 (OH)2 vitamin D (r=0.39 p=0.02) with plasma CTX (marker of bone resorption) at 3 months. TNF-α and IL-1β increased significantly at 3 months (p<0.05). The close association between several cytokines is influenced by vitamin D status. Acute increases in 1,25 (OH)2 vitamin D, achieved with loading doses of vitamin D, lead to increases in pro-resorptive cytokines.

The association of pure red cell aplasia with the antiphospholipid syndrome.

Sir — Pure red cell aplasia (PRCA) has been reported in association with a variety of autoimmune disorders including systemic lupus erythematosus (SLE). However PRCA has not previously been reported in association with antiphospholipid syndrome. We present the case of a 41-year-old lady with a background medical history of auto-immune hypothyroidism, coeliac disease and primary infertility. She was otherwise well until 1989 when she suffered a deep vein thrombosis of the right calf, treated with warfarin for 2 years. In 1998 she developed a Coombs-positive haemolytic anaemia treated with blood transfusion and high-dose oral corticosteroids for 4 months. In 1999 she developed chest pains following a transatlantic flight and subsequent angiography demonstrated a right coronary artery thrombosis which was treated with urokinase. Her INR at the time of the event was 1.0. She developed a right sided hemiplegia on recovery from the procedure and CT scan revealed a cerebrovascular infarct in the left middle cerebral artery territory. She was fully anticoagulated with warfarin and transferred back to the UK for rehabilitation. On admission, she was found to have an expressive dysphasia with a right-sided spastic hemiplegia. She was normotensive and there were no significant cardiac murmurs or carotid bruit. No synovitis or active vasculitis was clinically detectable. Her full blood count showed Hb 8.2 g=dl (MCV 78) platelets 340 10=l WBC 5.6 10=l. Renal function and liver function tests were normal. The inflammatory markers were raised with a C-reactive protein (CRP) of 26 mg=l and ESR of 130 mm=h. The ferritin, vitamin B12 and folate were within normal limits and the Coombs’ test was positive. An autoimmune screen showed a negative rheumatoid factor, extractable nuclear antigens, weakly positive ANA (titre of 1:20) and a positive Crithidia DNA (IgG titre 10, normal 0 – 1) with normal complement levels. A full thrombophilia screen including antithrombin III, protein C, protein S and factor V leiden was unremarkable. Her anticardiolipin antibody was strongly positive with IgG 79.0 GPL U=ml (normal< 20) and IgM 24.5 MPL U=ml (normal < 20) and this was confirmed on subsequent testing. It was therefore decided to perform a bone marrow biopsy to help establish the cause of her anaemia. This showed a markedly hypercellular marrow due to expansion of leucopoesis with a complete absence of red cell precursors. These findings were compatible with pure red cell aplasia with no evidence of myelodysplasia. She received a 4 unit blood transfusion and was commenced on prednisolone initially at a dose of 60 mg once daily. The anaemia responded well to this treatment and her corticosteroid dose is being gradually reduced.

Use of intravenous immunoglobulin in patients with active vasculitis associated with concomitant infection.

he vasculitides are a heterogeneous group of diseases, comT prising necrotizing and nonnecrotizing vessel diseases. Patients with vasculitis frequently develop infections, mainly as a consequence of treatments prescribed to treat their disease. Corticosteroids, immunosuppressants, and most immunomodulating agents (eg, anti–tumor necrosis factor or anti-CD20 monoclonal antibodies) facilitate infections, and combined therapies further increase that risk. In immunosuppressed patients, infections are sometimes life threatening and are one of the major causes of deaths. However, active vasculitis and infection can coexist, and treatment for these conditions is a challenge for physicians. Therefore, alternative therapeutic approaches rather than conventional immunosuppressants are needed to limit the disease activity when a concomitant infection is suspected. Intravenous immunoglobulin (IVIG) has been used as a replacement therapy in patients with primary and secondary immunodeficiencies and in the treatment of many autoimmune and systemic inflammatory disorders. Moreover, their potential role against infections has been speculated. In the spectrum of systemic vasculitis, there is clear evidence of the benefit of IVIG in Kawasaki disease, and it is now also considered a therapeutic option in refractory antineutrophil cytoplasmic antibody–associated vasculitis. 5 For other vasculitis, such as polyarteritis nodosa, Henoch-Schönlein purpura (HSP), or Behçet disease (BD), only a few case reports have described a beneficial effect of IVIG. We report the largest cohort focusing on clinical effects of IVIG in patients with active vasculitis and concomitant infection.

New Therapeutic Strategies in Lupus Nephritis

Lupus nephritis remains a major cause of morbidity and mortality in systemic lupus erythematosus (SLE). Despite overall advances in the clinical management of lupus nephritis in recent decades with earlier recognition of disease and optimization of the currently available immunosuppressive regimens, an estimated 10-15% of patients progress to end-stage renal disease (ESRD) requiring dialysis and/or renal transplantation (Mavragani et al, 2003). Proliferative lupus nephritis (International Society of Nephrology/Renal Pathology Society classes III & IV) is the most aggressive variant of nephritis; figures 1 and 2 illustrate the histology of Class IV nephritis.

Thalidomide in Cutaneous Lupus Erythematosus

practice in the mid-1950s; since that time, it has had a remarkable checkered history. It was used early on as an over-the-counter sedative (Mellin and Katzenstein 1962), and then in the treatment of morning sickness in pregnancy. However, in 1961, thalidomide was withdrawn from the market because of the discovery of its potential teratogenicity– it was associated with up to 12,000 cases of birth defects, particularly phocomelias (Mellin 1962, Randall 1990). Four years later, Sheskin serendipitously discovered that thalidomide had marked clinical efficacy in erythema nodosum leprosum (Sheskin 1965). Subsequently, a variety of conditions, including infectious, autoimmune, inflammatory, and malignant, have been shown to respond to thalidomide. Examples of these conditions include human immunodeficiency virus (HIV) infection (Reyes-Teran et al. 1996), rheumatoid arthritis (Gutierrez-Rodriguez et al. 1989), Behcet’s syndrome (Hamuryudan et al. 1998), graft-versus-host disease (Vogelsang et al. 1993), multiple myeloma (Singhal et al. 1999), and cutaneous features of lupus erythematosus (LE) (Knop et al. 1983). The latter include systemic LE (SLE) with cutaneous features, discoid LE (DLE), and subacute cutaneous LE (SCLE). The common denominator of the previously mentioned differing conditions seems to be that they are all characterized by inflammation, immune dysregulation, or both. Thalidomide has been shown to have immunomodulatory, immunosuppressive, and anti-inflammatory actions, which may explain its therapeutic efficacy. Furthermore, thalidomide is often effective in conditions in which standard therapies have failed to make an impression, for example, severe ulceration in Behcet’s syndrome or severe cutaneous lupus. Clinical use of thalidomide must, of course, be tightly regulated and supervised, not only because of the potential for teratogenicity, especially as many patients with lupus are young women, but also for the development of peripheral neuropathy.In this article,we discuss possible mechanisms of action and the clinical experience of thalidomide in the treatment of cutaneous features of LE.