Charles Mackworth-Young

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.

Antiphospholipid (Hughes') syndrome.

The antiphospholipid syndrome, first described in 1983,1 is now recognised as an important prothrombotic disorder associated with a specific group of antibodies. Its main clinical feature is thrombosis, both venous and arterial (especially recurrent cerebral ischaemic attacks). Other features include mild thrombocytopenia, chorea, heart valve disease, livedo reticularis, and, most commonly, recurrent pregnancy loss.2 The importance of the syndrome in general medicine, especially in vascular and neurological disease, is now acknowledged.nnThe syndrome has had various names. Hughes originally studied it in patients with systemic lupus erythematosus but recognised that most patients “had atypical lupus, or no lupus at all”–hence the concept of “primary” antiphospholipid syndrome.3 In the early 1990s it was found that a phospholipid binding protein, s2 glycoprotein I, …

Familial clustering of non-nuclear autoantibodies and C3 and C4 complement components in systemic lupus erythematosus.

OBJECTIVEnTo determine whether key features of systemic lupus erythematosus (SLE), namely, production of non-nuclear antibodies (anti-C1q and anticardiolipin antibodies [aCL]) and depletion of complement components C3 and C4, aggregate in families. In addition, we examined relationships between anti-C1q and C3 and C4 levels.nnnMETHODSnThe study cohort comprised 1,037 predominantly white (82%) nuclear families in which at least 1 member had SLE. Associations of antibody measurements between probands and their unaffected siblings were examined using parametric and nonparametric analyses, along with associations between unaffected siblings and their parents. The heritability of anti-C1q, C3, and C4 was estimated, and interdependencies between these factors were examined in a regression model accounting for the family structure of the data set.nnnRESULTSnWe demonstrated associations between siblings for anti-C1q (odds ratio [OR] 3.74, 95% confidence interval [95% CI] 2.65, 5.28) and IgG and IgM aCL (OR 4.08, 95% CI 1.83, 5.13 and OR 2.06, 95% CI 1.46, 2.91, respectively) and, for anti-C1q, association between unaffected parents and their unaffected offspring (OR 4.34, 95% CI 2.16, 8.72). We also demonstrated significant heritability of anti-C1q, C3, and C4 (approximately 45%). Anti-C1q was negatively associated with C3 and C4 in SLE probands but not in their healthy relatives.nnnCONCLUSIONnNon-nuclear antibodies and C3 and C4 cluster within the families of SLE probands, suggesting that specific autoantibody formation is partly genetically determined, even if the total genetic effect in unaffected relatives is insufficient to cause disease. Anti-C1q antibodies accelerate C3 and C4 depletion in patients with SLE but have no effect in the absence of disease.

Antiphospholipid (Hughes') syndrome: A treatable cause of recurrent pregnancy loss

The antiphospholipid syndrome, first described in 1983,1 is now recognised as an important prothrombotic disorder associated with a specific group of antibodies. Its main clinical feature is thrombosis, both venous and arterial (especially recurrent cerebral ischaemic attacks). Other features include mild thrombocytopenia, chorea, heart valve disease, livedo reticularis, and, most commonly, recurrent pregnancy loss.2 The importance of the syndrome in general medicine, especially in vascular and neurological disease, is now acknowledged.nnThe syndrome has had various names. Hughes originally studied it in patients with systemic lupus erythematosus but recognised that most patients “had atypical lupus, or no lupus at all”–hence the concept of “primary” antiphospholipid syndrome.3 In the early 1990s it was found that a phospholipid binding protein, s2 glycoprotein I, …

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 5.35u2005cm, average difference in change from baseline VAS 1.9 and 1.4u2005cm, 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.

Antiphospholipid antibodies as biomarkers in psychiatry: review of psychiatric manifestations in antiphospholipid syndrome

Antiphospholipid syndrome (APS) has been implicated in a range of neuropsychiatric presentations. However, there is a paucity of systematic studies on APS in psychiatry. This paper reports the clinical manifestations of APS that are relevant to psychiatrists. The aspects of APS pathogenesis, diagnosis, and treatment presented in this paper are based on a literature review. Treatment-resistant and atypical psychiatric illnesses, severe cognitive dysfunction, migraines, transient ischaemic attacks, and thromboembolic episodes, along with characteristic skin manifestations are the common clinical features of this syndrome. Antiphospholipid antibodies (aPL) may have a causal role in the development of some neuropsychiatric conditions. The existing criteria of APS may not apply to psychiatric patients, which may result in the underdiagnosis of APS in psychiatry. There is no evidence-based guidance available for the treatment of APS in patients with psychiatric symptoms. The treatment of APS with antithrombotic agents in case reports has been reported to yield dramatic improvements in complex and treatment-resistant cases. The possibility of a causal role of aPL in high-morbidity conditions, such as psychosis, depression, and dementia, requires the psychiatrist to be vigilant to the occurrence of this syndrome. There is an urgent need to conduct studies that elucidate the role of aPL in psychiatric presentations, identify patient characteristics, and consider whether new criteria with greater applicability in psychiatry are needed.

Randomised double-blind trial of combination antibiotic therapy in rheumatoid arthritis.

Objective. A combination of intravenous clindamycin and oral tetracycline has been used for many years as a treatment for active rheumatoid arthritis (RA), despite the absence of good evidence for its efficacy. A single-blind pilot study of this therapy suggested that a double-blind placebo-controlled trial was warranted. Methods. Patients with active RA were randomised in a 2u2009:u20091 ratio to receive active treatment or placebo for 25 weeks. The active treatment consisted of intravenous clindamycin in a reducing regime, and oral tetracycline twice daily three times a week. 50 patients were to be recruited. The primary outcome measure was the proportion of patients achieving an ACR20 response. Results. An interim statistical analysis was performed after 20 patients had completed the study. Two patients in the active group achieved an ACR20 response, with none in the placebo group (NS). There was a better ESR20 response in the placebo group (P = .02). There were no other significant differences between the groups. The results indicated that it was unlikely that a significant difference in ACR20 response would emerge if the remaining 30 patients were recruited. The trial was therefore halted. Conclusion. This antibiotic regime is unlikely to be a valuable therapy for active rheumatoid arthritis.

Primary antiphospholipid syndrome

PAPS has emerged as an important disease entity. Depending on the organ systems involved, it can produce a highly variable clinical picture, with severity ranging from mild asymptomatic disease (often undiagnosed) to major life-threatening events. It may be regarded as the pure form of a condition which is also frequently seen in the context of other autoimmune diseases. In particular it is intricately linked to APS seen in the context of SLE; and these two variants of the condition appear to behave in a similar fashion. Defining PAPS provides us with the opportunity to study the disease in the absence of other co-morbid conditions such as SLE. Advances in our understanding of the pathogenesis of PAPS should facilitate the development of improved treatment and outlook for patients with all forms of the APS.

Tocilizumab in refractory rheumatoid arthritis: long-term efficacy, safety, and tolerability beyond 2 years

Objectives To evaluate the long-term efficacy and safety of tocilizumab (TCZ) in clinical patients with rheumatoid arthritis (RA) refractory to synthetic disease-modifying antirheumatic drugs, anti-tumor necrosis factor agents, and B-cell depletion therapy with rituximab (RTX). Methods We conducted a single-center retrospective study of 22 patients with RA treated with TCZ. We collected data including demographics and medication histories. We recorded clinical parameters including tender joint counts and swollen joint counts, and laboratory parameters including inflammatory makers and lipid profiles over regular intervals of TCZ treatment. Results In all, 22 patients with RA were included, 20 of whom were female. The median age at the first dose of TCZ was 62 years (range: 35–75 years). The mean duration of the disease from diagnosis with RA to May 2015 was 15.7 years (range: 6–30 years). A total of 15 out of 22 patients remained on TCZ at the end of the study, and in all, there was an improvement in markers of disease activity following initiating TCZ. The effect was sustained for a mean of 35 months (SD±15.5 months, range: 9–72 months). Of the 17 patients who failed to respond to RTX previously, 12 patients remained on TCZ. In all, eight out of 22 patients developed adverse events, five of whom discontinued TCZ. In contrast to previously documented short-term data, TCZ did not result in a statistically significant (P<0.05) long-term deterioration in lipid profile for any of the lipid parameters measured in our cohort (mean ± SD at initiation of TCZ to most recent follow-up: total cholesterol 5.25±1.05 to 5.28±0.77 mmol/L, high-density lipoprotein 1.72±0.54 to 1.67±0.43 mmol/L, low-density lipoprotein 3.05±0.98 to 2.98±0.81 mmol/L, and cholesterol to high-density lipoprotein ratio 3.41±1.23 to 3.40±1.22). Conclusion The efficacy of TCZ in patients with RA refractory to disease-modifying drugs, including anti-tumor necrosis factor blockade and RTX, is sustained over 3 years. TCZ confers a good safety profile in the long term even in patients who previously developed adverse events to other rheumatic drugs. In the long run, there is no statistically significant deterioration in lipid profile during treatment with TCZ.

SAT0183 Long-Term Efficacy, Safety, and Tolerability of Tocilizumab in Rituximab-Refractory Rheumatoid Arthritis

Background Rheumatoid arthritis (RA) is an inflammatory autoimmune process, and the dysregulated overproduction of interleukin-6 (IL-6) plays an important role in its pathogenesis. Tocilizumab (TCZ) is a humanized monoclonal antibody targeting the IL-6 receptor, and is recommended for use in RA. (1) There is evidence demonstrating good outcomes with TCZ in patients who have disease refractory to B-cell depletion with rituximab (RTX), a chimeric monoclonal antibody targeting CD20 B-cells, with up to 18 months follow-up. (2) Long-term data, however, on the efficacy, safety and tolerability of TCZ in RA that is refractory to sDMARDs, anti-TNF and RTX are lacking. Objectives To evaluate the long-term efficacy and safety of TCZ in real patients with RA refractory to synthetic DMARDs, anti-TNF agents and B cell depletion therapy with RTX, beyond 2 years. Methods We retrospectively studied 45 patients from two centres who received TCZ for median 48-months (range, 9–72) duration. All patients received anti-TNF and RTX previously. Efficacy and safety was evaluated according to the EULAR response criteria and EMEA guidance, respectively. Wilcoxon matched ranks test was used to assess changes in outcomes. Results Of 45 patients, 36 (80%) had previously discontinued RTX due to inefficacy and 9 (20%) due to intolerance. At most recent follow-up, median 48 months, 30 of 45 (67%) patients were continuing TCZ and 15 (33%) had discontinued, 7 due to inefficacy and 8 others due to intolerance. Of 36 patients with RTX-refractory RA, 25 (69%) were continuing TCZ and 11 had discontinued due to, inefficacy in 6 (17%) and intolerance in 5 (14%): 2 patients due to diverticulitis, 2 due to upper respiratory tract infections and 1 due to discitis. Of the 9 patients with RTX-intolerance, 5 (56%) were continuing TCZ and 4 (44%) had discontinued: 1 patient due to inefficacy and 3 due to intolerance, who had a prior history of hypogammaglobulinemia and infections associated with RTX. There were no significant differences in lipid profile in 25 of 36 of patients continuing TCZ therapy whereas 11 required statin therapy. Conclusions A majority of patients with RA refractory to synthetic DMARDs, anti-TNF and RTX responded to TCZ. Lipid profile in a majority of patients was stable in the long-term. Key messages: 1. The efficacy of TCZ is sustained in the long-term in patients with RTX-refractory RA. 2. TCZ appears to be safe in patients previously treated with RTX. TCZ does not alter lipid profile in a majority of the patients with RTX-refractory RA. References NICE. National Institute of Health and Care Excellence: tocilizumab for the treatment of rheumatoid arthritis (rapid review of technology appraisal guidance 198). http://www.nice.org.uk/guidance/ta2472012 Addimando O, Possemato N, Macchioni P, Salvarani C. Efficacy and safety of tocilizumab in refractory rheumatoid arthritis: a real life cohort from a single centre. Clin. Exp. Rheumatol. 2014;32(4):460–464 Acknowledgement The authors would like to thank Angela Smith, Pauline Buck, Nicola Whitbread, Nicola Daly and Lindsay Kidd for their help with maintaining a record of patients receiving tocilizumab at the two centres. Disclosure of Interest None declared