Long-term effects of infliximab on bone and cartilage turnover markers in patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is associated with systemic bone loss, subchondral bone erosion and cartilage degradation under the control of pro-inflammatory cytokines, including tumour necrosis factor alpha (TNFalpha). Therefore, we tested the hypothesis that administration of infliximab, an anti-TNFalpha drug in the treatment of RA, would modulate systemic and local bone resorption and reduce cartilage degradation. METHODS: We performed a prospective study of a multicentric cohort of 48 women, mean (SD) age 54.2 (12.1) years old, with severe RA for 11.4 (7.8) years, who started infliximab after failure of other disease-modifying antirheumatic drugs. At baseline and 6, 22 and 54 weeks after initiating Infliximab therapy we measured the following biochemical markers: pro-collagen serum type I N-terminal propeptide (PINP), a marker of bone formation; serum C-terminal cross-linked telopeptide of type I collagen (CTX-I), a marker of cathepsin K-mediated bone collagen degradation believed to reflect systemic bone resorption; serum C-terminal cross-linked telopeptide of type I collagen (ICTP), an index of matrix metalloprotease (MMP) mediated type I collagen degradation reflecting preferential joint metabolism; and urinary CTX-II a biochemical markers of cartilage degradation. Total hip and lumbar spine bone mineral density (BMD) was assessed at baseline, and after 6 and 12 months by dual-energy x-ray absorptiometry (DXA). No patient received bisphosphonates while 77% were under oral glucocorticoids. RESULTS: BMD remained stable over 1 year. Serum CTX-I levels rapidly decreased by 19% and 28% at week 6 and week 22, respectively (analysis of variance (ANOVA) p = 0.032) values returning to pre-treatment level at week 54. By contrast, ICTP levels progressively declined with a maximal 25% decrease at week 54 (ANOVA p = 0.028). By contrast, PINP levels remained stable over time, which led to a 30 to 40% improvement in bone remodelling balance, as assessed by the ratios PINP/CTX and PINP/ICTP (p<0.05). There was no significant change of urinary CTX-II in the whole population, but a slight decrease (ANOVA p = 0.041) in those with pre-treatment levels above the upper limit of normal range. CONCLUSIONS: In summary, the improvement in the formation/resorption marker ratio suggests beneficial systemic and local bone effects of infliximab in patients with RA.

Maintenance and tolerability of infliximab in a cohort of 152 patients with rheumatoid arthritis.

OBJECTIVE: To determine the maintenance, tolerability and safety of infliximab in an unselected cohort of patients with rheumatoid arthritis (RA). PATIENTS AND METHODS: One hundred and fifty-two RA patients receiving at least one course of infliximab between 2000 and 2003 were included in this study. Response to treatment and safety were assessed through recording adverse events, physical examinations and standard laboratory tests. The dosage of infliximab was patient specifically modified, when therapeutic response was judged inadequate by the assessment of a physician. RESULTS: The mean duration of follow-up was 401 days (85-1221). One hundred and twenty-two patients (78%) continued to receive infliximab after one year. 40 patients (26.3%) stopped infliximab therapy: 14 (9.2%) for inefficacy, 21 (13.8%) for adverse events. Fifty nine patients (38.8%) required an increase of the dosage (n=23, 15%) or a shortening of the interval between the infusions (n=20, 13.2%), or both (n=16, 10.5%) for symptomatic control. Infliximab discontinuation tended to be more frequent in smokers (p=0.055). Ninety-four patients (62%) reported at least one adverse event during the study: 64 infections (43%), 35 infusion reaction events (23%) which led to a discontinuation for 10 patients. Infusion reactions were more frequent in patients with a history of allergy. Three cases of tuberculosis and 1 breast carcinoma were reported during the study. CONCLUSIONS: Adjustments in the treatment of RA patients treated with recommended doses of infliximab were common (38.8% of the treated patients). Furthermore, the observed rate of infections (43%), including three cases of tuberculosis, should alert physicians to be vigilant in the routine care of patients treated with infliximab.

Recruitment of new osteoblasts and osteoclasts is the earliest critical event in the pathogenesis of human multiple myeloma.

Considering the special relation of human multiple myeloma (MM) to bones, it is of importance to clarify the early steps of bone involvement in this disease. In this work, using bone histomorphometry (including histoenzymologic and kinetic studies for the first time), we have evaluated the bone remodeling (i.e., bone resorption and bone formation rates) of 16 individuals with early MM in comparison with that of 10 with benign monoclonal gammopathy (BMG) and that of 17 patients with previously untreated overt MM. A significantly increased osteoblastic recruitment was observed in the individuals with early MM when compared with those with BMG (P less than 0.01). A significant (P less than 0.01) increased bone resorption (i.e., eroded surfaces, osteoclast numbers and surfaces) was observed from the early stage of MM in comparison with the BMG status where bone resorption remained within the normal range. At the tissue level, there was no difference in terms of bone resorption between early and overt MM. On the other hand, osteoblast activity was significantly reduced in patients with overt MM (P less than 0.05 by comparison with those with early MM). A significant enhancement of osteoblastic recruitment with an increased generation of new osteoclasts is an early critical event in the pathogenesis of human MM. Of particular importance is the early stimulation of osteoblasts, since these cells produce high amounts of IL-6, a potent myeloma cell growth factor and a critical cytokine for the formation of osteoclasts in the bone marrow.

Acute effects of salmon calcitonin in multiple myeloma: a valuable method for serial evaluation of osteoclastic lesions and disease activity--a prospective study of 125 patients.

Hypocalcemia induced by salmon calcitonin (SCT) was evaluated in 125 patients with multiple myeloma (MM) and compared with 20 normal individuals (NCs) and 20 individuals with monoclonal gammopathy of undetermined significance (MGUS). It is now well documented that the maximum hypocalcemia (M delta CA) induced in man by SCT is related to the prevailing rate of osteoclastic resorption. In patients with MGUS, the level of M delta CA was normal. Conversely, the M delta CA was significantly abnormal in patients with MM (P less than .0001 for differences between NC/MGUS patients) and was correlated with (1) initial calcium levels (P less than .001), (2) the extent of lytic bone lesions (LBLs) (P less than .01), and (3) the myeloma cell mass (P less than .001) plus disease activity. The M delta CA was found to be of predictive value for new LBLs with or without hypercalcemia and to have dramatic influence on the survival of patients with MM. We conclude that the SCT-induced hypocalcemia test is of significant importance in the evaluation of the instantaneous rate of bone resorption and in the prognosis of patients with MM.

Prognostic factors and staging in multiple myeloma: a reappraisal.

To assess the important factors in the prognosis and staging of multiple myeloma (MM), we have correlated the presenting clinical features of 147 previously untreated patients with MM with the survival duration using multiple regression analyses. We have included the three major available myeloma-staging systems (MSS), ie, Durie-Salmon (DS), Medical Research Council (MRC), and Merlini-Waldenström-Jayakar (MWJ), plus two new variables related to disease activity: the serum beta 2-microglobulin level (S beta 2M) and the instantaneous rate of bone resorption. Our study confirms the validity of the three MSS in the prediction of survival duration, with a slight but significant advantage for the DS MSS. Among single variables, S beta 2M was the most powerful indicator of prognosis (P less than .0001), serum albumin level being the only variable adding to this significantly (P = .02). Of major interest, S beta 2M alone was a better indicator than MRC and MWJMSS. Finally, S beta 2M and the serum albumin level, variables not included in the three MSS, were better indicators than the classical DS MSS and could be combined simply to give a very powerful system of stratification.

Mechanisms of bone destruction in multiple myeloma: the importance of an unbalanced process in determining the severity of lytic bone disease.

In order to clarify the mechanisms involved in the occurrence of lytic bone lesions (BL) in multiple myeloma (MM), we have compared the presenting myeloma-induced histological bone changes of 14 previously untreated MM patients with lytic BL with those of seven MM patients lacking lytic BL at presentation despite similar myeloma cell mass. A major unbalanced bone remodeling (increased bone resorption with normal to low bone formation) was the characteristic feature of patients presenting lytic BL. Furthermore, this unbalanced process was associated with a significant reduction of bone mass. Unexpectedly, a balanced bone remodeling (increase of both bone resorption and bone formation, without bone mass reduction) rather than a true lack of an excessive bone resorption was the usual feature of patients lacking lytic BL. Our current work clearly shows that a majority (72%) of patients with MM present an important unbalanced bone remodeling at diagnosis, leading to bone mass reduction and bone destruction (unbalanced MM). Some patients (20%) retain a balanced bone remodeling with initial absence of bone destruction (balanced MM). Few (8%) patients have pure osteoblastic MM without bone destruction.

The efficiency of switching from infliximab to etanercept and vice-versa in patients with rheumatoid arthritis.

OBJECTIVE: To determine whether it may be successful to try another TNF-alpha antagonist (infliximab or etanercept) when one has failed due to non response or the development of side effects. METHODS: In a cohort of 282 patients with rheumatoid arthritis treated with infliximab or etanercept, we observed 38 patients who had received both agents. RESULTS: Twenty-four patients received infliximab first and 14 received etanercept first. Discontinuation was due to a lack of efficiency for 29 patients and to the occurence of an adverse effect for 9 patients. For 25 out of the 38 patients, the switch was a success according to the global physician's assessment 3 months after switching. This result was correlated to a significant decrease of DAS 28 measurements and CRP values (p < 0.05). The response after switching was recorded as a success for 18 out of the 24 patients who were treated with infliximab first, and for 12 out of the 14 patients who were treated with etanercept first. There was no statistical difference concerning the response after the switch between the two groups. Among the 29 patients who discontinued the first anti TNF-alpha treatment due to lack of efficiency, only 6 did not respond to the second anti TNF-alpha treatment. Only one out of the 9 patients who stopped a first anti TNF-alpha treatment after developing a side effect underwent an adverse event with the second anti TNF-alpha treatment. CONCLUSION: Our study suggests that switching between TNF-alpha antagonists seems to be relevant, regardless of which one was used first. It is legitimate to try to switch TNF-alpha blockers before contemplating other therapeutic strategies.

Visceral leishmaniasis infection in a rheumatoid arthritis patient treated with infliximab.

Anti-TNFalpha strategies can result in significant clinical benefits in rheumatoid arthritis (RA), but with an increased rate of opportunistic infections. Visceral leishmaniasis (VL) is a severe disease that can develop in immunocompromised hosts, principally in HIV patients. VL in RA patients treated with TNFalpha antagonists is an extremely rare event, and only one case has been described. Here we report a case of VL, occurring after 9 infusions of infliximab in association with azathioprine, in a patient who developed blood cytopenia, fluctuant fever, and splenomegaly.

Efficacy and tolerability of a new formulation of oral tiludronate (tablet) in the treatment of Paget's disease of bone.

We sought to assess efficacy and safety of a new oral formulation (tablet) of tiludronate in Paget's disease of bone. We studied 128 patients with Paget's disease in an open-label uncontrolled trial. Patients received a daily dose of 400 mg oral tiludronate (two tablets). Treatment was for 6 months. Serum alkaline phosphatase activity (SAP) and fasting urinary excretion of hydroxyproline/creatine (OH/Cr) were measured every 3 months, as were biochemical parameters reflecting renal, hepatic, and hematologic functions. Analgesic efficacy was self-evaluated from a visual analog scale (VAS). Statistical analysis revealed a significant reduction from baseline in SAP and OH/Cr levels, as well as VAS scores. In the whole population with evaluation under treatment, there was a reduction in initial SAP activity after 3 months (47.2 +/- 2.2%, mean +/- SEM) and 6 months (58.3 +/- 2.3%). In the population with SAP levels above twice the upper limit at inclusion and with evaluation at month 3 and month 6 (n = 96), the reduction in SAP levels was 49.3 +/- 2.4% after 3 months and of 59.5 +/- 2.6% after 6 months (ANOVA time effect, p = 0.0001). Aside from mild gastrointestinal disturbances, as experienced with other oral bisphosphonates, clinical tolerance was good. Exhaustive biochemical investigation failed to reveal significant toxicity of tiludronate tablets at the dose of 400 mg/day. The dose of 400 mg daily of this new formulation appears to be a satisfactory tiludronate regimen for the treatment of Paget's disease of bone.

Human placenta-eluted gammaglobulins in immunomodulating treatment of rheumatoid arthritis.

Thirty-one patients with severe rheumatoid arthritis were treated with intravenous perfusion of human placenta-eluted gammaglobulins. These gammaglobulins, which are IgG eluted from placental tissue, have strong immunomodulating properties in vitro. Several clinical trials were tested to find the optimal useful dosage. A 50 percent improvement was considered a good result and was obtained in 60 percent of patients with rheumatoid arthritis. The best results were obtained in patients receiving 1,500 mg daily seven days each month. Six subjects had a long remission of their disease after the end of treatment. The side effects were usually minor. In all patients, an immunostimulation of lymphocyte function was shown, even when they had no improvement. A control group of patients underwent perfusion with IgG from placental blood without any clinical or immunologic effect. It is suggested that the in vivo effects of placenta-eluted gammaglobulins might be mediated by polyspecific anti-HLA-DR antibodies.

In vivo migration of tonsil lymphocytes in rheumatoid synovial tissue engrafted in SCID mice: involvement of LFA-1.

Integrin-adressin binding is a critical step in lymphocte attachment to target tissues. The mucosal recognition systems (alpha E beta 7, alpha 4 beta 7, MADcam-1) have been implicated in the autoimmune process in rheumatoid arthritis. We developed a model for in vivo study of radio-labelled lymphocyte circulation and their attachment to human rheumatoid synovium. We studied the homing of tonsil lymphocytes, considered as mucosal lymphocytes, and the involvement of alpha E beta 7 integrin and LFA1 in the homing of tonsil lymphocytes. We engrafted human rheumatoid synovium subcutaneously in 6 week old SCID CB17 mice. Three weeks later, we injected intraperitoneally 20 IO6 human peripheral blood or tonsil mononuclear cells, previously labelled with 3 mCFi HMPAO-99mTc. A mouse total body scintigram was obtained 20 h postinjection. The same protocol was performed after treatment of the MNC and mAb against LFA-1 (CD11a) or alpha E beta 7 (CD103). Tonsil MNC retention in the rheumatoid synovial graft 20 h post-injection was enhanced compared to blood MNC (12731 +/- 8297cpm/200 pixel) versus 5982 +/- 4713cpm/200 pixel, p < 0.05). A monoclonal antibody against LFA 1 decreased the activity in the graft (4152 +/- 1287 cpm/200 pixel), p < 0.05. No significant difference in tonsil MNC attachment to rheumatoid synovial tissue was observed with a mAb against alpha E beta 7 (8057 +/- 5009 cpm/200 pixel). Our results showed an increase in radiolabelled mucosal MNC migration in synovial tissue engrafted in SCID mice compared with blood MNC. Moreover, the date suggest that LFA-1 but not the alpha E beta 7 integrin is involved in tonsil MNC binding to synovial tissue in RA.

Increase of class II HLA molecules on the membrane of B lymphocytes from patients with rheumatoid arthritis.

Using a novel cytofluorometric method of cellular antigen quantification, we examined peripheral blood mononuclear cells (PBMC) from patients suffering from rheumatoid arthritis (RA) for quantitative modification of class II human leucocyte antigen (HLA) molecules expressed on the surface. Class II HLA molecules were detected by indirect immunofluorescence with a monomorphic monoclonal antibody. No change was observed in the density of class II HLA molecules at the surface of monocytes of RA patients as compared to that of paired healthy subjects. We confirmed that the percentage of class II HLA-bearing T cells was slightly increased in RA patients versus controls, but the density of class II antigens per cell could not be determined accurately. An increase in the density of class II HLA molecules on RA B cells was shown, suggesting that a chronic activation stage of this population contributes to the disease.

Immunological treatment of rheumatoid arthritis.

Till now the therapeutic immunomodulation of rheumatoid arthritis (RA) has been non-specific, using either slow acting drugs which act mainly but not exclusively on macrophages (gold salts) or on T CD4+ cells (D penicillamine), or immunostimulating agents (Levamisole) or immunodepressive drugs which do not affect a specific subpopulation of lymphocytes. Various other therapeutic approaches such as dietic manipulations, steroid pulses and plasmapheresis have been proposed. Methotrexate is a very interesting development in the treatment of RA. However, the results of such treatments on the long term outcome of the disease have been unsatisfactory. Early and associated treatments must be studied. After the interesting experimental results obtained with thoracic duct drainage, a partially specific immunotherapy acting mainly on CD4+ T cells has been developed using cyclosporin A and total lymphoid irradiation. However, a more specific immunotherapy of RA may be considered, using monoclonal or polyclonal anti-HLA class II antibodies or anti-CD4 monoclonal antibodies. Immunomodulating treatments with cytokines or anticytokines, anti-T receptor monoclonal antibodies, anti-idiotypic antibodies, and vaccination with T cell clones or synthetic peptides are possibilities of major interest for the future.

Clinical and biological polymorphism of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a frequent disease, leading in more than 50% of cases to severe disability within 5 years of evolution, and sometimes to the premature death of the patient. It is therefore of crucial importance to diagnose, evaluate, and treat this crippling disease as soon as possible. We need accurate clinical, biological, immunological and radiographic parameters which will permit both early diagnosis and evaluation of the patient's prognosis. However, RA is a very heterogeneous disease which is sometimes considered as a clinical syndrome. The clinical heterogeneity of RA is well known; some cases are very mild and self-limiting, while others are seriously progressive and include extra-articular manifestations which can be life-threatening. There is also a biological and immunological heterogeneity of RA, depending on the presence or absence of: rheumatoid factor, high levels of serum IgA, and antinuclear, anti-Ro, antiperinuclear, or anti-stratum corneum antibodies. The association between HLA DR antigens and the severity of RA has been demonstrated in recent studies including some by our group. HLA DRB1*0401 or 0404 homozygous, or HLA DRB1*0401/0404/0408 heterozygous, or HLA DRB1*04 + HLA DRB1*0101 are associated with severe and erosive RA. Extra-articular manifestations such as nodules, vasculitis or Felty syndrome are very often observed in patients homozygous for HLA DRB1*0401 or 0404. The presence of HLA DR4 seems to be correlated with the articular erosions and not with rheumatoid factor. There is a clear need for a 'staging' of RA in order to define more homogeneous clusters of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of the immune response by the neuro-endocrine axis in rheumatoid arthritis.

The neuropeptides are involved in the immune response and in hormonal homeostasis. In this review, we analyse the interactions between the cytokine, the neuropeptide and the hormonal networks in rheumatoid arthritis (RA). We first consider pituitary-adrenal axis dysfunction in RA. An inappropriate response to cortisol in chronic inflammation has been reported, i.e., a decrease of the corticotropin-releasing-hormone (CRH) secretion by the hypothalamus. In contrast, the immunostimulant hormone prolactin (PRL) is upregulated. PRL is released by the pituitary after stimulation by neuropeptides [serotonin, thyroid-releasing-hormone (TRH), or vasoactive-intestinal-peptide (VIP)], and is down-regulated by pro-inflammatory cytokines (IL-1, IL-6). The decreased testosterone concentration observed in male RA patients is associated with HLA B 15. Thus, an altered sex hormone status and a genetic predisposition are related to HLA antigens, and increase the subject's susceptibility to the development of RA. The terminal C fibres release neurotransmitters such as substance P, neurokinin A and calcitonin-gene-related-peptide (CGRP) within the joints, and contribute to local inflammation, synoviocyte proliferation and collagenase production. The parasympathetic system may attenuate the immune response through the neuropeptide VIP. In contrast, the beta 2 adrenergic fibres of the sympathetic nervous system increase joints degradation in RA. This review presents the currently extensive knowledge regarding the immune-neuro-hormonal network, and its implication in the pathogenesis of RA.

Methotrexate as the initial second-line disease modifying agent in the treatment of rheumatoid arthritis patients.

OBJECTIVE: To assess the efficacy and toxicity profile of methotrexate (MTX) as the initial second-line disease modifying anti-rheumatic drug (DMARD) in rheumatoid arthritis (RA). METHODS: This was an observational retrospective cohort study comparing 28 patients who were treated with MTX as the first DMARD (MTX cases) and 55 matched patients treated with MTX after other DMARDs (MTX controls). RESULTS: The follow-up time was identical in the two groups: 19.4 +/- 14 months (2-56) for the MTX cases and 21.8 +/- 15.3 months (3-87) for MTX controls (NS). MTX efficacy was the same in the two groups, except for a higher incidence of remission in the MTX cases (8/28, 28.6% versus 5/55, 9.1%, p = 0.028). The toxicity profiles, frequencies, and reasons for MTX withdrawals were similar in the two groups. CONCLUSION: The results obtained in this study suggest a benefit from MTX prescribed as an initial second-line agent in the treatment of RA, but studies involving a larger number of patients are needed.

Association of methotrexate and corticosteroids in the treatment of patients with rheumatoid arthritis.

OBJECTIVE: To investigate whether the association of methotrexate (MTX) and corticosteroids introduced concomitantly is more effective than MTX alone in patients with rheumatoid arthritis (RA). METHODS: Twenty-eight RA patients (group 1) were treated with MTX (mean dose: 10 +/- 1.4 mg/week) and corticosteroids (mean dose: 14.9 +/- 5.6 mg/day, range: 5-25) introduced concomitantly, and were compared to 251 RA patients (group 2) treated with MTX alone (mean dose: 9.8 +/-1.5 mg/week). Variations in the clinical (number of swollen and painful joints, morning stiffness, Ritchie's articular index), biological (ESR, CRP), and radiological parameters were studied. Remission was defined according to Pinals' criteria. At baseline, there were no significant differences between the two groups, except for a greater number of swollen and painful joints in group 1 (p = 0.03 and p = 0.01, respectively). The total MTX dose and the duration of treatment (26 +/- 21.8 months in group 1 versus 33.5 +/- 27.2) months in group 2) did not differ between the two groups. RESULTS: We noted a more marked reduction in the number of swollen and the number of painful joints in group 1 (p = 0.03). No differences were noted for the other clinical and biological parameters. The proportion of patients fulfilling Pinals' remission criteria was higher in group 1 (25% versus 10.1% in group 2, p = 0.04). The steroid dosage could be significantly reduced in group 1 (-3.4 +/- 6.1 mg/day, p = 0.05) and corticosteroids were stopped in 11 patients. The frequency and type of side effects, as well as the frequency and reasons leading to MTX withdrawal, did not significantly differ between the two groups. CONCLUSION: The association of MTX and corticosteroids seems to bring about a greater improvement in the different clinical activity parameters of RA than MTX alone, without any significant increase in the frequency of side effects. These results need to be confirmed in larger scale prospective studies.

Vasculitis and psoriatic arthritis associated with Down's syndrome.

Only a few observations of inflammatory arthritis have been associated with Down's syndrome. We report a case of severe erosive, peripheral and axial psoriatic arthritis associated with cutaneous vasculitis in a 24-year old man with trisomy 21. A long standing remission of vasculitis and arthritis was achieved with corticoid and azathioprine treatment. The relationship between chromosomal abnormalities and synovial proliferation is further discussed.

Kinetics of prolactin release in rheumatoid arthritis.

OBJECTIVE: To study the dynamics of pituitary prolactin secretion in RA, and its association with the HLA DR4 status in patients. METHODS: TRH stimulation of the pituitary secretion of PRL was performed in 23 RA patients and 8 control subjects, all of whom were post-menopausal women. Hormone concentrations were assessed by radioimmunoassay. RESULTS: Basal prolactin concentrations were higher in RA patients compared to controls (579 +/- 80 mu UI/ml versus 187 +/- 47, (p < 0.01). An increase in the prolactin response to TRH at 30 min (2257 +/- 218 mu UI/l versus 1074 +/- 207, p < 0.005), independent of disease activity, was observed in the RA patients. In DR4+ RA patients, we observed a higher PRL peak at 60 min. (3913 +/- 506 mu UI/ml versus 2120 +/- 443, p < 0.01), and an increased residual value at 120 min compared to DR4- RA patients. The area under the curve of the PRL response was also increased in DR4+ RA patients, suggesting higher PRL secretion compared to DR4- RA patients. CONCLUSION: In female, post-menopausal RA patients an alteration in pituitary prolactin release, not linked to disease activity, can be observed. In DR4+ RA patients, the overall prolactin secretion reflected by the AUC is increased compared to DR4- patients. These results suggest a dysregulation of the pituitary response in RA.

Rheumatoid arthritis associated with high levels of immunoglobulin a: clinical and biological characteristics.

We measured the serum immunoglobulins in 191 patients with rheumatoid arthritis (RA) over an 8-month period, looking for a relationship between high IgA levels, disease activity, and clinical and biological features. Twenty-nine patients with a polyclonal hyperimmunoglobulin A (IgA) (15.2%) above 5 g/l constituted group A. A control group of 29 randomized RA patients with normal IgA levels was studied over the same period (group B). The mean serum IgA concentration was significantly elevated in group A: 6.6 +/- 1.8 g/l versus 2.8 +/- 0.9 g/l in group B (p < 0.01). In group A, microscopic haematuria occurred in 20.7% of the cases, as against 3.4% from group B (p < 0.05). Furthermore, the incidence of unilateral sacroiliitis and of arthritis of the distal interphalangeal joints was significantly increased in group A (41.4% and 34.5%, respectively) against 6.9% and 3.4% in group B (p < 0.01) and this correlated with a high IgA serum level (p < 0.01). On the other hand, neither disease activity nor the biological parameters of inflammation were influenced by the level of IgA. Patients with RA associated with high levels of IgA are characterized by a significant increase in the incidence of distal interphalangeal arthritis, unilateral sacroiliitis and microscopic haematuria. These clinical and biological features could define a distinct subgroup of patients with RA.