Man-in-a-barrel syndrome: a rare presentation of giant cell arteritis.

We present herein the case of a patient with brachial plexopathy, the first manifestation of giant cell arteritis (GCA). A 71-year-old woman presented with a subacute-onset weakness of her upper extremities; the patient had an initially good clinical response to steroid treatment. However, a few weeks after steroid discontinuation, she manifested fever and fatigue and increased serum markers consistent with a systemic inflammatory response. A PET-CT scan revealed an increased uptake in the subclavian arteries and a temporal biopsy was typical for GCA. Oral administration of high dosage steroids improved the patient's clinical symptoms and normalised her inflammatory serum markers.

Immune Checkpoint Inhibitor-Associated Scleroderma-Like Syndrome: A Report of a Pembrolizumab-Induced "Eosinophilic Fasciitis-Like" Case and a Review of the Literature.

Immune checkpoint inhibitors are a promising new therapeutic strategy in oncology that aims to eliminate cancer cells by enhancing patients' immune response against tumor antigens. Despite their beneficial effects, immune checkpoint inhibitors are also responsible for a plethora of autoimmune manifestations, known as immune-related adverse events. We present a case of eosinophilic fasciitis-like disorder in an 81-year-old patient treated with the programmed death cell protein 1 inhibitor pembrolizumab for non-small-cell lung cancer. The patient developed characteristic indurated skin lesions in his limbs after 1½ years of treatment with pembrolizumab and a typical "groove sign." Raynaud's syndrome was absent. A full-thickness biopsy confirmed the clinical diagnosis of an "EF-like" condition. Neither peripheral eosinophilia nor eosinophilic infiltrates in the skin biopsy were found. His symptoms improved after a 2.5-month CPI discontinuation and treatment with 16 mg of methylprednisolone slowly tapered to a dose of 4 mg. Eosinophilic fasciitis is a rare immune-related adverse event of CPI treatment; our literature search identified only 12 cases that fulfill the criteria of EF in patients receiving CPIs.

B cell depletion treatment decreases CD4+IL4+ and CD4+CD40L+ T cells in patients with systemic sclerosis.

Recent data suggests that rituximab may favorably affect skin fibrosis and lung function in patients with systemic sclerosis. Based on experimental data suggesting a key role of B and T cells in scleroderma we aimed to explore the effect(s) of rituximab treatment on T cell subpopulations. Fifteen patients with scleroderma who received rituximab treatment and six who received standard treatment alone were recruited. Peripheral CD4+IL4+, CD4+INFγ+, CD4+IL17+ and CD4+CD40L+ T cells were assessed using flow cytometry. Using ELISA, serum levels of IL4 were assessed. Skin CD4+IL4+ T cells were assessed with confocal microscopy from skin biopsies. Following rituximab treatment skin CD4+IL4+ T cells obviously decreased as seen with confocal microscopy. Moreover, peripheral CD4+IL4+ T cells decreased significantly compared to those from patients who received standard treatment alone: median (IQR): 14.9 (22.63-12.88) vs 7.87 (12.81-4.9)%, p = 0.005 and 9.43 (19.53-7.50)% vs 14.86 (21.96-6.75)%, p = NS at baseline and 6 months later respectively, whereas there was no difference in serum IL4 levels. Peripheral CD4+CD40L+ T cells also decreased significantly following rituximab treatment compared to those from patients who received standard treatment alone: median (IQR): 17.78 (25.64-14.44)% vs 8.15 (22.85-3.08)%, p = 0.04 and 22.13 (58.77-8.20)% vs 72.11 (73.05-20.45)%, p = NS at baseline and 6 months later respectively. Furthermore, peripheral CD4+INFγ+ and CD4+IL17+ T cells revealed no differences following rituximab treatment. Our study demonstrates a link between rituximab treatment and CD4+IL4+ T cell decrease both in the skin and peripheral blood of patients with SSc.

New onset of lupus nephritis in two patients with SLE shortly after initiation of treatment with belimumab.

PURPOSE: Belimumab is currently approved for the treatment of patients with active SLE despite standard treatment. However, it has not been formally tested for patients with lupus nephritis because such patients had been excluded from the clinical trials. In this report, we present two patients with SLE who developed lupus nephritis de novo shortly after belimumab treatment initiation; both patients improved rapidly upon belimumab discontinuation. RESULTS: The first patient (a 30-year-old female, with a 15-year disease duration, receiving prednisolone, hydroxychloroquine, and azathioprine, with no previous history of nephritis that was repeatedly anti-dsDNA negative) had exacerbation of a facial butterfly-like rash developed after 3 months of belimumab treatment initiation. Concomitantly, her urinalysis became abnormal for the first time during her long follow-up (15-20 red blood cells per hpf, and a 24-h urine protein of 1600mg), and a renal biopsy documented the diagnosis of a Class III (WHO classification). Her anti-dsDNA titers became highly positive for the first time. Belimumab was discontinued and her proteinuria and abnormal urinalysis reverted to normal rapidly, and before MMF administration was approved by local regulatory authorities. Our second patient (a 38-year-old female with a 19-year disease duration) was being treated with prednisone and azathioprine. Two months following belimumab treatment initiation, she became edematous and had an active urine sediment (50-60 rbc per hpf, dysmorphic, and a 24-h urine protein levelabove 6000mg) for the first time during her disease course. Her renal biopsy was compatible with a Class V membranous nephritis. Belimumab was discontinued and MMF (2g/d) was substituted for azathioprine with her urinary protein declining to 2.7g/d just 10 days afterwards. CONCLUSIONS: In this report, apart from our two patients, we discuss the relevant literature consisting of a handful of studies and case reports. The studies analyze patients with renal involvement treated with belimumab and are inconclusive. There are only a few case reports in which belimumab along with other agents had a potential benefit, although not straightforward. There is only one case report with striking similarities to the two patients with SLE we report herein. It could be claimed that belimumab was unable to prevent the appearance of lupus nephritis during a potentially serious disease exacerbation. Certainly, a causative association between belimumab treatment and the de novo appearance of lupus nephritis cannot be claimed because of our report. However, a potential association between belimumab treatment and the development of such a serious manifestation cannot be entirely excluded. In support of the latter hypothesis is the quick resolution/significant reduction of proteinuria shortly after belimumab discontinuation and before other treatment measures had any reasonable effect. Studies evaluating the potential usefulness of belimumab in patients with lupus nephritis are currently ongoing; until then, one should keep in mind unanswered questions as far as renal safety is concerned.

B cells tell scleroderma fibroblasts to produce collagen.

In fibrosis fibroblasts are activated and overproduce collagen in a process with unknown drivers and equally unknown brakes that recently implicated a novel and surprising player, the B cell. B cells may be crucially involved in fibrosis in several ways: B cells may produce autoantibodies that can directly stimulate fibroblasts; B cells can produce profibrotic cytokines such as IL-6 or transforming growth factor beta; and, finally, B cells could directly stimulate fibroblasts by a contact-dependent mechanism. Recent experimental evidence suggests that B cells can enhance collagen production by fibroblasts, by a contact-dependent mechanism, and therefore are profibrotic ex vivo. These data strengthen the rationale of pursuing B-cell targeting therapies in systemic sclerosis.

Treatment of systemic sclerosis-associated calcinosis: a case report of rituximab-induced regression of CREST-related calcinosis and review of the literature.

OBJECTIVES: Calcinosis is frequently encountered in patients with systemic sclerosis (SSc) and may be associated with significant morbidity. No treatment has shown so far an unequivocal beneficial effect. METHODS: We performed an extensive internet search (MEDLINE) using the keywords calcinosis, calcification, scleroderma, systemic sclerosis, and treatment. RESULTS: Our patient had extensive Calcinosis, Raynaud, Esophagitis, Sclerodactyly, telangiectasia (CREST)-related calcinosis, frequently ulcerating and painful. Following 2 rituximab courses (consisting of 4 weekly infusions, 375 mg/m(2) each), calcinosis significantly improved and pain disappeared. Pharmacologic agents used in the treatment of SSc-associated calcinosis include diltiazem, minocycline, warfarin, biphosphonates, and intravenous immunoglobulin. Other therapeutic approaches include surgical excision, laser vaporization, and extracorporeal shock wave lithotripsy. CONCLUSIONS: Evidence for all existing therapies is weak and therefore larger scale controlled studies are needed. Rituximab appears as a promising treatment especially in view of recent evidence that this therapy may be also effective in the underlying disease.

Effect of long-term treatment with rituximab on pulmonary function and skin fibrosis in patients with diffuse systemic sclerosis.

OBJECTIVES: To assess the safety and efficacy of long-term treatment with rituximab (RTX) in patients with systemic sclerosis (SSc). METHODS: Eight patients with SSc-associated interstitial lung disease (ILD) received 4 cycles of RTX and had a follow-up of 2 years. Lung involvement was assessed by pulmonary function tests and chest HRCT. Skin involvement was assessed both clinically and histologically. RESULTS: We found a linear improvement of lung function and skin thickening over the 2 years of RTX treatment. There was a significant increase of FVC at 2 years compared to baseline (mean ± SEM: 77.13±7.13 vs. 68.13±6.96, respectively, p<0.0001). Similarly, DLco increased significantly at 2 years compared to baseline (mean ± SEM: 63.13±7.65 vs. 52.25±7.32, respectively, p<0.001). Skin thickening, assessed with the MRSS, improved significantly at 2 years compared to baseline (mean ± SEM: 4.87±0.83 vs. 13.5±2.42, respectively, p<0.0001). A reduction in myofibroblast score was seen histologically following RTX treatment. CONCLUSIONS: Our results indicate that long-term treatment with RTX may favourably affect lung function and skin fibrosis in patients with SSc. Larger scale, multicentre, randomised, controlled studies are needed to further explore the efficacy of RTX in SSc.

Treatment with TNFα blockers induces phenotypical and functional aberrations in peripheral B cells.

To dissect the mechanisms of anti-TNFα-induced autoimmunity we examined the phenotype and function of B cells from anti-TNFα-treated patients. Levels of Lyn, Syk, SHP-1, tyrosine 348 phospho-Syk (Y348-Syk) and tyrosine phosphorylated (P-Y) proteins were evaluated and B-cell-surface CD20, CD21 and CD5 were also assessed in 29 patients treated with TNF-α blockers. Following treatment, Lyn, but not Syk or SHP-1, significantly increased particularly in patients with spondyloarthropathies. Increased Lyn levels following treatment correlated with increased Lyn activity as evidenced by a 2.9-fold increase of Y348-Syk (a Lyn target). Peripheral B-cells from 56.3% of the patients displayed a tendency towards increased P-Y levels without any BCR-initiated activation during treatment. CD20, but not CD21, significantly increased in patients with rheumatoid arthritis. Circulating CD5+ B-cells were also significantly expanded during treatment. Our findings suggest that B cells in anti-TNFα-treated patients display functional and phenotypical aberrations that may enhance our understanding of TNF-α blocker-induced autoimmunity.

Pathogenesis of human systemic lupus erythematosus: recent advances.

Systemic lupus erythematosus (SLE) is an autoimmune disease with manifestations derived from the involvement of multiple organs including the kidneys, joints, nervous system and hematopoietic organs. Immune system aberrations, as well as heritable, hormonal and environmental factors interplay in the expression of organ damage. Recent contributions from different fields have developed our understanding of SLE and reshaped current pathogenic models. Here, we review recent findings that deal with (i) genes associated with disease expression; (ii) immune cell molecular abnormalities that lead to autoimmune pathology; (iii) the role of hormones and sex chromosomes in the development of disease; and (iv) environmental and epigenetic factors thought to contribute to the expression of SLE. Finally, we highlight molecular defects intimately associated with the disease process of SLE that might represent ideal therapeutic targets and disease biomarkers.

Evidence that Dkk-1 is dysfunctional in ankylosing spondylitis.

OBJECTIVE: Dkk-1 is an inhibitory molecule that regulates the Wnt pathway, which controls osteoblastogenesis. This study was undertaken to explore the potential role of Dkk-1 in ankylosing spondylitis (AS), a prototypical bone-forming disease. METHODS: Serum Dkk-1 levels were measured in 45 patients with AS, 45 patients with rheumatoid arthritis (RA), 15 patients with psoriatic arthritis (PsA), and 50 healthy subjects by sandwich enzyme-linked immunosorbent assay (ELISA). A functional ELISA was used to assess the binding of Dkk-1 to its receptor (low-density lipoprotein receptor-related protein 6). Furthermore, we studied the effect of sera from patients with AS and healthy subjects on the activity of the Wnt pathway in the Jurkat T cell model, with and without a neutralizing anti-Dkk-1 monoclonal antibody, by Western immunoblotting. RESULTS: Serum Dkk-1 levels were significantly increased in patients with AS (mean +/- SEM 2,730 +/- 135.1 pg/ml) as compared with normal subjects (P = 0.040), patients with RA (P = 0.020), and patients with PsA (P = 0.049). Patients with AS receiving anti-tumor necrosis factor alpha (anti-TNFalpha) treatment had significantly higher serum Dkk-1 levels than patients with AS not receiving such treatment (P = 0.007). Patients with AS studied serially prior to and following anti-TNFalpha administration exhibited a significant increase in serum Dkk-1 levels (P = 0.020), in contrast to patients with RA, who exhibited a dramatic decrease (P < 0.001). Jurkat cells treated with serum from AS patients exhibited increased Wnt signaling compared with cells treated with control serum. In that system, Dkk-1 blockade significantly enhanced Wnt signaling in control serum-treated, but not AS serum-treated, Jurkat T cells. CONCLUSION: Our findings indicate that in patients with AS, circulating bone formation-promoting factors functionally prevail. This can be at least partially attributed to decreased Dkk-1-mediated inhibition.

Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study.

OBJECTIVE: To assess the efficacy of rituximab (RTX) in SSc. METHODS: Fourteen patients with SSc were evaluated. Eight patients were randomized to receive two cycles of RTX at baseline and 24 weeks [each cycle consisted of four weekly RTX infusions (375 mg/m(2))] in addition to standard treatment, whereas six patients (control group) received standard treatment alone. Lung involvement was assessed by pulmonary function tests (PFTs) and chest high-resolution CT (HRCT). Skin involvement was assessed both clinically and histologically. RESULTS: There was a significant increase of forced vital capacity (FVC) in the RTX group compared with baseline (mean +/- s.d.: 68.13 +/- 19.69 vs 75.63 +/- 19.73, at baseline vs 1-year, respectively, P = 0.0018). The median percentage of improvement of FVC in the RTX group was 10.25%, whereas that of deterioration in the controls was 5.04% (P = 0.002). Similarly, diffusing capacity of carbon monoxide (DL(CO)) increased significantly in the RTX group compared with baseline (mean +/- s.d.: 52.25 +/- 20.71 vs 62 +/- 23.21, at baseline vs 1-year respectively, P = 0.017). The median percentage of improvement of DL(CO) in the RTX group was 19.46%, whereas that of deterioration in the control group was 7.5% (P = 0.023). Skin thickening, assessed with the Modified Rodnan Skin Score (MRSS), improved significantly in the RTX group compared with the baseline score (mean +/- s.d.: 13.5 +/- 6.84 vs 8.37 +/- 6.45 at baseline vs 1-year, respectively, P < 0.001). CONCLUSION: Our results indicate that RTX may improve lung function in patients with SSc. To confirm our encouraging results we propose that larger scale, multicentre studies with longer evaluation periods are needed.

Wnt pathway and IL-17: novel regulators of joint remodeling in rheumatic diseases. Looking beyond the RANK-RANKL-OPG axis.

OBJECTIVES: During the last decade research has focused on the RANK-RANKL-OPG (Receptor Activator of Nuclear factor KappaB-Receptor Activator of Nuclear factor KappaB Ligand-Osteoprotegerin) pathway that is currently considered the final common route to bone and joint remodeling. The potential role of novel additional mediators has been highlighted by several reports. This review focuses on the recent information about the pathophysiology of the Wingless (Wnt) pathway and interleukin-17 (IL-17) in relation of their role in bone and joint remodeling. METHODS: An extensive internet search was performed (PubMed) from 1998 and onward using the following keywords: Wnt, bone remodeling, bone, rheumatic diseases, rheumatoid arthritis, IL-17, Th17, osteoblastogenesis, and osteoclastogenesis. RESULTS: Several members of the Wnt pathway play an important role in bone remodeling. Recent experimental data indicate a key role for Dickkopf-1, a soluble inhibitor of the Wnt pathway, in bone remodeling. Increased Dickkopf-1 levels are linked to bone resorption and decreased levels to new bone formation. Low-density lipoprotein receptor-related protein-5, the main receptor that mediates Wnt signaling, plays a critical role in bone mass regulation. Gain-of-function mutations of lipoprotein receptor-related protein-5 cause high bone mass phenotypes, whereas loss-of-function mutations are linked to severe osteoporosis. IL-17 is a proinflammatory cytokine that is produced by a recently described T-cell subset, known as Th17 cells. Evidence suggests that IL-17 is a critical mediator of joint destruction in animal models of arthritis. IL-17 blockade has beneficial effects on murine arthritis, a fact that points to the direction of this cytokine as a potential therapeutic target in human inflammatory arthritides as well. CONCLUSIONS: The available data suggest that mediators in these 2 biologic systems are critical in joint remodeling and may be appropriate targets in the treatment of bone and joint abnormalities that characterize a variety of inflammatory arthritides and bone diseases.

The pathophysiologic role of monocytes and macrophages in systemic lupus erythematosus: a reappraisal.

OBJECTIVES: To review current developments, regarding the pathophysiologic role of monocytes and macrophages in systemic lupus erythematosus (SLE). METHODS: We searched Medline for articles written in the English language using the following terms: monocyte(s) or macrophage(s) and lupus. Although our search spanned the years 1971 to 2008, the majority of the short-listed articles belonged to the period 2000 to 2008. Published literature on phenotypic and functional properties of monocytes/macrophages (Mo/Mphi) in SLE was reviewed. References from identified articles were also selected. Currently available experimental data and their relevance to the pathogenesis of SLE are critically discussed. RESULTS: It has traditionally been held that impaired phagocytosis by monocytes and macrophages in SLE allows for the accumulation of apoptotic debris leading to a sequel of autoimmune phenomena. Recent paradigms derived from animal models of systemic autoimmunity, however, has broadened our understanding regarding the possible pathophysiologic roles of Mo/Mphi in SLE. Data derived from studies in patients with SLE show multiple aberrations in activation status and secretory functions of circulating and tissue-infiltrating Mo/Mphi. Such aberrations may be associated with dysregulation of T-cell function and autoantibody production in SLE. Moreover, emerging evidence suggests that phagocytic capacity and antigen-presenting properties of Mo/Mphi are enhanced in some patients with SLE. CONCLUSIONS: While defective phagocytosis represents a distinctive feature of monocyte function in some patients with SLE, aberrant activation of the Mo/Mphi system may be a more appropriate concept to encompass the broad spectrum of Mo/Mphi disorders in SLE. Aberrant function of lupus Mo/Mphi appears to play a dynamic role in the initiation and perpetuation of the systemic autoimmune response and organ damage. Delineation of the altered biology of lupus Mo/Mphi could provide possible future therapeutic targets for patients with SLE.

Rituximab-induced B cell depletion in autoimmune diseases: potential effects on T cells.

Peripheral B cell depletion strategies have been employed recently in the treatment of systemic autoimmune diseases and the initial clinical results have been encouraging. Although the major target of rituximab-based treatments was to reduce the levels of circulating autoantibodies, additional mechanisms of action may operate. Recent studies have addressed the question of potential effects of transient B cell depletion on other, non-B cell populations. The data, albeit uncontrolled, suggest that anti-CD20 monoclonal antibody treatment is associated with significant effects in the T cell pool, whereas individual clinical responses do not always correlate with changes in autoantibody titers. More specifically, it has been reported that rituximab administration may decrease the activated phenotype of peripheral and tissue-resident T cells by abolishing antigen presentation by B cells, and may enhance the numbers and function of regulatory T cells. In this review we analyze and discuss available data emerging from B cell depletion studies in patients with systemic lupus erythematosus, rheumatoid arthritis and other autoimmune conditions. Further controlled studies are needed to confirm the role of B cell depletion in modifying T cell function in vivo.

Monoclonal antibodies and fusion proteins in medicine.

Humanized antibodies and decoy receptors have been introduced in clinical practice to treat malignancies and systemic autoimmune disease because they ablate specific cells or disrupt pathogenic processes at distinct points. Reported clinical responses offer hope to treatment-resistant patients, particularly those with lymphomas and rheumatic diseases. Side effects from the use of biologic agents include lymphokine release syndrome, reactivation of tuberculosis, and immunosuppression. Further insights are needed regarding limitation of adverse effects, correct use in conjunction with existing drugs, and treatment of patients in whom resistance develops.

Aberrant expression of the costimulatory molecule CD40 ligand on monocytes from patients with systemic lupus erythematosus.

CD40 ligand (CD40L, CD154) is overexpressed on T and B cells in systemic lupus erythematosus (SLE). Monocytes have been shown to contribute to immune-mediated pathology in SLE and to express CD40L under certain conditions. Therefore, we studied CD40L expression on lupus monocytes ex vivo, as well as after activation in vitro. A highly significant sevenfold increase in the frequency of CD40L-expressing peripheral monocytes from 23 SLE patients, compared to 16 healthy individuals (mean percentage of CD40L(+)CD14(+) among CD14(+) cells, 11.7 versus 1.6), was found by flow cytometry. Increased CD40L expression on monocytes correlated significantly with disease activity, elevated gamma-globulin serum levels, as well as increased CD40L expression on T cells. CD40L expression by lupus monocytes was verified at both the mRNA and protein levels, while LPS stimulation was found to upregulate CD40L mRNA accumulation and surface protein expression. CD40L expression on activated lupus monocytes within anti-CD3-stimulated, mononuclear cell cultures was also enhanced compared to control-derived monocytes. These novel findings underscore the multiplicity of pathways through which monocytes may contribute to SLE pathology and suggest that T cell-independent CD40L-mediated cell to cell interactions may be also involved in humoral immune activation in SLE.