Impact of treatment with infliximab on anticyclic citrullinated peptide antibody and rheumatoid factor in patients with rheumatoid arthritis.Objective: To investigate the impact of infliximab treatment on anticyclic citrullinated peptide (anti-CCP) antibody and rheumatoid factor rheumatoid factor
n. Abbr. RF
Any of the immunoglobulins found in the serum of individuals with rheumatoid arthritis that enhance the agglutination of suspended particles that are coated with pooled human gamma globulin and that are used (RF) levels in patients with rheumatoid arthritis rheumatoid arthritis
Chronic, progressive autoimmune disease causing connective-tissue inflammation, mostly in synovial joints. It can occur at any age, is more common in women, and has an unpredictable course. (RA).
Methods: Sera from 33 RA patients receiving infliximab and disease modifying antirheumatic drugs Antirheumatic Drugs Definition
Antirheumatic drugs are drugs used to treat rheumatoid arthritis.
Rheumatoid arthritis is a progressive form of arthritis that has devastating effects on joints and general health. were tested for anti-CCP antibody, IgA-, lgG- and IgM-RF using a commercially available semi-quantitative ELISA ELISA (e-li´sah) Enzyme-Linked Immuno-Sorbent Assay; any enzyme immunoassay using an enzyme-labeled immunoreactant and an immunosorbent.
n. at baseline, 30 and 54 weeks after treatment.
Results: The serum levels of anti-CCP antibody and IgA-RF decreased significantly after 30 weeks (P = 0.002 and 0.024); however, the decrease was not significant at week 54 (P = 0.147 and 0.207). The decrease in IgG-RF level was not significant at 30 and 54 weeks (P = 0.059 and 0.097). IgM-RF levels, however decreased significantly at 30 and 54 weeks (P = 0.002 and 0.004). A strong correlation between anti-CCP and IgA-, IgG- and IgM-RF was observed at baseline ([r.sub.s] = 0.48, 0.43, 0.65, P = <0.05) and after infliximab treatment at 30 ([r.sub.s] = 0.45, 0.46, 0.62, P = <0.05) and 54([r.sub.s] = 0.49, 0.45, 0.60, P = <0.05) weeks.
Conclusion: Treatment with infliximab results in decreased anti-CCP antibody and IgA-RF early in the course of therapy that is not sustained. IgM-RF declines and remains decreased for at least 54 weeks. Investigations in larger cohorts of RA patients (especially early RA) with longer follow-up are needed to assess the impact of specific therapeutic interventions on anti-CCP antibody and RF levels and the relationship of their levels to disease activity.
Key Words: Rheumatoid arthritis, rheumatoid factor, anticyclic citrullinated peptide antibody, TNF-[alpha] inhibitors, infliximab
Rheumatoid arthritis (RA) is one of the most common systemic autoimmune diseases affecting approximately 1% of the world population. (1) It is characterized by synovial synovial /sy·no·vi·al/ (-al)
1. pertaining to a synovial membrane.
2. pertaining to or secreting synovia.
of, pertaining to, or secreting synovia. inflammation and subsequent pannus pannus /pan·nus/ (pan´us) [L.]
1. superficial vascularization of the cornea with infiltration of granulation tissue.
2. an inflammatory exudate overlying the synovial cells on the inside of a joint.
3. formation causing cartilage destruction and bone erosion, severe disability and increased mortality. The diagnosis of RA is based primarily on the clinical manifestations of the disease. Rheumatoid factor (RF) and more recently, anticyclic citrullinated peptide (anti-CCP) antibodies have been suggested to be useful diagnostic tools, especially in the early stages of the disease and may be detected in approximately half of the patients with RA before the onset of clinical disease. (2-5) In addition, anti-CCP antibodies are also detected in 34.5% of all patients with RA when all measured RF isotypes (IgG-RF, IgA-RF, and IgM-RF) were negative. (6) The presence of these antibodies may also be predictive of disease progression and radiological damage. (7-9) In particular, anti-CCP antibodies appear to be highly sensitive (approximately 80%) and specific (98%) for rheumatoid arthritis. (10-12) Although there is a considerable overlap between the presence of RF and anti-CCP antibodies, there is evidence that they belong to two separate autoantibody autoantibody /au·to·an·ti·body/ (-an´ti-bod?e) an antibody formed in response to, and reacting against, an antigenic constituent of one's own tissues.
n. systems. Anti-CCP antibodies are associated with the shared epitope epitope: see immunity. , whereas RF is not strongly associated with the presence of the shared epitope. (13-16) Moreover, extra-articular manifestations of RA (including subcutaneous nodules Nodules
A small mass of tissue in the form of a protuberance or a knot that is solid and can be detected by touch.
Mentioned in: Leprosy , vasculitis Vasculitis Definition
Vasculitis refers to a varied group of disorders which all share a common underlying problem of inflammation of a blood vessel or blood vessels. The inflammation may affect any size blood vessel, anywhere in the body. , leg ulcers, and neuropathy) are related to the presence of high titers of RF but not anti-CCP antibodies. (13,14) Several studies have detected that the level of IgM-RF decreases with the administration of effective disease-modifying therapies, especially methotrexate methotrexate, drug used in halting the growth of actively proliferating tissues. Introduced in the 1950s, it is used in the treatment of leukemia, psoriasis, and non-Hodgkin's lymphoma. and parenteral parenteral /pa·ren·ter·al/ (pah-ren´ter-al) not through the alimentary canal, but rather by injection through some other route, as subcutaneous, intramuscular, etc.
1. gold, suggesting a link with disease activity. (17,18) In contrast, few studies have analyzed the variations in the titer of anti-CCP antibodies and RF during treatment with biologic agents such as TNF-[alpha] inhibitors. (19-22) The presence of citrullinated proteins in the inflamed joints and evidence of local production of anti-CCP antibodies suggests a pathogenic role. Given the proposed role of anti-CCP antibody in both the pathogenesis and the early diagnosis of RA, (2,3,23,24) it is important to study the relationship of their levels with therapeutic interventions and the resulting disease activity. The aim of this study was to analyze the effect of infliximab treatment on anti-CCP antibody, RF and acute phase reactant Acute phase reactant
A substance in the blood that increases as a response to an acute conditions such as infection, injury, tissue destruction, some cancers, burns, surgery, or trauma.
Mentioned in: Erythrocyte Sedimentation Rate, Haptoglobin Test levels in patients with RA and to correlate these changes with clinical responses.
Patients and Samples
Sera from 33 patients (28 females and 5 males, 18 whites, 14 blacks and one Hispanic, median age 57 yr, mean age 54.6 [+ or -] 12.1 yr, range 25-74 yr, mean disease duration 12.9 [+ or -] 8.3 year) meeting the American College of Rheumatology rheumatology /rheu·ma·tol·o·gy/ (-tol´ah-je) the branch of medicine dealing with rheumatic disorders, their causes, pathology, diagnosis, treatment, etc.
n. (ACR See riser card. ) (25) criteria for RA, who required therapy with multiple disease-modifying antirheumatic drugs (DMARDS) and infliximab, were selected for testing for anti-CCP antibody, IgA-, IgG- and IgM-RF. Sera from every RA patient treated with infliximab had been collected and stored at -70[degrees]C before each infliximab infusion until the time of the assays. We tested the baseline sera before initiation of infliximab treatment and at 30 weeks in 33 patients and at 54 weeks in 28 patients. Sera at 54 weeks on 5 patients were not available. In addition to infliximab, all patients received other DMARDS, including methotrexate, sulfasalazine sulfasalazine /sul·fa·sal·a·zine/ (-sal´ah-zen) a sulfonamide used in the treatment and prophylaxis of inflammatory bowel disease and the treatment of rheumatoid arthritis. , lefluno-mide, azathioprine azathioprine: see metabolite. , hydroxychloroquine, gold and nonsteroidal anti-inflammatory drugs Nonsteroidal Anti-Inflammatory Drugs Definition
Nonsteroidal anti-inflammatory drugs are medicines that relieve pain, swelling, stiffness, and inflammation. (Table 1). Infliximab was administered initially at 3 mg/kg at baseline, then at 2 weeks, 6 weeks and subsequently every 8 weeks. Some patients required a dose adjustment between 3 and 10 mg/kg based on their clinical response and some required more frequent dosing at every six weeks. We also tested 44 patients with other rheumatic diseases (18 with SLE SLE systemic lupus erythematosus.
systemic lupus erythematosus
Systemic lupus erythematosus (SLE) , 15 with scleroderma scleroderma
or progressive systemic sclerosis
Chronic disease that hardens the skin and fixes it to underlying structures. Swelling and collagen buildup lead to loss of elasticity. The cause is unknown. , 7 with polymyositis Polymyositis Definition
Polymyositis is an inflammatory muscle disease causing weakness and pain. Dermatomyositis is identical to polymyositis with the addition of a characteristic skin rash. , and 4 with psoriatic arthritis) for anti-CCP antibody, IgA-, IgG-, and IgM-RF.
Clinical and Laboratory Assessments
All patients had history and physical examinations before each infliximab infusion. A complete blood count, electrolytes, blood urea nitrogen blood urea nitrogen
n. Abbr. BUN
Nitrogen in the form of urea in the blood or serum, used as a indicator of kidney function.
Blood urea nitrogen (BUN) , creatinine, aspartate aminotransferase, alanine aminotransferase, albumin, erythrocyte sedimentation rate Erythrocyte Sedimentation Rate Definition
The erythrocyte sedimentation rate (ESR), or sedimentation rate (sed rate), is a measure of the settling of red blood cells in a tube of blood during one hour. (ESR ESR - Eric S. Raymond ) and C-reactive protein (CRP C-reactive protein (CRP)
A protein present in blood serum in various abnormal states, like inflammation.
Mentioned in: Pelvic Inflammatory Disease
n.pr See C-reactive protein. ) were measured before each infliximab treatment. The clinical and laboratory results were evaluated at baseline and at 30 and 54 weeks of infliximab treatment.
Anti-CCP and RF
Anti-CCP antibodies were detected using a commercially available second generation, semiquantitative enzyme-linked immunosorbent assay enzyme-linked immunosorbent assay
Enzyme-linked immunosorbent assay (ELISA)
A diagnostic blood test used to screen patients for AIDS or other viruses. (ELISA) kit (QUANTA quan·ta
Plural of quantum. Lite CCP (Certified Computer Professional) The award for successful completion of a comprehensive examination on computers offered by the ICCP. See ICCP and certification.
1. (language) CCP - Concurrent Constraint Programming.
2. IgG ELISA of INOVA Diagnostics Inc., San Diego, CA, USA), following the manufacturer's instructions. The microtitre plates, precoated with highly purified synthetic cyclic citrullinated peptides (CCP) containing modified arginine arginine (är`jənĭn), organic compound, one of the 20 amino acids commonly found in animal proteins. Only the l-stereoisomer participates in the biosynthesis of proteins. residues, were incubated for 30 minutes at room temperature with patients' serum samples diluted at 1:101 by adding 5 [micro]L of sample to 500 [micro]L of horseradish peroxidase (HRP) sample diluent diluent /dil·u·ent/ (dil´oo-int)
1. causing dilution.
2. an agent that dilutes or renders less potent or irritant.
Serving to dilute.
n. . Prediluted anti-CCP standards and positive and negative controls were added to each plate. After three washes with HRP wash concentrate (containing Tris-buffered saline and Tween tween
A child between middle childhood and adolesence, usually between 8 and 12 years old.
[Blend of teen1 and between.] 20), the plates were incubated for 30 minutes at room temperature with an HRP enzyme labeled antihuman IgG conjugate conjugate /con·ju·gate/ (kon´jdbobr-gat)
1. paired, or equally coupled; working in unison.
2. a conjugate diameter of the pelvic inlet; used alone usually to denote the true conjugate diameter; see . After three more washes with HRP wash concentrate, the enzyme reaction was developed by adding tetramethylbenzene chromogen chromogen /chro·mo·gen/ (kro´mah-jen) any substance giving origin to a coloring matter.
1. A substance that lacks definite color but may be transformed into a pigment. and incubating in the dark for 30 minutes at room temperature. The reaction was terminated with HRP stop solution (0.344M sulfuric acid). The absorbance absorbance /ab·sor·bance/ (-sor´bans)
1. in analytical chemistry, a measure of the light that a solution does not transmit compared to a pure solution. Symbol .
2. of each well was read at 450 nm within one hour of adding the HRP stop solution. Anti-CCP antibody was considered positive when the absorbance value was higher than the cut off of the kit (<20 U/mL). The concentration of anti-CCP antibody was calculated from a dose-response curve based on standards; all sera were tested in triplicate and the results reflect the mean. IgA-, IgG- and IgM-RF were also detected by using semiquantitative ELISA kits (QUANTA Lite RF IgA, IgG and IgM ELISA of INOVA Diagnostics, Inc., CA, USA) using the same technique. RF was considered positive when the absorbance value was higher than the cut off of the kit (>6 U) (Fig. 1).
We analyzed our data using SAS (1) (SAS Institute Inc., Cary, NC, www.sas.com) A software company that specializes in data warehousing and decision support software based on the SAS System. Founded in 1976, SAS is one of the world's largest privately held software companies. See SAS System. 9.0 statistical software (SAS, Cary, NC) and performed Repeated Measures ANOVA anova
see analysis of variance.
ANOVA Analysis of variance, see there Analysis to investigate the effect of infliximab on ESR, CRP, and anti-CCP antibodies, IgA-, IgG- and IgM-RF. Wilcoxon signed rank test was used for paired analysis. Correlations were sought using Spearman spear·man
A man, especially a soldier, armed with a spear. correlation coefficients ([r.sub.s]). A probability (p) value of <0.05 was considered significant.
At baseline, 27 of the 33 patients (81.8%) with RA were positive for anti-CCP antibodies, 28 (84.8%) for IgA-RF, 27 (81.8%) for IgG-RF and 29 (87.8%) for IgM-RF. In 25 cases, (75.7%) all 4 antibodies were detected. A strong correlation between anti-CCP and IgA-, IgG- and IgM-RF was observed at baseline ([r.sub.s] = 0.48, 0.43, 0.65, P = <0.05) and after infliximab treatment at 30 ([r.sub.s] = 0.45, 0.46, 0.62, P = <0.05) and 54 ([r.sub.s] = 0.49, 0.45, 0.60, P = <0.05) weeks. No clinical differences at baseline were observed among the patients according to whether they were positive or negative for anti-CCP or RF. The proportion of patients who were positive for anti-CCP and RF antibodies was similar at baseline and at weeks 30 and 54; anti-CCP antibodies (81.8% versus 78.7% versus 78.5%), IgA-RF (84.8% versus 84.8% versus 85.7%), IgG-RF (81.8% versus 84.8% versus 85.7%) and IgM-RF (87.8% versus 87.8% versus 89.2%) (Table 2). After infliximab treatment, one positive patient with anti-CCP antibody became negative at 30 weeks and remained negative at 54 weeks. No patient with a positive IgA-, IgG- or IgM-RF became negative during the study period. One patient who was negative for anti-CCP antibody and IgM-RF at 0 and 30 weeks became weakly positive for both at 54 weeks. One patient who was negative for IgA-RF before treatment became weakly positive at 54 weeks. One patient with negative IgG-RF at baseline and 30 weeks became positive at 54 weeks.
The serum levels of anti-CCP antibody and IgA-RF decreased significantly after 30 weeks (P = 0.002 and 0.024); however, the decrease was not sustained at week 54 (P = 0.147 and 0.207). The decrease in IgG-RF titers was not significant at 30 and 54 weeks (P = 0.059 and 0.097). IgM-RF titers, however, decreased significantly at 30 and 54 weeks (P = 0.002 and 0.004 respectively) (Table 3). Although a decrease in both ESR and CRP was observed after treatment, the differences were not statistically significant. The variations in ESR and CRP correlated with variations in tender and swollen joint counts ([r.sub.s] = 0.49 and 0.48, P = <0.05). At baseline, only IgM-RF correlated with swollen joint count; however, we did not find any correlation between variations in IgA-RF, IgG-RF, IgM-RF, anti-CCP antibody titers and variations in clinical and laboratory indices in response to infliximab treatment. Among 44 patients with other rheumatic diseases, 7 (15.9%) were positive for anti-CCP antibodies, (2 with SLE, 4 with scleroderma and I with polymyositis). Four patients (9%) were noted to be strongly positive (1 with SLE, 2 with scleroderma and I with polymyositis). Forty one of the 44 patients were positive for IgA-RF, 34 for IgG-RF and 30 for IgM-RF (Table 4).
Circulating antibodies are the main effector effector /ef·fec·tor/ (e-fek´ter)
1. an agent that mediates a specific effect.
2. an organ that produces an effect in response to nerve stimulation. molecules of the humoral hu·mor·al
1. Relating to body fluids, especially serum.
2. Relating to or arising from any of the bodily humors.
Pertaining to or derived from a body fluid. immune system and at present, represent the only practical indices for monitoring the immune response in certain autoimmune diseases. Pathogenic autoantibodies have been well documented in a number of different autoimmune diseases including autoimmune thrombocytopenia Thrombocytopenia Definition
Thrombocytopenia is an abnormal drop in the number of blood cells involved in forming blood clots. These cells are called platelets. , myasthenia gravis myasthenia gravis (mīəsthē`nēə grä`vĭs), chronic disorder of the muscles characterized by weakness and a tendency to tire easily. , and systemic lupus erythematosus Systemic Lupus Erythematosus Definition
Systemic lupus erythematosus (also called lupus or SLE) is a disease where a person's immune system attacks and injures the body's own organs and tissues. Almost every system of the body can be affected by SLE. . Until recently, the only serologic test routinely used to confirm the diagnosis of RA was the determination of the presence of IgM-RF in the serum. RFs are antibodies directed against the constant region of immunoglobulins of the IgG class. RF can be of the IgM, IgG, IgA and IgE immunoglobulin classes. The presence of IgM-RF is a hallmark of RA, found in approximately 50 to 90% of these patients. (26,27) However, IgM-RF is nonspecific nonspecific /non·spe·cif·ic/ (non?spi-sif´ik)
1. not due to any single known cause.
2. not directed against a particular agent, but rather having a general effect.
1. and is found in infections, malignancies, other auto-immune diseases, and some healthy individuals. (26,27) IgG-RF is less sensitive but more specific for RA than IgM-RF. (27)
It has been known for many years that antiperinuclear autoantibodies, also called antikeratin, are found in people with RA. (28,29) These antibodies recognize an epitope that contains the deaminated deaminated (dēam´inātd),
adj form of arginine called citrulline citrulline /cit·rul·line/ (sit´rul-en) an alpha-amino acid involved in urea production; formed from ornithine and itself converted into arginine in the urea cycle.
n. . (30) A synthetic circular peptide containing citrulline called CCP was found to be better at discriminating RA patients from other arthritis patients than either the perinuclear perinuclear /peri·nu·cle·ar/ (-noo´kle-ar) near or around a nucleus. autoantibody test or the RF assays. (4,7,31-33) Schellekens et al, (5) Bas et al, (14) and Pinheiro et al (34) reported that anti-CCP antibodies may be present in over 70% of RA patients but in fewer than 5% of healthy individuals. Anti-CCP antibodies have been found in early stages of the disease, with a significantly greater prevalence in the sera of patients who subsequently develop more severe radiological damage. (2-9) This suggests that posttranslational modifications of arginine residues (citrullination of proteins) by the enzyme peptidyl arginine deaminase deaminase /de·am·i·nase/ (de-am´i-nas) an enzyme causing deamination, or removal of the amino group from organic compounds, usually cyclic amidines.
n. (PAD) are important early processes in the progression to disease. Increased expression of PAD isoenzyme isoenzyme /iso·en·zyme/ (-en´zim) isozyme.
i 4 (PADI4) by neutrophils neutrophils (ner·ō·trōˑ·filz),
n.pl white blood cells with cytoplasmic granules that consume harmful bacteria, fungi, and other foreign materials. was seen in the presence of inflammation, and the expression appeared to correlate with the degree of inflammation in the murine murine /mu·rine/ (mur´en) pertaining to, derived from, or characteristic of mice or rats.
adj. models of RA. (35) A case-control association study has shown that polymorphisms of the gene that encode the PADI4 is associated with RA in Japanese populations. (36) A recent study found citrullinated proteins in the joints of patients with RA, leading to speculation that these proteins may trigger specific autoimmune responses in RA. (37) However, in another study, immunohistochemical staining of citrullinated proteins was observed in the lining layer, the sublining layer, and in extravascular ex·tra·vas·cu·lar
1. Located or occurring outside a blood or lymph vessel.
2. Lacking vessels; nonvascular.
situated or occurring outside a vessel or the vessels. fibrin fibrin: see blood clotting. deposits in inflamed synovial tissue from RA as well as non-RA patients. Thus, the presence of citrullinated proteins in the inflamed synovium may be related to inflammation rather than the specific disease process of RA. It is speculated that a low level of inflammation, secondary to trauma or infection that causes death of PAD-expressing cells, leads to activation of the PAD enzyme and citrullination of proteins in the joints. While this process is nonspecific, the presence of specific anti-CCP antibodies in RA patients is probably the result of an abnormal but disease-specific humoral response to citrullinated proteins. It appears that genetic factors such as HLA-DR4 and PAD gene polymorphisms are involved in the process that determines whether anticitrullinated protein antibodies are made. (38,39) Anti-CCP antibody production amplifies this low level of inflammation and may contribute to perpetuation of joint inflammation and thereby to chronicity and severity of RA. Reparon-Schuijt et al (40) identified anti-CCP antibody producing B cells within inflamed joints of patients with RA and Vossenaar et al (38) found that anti-CCP antibodies were enriched in synovial fluid compared with serum, indicating local production. As effector cells of the humoral immune response humoral immune response
The immune response involving the transformation of B cells into plasma cells that produce and secrete antibodies to a specific antigen. See Note at antibody.
Noun 1. , B cells may contribute to both the initiation and perpetuation of the immune response that leads to chronic synovitis synovitis /syno·vi·tis/ (sin?o-vi´tis) inflammation of a synovial membrane, usually painful, particularly on motion, and characterized by fluctuating swelling, due to effusion in a synovial sac. . Animal studies involving K/BxN transgenic mice have shown that antigen-specific antibodies (an-tiglucose-6-phosphate isomerase isomerase /isom·er·ase/ (i-som´er-as) a major class of enzymes comprising those that catalyze the process of isomerization.
n. [GPI (Graphical Programming Interface) A graphics language in OS/2 Presentation Manager. It is a derivative of the GDDM mainframe interface and includes Bezier curves. ] antibody) may initiate inflammatory arthritis, and may link the adaptive and innate immune systems. The arthritogenic antibodies from this transgenic model induced the same pattern of arthritis when transferred to healthy mice. (41) The antigen-antibody complexes may stimulate the neutrophils, and mast cells through complement- and Fc gamma receptor-dependent pathways, ultimately resulting in arthritis. (42) It is also interesting that both IL-1 and TNF-[alpha] are prominently involved in the K/BxN model of arthritis; the cytokines Cytokines
Chemicals made by the cells that act on other cells to stimulate or inhibit their function. Cytokines that stimulate growth are called "growth factors. centrally implicated im·pli·cate
tr.v. im·pli·cat·ed, im·pli·cat·ing, im·pli·cates
1. To involve or connect intimately or incriminatingly: evidence that implicates others in the plot.
2. in the pathogenesis of RA. (43) These results suggest a possible pathogenic role for autoantibodies which may be directly involved in the tissue damage in RA. Given the proposed role of anti-CCP antibodies in both the pathogenesis and the early diagnosis of RA, it is important to study the relationship of their levels and various therapeutic interventions. (2,3,23,40)
Only a few studies have analyzed the variations in the titer of anti-CCP antibodies and RF during treatment with TNF-[alpha] inhibitors with inconsistent results. (19-22) Caramaschi et al (19) measured the levels of IgM-RF, anti-CCP antibodies and CRP in 27 RA patients after 22 weeks of treatment with infliximab. They found that RF level and positivity, as well as CRP decreased significantly; however, the levels of anti-CCP antibodies remained stable. De Rycke et al (20) analyzed the effect of methotrexate and infliximab treatment on IgM-RF and anti-CCP antibodies in 62 RA patients. At baseline and at week 30, IgM-RF titers were reduced significantly during infliximab treatment (P < 0.001 and P = 0.038, respectively), whereas anti-CCP antibodies remained unchanged (P = 0.240). However, they described a subset of patients (23/38) who experienced a marked (>20%) decline in the anti-CCP antibody level. Alessandri et al (21) observed significant declines in the levels of both RF and anti-CCP antibodies in patients who had clinical improvement after six months of treatment with infliximab. They suggested that modification of serum anti-CCP appears to parallel the improvement in clinical and laboratory variables observed during treatment with infliximab. In another study, Bobbio-Pallavicini et al (22) tested serum samples from 30 RA patients treated with infliximab and methotrexate at baseline and after 30, 54 and 78 weeks. The median IgM-RF titer declined progressively and significantly from baseline to 30, 54 and 78 weeks. In contrast, the anti-CCP antibody titer decreased significantly at 30 weeks but returned to baseline thereafter.
In the present study, we detected a significant decrease in the titer of anti-CCP antibodies, IgA-RF and IgM-RF in the sera of patients after 30 weeks of treatment with infliximab. This trend continued at 54 weeks, but while the decrease remained significant for IgM-RF titers, it was not statistically significant for anti-CCP antibodies and IgA-RF. This is the first study analyzing the effect of infliximab treatment on anti-CCP antibodies and all the isotypes of RF. The relatively high prevalence of patients who were positive for anti-CCP and IgA-, IgG- and IgM-RF reflects the probable selection of patients with more aggressive disease, and were candidates for anti-TNF-[alpha] therapy, indicating an association between these autoantibodies and a more severe disease course.
Two recent studies analyzed the variation in anti-CCP antibody titers in response to treatments other than infliximab. (24-44) Cambridge et al (24) reported a significant decrease in anti-CCP antibodies, IgG-, IgA- and IgM-class RF and CRP in RA patients who responded to B-lymphocyte depletion therapy obtained by rituximab administration with or without cyclophosphamide cyclophosphamide /cy·clo·phos·pha·mide/ (-fos´fah-mid) a cytotoxic alkylating agent of the nitrogen mustard group; used as an antineoplastic, as an immunosuppressant to prevent transplant rejection, and to treat some diseases and/or prednisone prednisone (prĕd`nĭsōn): see corticosteroid drug. . The fall of anti-CCP antibody levels was significantly greater than that of total serum IgG. The decrease was observed rapidly after treatment; the median time taken for serum levels of anti-CCP antibodies to fall by 50% of pretreatment pretreatment,
n the protocols required before beginning therapy, usually of a diagnostic nature; before treatment.
n See predetermination. levels occurred within 5 weeks. Nonresponding patients did not present any significant variation in either anti-CCP antibodies or RF levels. The B-lymphocyte count took as long as 21 months to reach baseline. The time for return of synovitis, after B-lymphocyte return was often long and unpredictable (range 0-17 mo); however, was closely correlated with rises in the level of at least one autoantibody. Increased autoantibody levels were rarely observed in the absence of clinical change. In another study, Mikuls et al (44) reported a decline in the serologic se·rol·o·gy
n. pl. se·rol·o·gies
1. The science that deals with the properties and reactions of serums, especially blood serum.
2. levels of circulating autoantibodies among RA patients, the majority of whom received active therapy with DMARDs. Although autoantibody levels only rarely normalized with treatment, one-half of patients experienced a 25% or greater reduction and one-third had at least a 50% reduction in the level of anti-CCP antibody and RF. Although there was no association of treatment response with changes in anti-CCP levels, RA patients with disease duration of <1 year were substantially more likely than those with more established disease to experience a significant decrease in the anti-CCP antibody level. Conversely, treatment response (not disease duration) was the primary determinant of treatment-related declines in the RF level.
The majority of the patients in our study and the other studies examining the effect of infliximab treatment on anti-CCP antibody level had chronic severe RA. The success of clinical interventions in lowering anti-CCP antibody levels appears to depend on the patient's response to therapy and the disease duration. (21,24,44) Lower levels of anti-CCP antibodies at baseline also seemed to predict a better clinical response. (21) The association of shorter disease duration with greater declines in anti-CCP antibody levels is highly consistent with the growing body of evidence showing improved clinical outcomes with earlier disease intervention in RA. (45,46) It is possible that the early disease period represents an important therapeutic window in RA.
This and other studies suggest that in addition to being an important diagnostic tool, serial evaluation of these antibodies could be useful in monitoring the clinical course of the disease. It is unknown whether decrements in the levels of circulating autoantibodies translate directly into improvements in long-term outcomes in RA. It is possible that anti-CCP antibody level declines may predict improvement only over longer periods of follow-up or improvements in radiographic radiographic (rā´dēōgraf´ik),
adj relating to the process of radiography, the finished product, or its use. or other outcome measures including morbidity and mortality Morbidity and Mortality can refer to:
1. Feldman M, Brennan FM, Maini RN. Rheumatoid arthritis. Cell 1996;85:307-310.
2. Nielen MM, van Schaardenburg D, Reesink HW, et al. Specific auto-antibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum rheum (rldbomacm) any watery or catarrhal discharge.
A watery or thin mucous discharge from the eyes or nose.
any watery or catarrhal discharge. 2004;50:380-386.
3. Rantapaa-Dahlqvist S, de Jong BA, Berglin E, et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum 2003;48:2741-2749.
4. Schellekens GA, Visser H, de Jong BA, et al. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum 2000;43:155-163.
5. Schellekens GA, de Jong BA, van den Hoogen F, et al. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest 1998;101:273-281.
6. Vallbracht I, Rieber J, Oppermann M, et al. Diagnostic and clinical value of anti-cyclic citrullinated peptide antibodies compared with rheumatoid factor isotypes in rheumatoid arthritis. Ann Rheum Dis 2004;63:1079-1084.
7. Kroot EJ, de Jong BA, van Leeuwen MA, et al. The prognostic value of anti-cyclic citrullinated peptide antibodies in patients with recent-onset rheumatoid arthritis. Arthritis Rheum 2000;43:1831-1835.
8. Bas S, Genevay S, Meyer O, et al. Anti-cyclic citrullinated peptide antibodies, IgM and IgA rheumatoid factors in the diagnosis and prognosis of rheumatoid arthritis. Rheumatology 2003;42:677-680.
9. Meyer O, Labarre C, Dougados M, et al. Anticitrullinated protein/peptide antibody assays in early rheumatoid arthritis for predicting five year radiographic damage. Ann Rheum Dis 2003;62:120-126.
10. Vasishta A. Diagnosing early-onset rheumatoid arthritis: the role of anti-CCP antibodies. Am Clin Lab 2002;21:34-36.
11. van Venrooij WJ, Hazes JM, Visser H. Anticitrullinated protein/peptide antibody and its role in the diagnosis and prognosis of early rheumatoid arthritis. Neth J Med 2002;60:383-388.
12. Vossenaar ER, van Venrooij WJ. Anti-CCP antibodies, a highly specific marker for (early) rheumatoid arthritis. Clin Appl Immunol Rev 2004;4:225-294.
13. De Rycke L, Peene I, Hoffman IEA IEA International Energy Agency
IEA International Environmental Agreements
IEA International Association for the Evaluation of Educational Achievement
IEA Institute of Economic Affairs
IEA Inferred from Electronic Annotation
IEA International Ergonomics Association , et al. Rheumatoid factor and anti-citrullinated protein antibodies in rheumatoid arthritis: diagnostic value, associations with radiological progression rate, and extra-articular manifestations. Ann Rheum Dis 2004;63:1587-1593.
14. Bas S, Perneger TV, Mikhnevitch E, et al. Association of rheumatoid factors and anti-filaggrin antibodies with severity of erosions in rheumatoid arthritis. Rheumatology (Oxford) 2003;39:1082-1088.
15. Hill JA, Southwood S, Sette A, et al. Cutting edge: the conversion of arginine to citrulline allows for a high affinity peptide interaction with the rheumatoid arthritis-associated HLA-DRBI *0401 MHC class II MHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells (APCs). molecule. J Immunol 2003;171:538-541.
16. van Gaalen FA, van Aken J, Huizinga TW, et al. Association between HLA HLA human leukocyte antigens.
human leukocyte antigen
HLA (human leuckocyte antigen) class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis. Arthritis Rheum 2004;50:2113-2121.
17. Alarcon GS, Schrohenloher RE, Bartolucci AA, et al. Suppression of rheumatoid factor production by methotrexate in patients with rheumatoid arthritis: evidence for differential influences of therapy and clinical status on IgM and IgA rheumatoid factor expression. Arthritis Rheum 1990;33:1156-1161.
18. Olsen NJ, Teal GP, Brooks RH. IgM-rheumatoid factor and responses to second-line drugs in rheumatoid arthritis. Agents Actions 1991;34:169-711.
19. Caramaschi P, Biasi D, Tonolli E, et al. Antibodies against cyclic citrullinated peptides in patients affected by rheumatoid arthritis before and after infliximab treatment. Rheumatol Int 2005;26:58-62.
20. De Rycke L, Verhelst X, Kruithof E, et al. Rheumatoid factor, but not anti-citrullinated protein antibodies, is modulated by infliximab treatment in rheumatoid arthritis. Ann Rheum Dis 2005;64:299-302.
21. Alessandri C, Bombardieri M, Papa N, et al. Decrease of anti-cyclic citrullinated peptide antibodies and rheumatoid factor following anti-TNFalpha therapy (infliximab) in rheumatoid arthritis is associated with clinical improvement. Ann Rheum Dis 2004;63:1218-1221.
22. Bobbio-Pallavicini F, Alpini C, Caporali R, et al. Autoantibody profile in rheumatoid arthritis during long-term infliximab treatment. Arthritis Res Ther 2004;6:R264-R272.
23. Saraux A, Berthelot JM, Devauchelle V, et al. Value of antibodies to citrulline-containing peptides for diagnosing early rheumatoid arthritis. J Rheumatol 2003;30:2535-2539.
24. Cambridge G, Leandro MJ, Edwards JC, et al. Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis. Arthritis Rheum 2003;48:2146-2154.
25. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism rheumatism (r`mətĭzəm), general term for a number of disorders that cause inflammation and pain in muscles, bones, joints, or nerves. Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315-324.
26. Wener MH. Rheumatoid factors. In: Rose NR, et al, eds. Manual of Clinical Laboratory Immunology. American Society for Microbiology The American Society for Microbiology (ASM) is a scientific organization, based in the United States although with over 43,000 members throughout the world. It is the largest single life science professional organization and its members include those whose interests encompass basic Press, 2002, pp 961-972.
27. Borretzen M et al. Rheumatoid factors. In: Peter JB, Shoenfeld Y, eds. Autoantibodies. Elsevier Science BV, 1996, pp 706-715.
28. Vincent C, Simon M, Sebbag M, et al. Immunoblotting immunoblotting,
n the immunologic methods for isolating and quantitatively measuring immunoreactive substances. When used with immune reagents such as monoclonal antibodies, the process is known generically as
Western blot analysis. detection of autoantibodies to human epidermis filaggrin: a new diagnostic test for rheumatoid arthritis. J Rheumatol 1998;25:838-846.
29. Serre G et al. Filaggrin (keratin keratin (kĕr`ətĭn), any one of a class of fibrous protein molecules that serve as structural units for various living tissues. The keratins are the major protein components of hair, wool, nails, horn, hoofs, and the quills of feathers. ) autoantibodies. In: Peter JB, Shoenfeld Y, eds. Autoantibodies. Elsevier Science BV, 1996, pp 271-276.
30. Van Venrooj WJ, Pruijn GJ. Citrullination: a small change for a protein with great consequences for rheumatoid arthritis. Arthritis Res 2000;2:249-251.
31. van Jaarsveld CHM chm - Compiled HTML et al. The prognostic value of the antiperinuclear factor, anti-citrullinated peptide antibodies and rheumatoid factor in early arthritis. Clin Exp Rheum 1999;17:1689-1697.
32. Bizzaro N, Mazzanti G, Tonutti E, et al. Diagnostic accuracy of the anti-citrulline antibody assay for rheumatoid arthritis. Clin Chem 2001;47:1089-1093.
33. Combe combe
same as coomb B, Dougados M, Goupille P, et al. Prognostic factors for radiographic damage in early rheumatoid arthritis: a multiparameter prospective study. Arthritis Rheum 2001;44:1736-1743.
34. Pinheiro GC, Scheinberg MA, Aparecida da Silva M, et al. Anti-cyclic citrullinated peptide antibodies in advanced rheumatoid arthritis. Ann Intern Med 2003;139:234-235.
35. Vossenaar ER, Nijenhuis S, Helsen MM, et al. Citrullination of synovial proteins in murine models of rheumatoid arthritis. Arthritis Rheum 2003;48:2489-2500.
36. Suzuki A, Yamada R, Chang X, et al. Functional haplotypes of PAD14, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet genet: see civet. 2003;34:395-402.
37. Baeten D, Peene I, Union A, et al. Specific presence of intracellular citrullinated proteins in rheumatoid arthritis synovium: relevance to an-tifilaggrin autoantibodies. Arthritis Rheum 2001;44:2255-2262.
38. Vossenaar ER, Smeets TJ, Kraan MC, et al. The presence of citrullinated proteins is not specific for rheumatoid synovial tissue. Arthritis Rheum 2004;50:3485-3494.
39. Vossenaar ER, van Venrooij WJ. Citrullinated proteins: sparks that may ignite the fire in rheumatoid arthritis. Arthritis Res Ther 2004;6:107-111.
40. Reparon-Schuijt CC, van Esch WJ, van Kooten C, et al. Secretion of anti-citrulline-containing peptide antibody by B lymphocytes in rheumatoid arthritis. Arthritis Rheum 2001;44:41-47.
41. Matsumoto 1, Staub A, Benoist C, et al. Arthritis provoked by linked T and B cell recognition of a glycolytic enzyme. Science 1999;286:1732-1735.
42. Ji H, Ohmura K, Mahmood U, et al. Arthritis critically dependent on innate immune system players. Immunity 2002;16:157-168.
43. Ji H, Pettit A, Ohmura K, et al. Critical roles for interleukin 1 and tumor necrosis factor-alpha Tumor necrosis factor (TNF, cachexin or cachectin and formally known as tumor necrosis factor-alpha) is a cytokine involved in systemic inflammation and is a member of a group of cytokines that all stimulate the acute phase reaction. in antibody-induced arthritis. J Exp Med 2002;196:77-85.
44. Mikuls TR, O'Dell JR, Stoner ston·er
1. One that stones.
a. One who is habitually intoxicated by alcohol or drugs.
b. One who is a delinquent or failure. JA, et al. Association of rheumatoid arthritis treatment response and disease duration with declines in serum levels of IgM rheumatoid factor and anti-cyclic citrullinated peptide antibody. Arthritis Rheum 2004 Dec;50:3776-3782.
45. Egsmose C, Lund B, Borg G, et al. Patients with rheumatoid arthritis benefit from early 2nd line therapy: 5 year followup of a prospective double blind placebo controlled study. J Rheumatol 1995;22:2208-2213.
46. Tsakonas E, Fitzgerald AA, Fitzcharles MA, et al. Consequences of delayed therapy with second-line agents in rheumatoid arthritis: a 3 year followup on the hydroxychloroquine in early rheumatoid arthritis (HERA) study. J Rheumatol 2000;27:623-629.
M. Mubashir Ahmed, MD, Eisha Mubashir, MD, Robert E. Wolf, MD, Samina Hayat, MD, Vicky Hall, PhD, Runhua Shi, MD, PhD, and Seth Mark Berney, MD
From the Center of Excellence for Arthritis and Rheumatology and the Section of Rheumatology, the Division of Hematology/Oncology, the Department of Medicine, and Overton Brooks Veterans Administration Hospital, Louisiana State University Louisiana State University and Agricultural and Mechanical College, generally known as Louisiana State University or LSU, is a public, coeducational university located in Baton Rouge, Louisiana and the main campus of the Louisiana State University System. Health Sciences Center, Shreveport, LA.
Reprint requests to Mohammed Mubashir Ahmed, MD, Assistant Professor of Medicine, Center of Excellence for Arthritis and Rheumatology, LSU-HSC-S, 1501 Kings Highway, Shreveport, LA 71130. Email email@example.com
Accepted June 14, 2006.
RELATED ARTICLE: Key Points
* Treatment with infliximab results in decreased anti-cyclic citrullinated peptide (anti-CCP) antibodies and IgA-RF early in the course of therapy that is not sustained.
* The decrease in IgG-RF level was not significant at 30 and 54 weeks.
* IgM-RF declines and remains decreased for at least 54 weeks.
* Investigations in larger cohorts of rheumatoid arthritis (RA) patients (especially early RA) with longer follow-up are needed to assess the impact of specific therapeutic interventions on anti-CCP antibody and RF levels and the relationship of their levels to disease activity.
Table 1. Demographic and baseline clinical characteristics of 33 patients with rheumatoid arthritis Characteristic Value Age 54.6 [+ or -] 12.1 Female/male 28/5 Caucasian 18 African American 14 Hispanic 1 Disease duration (years) 12.9 [+ or -] 8.3 Number of tender joints 18.06 [+ or -] 11.38 Number of swollen joints 18.42 [+ or -] 7.68 ESR 37.34 [+ or -] 25.26 CRP (mg/dL) 2.38 [+ or -] 1.76 DMARDs Previous Current Methotrexate 32 27 Hydroxychloroquine 7 1 Sulfasalazine 15 14 Leflunomide 23 15 Gold 12 2 Azathioprine 5 2 Minocycline 1 0 Cyclosporin A 1 0 Etanercept 3 0 Where applicable, values are expressed as mean [+ or -] SD. Anti-CCP. anticyclic citrullinated peptide antibody; RF. rheumatoid factor; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; DMARDs, disease modifying antirheumatic drugs. Table 2. Percentages of rheumatoid arthritis patients with autoantibodies at baseline and after treatment. At baseline Week 30 Week 54 Autoantibody (n = 33) (n = 33) (n = 28) Anti-CCP antibody positivity 81.8% 78.7% 78.5% IgA-RF positivity 84.8% 84.8% 85.7% IgG-RF positivity 81.8% 84.8% 85.7% IgM-RF positivity 87.8% 87.8% 89.2% anti-CCP, anticyclic citrullinated peptide antibody; RF, rheumatoid factor. Table 3. Changes in clinical characteristics of patients with rheumatoid arthritis from baseline and at different times after infliximab treatment Variable Week 0 Week 30 Week 54 Tender joint count 18.06 (11.38) 8.31 (9.92) 9.89 (9.78) Swollen joint count 18.42 (7.68) 10.63 (6.47) 10.57 (7.2) ESR (mm/h) 37.34 (25.26) 34.88 (27.42) 34.75 (25.55) CRP (mg/dL) 2.38 (1.76) 1.81 (1.52) 1.78 (0.96) Anti-CCP (IU) 172.23 (119.63) 163.38 (113.99) 153.77 (121.62) IgA-RF (IU) 60.97 (49.38) 52.82 (47.89) 53.2 (54.26) IgG-RF (IU) 54.24 (42.14) 49.15 (41.01) 44.46 (39.83) IgM-RF (IU) 85.27 (43.65) 76.79 (43.16) 70.32 (43.69) P Value Variable Week 0 vs. 30 Week 0 vs. 54 Tender joint count 0.001* 0.003* Swollen joint count 0.001* 0.001* ESR (mm/h) 0.129 0.475 CRP (mg/dL) 0.265 0.222 Anti-CCP (IU) 0.002* 0.147 IgA-RF (IU) 0.024* 0.207 IgG-RF (IU) 0.059 0.097 IgM-RF (IU) 0.002* 0.004* Values are mean (SD). *P < 0.05 ESR, erythrocyte sedimentation rate: CRP, C-reactive protein; anti-CCP, anticyclic citrullinated peptide antibody; RF, rheumatoid factor. Table 4. Anticyclic citrullinated peptide antibody, IgA-, IgG- and IgM-RF in 44 patients with other rheumatic diseases. Disease No. anti-CCP IgA-RF IgG-RF IgM-RF Psoriatic arthritis 4 0 (0%) 3 (75%) 4 (100%) 2 (50%) SLE 18 2 (11%) 17 (94%) 9 (50%) 7 (39%) Scleroderma 15 4 (27%) 15 (100%) 14 (93%) 14 (93%) Polymyositis 7 1 (14%) 6 (86%) 7 (100%) 6 (86%) No., number of patients; anti-CCP, anticyclic citrullinated peptide antibody; RF, rheumatoid factor; SLE, systemic lupus erythematosus.