The history of antiphospholipid syndrome.

Antiphospholipid Syndrome (APS) is an autoimmune disease which was defined in the early 1980s. The principal features include thromboembolic events and/or pregnancy losses in association with antiphospholipid antibodies (aPL). As an historical note, the full-blown picture of the syndrome resembles the illness suffered by Anne Stuart, Queen of England in the XVIII century, whose repeated miscarriages caused the end of the royal Stuart line and the Hanoverian succession. The identification of aPL started in the early XX century and was linked to the introduction of the serological test for the diagnosis of syphilis. This involves a reaction between an antibody (reagin) and a phospholipid antigen derived from bovine heart (cardiolipin). Later on, it was observed that not all subjects with a positive test had syphilis, and that the so called "false positive reaction" was often reported in patients with systemic lupus erythematosus. Different tests for the identification of aPL were subsequently developed: first lupus anticoagulant (1971) and then immunoassays for anticardiolipin (1983) and anti-beta2 glycoprotein I (1990) antibodies. In the same period the association between the presence of circulating aPL and thrombotic and obstetric events was established, both in patients with autoimmune diseases and in otherwise healthy subjects, leading to the identification of APS as a distinct autoimmune disease. This has allowed better diagnosis and more targeted treatment for many patients.

Academic training in rheumatology in 2009: a UK trainee survey.

Significant changes to the structure and entry into specialist training continue to be implemented. This is likely to have had a long-term impact on rheumatology service provision and the proportion of trainees undertaking academic medicine. An online questionnaire was sent to all trainees on the Joint Royal Colleges Postgraduate Training Board (JRCPTB) database. Out of 211 trainees, 141 responded (66.8%). Of these, 33 (23%) were registered for, or had been awarded, an MD or PhD with a wide variety of funding sources. Mainstream funding sources included Arthritis Research UK, the Medical Research Council, the National Institute for Health Research and the Wellcome Trust, but a substantial number of trainees (n = 17, 51.5%) also utilised other sources of funding. The data from this study will be valuable in the planning of future rheumatology training and academic career pathways and provide useful comparative data for other medical specialties.

A randomised controlled trial of subcutaneous sodium salicylate therapy for osteoarthritis of the thumb.

BACKGROUND: Current treatment for osteoarthritis (OA) is limited. Many patients with OA of the hand have areas of tender subcutaneous thickening in the forearm and upper scapular region. A pilot study showed an improvement in pain from OA at the first carpometacarpal joint after injection of such areas with 0.5% sodium salicylate or saline, an inexpensive treatment that can be administered by general practitioners and nurses. The study indicated that a randomised, sham-controlled trial was justified. METHODS: 40 patients with OA of the first carpometacarpal joint were randomised to receive either injections of sodium salicylate into tender, thickened areas of subcutaneous tissue on the forearm (baseline) and upper scapular region (week 1) or sham injections consisting of pressure without skin penetration. Blinded assessments were made at weeks 3, 7 and 13 after baseline. RESULTS: Pain and tenderness during follow-up were both significantly lower in the active treatment group compared with the sham group: 19% and 14% greater reduction in mean visual analogue scale (VAS) score, respectively (p=0.007 and 0.02, baseline mean 5.65 and 5.35 cm, average difference in change from baseline VAS 1.9 and 1.4 cm, 95% CI 0.6 to 3.2 and 0.2 to 2.5). Active and sham injections were painful, the former significantly more so; however, there was no significant correlation between the pain of active injections and response. CONCLUSION: The data show that subcutaneous sodium salicylate injections are an effective symptomatic treatment for OA of the thumb. The results provide a basis for further physiological and therapeutic research in this area.

Idiotypic markers of polyclonal B cell activation. Public idiotypes shared by monoclonal antibodies derived from patients with systemic lupus erythematosus or leprosy.

We investigated idiotypic markers of monoclonal antibodies derived from patients with polyclonal B-cell activation. Four monoclonal antibodies with different ligand binding specificities derived from a patient with lepromatous leprosy and three monoclonal anti-DNA antibodies from two patients with SLE were studied. Three new public idiotopes, which were common to monoclonal antibodies from all three patients, were defined by five polyclonal rabbit antiidiotypes, two monoclonal mouse antiidiotopes, and a monoclonal mouse antibody against a synthetic peptide that contains residues of the heavy chain CDR-1 of a monoclonal lupus anti-DNA antibody. The antibody against the synthetic idiotype was found to react with native immunoglobulins in solution. One idiotope was found to be consistently immunogenic in all animals tested. Since the three patients are of different ethnic origins, these shared idiotypes are probably encoded by germline V genes. These genes may be recurrently expressed in states of polyclonal B-cell activation, regardless of etiology. The results suggest that some autoantibodies arise by expansion of a pool of precursors in the normal antibody repertoire.

Autoantibodies to DNA.

Naturally occurring antibodies directed against the principal component of the gene are conceptually remarkable as well as of great interest to both basic and applied immunologists. In this article, some of the important literature concerning these antibodies are reviewed, concentrating on studies performed during the last 5 years. One of the major recent advances has been the generation of monoclonal anti-DNA antibodies, studies of which have shed light on the ligand-binding characteristics, idiotypic properties, and genetic origin of anti-DNA and other autoantibodies. The major current hypotheses for the origin of autoantibodies and, in particular, present evidence that anti-DNA antibodies are part of the normal immune repertoire are also discussed. Finally, the evidence that certain subgroups of anti-DNA antibodies may be pathogenic is examined.

The role of citrullinated protein antibodies in predicting erosive disease in rheumatoid arthritis: a systematic literature review and meta-analysis.

Background. Autoantibodies to citrullinated peptides have been shown to be valuable in the diagnosis of rheumatoid arthritis (RA). The expanding repertoire of antibodies to citrullinated peptide antigens (ACPA) has been a topic of great interest in recent reviews and research studies, as has the ability of these autoantibodies to predict disease outcome. Objectives. The aim of this review was to provide an update on the relevance of ACPA as prognostic markers in RA. The ability to identify patients predisposed to an aggressive outcome at the time of initial diagnosis greatly facilitates the selection of appropriate and cost-effective treatment. Methods. A systematic review of the literature was carried out. Studies from 1967 up to June 2014 with data on prognostic value of ACPA were included. Quality assessment was done by using the modified Hayden list for prognostic studies. Meta-analysis was performed using BioStat software. Results. The results of 25 studies were selected for the final review. A total of 6421 patients with RA were included, mainly in inception cohorts, with follow-up duration ranging from one year to ten years. All studies carried prognostic data on all available isotypes of anticyclic citrullinated protein (CCP), while four had data on antimutated citrullinated vimentin (MCV). There was a single relevant study each on anticitrullinated enolase peptide 1 (CEP1) and antichimaeric fibrin/filaggrin citrullinated peptide 1 (CFFCP1). All studies showed ACPA to be strong predictors of joint erosions in RA. Other factors, particularly baseline erosions, showed an additive effect. Anti-MCV appeared to be a marker of a more aggressive form of disease. Ten studies had data on which a meta-analysis could be performed. This gave an overall odds ratio of 4.85 for ACPA (anti-CCP/MCV) positivity being predictive for the development of joint erosions. Two studies with data on anti-CEP1 and anti-CFFCP1 also showed this positive predictive role of ACPA for joint erosions. Conclusions. ACPA are strong predictors of severity in RA. Their use should be part of routine rheumatology practice.

A monoclonal antibody with broad anti-HLA-DR activity fails to bind to DRw11/Dw5: possible effect of a unique polymorphism on the beta 1 domain alpha-helix.

We describe the generation and characterization of a murine monoclonal antibody with broad anti-HLA-DR beta activity, but which does not recognize DRw11/Dw5. A BALB/c mouse was immunized with a human alloreactive T-cell clone, with the intention of generating monoclonal anti-T-cell-receptor antibodies. In the course of screening the resulting hybridomas, a clone was detected which secreted an antibody (MP2) with anti-HLA-DR activity. This was shown by flow cytometry as well as immunoprecipitation followed by gel electrophoresis. Flow cytometry experiments using transfectants bearing hybrid human/murine class II molecules demonstrated that MP2 binds to the DR beta chain. MP2 bound to a wide range of Epstein-Barr-Virus-transformed cell lines and transfectants expressing different DR beta 1 and DR beta 3 subtypes: the only exceptions were three transfectants expressing DRw11/Dw5. One of these (RGT1) was shown to be functionally normal in DRw11-restricted alloreactive and antigen-specific systems. The specificity of MP2 was confirmed in functional assays: it was able to inhibit the recognition of DR1 and DRw15 but not DRw11 by alloreactive T-cell clones. Previously reported sequence data show that the beta chain of DRw11 differs from all other DR and DQ beta chains at position 58 by a glutamic acid for alanine substitution. This may account for the inability of DRw11/Dw5 to be recognized by MP2. The data emphasize the value of transfectants in defining precisely the allelic and chain specificity of anti-major-histocompatibility-complex (MHC) antibodies, and illustrate the influence that inaccessible residues can have on the conformation of MHC molecules.

Sequential musical symptoms in a professional musician with presumed encephalitis.

The case of a middle-aged professional musician with a presumed encephalitis is reported. Clinical and radiological evidence suggested a mainly right-sided lesion. He complained of a wide variety of musical symptoms which occurred in a mainly sequential manner: these are described and classified. Their relationship to a predominantly right-sided lesion is discussed.

Juvenile rheumatoid arthritis in two siblings: co-existence with polyarteritis nodosa in one parent.

Two siblings with identical HLA profiles developed the clinical picture of Juvenile Rheumatoid Arthritis of the pauciarticular variety with iritis. One parent had Polyarteritis Nodosa while both parents and siblings demonstrated the B15 DR5 antigens.

Aortic valvotomy in the treatment of congenital aortic stenosis.

Forty patients aged 1.5-23 (mean 11) years underwent open aortic valvotomy for congenital aortic stenosis. Mean preoperative peak aortic gradient for the group was 88 (SD +/- 24) mmHg. Follow-up data was available on all patients for a total of 269 patient-years (means 6.6 year). There was no early mortality, and only one (2.5%) late death. During the follow-up period 3 patients (7.5%) required aortic valve replacement. Actuarial survival curves predict a 7 year survival of 95.7 (SE +/- 8.4%) for all patients, and a freedom from reoperation rate at 6 years of 8.7 (SE +/- 9.3)%. Symptomatic results in the survivors were excellent (97.5% NYHA Class I). Data from this series compares favourably with the literature which is reviewed for a total of 1136 patients undergoing open aortic valvotomy.

Possible familial Mediterranean fever in a Caucasian patient with systemic lupus erythematosus.

We report the case of a Caucasian man with systemic lupus erythematosus who had recurrent fevers and abdominal pain. He was later found to carry E148Q polymorphism of MEFV, the gene responsible for familial Mediterranean fever.

Antiphospholipid antibodies: more than just a disease marker?

Considerable interest has arisen over the past few years in a clinical syndrome characterized by a tendency to arterial or venous thrombosis, and the presence in the serum of antibodies to anionic phospholipids. In this article, Charles Mackworth-Young reviews the clinical features of this so-called 'anti-phospholipid syndrome', the characteristics of the anti-phospholipid response and the evidence for a possible role for these antibodies in pathogenesis.

Cross-reactive idiotypes in sera from patients with leprosy, lupus and Lyme disease and from healthy individuals.

Monoclonal IgM autoantibodies have previously been generated from a patient with lepromatous leprosy. Polyclonal anti-idiotypes raised against two of these monoclonal antibodies (8E7 and TH9) were used in an immunoassay to detect the presence of idiotype in human serum. The anti-idiotypes recognize different but overlapping sets of idiotypic determinants, some of which are present on antibodies which bind to Mycobacterium leprae. Sera were tested from 16 individuals with leprosy, 45 with systemic lupus erythematosus, 20 with Lyme disease, and 80 healthy subjects. Positive sera were detected in all groups (seven, two, three, and four, respectively). In most cases the serum bound to both anti-idiotypes, the idiotype being present in the IgM and/or IgG fraction. Levels of the two idiotypes varied independently of total serum IgG concentration and, in serial samples from one patient, independently of each other. The results indicate that 8E7 and TH9 may be representative of serum antibodies which are commonly expressed in leprosy, but may also be expressed in other diseases and in health; and they suggest that such serum antibodies are encoded by a widely shared set of variable region genes.

An idiotope-specific autoantibody in SLE.

The public idiotype Id-16/6 and the public idiotope Id-LLa were originally defined on the same human monoclonal anti-DNA antibody, but they are also known to occur separately on other anti-DNA antibodies. We sought the presence of these immunoglobulin variable region markers in purified immunoglobulins from the serum of nine patients with systemic lupus erythematosus (SLE) and 33 healthy donors. Sera from five patients were positive for Id-16/6, and five were positive for Id-LLa. The immunoglobulin preparations were passed over a Sepharose-Id-16/6 column in order to recover auto-anti-idiotypes. An eluate of that column was obtained from the immunoglobulin preparation of one patient whose serum was Id-16/6+ and Id-LLa-. This eluate was shown by competition assay to bind to IdLLa. This is the first demonstration of spontaneously arising human auto-anti-idiotypes against a specific idiotypic system in SLE. The results suggest that antibodies against the Id-LLa idiotope may play a role in immunoregulation.

Primary antiphospholipid syndrome: features of patients with raised anticardiolipin antibodies and no other disorder.

Raised levels of serum antiphospholipid antibodies have most commonly been reported in patients with systemic lupus erythematosus (SLE). There remains, however, a group of patients with raised antiphospholipid antibody levels who do not have any other well defined disease, but do have clinical features associated with these raised antibodies. The clinical, haematological, and serological features of 20 such patients are reported. Antiphospholipid antibody levels were measured by a solid phase assay for anticardiolipin activity. Fourteen patients had raised IgG antiphospholipid antibodies, 12 had raised IgM, and six had both. Nine out of 19 had raised antinuclear antibody levels; however, non fulfilled criteria for the diagnosis of SLE. Seven patients had a history of venous thrombosis and five of definite or presumed arterial thrombosis-for example, stroke. Of the 15 female patients who underwent pregnancy, 12 experienced fetal loss with up to eight abortions each (mean 3.6). Six individuals had thrombocytopenia and four others had migraines. Other clinical features included livedo reticularis, cardiac and neuropsychiatric disorders, arthralgias, and Raynaud's phenomenon. These findings confirm that the clinical features of individuals with what may be called the 'primary antiphospholipid syndrome' are similar to those in patients with other diagnoses who have raised antiphospholipid antibodies. They indicate that the antiphospholipid syndrome may be related to SLE and other autoimmune diseases, but that, although it frequently overlaps with these disorders, it also exists as a distinct entity.

A double blind, placebo controlled trial of intravenous methylprednisolone in systemic lupus erythematosus.

A double blind, placebo controlled trial was performed in 25 patients to study the use of intravenous methylprednisolone (IVMP) in the treatment of active systemic lupus erythematosus (SLE). The trial examined the additive effect of IVMP on a background of conventional oral steroid treatment. Patients were followed up for six months. The results showed a trend towards more consistent overall improvement in the first two weeks after IVMP administration compared with placebo, but this difference was not maintained at one month or subsequently. They also suggested a quicker resolution of hypocomplementaemia in the treatment group. Other parameters of disease activity showed no difference. Side effects were generally mild and were similar in incidence between the two groups. Thus it is concluded that IVMP may improve initial suppression of active lupus in some patients when added to conventional oral steroid treatment, but that this additional benefit is not maintained; IVMP is, however, a relatively safe treatment when used in this way.

Nucleic acid-binding specificity and idiotypic expression of canine anti-DNA antibodies.

Serum samples collected from eleven lupus dogs during an active phase of the disease all bound native and denatured DNA, poly(dT), poly(I) and poly(G). Nine bound poly(C); 10 bound poly(U); and 3 bound poly(A). Sera from 22 normal dogs were negative with all of these antigens. The canine sera were also probed for the presence of three idiotypic markers, one related to human lupus anti-DNA antibodies and two related to murine lupus antibodies. One canine lupus serum expressed idiotopes related to murine anti-DNA idiotype (Id) termed H130: (a) the canine serum bound to anti-H130 anti-Id; (b) it inhibited the binding of anti-H130 Id to its homologous Id; and (c) the anti-H130 Id inhibited the binding of the canine serum to DNA. These findings suggest that anti-DNA variable regions exhibit interspecies similarities, probably reflecting the conservation of the encoding gene segments through evolution.