Evolution of bone metastases in patients receiving at least three months of checkpoint inhibitors.

BACKGROUND: To investigate the evolution of bone metastases in patients receiving immune checkpoint inhibitors (ICI). METHODS: A single-center retrospective study included cancer patients with bone metastases treated with ICI at our institution between January 2014 and September 2019. Clinical and biological data were collected from medical records and independent expert review of imaging was performed. Target and non-target lesions were identified and followed up to 1 year. Patients were then classified as bone responder or non-responder. Comparisons between groups were performed with Student's t test or Mann-Whitney test. RESULTS: Among 1108 patients screened, 192 patients had bone metastases and 48 patients were included in the final analysis, with lung cancer, renal carcinoma and melanoma as most represented cancer type. Half of the patients experienced stability, condensation or peripheral sclerosis of bone lesions. Initial progression before stabilization with or without sclerosis of bone lesion occurred for 19% of patients (pseudoprogression). There was an association between bone response and global oncological outcomes. Bone responder patients had a significant decrease in morphine and co-analgesic prescription as well as a significant decrease in alkaline phosphatases compared to non-responder patients. CONCLUSION: Bone response was observed in half of patients with available imaging and follow-up after 3 months of ICI treatment, with sclerosis observed in one-third of bone lesions at month 3, in all tumor types. Up to 20% of patients experienced a pseudoprogression of bone lesions such as previously described in primary tumor and other metastatic sites. Bone response was associated with improvement of pain and survival.

Predictive risk factors of serious infections in patients with rheumatoid arthritis treated with abatacept in common practice: results from the Orencia and Rheumatoid Arthritis (ORA) registry.

OBJECTIVES: Little data are available regarding the rate and predicting factors of serious infections in patients with rheumatoid arthritis (RA) treated with abatacept (ABA) in daily practice. We therefore addressed this issue using real-life data from the Orencia and Rheumatoid Arthritis (ORA) registry. METHODS: ORA is an independent 5-year prospective registry promoted by the French Society of Rheumatology that includes patients with RA treated with ABA. At baseline, 3 months, 6 months and every 6 months or at disease relapse, during 5 years, standardised information is prospectively collected by trained clinical nurses. A serious infection was defined as an infection occurring during treatment with ABA or during the 3 months following withdrawal of ABA without any initiation of a new biologic and requiring hospitalisation and/or intravenous antibiotics and/or resulting in death. RESULTS: Baseline characteristics and comorbidities: among the 976 patients included with a follow-up of at least 3 months (total follow-up of 1903 patient-years), 78 serious infections occurred in 69 patients (4.1/100 patient-years). Predicting factors of serious infections: on univariate analysis, an older age, history of previous serious or recurrent infections, diabetes and a lower number of previous anti-tumour necrosis factor were associated with a higher risk of serious infections. On multivariate analysis, only age (HR per 10-year increase 1.44, 95% CI 1.17 to 1.76, p=0.001) and history of previous serious or recurrent infections (HR 1.94, 95% CI 1.18 to 3.20, p=0.009) were significantly associated with a higher risk of serious infections. CONCLUSIONS: In common practice, patients treated with ABA had more comorbidities than in clinical trials and serious infections were slightly more frequently observed. In the ORA registry, predictive risk factors of serious infections include age and history of serious infections.

Comparison of the long-term outcome for patients with rheumatoid arthritis with persistent moderate disease activity or disease remission during the first year after diagnosis: data from the ESPOIR cohort.

OBJECTIVE: To investigate if patients with early RA with persistent moderate disease activity during the first year after diagnosis have a worse 3-5 year outcome than those who achieve sustained clinical remission within the first year, in a daily life setting. METHODS: The ESPOIR cohort included patients with early arthritis of <6 months' duration. Treatment was the standard of care. We had 5-year follow-up data for 573 patients. This study compared patients who had persistent moderate disease activity (Disease Activity Score in 28 joints (DAS28)>3.2 and ≤5.1) at both the 6- and 12-month visits, with those who were in sustained DAS28 remission. The primary outcome was radiographic progression at the 36-month visit. Secondary endpoints were clinical remission (DAS28 score, Simplified Disease Activity Index, ACR/EULAR criteria), Health Assessment Questionnaire-Disability Index (HAQ-DI) and number of missed workdays at months 36 and 60. A Fisher exact test was used to compare categorical variables, and the Kruskal-Wallis test for quantitative variables. Logistic regression analysis was used to determine predictors of outcome. RESULTS: Patients were aged 48.1±12.5 years and their duration of symptoms was 103.2±52.1 days. Mean baseline DAS28 was 5.1±1.3. Persistent moderate disease activity (107 patients) rather than sustained remission (155 patients) during the first year was associated with increased radiographic disease progression at 3 years (OR=1.99 (95% CI 1.01 to 3.79)), increased HAQ-DI at 3 and 5 years (5.23 (2.81 to 9.73) and 4.10 (2.16 to 7.80), respectively), a 7-11 times smaller chance of achieving clinical remission and a five times greater number of missed workdays. CONCLUSIONS: Patients with early RA with persistent moderate disease activity during the first year had a worse outcome than patients who achieved sustained clinical remission. Persistent moderate disease activity affects long-term structure, remission rate and functional and work disability. Such patients may benefit from intensive treatment.

Safety of surgery after rituximab therapy in 133 patients with rheumatoid arthritis: data from the autoimmunity and rituximab registry.

OBJECTIVE: We used data from the AutoImmunity and Rituximab (AIR) registry to investigate the safety of surgery for patients with rheumatoid arthritis receiving rituximab (RTX) in routine care. METHODS: Data for patients included in the AIR registry and undergoing surgery during the year following an infusion of RTX were reviewed to describe the frequency of postsurgical complications, compare patients with and without complications, and identify factors associated with complications. RESULTS: We examined data for 133 patients with a known date of surgery and at least 1 followup visit, corresponding to 140 procedures, including 94 orthopedic surgeries (67%) and 23 abdominal surgeries (16.5%). The median delay between surgery and the last RTX infusion was 6.4 months (interquartile range 4.3­ 8.7 months), without any difference between patients with and without complications. Nine patients (6.7%) experienced 12 complications (8.5%), including 8 surgical site infections (5.7%) and 1 death due to septic shock. Postoperative complications occurred after 4.3% of abdominal surgeries (1 of 23) and 7.4% of orthopedic surgeries (7 of 95). On univariate analysis, spine surgery was associated with postoperative complications (P = 0.048). CONCLUSION: In common practice, the risk of complications may be more important in case of spine surgery, but does not seem to be linked to the time between the last RTX infusion and surgery.

Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab registry.

OBJECTIVE: The risk of severe infection is a crucial factor in the assessment of the short-term risk:benefit ratio of biologic drugs in rheumatoid arthritis (RA). There is no increase in severe infections in RA patients treated with rituximab (RTX) in controlled trials, but this has not yet been assessed in daily practice. We undertook this study to investigate the occurrence of and risk factors for severe infections in off-trial patients using data from the AutoImmunity and Rituximab (AIR) registry. METHODS: The AIR registry was set up by the French Society of Rheumatology. The charts of patients with severe infections were reviewed. RESULTS: Of the enrolled patients, 1,303 had at least 1 followup visit at 3 months or later, with a mean ± SD followup period of 1.2 ± 0.8 years (1,629 patient-years). Eighty-two severe infections occurred in 78 patients (5.0 severe infections per 100 patient-years), half of them in the 3 months following the last RTX infusion. Multivariate analysis showed that chronic lung disease and/or cardiac insufficiency (odds ratio 3.0 [95% confidence interval 1.3-7.3], P = 0.01), extraarticular involvement (odds ratio 2.9 [95% confidence interval 1.3-6.7], P = 0.009), and low IgG level (<6 gm/liter) before initiation of RTX treatment (odds ratio 4.9 [95% confidence interval 1.6-15.2], P = 0.005) were significantly associated with increased risk of a severe infection. CONCLUSION: The rate of severe infections in current practice is similar to that reported in clinical trials. The risk factors for severe infections include chronic lung and/or cardiac disease, extraarticular involvement, and low IgG before RTX treatment. This suggests that serum IgG should be checked and the risk:benefit ratio of RTX discussed for patients found to have low levels of IgG.

Lymphoma in patients treated with anti-TNF: results of the 3-year prospective French RATIO registry.

OBJECTIVE: To describe cases of lymphoma associated with anti-TNF therapy, identify risk factors, estimate the incidence and compare the risks for different anti-TNF agents. METHODS: A national prospective registry was designed (Research Axed on Tolerance of bIOtherapies; RATIO) to collect all cases of lymphoma in French patients receiving anti-TNF therapy from 2004 to 2006, whatever the indication. A case-control analysis was conducted including two controls treated with anti-TNF per case and an incidence study of lymphoma with the French population was used as the reference. RESULTS: 38 cases of lymphoma, 31 non-Hodgkin's lymphoma (NHL) (26 B cell and five T cell), five Hodgkin's lymphoma (HL) and two Hodgkin's-like lymphoma were collected. Epstein-Barr virus was detected in both of two Hodgkin's-like lymphoma, three of five HL and one NHL. Patients receiving adalimumab or infliximab had a higher risk than those treated with etanercept: standardised incidence ratio (SIR) 4.1 (2.3-7.1) and 3.6 (2.3-5.6) versus 0.9 (0.4-1.8). The exposure to adalimumab or infliximab versus etanercept was an independent risk factor for lymphoma in the case-control study: odds ratio 4.7 (1.3-17.7) and 4.1 (1.4-12.5), respectively. The sex and age-adjusted incidence rate of lymphoma was 42.1 per 100 000 patient-years. The SIR was 2.4 (95% CI 1.7 to 3.2). CONCLUSION: The two to threefold increased risk of lymphoma in patients receiving anti-TNF therapy is similar to that expected for such patients with severe inflammatory diseases. Some lymphomas associated with immunosuppression may occur, and the risk of lymphoma is higher with monoclonal-antibody therapy than with soluble-receptor therapy.

Cytokine imbalance with increased production of interferon-alpha in psoriasiform eruptions associated with antitumour necrosis factor-alpha treatments.

BACKGROUND: Psoriasiform eruptions occur in association with antitumour necrosis factor (TNF)-alpha treatments in autoinflammatory diseases. The major reported clinical presentation is palmoplantar pustulosis, sometimes accompanied with plaque-like psoriasis. In some reports, histological findings suggest psoriasis whereas others favour a lichenoid drug reaction. We present a case series with a comprehensive clinical, histopathological and immunohistochemical study. OBJECTIVES: To investigate the mechanism involved in psoriasiform eruptions in patients receiving anti-TNF-alpha inhibitors. METHODS: Between July 2004 and May 2008, 13 patients with psoriasiform eruptions arising under anti-TNF-alpha treatment were enrolled in the study. Punch biopsy specimens of lesions were processed for standard and immunohistochemical analyses using antibodies against CD3, CD4, CD8, CD20, CD1a, KP1, CXCR3, CXCL9, Tia1 and MxA, which is specifically induced by type I interferons (IFNs). Additionally, we analysed biopsies from lesional skin of patients with cutaneous discoid lupus erythematosus, lichen planus and psoriasis. Control biopsies were taken from unaffected skin. RESULTS: All patients developed psoriasiform plaques on the body accompanied with palmoplantar keratoderma or pustulosis in three patients. Histological and immunohistochemical findings showed a psoriasiform pattern with focal lichenoid and spongiotic features. We detected strong production of the MxA protein in inflammatory cells, indicating involvement of type I IFNs, and the expression was higher than in control psoriasis samples. Expression of MxA was closely associated with the recruitment of CXCR3+ lymphocytes in the skin bearing markers of cytotoxic capacity. CONCLUSIONS: Results support the hypothesis that psoriasiform eruptions are a new model of drug reaction characterized by an increased expression of type I IFNs induced by anti-TNF-alpha.

Influence of FCGR3A-V212F and TNFRSF1B-M196R genotypes in patients with rheumatoid arthritis treated with infliximab therapy.

OBJECTIVE: Anti-TNF-alpha therapies are widely used in rheumatoid arthritis (RA) patients. Despite their clearly proven efficacy, some discrepancies were observed in the treatment response with 40% of non-responder patients. The aim of this study is to determine whether two functional single-nucleotide polymorphisms, V212F in the FCGR3A, and M196R in the TNFRSF1B genes correlate with rheumatoid arthritis susceptibility and response to anti-TNF-alpha therapy. METHODS: The population study was composed of a French cohort of 78 RA patients and 70 healthy controls. Allele and genotype frequencies were compared between patients and controls, according to their response to infliximab therapy, using the American College of Rheumatology (ACR) response criteria. RESULTS: No association was found between these two SNPs and RA susceptibility. A significant correlation was found between 196R allele carriers and low response to infliximab therapy. CONCLUSION: This is the first report of a statistically significant association between the TNFRSF1B-M196R SNP and response to infliximab in a French cohort. Larger studies are needed to confirm the relevance of this association.

Anti-nuclear antibodies, anti-DNA and C4 complement evolution in rheumatoid arthritis and ankylosing spondylitis treated with TNF-alpha blockers.

OBJECTIVE: To investigate autoantibody induction in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) in a cohort of French patients treated with TNF-alpha blockers. METHODS: We tested the serum of patients for antinuclear antibodies (ANA), anti-DNA antibodies and C4 complement at baseline, and for each infusion for infliximab, and at month 3, 6 and 12 for etanercept. We looked for all signs suggesting a drug-induced lupus. We tried to correlate ANA and anti-DNA development with various clinical data, especially the response to treatment. RESULTS: 229 patients were included in the study. 159 were treated with infliximab (98 RA and 61 AS) and 125 with etanercept (116 RA and 9 AS). In the infliximab group, 43.6% of RA patients and 27.1% of AS had significant levels of ANA at baseline. This proportion increased during the follow up to 73% in RA patients and 52% in AS patients. The proportion of patients positive for anti-DNA antibodies increased from 0% to 9.5% in RA group, and from 0% to 2% in AS group. In the etanercept group, 58.5% of these patients had significant levels of ANA at baseline; this proportion raised to 63.3% in patients previously treated with infliximab, and fell to 20.6% in the patients who never received TNF-alpha blockers. No significant variation of ANA, anti-DNA and C4 levels was observed in the etanercept group. Only three patients developed clinical manifestations (chilblain lupus) possibly related to these auto-antibodies, two with infliximab and one with etanercept. CONCLUSION: The ANA induction was only observed under infliximab therapy. Thus, ANA induction seems not to be a therapeutic class effect. This difference between infliximab and etanercept treatment may be the consequence of differential capacity of a monoclonal antibody and a soluble receptor in inducing apoptotic cell death of the cells expressing TNF on their membrane.

Role of anti-tumour necrosis factor-alpha therapeutic agents in the emergence of infections.

There is increasing interest concerning the possible impact of anti-tumour necrosis factor (TNF)-alpha therapeutic agents on the emergence of infections. However, these agents do not seem to increase the incidence of adverse infectious events significantly. Published observations concern mostly infections of the urinary and upper respiratory tracts that develop in the setting of co-morbidities, such as anterior or concomitant immunosuppressive treatment. Infliximab appears to increase the risk of tuberculosis, but this effect has not been observed with other anti-TNF-alpha agents. To better characterise the adverse infectious effects associated with these agents, physicians should be encouraged to notify the microbiological data relating to all cases.

Neuropathy resembling CIDP in patients receiving tumor necrosis factor-alpha blockers.

Tumor necrosis factor-alpha (TauNuFalpha) blockers are effective in the treatment of inflammatory arthritis but can induce autoimmune disorders including multiple sclerosis. Described are two patients who developed chronic inflammatory demyelinating polyneuropathy after initiation of anti-TNFalpha treatment.

Successful treatment of relapsing polychondritis with infliximab.

Relapsing polychondritis (RP) is a rare and potentially fatal autoimmune disease in which an inappropriate immune response destroys the cartilage of the ears, larynx and nose. Many therapeutic approaches have been reported. We describe the results obtained with infliximab in a patient with RP unresponsive to conventional therapy. This therapy could be a new weapon to treat refractory RP.

Chondrosarcoma in a patient with McCune-Albright syndrome. Report of a case.

A case of McCune-Albright syndrome with acromegaly and chrondrosarcoma is reported. The potential role of chronic growth hormone overproduction in the occurrence of malignant transformation and the possible value of bisphosphonates in the treatment of bone fibrous dysplasias are discussed.

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE): a form of paraneoplastic polyarthritis?

OBJECTIVE: To describe the clinical and laboratory features and outcome of 6 patients presenting with remitting seronegative symmetrical synovitis with pitting edema (RS3PE) revealing a solid tumor. METHODS: Patients with RS3PE who presented with a solid tumor and who had been seen between January 1, 1994, and December 31, 1996, were included in a retrospective multicenter analysis. These patients fulfilled McCarty's description of RS3PE and the following criteria: (1) bilateral pitting edema of both hands, (2) sudden onset of polyarthritis, (3) age >50 years, and (4) absence of rheumatoid factor (RF). RESULTS: Six male patients with RS3PE are described, of mean age 74 years (range 72-78), presenting prostatic (n = 4), gastric (n = 1), and colic (n = 1) adenocarcinomas. The clini cal picture was characterized by the classical form of RS3PE syndrome and by a deterioration in general condition, sometimes with fever. All patients were negative for RF and antinuclear antibodies. In 2 cases of prostatic adenocarcinoma serum levels of interleukin 6 (IL-6) were high, but decreased with treatment. In these 6 patients, the articular manifestations regressed totally or partially in response to corticosteroids, sometimes at low doses, associated in most cases with specific antitumoral therapy. None displayed erosion or distal bone destruction. The mean survival following discovery of RS3PE was 11 months (range 6-18), 5 patients dying of metastatic dissemination of their cancer and the 6th of myocardial infarction. CONCLUSION: RS3PE is a heterogeneous syndrome that can reveal a solid tumor, notably an adenocarcinoma. There exist no specific criteria to define its forms, but this syndrome should be kept in mind in the face of a deterioration in general health. Although the pathogenic mechanism is unknown, this could involve a type of paraneoplastic polyarthritis linked to the synthesis of a factor such as IL-6.

Chronic immunity-driven polyarthritis in hairy cell leukemia. Report of a case and review of the literature.

Hairy cell leukemia can be responsible for polyarthritis due either to leukemic infiltration or to immunity-drive inflammation. The second variant can antedate or post-date the clinical onset of leukemic symptoms and usually presents as rheumatoid arthritis, more rarely as lupus or scleroderma. The presence of hairy cells in the joint fluid does not rule out autoimmune polyarthritis. The main differential diagnoses are Felty's syndrome and large granular lymphocyte leukemia. We report a case of hairy cell leukemia with seropositive rheumatoid arthritis.

Fibrogenesis imperfecta ossium: ineffectiveness of melphalan.

Fibrogenesis imperfecta ossium (FIO) is an extremely rare, acquired, metabolic bone disease related to a collagen defect in bone matrix inducing spontaneous fractures. Among the 17 cases of FIO reported to date, four patients exhibited a monoclonal gammopathy (MCG) and one, treated with melphalan, was the first patient to present clinical and histological remission of the bone and plasma cell manifestations. We report the case of a 56-year-old woman who suffered spontaneous fractures of both patellae and olecranons. Skeletal X-rays showed generalized coarse, ill-defined trabeculae. The following biological parameters were abnormal: ESR: 50 mm/hour, alkaline phosphatase (AP) 256 IU/liter [normal (N): 40-110], serum IgG kappa light chain 11 g/liter, bone marrow aspirate 9% atypical plasma cells. Iliac crest biopsy showed the features of FIO including evidence of osteomalacia and nonbirefringent osteoid seams under polarized light. Eroded surfaces were increased, and trabecular bone volume was decreased. Melphalan (4 mg/day) was given in 1988 and was interrupted 1 year later because of leucopenia. Clinical status worsened. A second bone biopsy in 1989 showed identical features of FIO. In November 1990, an X-ray film showed several fractures, and coarser trabeculae. The patient died in December 1991. Regarding the prevalence of MCG and FIO, their association is unlikely accidental. The collagen defect might be related to a plasma cell-induced osteoblast impairment.

Mycoplasma fermentans, but not M penetrans, detected by PCR assays in synovium from patients with rheumatoid arthritis and other rheumatic disorders.

AIM/BACKGROUND: Mycoplasmas, especially Mycoplasma fermentans, were suggested more than 20 years ago as a possible cause of rheumatoid arthritis but this hypothesis was never substantiated. In view of the superior sensitivity of the polymerase chain reaction (PCR) assay over culture, the aim was to use this method to seek M fermentans and M penetrans in synovial samples from patients with various arthritides. METHODS: Synovial fluid samples (n = 154) and synovial biopsy specimens (n = 20) from 133 patients with various rheumatic disorders were stored at -80 degrees C for between one and 40 months. Aliquots (500 microliters) of the synovial fluid samples were centrifuged and the deposit, and also the synovial biopsy specimens (approximately 1 g) were placed in lysis buffer with proteinase K for DNA extraction. The DNA was tested by using a semi-nested PCR assay for M fermentans and a single-round PCR for M penetrans. RESULTS: M fermentans was detected in the joints of eight (21%) of 38 patients with rheumatoid arthritis, two (20%) of 10 patients with spondyloarthropathy with peripheral arthritis, one (20%) of five patients with psoriatic arthritis, and four (13%) of 31 patients with unclassified arthritis. M fermentans was not found in the joints of the seven patients with reactive arthritis, the 29 with osteoarthritis or post-traumatic hydrarthrosis, the nine with gouty arthritis, nor the four with chronic juvenile arthritis. M penetrans was not detected in any sample. CONCLUSIONS: These findings show that the presence of M fermentans in the joint is associated with inflammatory rheumatic disorders of unknown cause, including rheumatoid arthritis. However, whether this organism triggers or perpetuates disease of behaves as a passenger remains conjectural.