Background Anakinra, a recombinant human form of interleukin-1 receptor antagonist, is used to treat patients with active rheumatoid arthritis (RA). Objectives To report five patients with cutaneous adverse drug reactions due to anakinra and to evaluate the histopathological and immunohistochemical findings with the aim of understanding the possible mechanisms involved. Methods Five patients of a series of 10 patients with RA undergoing treatment with anakinra in a clinical trial presented inflammatory lesions at the anakinra injection sites. In each case, clinical features were recorded and skin biopsy specimens were obtained. In one patient sequential biopsy specimens were obtained from skin lesions at different stages of development. Tissue sections of the biopsy specimens were stained with haematoxylin and eosin and May-Grünwald-Giemsa, and were immunoreacted with antibodies to leucocyte common antigen, CD68, CD3, CD45RO, CD20 and CD45RA. Results The onset of reaction was within the first month of treatment and appeared as well-defined erythema and oedema involving the injection sites. In two patients the treatment had to be discontinued because of the skin reaction, and in one patient it was associated with systemic involvement. All biopsy specimens exhibited marked dermal oedema and a lichenoid dermal infiltrate composed mainly of lymphomononuclear cells with prominent populations of eosinophils and large CD68+ dermal macrophages and an increase in the number of mast cells, which were spindle shaped in a significant proportion. Conclusions Cutaneous toxicity is a frequent, usually well-tolerated complication of treatment with anakinra in patients with RA, although in some cases it can be associated with systemic involvement. The most relevant histopathological findings include dermal oedema and a lichenoid, perivascular and periadnexal predominantly lymphomononuclear infiltrate, with many eosinophils and the presence of enlarged CD68+ macrophages. These findings resemble those seen in skin reactions in patients receiving chemotherapy and colony-stimulating factors. We also found an increase in mast cell numbers that could be a specific effect of anakinra.

In this observational study, the absence of response, probably due to the low-dose scheme used, was the major cause of AZA withdrawal in our series of RA patients. TPMT genotyping may allow the use of high doses of AZA in patients with normal TPMT alleles to improve the efficacy of this immunosuppressive drug. Our data support the relationship between gastrointestinal intolerance and thiopurine metabolic imbalance.

The cytokines interleukin (IL)-12 and IL-23 have been involved in the pathogenesis of psoriasis and psoriatic arthritis. Ustekinumab is a fully human monoclonal antibody targeting the p40 subunit shared by IL-12 and IL-23. Ustekinumab prevents the interaction of IL-12 and IL-23 binding to their receptors, blocking the T1 and T17 inflammatory pathways. Ustekinumab has been evaluated for the treatment of various chronic immune mediated diseases including psoriasis and psoriatic arthritis (PsA). Most of the data regarding the safety of ustekinumab come from the experience treating patients with psoriasis, but clinical trials have demonstrated its efficacy and safety in the treatment of both diseases. The most common adverse events observed during the clinical trials are mild in intensity, and include respiratory tract infections, nasopharyngitis, headache and injection site reactions. Throughout long-term ustekinumab treatment, serious infections or major cardiovascular adverse events occurred rarely. Areas covered: In this review we report the safety data that come from phase II and phase III clinical trials that assay the efficacy and safety of ustekinumab in PsA, including recently published data corresponding to long-term studies. Relevant references were obtained through a literature search in MEDLINE/Pubmed (search strategy: ustekinumab AND psoriatic arthritis) for articles published until November 2016, complemented by a manual search. Expert opinion: In clinical practice, ustekinumab is generally a well-tolerated treatment, and the safety profile in psoriatic arthritis is similar to that reported in plaque psoriasis.

There is evidence for a genetic contribution to bone mineral density (BMD×). Different loci affecting BMD have been identified by diverse linkage and genome-wide association studies. We studied the heritability of and the correlations among six densitometric phenotypes and four bone mass/fracture phenotypes. For this purpose, we used a family-based study of the genetics of osteoporosis, the Genetic Analysis of Osteoporosis Project. The primary aim of our study was to examine the roles of genetic and environmental factors in determining osteoporosis-related phenotypes. The project consisted of 11 extended families from Spain. All of them were selected through a proband with osteoporosis. BMD was measured using dual-energy X-ray absorptiometry. The proportion of variance of BMD attributable to significant covariates ranged from 25% (for femoral neck BMD) to 48% (for whole-body total BMD). The vast majority of the densitometric phenotypes had highly significant heritability, ranging from 0.252 (whole-body total BMD) to 0.537 (trochanteric BMD) after correcting for covariate effects. All of the densitometric phenotypes showed high and significant genetic correlations (from -0.772 to -1.000) with a low bone mass/osteopenia condition (Affected 3). Our findings provide additional evidence on the heritability of BMD and a strong genetic correlation between BMD and bone mass/fracture phenotypes in a Spanish population. Our results emphasize the importance of detecting genetic risk factors and the benefit of early diagnosis and especially therapeutic and preventive strategies.

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This observational, longitudinal retrospective, noncomparative study was designed to assess the persistence and effectiveness of golimumab as a second anti-tumor necrosis factor (TNF) drug in patients with spondyloarthritis requiring discontinuation from a first anti-TNF drug. Data were collected retrospectively for all patients with axial spondyloarthritis or psoriatic arthritis from 20 rheumatology clinics in Spain who started golimumab as a second anti-TNF drug between January 2013 and December 2015. Golimumab persistence was assessed with Kaplan-Meier survival analysis, and associated factors were assessed with Cox regression analysis. 210 patients started golimumab as a second anti-TNF drug: 131 with axial spondyloarthritis and 79 with psoriatic arthritis. In axial spondyloarthritis patients, the mean (standard deviation) Bath Ankylosing Spondylitis Disease Activity Index score at baseline was 5.5 (2.1), decreasing to 3.9 (2.0) at month 3 and 3.5 (2.0) at year 1, and remaining stable thereafter. In psoriatic arthritis patients, mean (standard deviation) baseline Disease Activity Score was 4.0 (1.3), reducing to 2.5 (1.2) at month 3 and to 2.2 (1.3) at year 1. Corresponding improvements were recorded from baseline in C-reactive protein levels and erythrocyte sedimentation rates. The probability of persistence of treatment with golimumab was 80% at year 1, 70% at year 2 and 65% at years 3 and year 4, and was similar in those who had stopped the first anti-TNF due to loss of efficacy or other reasons. Cox regression analysis showed that the probability of survival with golimumab was higher in patients with higher erythrocyte sedimentation rate, in patients with axial spondyloarthritis than with psoriatic arthritis, and in those who had discontinued adalimumab as first anti-TNF. Seventy-two patients (34.3%) discontinued golimumab during follow-up, 50 of them due to lack of efficacy. In patients with spondyloarthritis requiring discontinuation from a first anti-TNF drug, treatment with golimumab was effective and showed a high probability of persistence up to 4 years of treatment.

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