Theodora E. Markatseli

Granuloma annulare induced by anti-tumour necrosis factor therapy

Objective: To describe granuloma annulare (GA) skin lesion development in patients during anti-tumour necrosis factor (TNF) therapy. Methods: 199 patients with rheumatoid arthritis and 127 suffering from spondyloarthropathies treated with anti-TNF antagonists were analysed to identify skin lesions suggesting GA. Results: Nine cases of GA during anti-TNF therapy (123 treated with infliximab, 57 with adalimumab and 17 with etanercept) for rheumatoid arthritis were identified. Two have been treated with infliximab, six with adalimumab and one with etanercept, and here the development of GA was 4.5%. No patient with spondyloarthropathies developed such skin lesions. All patients developed the generalised form of GA. None had or developed diseases, or conditions known to be associated with GA. In seven patients the skin eruptions developed during the first year of anti-TNF treatment, while they developed in two patients during the second year. Two patients had to stop anti-TNF therapy due to the extent of skin lesions. All patients responded well to the local corticosteroid therapy. Conclusions: Our series strongly supports a link between TNF inhibition and the development of GA in some patients. When dealing with patients on these agents physicians should be aware of possible adverse events and the potential development of such complications.

Comparative effectiveness and survival of infliximab, adalimumab, and etanercept for rheumatoid arthritis patients in the Hellenic Registry of Biologics: Low rates of remission and 5-year drug survival

OBJECTIVE To compare effectiveness, drug survival, and safety between infliximab, adalimumab, and etanercept, in a nationwide cohort of rheumatoid arthritis (RA) patients. METHODS This study is a prospective cohort study of 1208 active RA patients. Effectiveness, drug survival, and serious adverse events during entire follow-up (median 2.9 years) were monitored. RESULTS EULAR and CDAI responses were comparable between the three agents (EULAR good/moderate responses at 12 months ranged 76-79%). At 12 months, 15-23% achieved remission. For adalimumab and etanercept, adjusted hazard rate (HR) for EULAR/ACR remission (reference: infliximab) was 2.7 and 2.1 (95% confidence interval was 1.7-4.1 and 1.3-3.4, respectively); males (HR 1.6; 1.1-2.4), use of glucocorticoids (HR 2.0; 1.3-3.0), and swollen joint count >7 (HR 0.36; 0.24-0.55) were independent predictors. Five-year drug survival was 31%, 43%, and 49% for infliximab, adalimumab, and etanercept, respectively (p = 0.010). Infliximab was associated with significantly more withdrawals due to adverse events. Disease activity, CRP, and use of glucocorticoids predicted efficacy-related drug survival; age, use of methotrexate, and prior DMARDs failures predicted safety-related survival. Risk for serious infections was lower with adalimumab (odds ratio [OR] 0.62; 0.38-1.00) or etanercept (OR 0.39; 0.21-0.72) than infliximab, independent of the effects of age (OR 1.65; 1.37-2.00 per 10 years), tender joint count >10 (OR 1.86; 1.21-2.86), and glucocorticoids >35mg/week (OR 1.83; 1.12-2.99). CONCLUSIONS Response rates were comparable among anti-TNF agents. Overall, 5-year drug survival was below 50%, with infliximab demonstrating increased safety-related discontinuations. Remission rates are low in clinical practice. Strategies to increase effectiveness and long-term survival of anti-TNF agents in RA are needed.

Prognostic Factors of Radiological Damage in Rheumatoid Arthritis: A 10-year Retrospective Study

Objective. To describe the longterm clinical and radiological outcomes in rheumatoid arthritis (RA) in a cohort in northwestern Greece; and to investigate predictive factors of radiological damage at the 10-year followup in patients with RA. Methods. We studied the disease course and outcome of 144 patients with RA and radiographs of the hands and wrists available at baseline and at 10 years. Baseline measurements and time-averaged measures of swollen joint count (SJC) and inflammatory markers [erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)] were tested in univariate analysis, and then those presenting a statistically significant association with either Larsen score at 10 years or annual progression rate were included in 2 logistic regression models in order to determine relevant independent prognostic factors. Results. A significant clinical improvement was noted, associated with a decrease of inflammatory markers along the timepoints. Larsen score and the number of erosive joints were increased. In the univariate analysis, both final Larsen score at 10 years and accelerated annual radiological progression rate were significantly associated with baseline radiographic measurements (Larsen score and number of erosive joints), the presence of autoantibodies [anticyclic citrullinated peptide antibodies (anti-CCP) and rheumatoid factor of IgA and IgM isotype], disease duration, and time-averaged measures of ESR, CRP, and SJC. In the logistic regression analysis, the baseline Larsen score, anti-CCP antibodies, and time-averaged CRP presented significant and independent associations with Larsen score at 10 years. An accelerated annual radiological progression rate was also predicted by baseline Larsen score and time-averaged measures of SJC and CRP. Conclusion. Despite clinical improvement, the radiologic progression of RA continues over time, because of the underlying inflammatory process. Baseline radiographic damage, anti-CCP antibodies, and time-averaged CRP constitute the main predictive factors of poor radiologic outcome in the long term.

Sustained Clinical Response in Psoriatic Arthritis Patients Treated with Anti-TNF Agents: A 5-year Open-Label Observational Cohort Study

OBJECTIVE To investigate the efficacy, toxicity, and drug discontinuation in patients with psoriatic arthritis treated with anti-tumor necrosis factor agents. METHODS Sixty-five patients with active disease were included in this open-label study. They had tender or swollen joint count ≥5, Psoriatic Arthritis Severity Index (PASI) score ≥10, and erythrocyte sedimentation rate ≥28 mm Hg/1st hour and/or C-reactive protein ≥10 mg/L. All were refractory to at least 2 disease-modifying antirheumatic drugs. Thirty were treated with infliximab, 25 with etanercept, and 10 with adalimumab. Infliximab (5 mg/kg body weight) was given intravenously at weeks 0, 2, 6, and every 8 weeks thereafter; etanercept was given subcutaneously (25 mg twice a week), while adalimumab was given subcutaneously (40 mg every other week) for a period of 5 years. Data concerning anti-tumor necrosis factor efficacy tolerability, adverse events, and drug discontinuation were recorded. The percentage of patients who achieved the Psoriatic Arthritis Response Criteria (PSARC), the improvement of PASI, the improvement according to the American College of Rheumatology (ACR) criteria, and the disease activity for 28 joint indices score (DAS-28) were recorded. RESULTS After 5 years, PSARC was 60%, PASI 70 was 66.7%, PASI 90 was 63.3%, while ACR 50 was 56.7% for the patients treated with infliximab. Moreover, PsARC was 64%, PASI 70 and PASI 90 were 68%, while ACR 50 was 56% for those treated with etanercept. Furthermore, in the adalimumab group PsARC was 56%, PASI 70 and PASI 90 were 58% and 50%, respectively, while ACR 50 was 50%. Additionally, DAS-28 scores were significantly improved. Thirteen patients treated with infliximab, 6 with etanercept, and 5 patients with adalimumab were withdrawn. At the end of treatment, the survival of infliximab was 56.7%, for etanercept 76%, and for adalimumab 50%. CONCLUSION All drugs were effective, safe, and well-tolerated. The clinical improvement was maintained through the 5 years with satisfying infliximab and adalimumab survival and high etanercept survival.

A multicenter, open-label, comparative study of B-cell depletion therapy with Rituximab for systemic sclerosis-associated interstitial lung disease

OBJECTIVES Rituximab (RTX) may favorably affect lung function and skin fibrosis in patients with systemic sclerosis (SSc). We aimed to assess long-term efficacy and safety of RTX in SSc compared to standard treatment. METHODS A total of 51 patients with SSc-associated interstitial lung disease were recruited and treated with RTX (n = 33) or conventional treatment (n = 18). Median follow-up was 4 years (range: 1-7). Conventional treatment consisted of azathioprine (n = 2), methotrexate (n = 6), and mycophenolate mofetil (n = 10). RESULTS Patients in the RTX group showed an increase in FVC at 2 years (mean ± SD of FVC: 80.60 ± 21.21 vs 86.90 ± 20.56 at baseline vs 2 years, respectively, p = 0.041 compared to baseline). In sharp contrast, patients in the control group had no change in FVC during the first 2 years of follow-up. At the 7 year time point the remaining patients in the RTX group (n = 5) had higher FVC compared to baseline (mean ± SD of FVC: 91.60 ± 14.81, p = 0.158 compared to baseline) in contrast to patients in the control group (n = 9) where FVC deteriorated (p < 0.01, compared to baseline). Direct comparison between the 2 groups showed a significant benefit for the RTX group in FVC (p = 0.013). Improvement of skin thickening was found in both the RTX and the standard treatment group; however, direct comparison between groups strongly favored RTX at all-time points. Adverse events were comparable between groups. CONCLUSIONS Our data indicate that RTX has a beneficial effect on lung function and skin fibrosis in patients with SSc. Randomized controlled studies are highly needed.

Cardiovascular risk profile in patients with spondyloarthritis

OBJECTIVES The spondyloarthritides (SpA) are associated with an increased cardiovascular risk. We studied cardiovascular risk factors in patients with SpA. METHODS The following risk factors were assessed in SpA patients and healthy controls: smoking, family history of premature ischemic heart disease, obesity, serum lipids, apolipoproteins, urate and carotid intima media thickness (IMT). RESULTS Overall 150 patients (73 with ankylosing spondylitis [AS], 71 with psoriatic arthritis [PsA] and six with other SpA types) were included. Generally SpA patients were significantly more often smokers, while PsA patients had greater values of abdominal obesity. AS patients had significantly lower levels of triglyceride, HDL, ApoB, ApoE and Lp(a) and a higher atherogenic index (total cholesterol/HDL). PsA patients had significantly lower levels of HDL, ApoAI and ApoE, an elevated atherogenic index and higher serum urate. In multivariate analysis the atherogenic index was positively associated with SpA across all patient groups independently of smoking and other lipid parameters. Carotid IMT in SpA patients (0.71 mm) was higher than controls (0.63 mm, P=0.017), although after adjusting for smoking this ceased to be significant. Treatment of patients with previously untreated disease resulted in a small but significant decline in ApoB levels at 6 months (P=0.045), which, however, was no longer evident at 12 months. CONCLUSION Spondyloarthritis patients are at a greater cardiovascular risk owing to the higher prevalence of smoking and a higher atherogenic index. PsA patients have more abdominal fat and higher urate levels. Immunosuppressive treatment of SpA produces minor and temporary effects on the lipid profile.

Fertility in male patients with seronegative spondyloarthropathies treated with infliximab

OBJECTIVES The majority of patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are affected during their peak reproductive years. Tumor necrosis factor (TNF)α plays a pivotal role in the pathogenesis of both diseases. Today, anti-TNFα blockers are an essential treatment for these patients. To identify male patients who achieved pregnancy development during their management with anti-TNFα blockers (infliximab). METHODS We reviewed the data of 65 patients with AS and 30 patients with PsA who were followed-up in our rheumatology outpatients clinic and they were on infliximab therapy between January 2001 and December 2010. RESULTS We identified overall seven male patients with AS and three male patients with PsA who had fathered 14 healthy infants. Moreover, we recognized one man with PsA who was on infliximab and on concomitant therapy with MTX at the time of conception, whose wife had to proceed to therapeutic abortion due to congenital abnormalities of the fetus (hydrocephalia), while she was on the first trimester of pregnancy. CONCLUSIONS We described male patients with AS and PsA who demonstrated no fertility problems while they were on infliximab treatment. The data designated in this report provide some supportive evidence for the safe use of infliximab in male patients who are affected of those inflammatory diseases during their peak reproductive years.

Maintained clinical response of infliximab treatment in ankylosing spondylitis: A 6-year long-term study

OBJECTIVES To investigate the efficacy, safety and drug discontinuation in patients with ankylosing spondylitis treated with infliximab, as well as the drug survival over a period of 6 years. METHODS Forty patients with ankylosing spondylitis treated with infliximab were included in this open label study. All patients fulfilled the New York revised criteria for ankylosing spondylitis. Infliximab was given intravenously (5 mg/kg/body weight) at weeks 0, 2, 6 and every 8 weeks thereafter for a period of 6 years. Data concerning infliximab efficacy, tolerability, adverse events and drug discontinuation, were recorded. Clinical improvement according to the Bath Ankylosing Spondylitis Disease Activity Index 50% and the Ankylosing Spondylitis Assessment Study Group 20% and 40% were also recorded. RESULTS A significant improvement in the Bath Ankylosing Spondylitis Disease Activity Index and Ankylosing Spondylitis Assessment Study Group scores was noted in the first year which sustained through the sixth year of treatment. More specifically, after the sixth year of treatment, Bath Ankylosing Spondylitis Disease Activity Index 50% was achieved by 65% of patients (26/40), Ankylosing Spondylitis Assessment Study Group 20% by 72.5% (29/40) and Ankylosing Spondylitis Assessment Study Group 40% was reached by 70% (28/40) of patients. Clinical improvement was associated with the reduction of acute phase reactants, such as C-reactive protein levels. After the first and the second year of treatment, the survival rate of infliximab reached 95%, after the third year it was 80%, while after the fourth year it was 72.5%, which was maintained throughout the fifth and sixth year of therapy. Five patients were increased the dose of infliximab and three of them had shortened the interval infusion. Overall, 11 patients were withdrawn during the observational period, three because of adverse events, two because of lack of efficacy, while six were lost from follow-up. CONCLUSION Infliximab was effective, safe and well-tolerated in patients with ankylosing spondylitis. The clinical response was maintained for a period of 6 years, with high infliximab survival rate, reaching the percentage of 72.5%.

Effect of Hydroxychloroquine on the Lipid Profile of Patients with Sjögren Syndrome

Objective. Many studies have highlighted the hypolipidemic action of hydroxychloroquine (HCQ). We investigated the effect of HCQ on the lipid profile of patients with Sjögren syndrome (SS). Methods. The present retrospective observational study included 71 female patients with SS treated with HCQ. The levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol, triglycerides (TG), and atherogenic index (TC/HDL) were measured at baseline, after 6 months, and 1, 3, and 5 years after initiation of HCQ treatment. Analysis to investigate changes over time was performed in the entire patient group and in the separate subgroups: those receiving (21 patients) and those not receiving (50 patients) hypolipidemic treatment. Results. For the entire group of patients a statistically significant decrease in TC was noted (levels before treatment 220 ± 41 mg/dl, and at 5 yrs 206 ± 32 mg/dl, p = 0.006). A statistically significant difference was observed in the levels of HDL (57 ± 14 mg/dl vs 67 ± 17 mg/dl, p < 0.001) and in atherogenic index (4.0 ± 1.3 vs 3.3 ± 0.9, p < 0.001). Patients not receiving a hypolipidemic agent during the same period demonstrated a decrease in TC (214 ± 40 mg/dl vs 208 ± 34 mg/dl, p = 0.049), an increase in HDL levels (55 ± 15 mg/dl vs 67 ± 18 mg/dl, p < 0.001), and a decrease in atherogenic index (4.0 ± 1.4 vs 3.3 ± 0.9, p < 0.001). In the subgroup of patients receiving hypolipidemic treatment, the respective changes in their lipid profile were not significant in the first years but became significant in the long term. Conclusion. Use of HCQ in patients with SS was related to a statistically significant decrease in TC, an increase in HDL, and improvement in the atherogenic index.

SAT0222 B Cell Depletion Therapy in Systemic Sclerosis Associated Interstitial Lung Disease. A Multicenter, Open Label, Comparative Study with A Follow up of 94 Patient-Years

Background We have previously shown that rituximab (RTX) may favorably affect lung function and skin fibrosis in patients with systemic sclerosis (SSc). Objectives To assess long term efficacy and safety of RTX in SSc compared to standard treatment. Methods Fifty one patients with SSc associated interstitial lung disease were recruited and treated with RTX (n=33) or standard treatment (n=18). RTX cycles were repeated every 6 months throughout follow up apart from 6 patients where RTX was discontinued following 2 years of continuous treatment. Mean follow up was 2.9 years (range 1–7). Standard treatment consisted of azathioprine (n=2), methotrexate (n=6) and mycophenolate (n=10). Results Patients in the RTX group showed an increase in FVC during the first year of treatment (mean ± SEM of FVC: 80.60 ± 3.69 vs 83.02 ± 3.37 at baseline vs 1-year, respectively, p=0.13); this beneficial effect was further augmented at 2 years (86.90 ± 4.72, p=0.04 compared to baseline). In sharp contrast, patients in the control group had no change in FVC during the first 2 years of follow up. At 2 years, the RTX group was numerically better than the control group; however, differences tended but did not reach statistical significance (p=0.063). At the 7 year time point patients in the RTX group had higher FVC compared to baseline (mean ± SEM of FVC: 91.60 ± 6.62, p=0.15 compared to baseline) in contrast to patients in the control group where FVC deteriorated (p<0.01, compared to baseline). Direct comparison between the 2 groups showed a significant benefit for the RTX group (p=0.013). DLCO also improved following 2 years of RTX treatment (mean ± SEM of DLCO: 59.22 ± 3.16 vs 61.51 ± 4.02 at baseline vs 2-years, respectively, p=0.05). In the standard treatment group DLCO constantly deteriorated throughout follow up. In 6 patients where RTX was stopped following 2 years of continuous treatment a decline in PFTs was evident. Improvement of skin thickening was found in both the RTX and the standard treatment group, however, direct comparison between groups strongly favored RTX at all time points (p=0.002, 0.015, 0.002, 0.053 0.029 for the 1, 2, 3, 4 and 5-year time point, respectively). In the RTX group, six cases of respiratory infection requiring hospitalization, one case of hepatitis B reactivation and one case of herpes zoster were recorded. Two patients were diagnosed with cancer (lung and prostate). Five deaths were recorded: end stage respiratory failure (n=2), lung cancer (n=1), sudden death (n=1), unknown (n=1). In the control group, five patients with respiratory and four patients with urinary infection were hospitalized. In four cases, infections were recurrent. Two deaths were reported due to respiratory infection. Conclusions Our data indicate that continuous treatment with RTX has a beneficial effect on lung function and skin fibrosis in patients with SSc. Treatment was well-tolerated. Randomized controlled studies are highly needed. Disclosure of Interest None declared