Immunoglobulin G amplifies the production of regulatory rheumatoid factor in vitro through idiotype-anti-idiotype interactions.

Immunoglobulin G can inhibit antibody response. The mechanism of immunosuppression by immunoglobulins remains unknown. Recently, we found a new factor of immunoregulation referred to as regulatory rheumatoid factor (regRF). RegRF prevents autoimmunity and reduces experimental autoimmune reactions. RegRF comprises a population of anti-idiotypic antibodies that have a unique paratope specific to the antigen-binding sites of the antibodies, and a shared paratope specific to neoepitopes of IgG Fc fragments. Given the specificity of regRF, we can anticipate that IgG would be able to induce regRF production, and consequently that the immunosuppressive effect of IgG may be mediated by regRF. We found that IgG induces regRF production in a culture of B lymphocytes obtained from the red bone marrow of intact rats. IgG does not expose neoepitopes recognized by the shared paratope of regRF, and does not acquire them in culture. Therefore, the stimulation of regRF production induced by IgG is not a result of the interaction between the shared paratope of regRF and the neoepitopes of IgG. Fc fragments of IgG are unable to stimulate regRF production. Fab fragments inhibit spontaneous regRF production. F(ab´)2 fragments stimulate regRF production in lymphocyte culture. We theorize that IgG activates regRF-producing lymphocytes through idiotype-anti-idiotype interactions.

Elevated serum resistin in juvenile idiopathic arthritis: relation to categories and disease activity.

BACKGROUND: Juvenile Idiopathic Arthritis (JIA) is one of the more common chronic diseases of childhood that often persists into adulthood and can result in significant long-term morbidity, including physical disability. The aim of the present study was to assess the serum level of resistin in JIA patients and compare its levels according to the categories, clinical manifestations and disease activity. METHODS: Sixty-eight JIA patients and 33 age and sex matched control children were included in the present study. All patients included in this study were subjected to full history taking, clinical examination. Juvenile arthritis disease activity score in 27 joints (JADAS-27) was calculated and Childhood Health Assessment Questionnaire (CHAQ) was used to measure the functional status. Serum resistin levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The mean serum resistin was significantly higher in the JIA patients (4.01 ± 2.46 ng/ml) compared to the control (2.08 ± 1.23 ng/ml) (p<0.001) especially those with systemic-onset. Its level was significantly higher in those receiving steroids and those with a positive antinuclear antibody. Resistin significantly correlated with the JADAS27 (r 0.26, p 0.035) and CHAQ (r 0.4, p 0.001). The JIA patients were 50 females and 18 males; however, the level of resistin was insignificantly different according to the gender although there was a tendency to be higher in females. CONCLUSION: Our results reinforce the proposition of an important role for resistin in JIA and may be considered an interesting biomarker for disease activity especially those with systemic onset.

Rheumatoid arthritis: from autoimmunity to synovitis and joint destruction.

Rheumatoid arthritis is an autoimmune disease characterized by the production of two known antibodies - rheumatoid factor and anti-citrullinated peptide antibody (ACPA) - against common autoantigens that are widely expressed within and outside the joints. The interactions between genes and environment are crucial in all stages of the disease, involving namely genes from major histocompatibility complex locus, and antigens such as tobacco or microbes (e.g. Porphyromonas gingivalis). T and B cells are activated as soon as the earliest phases of the disease, rheumatoid arthritis appearing as a Th1 and Th17 disease. Inflammatory cytokines have a considerable importance in the hierarchy of the processes involved in RA. The joint destruction seen in RA is caused not only by cytokine imbalances, but also by specific effects of the Wnt system and osteoprotegerin on osteoclasts and by matrix production dysregulation responsible for cartilage damage. Both innate and adaptative immunity demonstrated their respective cornerstone position in rheumatoid arthritis, since targeted treatments has been efficiently developed against TNF-α, IL-6 receptor, IL-1ß, CD20 B cells and T-cell/Dendritic cell interactions.

Role of PIR-B in autoimmune glomerulonephritis.

PIR-B, an inhibitory receptor expressed on murine B cells and myeloid cells, regulates humoral and cellular immune responses via its constitutive binding to the ligand, MHC class I molecules, on the same cells (cis) or on different cells (trans). Although it has been speculated that PIR-B is important for maintaining peripheral tolerance, PIR-B single deficiency does not cause overt autoimmune diseases. Recently, however, the combination of its deficiency with the Fas lpr mutation was found to result in augmented production of autoantibodies such as IgG rheumatoid factor and anti-DNA IgG, leading to glomerulonephritis in mice. Although the precise molecular mechanism for the overall scenario is unclear, PIR-B was found to suppress TLR9-mediated production of naturally autoreactive antibodies by innate B cells or B-1 cells by inhibiting the activation of Bruton's tyrosine kinase. Thus, PIR-B is an important regulator of innate immunity mediated by TLR9 in B-1 cells, which can otherwise provoke autoimmunity when overactivated.

I-E-linked control of spontaneous rheumatoid factor production in normal mice.

The concentration of serum IgM molecules binding to IgG2a (rheumatoid factor [RF]) in solid phase assays is 10-100-fold higher in normal, unmanipulated C3H/HeJ (H-2k) than in C57BL/6 (H-2b) mice. Analysis of MHC-congenic mice with the prototype strains show that C3H SW (H-2b) are low, and B6.H-2k are high RF expressor strains, respectively. Furthermore, segregation of RF phenotypes in progenies from backcrosses to C3H/HeJ of (C3H/HeJ x C57BL/6)F1 hybrid mice shows MHC- and IgH-linked controls. RF phenotypes also segregate as if they are MHC linked in crosses between H-2-congenic strains (C3H/HeJ and C3H.SW). The study of intra-H-2 (k/b and k/s) recombinant mice suggested that RF phenotype control is linked to the I-E region. This was confirmed by the typing of C57BL/6 mice expressing a transgenic E alpha chain, and thus, I-E+, which, in contrast to nontransgenic littermates, are high expressors of RF.

Function of B cells expressing a human immunoglobulin M rheumatoid factor autoantibody in transgenic mice.

We have generated transgenic mice that express the immunoglobulin (Ig)M heavy chain and kappa light chain genes coding for a human IgM rheumatoid factor (RF), Les. Transgenic B cells expressing human IgM RF show striking similarities to their counterparts in normal humans. They comprise a significant proportion of the adult B cell population, but secrete only low levels of RF into the serum. The RF transgene-expressing B cells localize to primary B cell follicles and the mantle zone regions of secondary follicles in the spleen. Using these mice we have been able to show that one of the central functions of normal RF-expressing B cells may be to act as highly efficient antigen-presenting cells for low concentrations of immune-complexed antigen. High levels of secretion of IgM RF can not be induced under normal circumstances, although RF-expressing B cells proliferate well in vitro to both aggregated human IgG and anti-human IgM antibodies. However, these mice are not intrinsically secretion deficient. By crossing the RF transgenic mice with the autoimmune MRL/lpr background, we find a dramatic increase, > 200-fold, in levels of serum RF. The results strongly suggest that a major function of normal resting RF B cells is unrelated to antibody secretion. Rather, the RF B cells in the follicles may play a role in antigen presentation and regulation of immune responses to antibody-bound nonself-, and possibly self-antigens. This physiologic role of RF B cells may be disrupted in RF-associated autoimmune disease.

Rheumatoid factors in 129XB recombinant inbred strains. Igh-1-linked control of allotypic and isotypic specificities.

To examine the role of autologous IgG in the induction of murine rheumatoid factors (RF) we have analyzed the allotypic specificity of anti-IgG2a RF in recombinant inbred strains derived from 129/Sv (Igh-1a) and C57BL/6 (Igh-1b) mice. In five of six Igh-1a strains, anti-IgG2a RF reacted with IgG2aa but failed to react with IgG2ab. In contrast, isotype-specific RF, which reacted equally well with a and b allotypes of IgG2a, represented the major RF species in one Igh-1a and all five Igh-1b strains tested. An additional form of RF specific for IgG2ab and not reactive with IgG2aa was detected in one Igh-1b strain. RF specific for a give allotype was thus only found in the presence of that allotype, which strongly suggests the involvement of autologous IgG in the induction of mouse RF synthesis. The specificity of RF was apparently further controlled by genes linked to but different from the Igh-C locus, as indicated by the absence of IgG2aa-specific RF in one of the 6 Igh-1a strains tested. Because this strain, 129XBG, has been shown to express idiotypic markers characteristic of Igh-1b mice, it is likely that the genes, which in the presence of a given allotype induce the production of isotype rather than allotype-specific RF, are identical to those that control the expression of idiotypes. Evidence was also obtained to indicate that Igh-1-linked genes influence the isotypic specificity and the isotype of RF itself: IgA anti-IgG2a predominated in Igh-1a strains and IgM anti-IgG1 in Igh-1b strains. Interestingly enough, total IgA and IgG2a levels also were higher in Igh-1a than in Igh-1b strains.

A gene linked to the Igh-C locus controls the production of rheumatoid factor in the mouse.

In certain specific pathogen-free colonies, mice, upon aging, produce autoantibodies (RF) specific for the Fc portion of their IgG. In our colony, 129/Sv mice (H-2bvl; Igh-1a) have 10-20 times higher RF levels than C5BL/6 (h-2b; Igh-1b). In addition, the 129 have mainly IgA anti-IgG2a, and the B6 have mainly IgM anti-IgGl. We analyzed the genetic factors that control these differences. The high RF-producer phenotype of strain 129 was inherited as a recessive trait as indicated by the low RF levels of (129 X B6) F1 mice. About 1 of 4 129 X F1 (129 X B6) backcrosses and 1 of 10 (129 X B6) F2 mice had high RF levels, suggesting the involvement of two recessive genes in the control of this RF production. All F2 mice and all but one backcross with high IgA anti-IgG2a levels were homozygous for the Ihg-1a allele of the 129 mouse. In contrast, the B6-type RF was eight times more frequent in Igh-1bb than in Igh-1ab or Igh-1aa mice. High RF titers of either type were suppressed in Igh-1ab mice.

Efficient and selective presentation of antigen-antibody complexes by rheumatoid factor B cells.

Using Epstein-Barr virus B cell clones and antigen-specific T cell clones, we asked how antigen-antibody complexes are handled by B cells. We found that the only B cells capable of efficient presentation of antigen-antibody complexes are those that bind the complexes via membrane immunoglobulin, i.e., rheumatoid factor-producing B cells and, to a lower extent, antigen-specific B cells. On the contrary, nonspecific B cells, although capable of binding antigen-antibody complexes, fail to present them to T cells. Thus, rheumatoid factor B cells can present any antigen in the context of an immune complex and be triggered by T cells specific for a variety of foreign antigens. These results demonstrate a mechanism of intermolecular help that may be responsible for the production of rheumatoid factor and possibly of other types of autoantibodies.

Induction of rheumatoid antibodies in the mouse. Regulated production of autoantibody in the secondary humoral response.

A/J mice were found to produce autoreactive IgM anti-IgG1 in response to secondary immunization with a number of protein antigens. No anti-IgG1 was produced after a single such immunization, indicating that antigen: IgG1 antibody complexes were responsible for inducing the autoreactive response. The size of the anti-IgG1 response was in some cases massive and of the same order of magnitude as the response to the foreign immunizing material. No significant anti-IgG2a, anti-IgG2b, or anti-IgG3 response was found in mice producing anti-IgG1. Virtually all of the anti-IgG1 material produced was of the IgM class and bound to the Fc region of autologous IgG1. A component of the anti-IgG1 was shown to be able to distinguish between the two mouse IgG1 allotypes. These results suggest that self-reactive anti-IgG is a common component of the secondary immune response of mice that may have powerful physiological and immunoregulatory effects.

Immune complexes can trigger specific, T cell-dependent, autoanti-IgG antibody production in mice.

Immunization of mice with a combination of passively administered syngeneic IgG (anti-p-azophenylarsonate [anti-Ars]) antibody and a soluble, multivalent form of the antibody's corresponding antigen (Limulus polyphemus hemocyanin conjugated with Ars [Lph-Ars]) resulted in specific autoanti-IgG Fc (rheumatoid factor) production. The response was rapid and only anti-IgG of the IgM isotype is found. Because immunization with either the IgG antibody or the antigen alone did not result in rheumatoid antibody production, immune complexes appear to be the active form of the immunogens. Antibody/antigen ratios that resulted in maximal anti-IgG antibody responses were the same as those required for peak in vitro immunoprecipitation, i.e., equivalence. Previous exposure of the mice to the exogenously supplied antigen was not required for the response. The response to immune complexes is specific because mice immunized with IgG2a-containing complexes produced autoanti-IgG2a, while mice immunized with IgG1-containing complexes produced anti-IgG1 with little reactivity to other IgG isotypes. IgG2a blocked in its complement-fixing capacity was more effective in eliciting the anti-IgG2a response than native IgG2a, suggesting a possible role for the complement system in modulating the anti-IgG2a response. Induction of rheumatoid factor production by immune complexes could be induced in xid mice but not in nu/nu mice, indicating T lymphocyte dependence of the response. In contrast, the B lymphocyte activator lipopolysaccharide was able to elicit vigorous rheumatoid factor production in both nu/nu and normal mice, demonstrating that nu/nu mice contain B cells capable of making the response. Rheumatoid antibody produced in the immune complex- or LPS-induced responses is Fc specific and has relatively low affinity for IgG that is not bound to antigen.

Rheumatoid factor (RF) production during anamnestic immune responses in the mouse. III. Activation of RF precursor cells is induced by their interaction with immune complexes and carrier-specific helper T cells.

IgG1 immune complexes were identified as the humoral stimuli responsible for the synthesis of IgG1-specific IgM rheumatoid factor (RF), which occurs in the mouse during the early stages of secondary immune responses to protein antigens. The specificity of this phenomenon was illustrated by the fact that complexes made with IgG1 F(ab')2 fragments or with antibodies of a different isotype failed to induce significant anti-IgG1 RF synthesis. The importance of immune complexes in the induction of RF was further underscored by the substantial increase in the titers of isotype-specific RF observed in the serum of mice immunized with IgG1- or IgG2a-complexed antigen rather than with antigen alone. The RF-inducing capacity of the complexes varied with the antigen/antibody ratio: it was maximal in antibody excess or at equivalence, but dramatically reduced in large antigen excess. The importance of T cell priming in RF precursor cell activation by immune complexes was demonstrated by the failure of T cell-deprived spleen cells to reconstitute the capability of irradiated mice to produce RF, and by the optimal RF responses observed after reconstitution of irradiated recipients with primed T cells and naive B cells. The involvement of T cells in this process could not be explained by the release of nonspecific B cell activators, because antigenic stimulation of primed T cells failed to enhance the activation of RF precursor cells by immune complexes of unrelated antigen.

Induction of severe autoimmune disease in normal mice by simultaneous action of multiple immunostimulators.

Either of two immunostimulating factors (lpr, lipopolysaccharide) enhanced the pathogenic autoimmune responses of MRL/n mice, but the serologic and immunopathologic characteristics differed. In contrast, either factor acting alone, caused minimal immunopathology in normal mice, despite autoantibody induction. Combined immunostimulation, however, caused fatal glomerulonephritis in normal-background C57BL/6 mice. These results show the profound influence of the background genome on the effects of immunostimulating agents, and show that resistance to autoimmune disease in immunologically normal mice is not absolute.

Delineation of a cross-reactive idiotype on human autoantibodies with antibody against a synthetic peptide.

Antibody against a cross-reactive idiotype (CRI) on human IgM-rheumatoid factor (RF) antibodies was induced by immunization of rabbits with a synthetic peptide ( PSL2 ) corresponding to the second complementarity-determining region (CDR), and adjacent amino acid residues of the kappa light chain of the IgM-RF Sie . The anti-peptide antibody bound efficiently to IgM-RF proteins known to share a cross-reactive idiotype, and to their isolated kappa chains. The anti-CRI was absorbed by, and eluted from, a peptide-Sepharose affinity column. The antibody activity was inhibited by the free peptide in solution. The anti-peptide antibody thus identifies a public idiotype on human IgM-RF, that is largely dependent on the primary sequence of the second CDR of the light chain. Such peptide-induced antiidiotypes of predefined specificity may facilitate studies of the molecular basis of idiotypic cross-reactions, the inheritance and somatic diversification of antibody molecules, and the regulation of the idiotype network.

Autologous stromal vascular fraction cells: a tool for facilitating tolerance in rheumatic disease.

Since the days of Medawar, the goal of therapeutic tolerogenesis has been a "Holy Grail" for immunologists. While knowledge of cellular and molecular mechanisms of this process has been increasing at an exponential rate, clinical progress has been minimal. To provide a mechanistic background of tolerogenesis, we overview common processes in the naturally occurring examples of: pregnancy, cancer, oral tolerance and anterior chamber associated immune deviation. The case is made that an easily accessible byproduct of plastic surgery, the adipose stromal vascular fraction, contains elements directly capable of promoting tolerogenesis such as T regulatory cells and inhibitory macrophages. The high content of mesenchymal and hematopoietic stem cells from this source provides the possibility of trophic/regenerative potential, which would augment tolerogenic processes by decreasing ongoing inflammation. We discuss the application of this autologous cell source in the context of rheumatoid arthritis, concluding with some practical examples of its applications.

Autoantibodies in silicosis patients and in silica-exposed individuals.

The aim of this study was to evaluate the prevalence of autoantibodies in silica-exposed patients with and without silicosis and without any known rheumatic disease. We studied 61 males exposed to silica for a mean time of 12.2 +/- 10.2 years of exposure. A total of 72.1% (44/61) of them presented with pulmonary silicosis. As control group we included 62 healthy males. In all samples we screened for rheumatoid factor (latex agglutination), antinuclear antibodies (indirect immunofluorescence), anti Scl-70 (ELISA) and ANCA (indirect immunofluorescence technique). One patient (1.6%) of the silica group had weakly positive ANA (titer 1:80, centromeric pattern); one (1.6%) had atypical ANCA and seven patients (11.4%) presented positive rheumatoid factor (values range from 8 to 32 UI/ml). One control patient had a positive RF and none of them had positive ANA or ANCA. All patients and controls were negative for anti-Scl-70. The finding of positive RF was higher in the silica-exposed patients (p = 0.032; Fisher). All patients with positive RF had pulmonary silicosis. In the silica-exposed group we could not find a relationship between the presence of RF and age (p = 0.21; Mann-Whitney), smoking habits (p = 0.25; Fisher) but a positive relationship was found with exposure time to silica dust (p = 0.005; Mann-Whitney). We conclude that there was 11.4% prevalence of low titer RF in the silica-exposed patients without known rheumatic disease. RF was more common in patients with longer exposure to silica dust and appeared only in those with silicosis. The presence of ANA, Scl-70 and ANCA was the same as in the control population.

[Incidence of serum rheumatoid factors in elder non-rheumatic individuals].

With the aging of the Japanese population, an increase in the number of elderly patients with rheumatoid arthritis (RA) has been noted in recent years. Although rheumatoid factor (RF) is found in a high proportion of RA patients, it is also known to be present in non-rheumatoid patients. However, no studies have investigated the rate of RF positivity in elderly non-rheumatoid individuals. In this study, we examined the rate of RF positivity in such individuals and the association between smoking and RF production. The subjects were 25 men (aged 67 to 87 years, with a mean of 74.0) and 24 women (aged 60 to 86 years, with a mean of 70.7). Of these subjects, nine (18.4%), including seven men, were RF-positive. A significant positive correlation was observed between age and RF values (n=49, p<0.05). Of 23 subjects with a smoking habit, eight (34.8%) were RF-positive. In contrast, only one (3.8%) of 26 nonsmokers was RF-positive. This difference in the rate of RF positivity was significant (p<0.01). In addition, a significant positive correlation was noted between the duration of smoking and rate of RF positivity (p<0.05), particularly in men (p<0.01). These results suggest that smoking is closely involved in RF production in the elderly.

Human lymphocytes making rheumatoid factor and antibody to ssDNA belong to Leu-1+ B-cell subset.

B lymphocytes bearing the Leu-1 cell-surface antigen (Leu-1+), the human equivalent of mouse Ly-1+ B lymphocytes, have been detected in human peripheral blood, but there is little information on their frequency and properties. Analysis by fluorescence-activated cell sorter and double immunofluorescence showed that Leu-1+ B cells are consistently present in the peripheral blood and spleens of healthy subjects and constitute 17.0 +/- 5.0% (mean value +/- standard deviation) and 17.3 +/- 3.9%, respectively, of total B cells. When purified Leu-1+ and Leu-1- B lymphocytes were transformed into immunoglobulin-secreting cells by infection with Epstein-Barr virus and the culture fluids were tested for reactivity with self-antigens, at least two important autoantibodies, antibody to the Fc fragment of human immunoglobulin G (rheumatoid factor) and antibody to single-stranded DNA, were found to be made exclusively by Leu-1+ B cells. It is concluded that the Leu-1+ lymphocytes represent a major subset of the normal human B cell repertoire and include the B cells capable of making autoantibodies similar to those found in systemic lupus erythematosus and rheumatoid arthritis.

Ongoing somatic hypermutation of the rearranged VH but not of the V-lambda gene in EBV-transformed rheumatoid factor-producing lymphoblastoid cell line.

Epstein-Barr virus (EBV) transforms human peripheral B cells into lymphoblastoid cell lines (LCLs) that secrete specific antibodies. In contrast to peripheral blood B cells, LCLs express the activation-induced cytidine deaminase (AID) gene, a key enzyme in the generation of somatic hypermutation (SHM) in immunoglobulin variable genes. We have previously studied an LCL that secretes a rheumatoid factor (RF: an IgM(lambda) anti-IgG antibody) and identified the accumulation of SHM at a frequency of 1.5 x 10(-3)mut/bp in the rearranged variable region heavy chain gene (VH) of its RF sub-culture (i.e., RF-2004). The aim of the present work was to find out whether SHM was initiated as an early event following EBV transformation. Our results show that already the earliest RF-culture (RF-1983) mutates its VH at a somewhat higher frequency of 1.9 x 10(-3). Overall, we detected 17 point mutations in the RF-2004 culture and in 26 cellular clones derived from the RF-1983 and RF-2004 cultures. Most of the mutations were due to C to T or G to A transitions, with preferential targeting to WRCH/DGYW hotspot motifs, indicating that they were due to the initial phase of AID-directed mutations. A genealogical tree demonstrates that mutations were accumulated in a stepwise manner with 1-2 mutations per cell division. However, no mutations were found in the rearranged V-lambda (Vlambda) gene in the same RF-cultures and their subclones (i.e., <1.2 x 10(-4)mut/bp). To our knowledge this is the first reported clonal cell line that generates SHM in the VH, but not in the Vlambda. It may be due to abrogation of a cis-regulatory element(s) in the Vlambda or to a lack of a specific trans-acting factor which differentially direct the SHM machinery to this gene. Out of the 17 point mutations detected in both cell lines there were, 1 stop codon, 3 mutations which obliterated the binding of the RF antibody to its IgG antigen and 1 or 2 mutations which enhanced antigen-binding affinity. These results show that the evolutionary developed germline encoded antibody combining site is highly sensitive to amino acid replacements. Our combined findings that the RF cells accumulate in a stepwise manner up to 1-2 point mutations/sequence per cell division and the generation of high percentage of functionally deleterious mutations, are in accord with the 'multiphase-recycling model' of SHM, which states that B cells in the germinal center are subjected to multiple rounds of somatic mutations interchanged with periods of antigenic selection.

Rheumatoid factor as predictor of response to treatment with anti-TNF alpha drugs in patients with rheumatoid arthritis: Results of a cohort study.

We determined whether rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA) can predict remission or severe disability in rheumatoid arthritis (RA) patients treated with anti-tumor necrosis factor (TNF) alpha drugs.We performed a cohort study based on the clinical data from a referral center for the treatment of RA in Bogotá, Colombia, were included patients aged ≥18 years with diagnosis of RA with an active disease and for whom a treatment scheme was begun with anti-TNF alpha medication, with a minimum follow-up time of 12 months. Disease activity of Rheumatoid Arthritis was assessed through measurement of RF, ACPA, disease activity score (DAS28), and health assessment questionnaire (HAQ). We calculated the incidence rates (IRs) for remission and severe disability. We also calculated the incidence rate ratio (IRR) for each outcome by adjusting for possible confounders using the Poisson regression method. The hypothesis was tested with a P value of <.05. Statistical analysis was performed in Stata 15.We included 400 patients receiving an anti-TNF alpha agent. Median age was 60 years, and 322 patients were women (80.5%). RF was positive in 357 patients (89%), ACPA in 348 patients (87%), and co-positivity in 324 patients (81%). Median follow-up was 41 months (range, 12-79 months). The IR for remission was 23 per 100 person-years in RF-negative patients and 16 per 100 person-years in RF-positive patients. The adjusted IRR (age sex, treatment, and ACPA) was 1.51 (95%CI, 1.05-2.18). The IR for severe disability was 10.8 per 100 person-years in the RF-positive cohort and 2.3 per 100 person-years in the RF-negative cohort. The IRR adjusted for these factors was 4.37 (95%CI, 1.6-12). Co-positivity had a similar behavior to RF. No differences were recorded in the rates of remission or disability in ACPA-positive and ACPA-negative patients.Our findings suggest that remission is less frequent and severe disability more frequent in RF-positive patients treated with anti-TNF alpha agents than in RF-negative patients.