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382 Annals of the Rheumatic Diseases 1995; 54: 382-385

Long term treatment of rheumatoid arthritis with Ann Rheum Dis: first published as 10.1136/ard.54.5.382 on 1 May 1995. Downloaded from high doses of intravenous immunoglobulins: effects on disease activity and serum cytokines

Christopher Muscat, Alberto Bertotto, Raffaella Ercolani, Onelia Bistoni, Elisabetta Agea, Monica Cesarotti, Giuliana Fiorucci, Fabrizio Spinozzi, Roberto Gerli

Abstract of interleukins- 1cx, -1 P and -6, and tumour Objective-To evaluate the effects of long necrosis factor ot (IL-lcx, IL-1I3, IL-6, TNFcx) term treatment of rheumatoid arthritis were measured as indicators of (RA) with high doses of intravenous activity, and soluble interleukin-2 receptor immunoglobulins (IVIg). (sIL-2R) and interferon gamma (IFNy) Methods-Ten patients with active RA and measured as expressions of activation. prior unsuccessful treatment with at least one slow acting antirheumatic were treated with 400 mg/kg of IVIg for the first Patients and methods three days and then once a month for 12 PATIENTS months. Clinical evaluation and labora- Ten subjects (seven female) aged 38-72 years tory analysis were performed every (mean 54.5), were enrolled in the study. Six month. Serum levels of tumour necrosis had serological evidence of rheumatoid factor factor a (TNFoa), soluble interleukin-2 (RF) and four of antinuclear receptor (sIL-2R), IL-1a, IL-ll, IL-6 and (ANA). Disease duration ranged from two to interferon gamma (IFNy) were measured 22 years (mean 7 8). All patients fulfilled the at baseline and at three monthly intervals American College of diagnostic for 15 months. criteria for RA,7 had moderately active disease Results-Although laboratory parameters as previously defined (table)8 9 and were were not influenced by the treatment, a receiving long term treatment with late but significant clinical improvement 2 5-10 mg/day. Unsuccessful treatment with at was observed after six months. Serial least one SAARD (hydroxycloroquine, peni- measurement of cytokines revealed a cillamine or auranofin) was a prior requisite for rapid and persistent decrease in serum inclusion in the study. Exclusion criteria were: http://ard.bmj.com/ TNFa and a late and significant reduction age less than 18 years or disease onset before in sIL-2R concentrations. 16 years, Steinbroker functional class IV, prior Conclusion-This study suggests that IVIg immunosuppressive with metho- can ameliorate the symptoms and trexate, azathioprine, cyclophosphamide or improve the functional capability of RA cyclosporine A, intra-articular or systemic patients. This effect is associated with a steroid treatment with more than 15 mg in the partial modulation of serum concen- 30 days preceding the study, humoral on September 25, 2021 by guest. Protected copyright. trations of inflammatory cytokines and, immunodeficiency associated with RA. more interestingly, with a late decrease in Written informed consent was obtained from Institute of Internal sIL-2R which correlated with the late each subject. Patient follow up was also and reduction in disease activity. performed during the three months after Oncological Sciences, University ofPerugia, stopping IVIg therapy. Perugia, Italy (Ann Rheum Dis 1995; 54: 382-385) C Muscat R Ercolani O Bistoni Intravenous immunoglobulins (IVIg) have IVIg TREATMENT E Agea been successfully used as replacement During the first three days, 400 mg/kg/day of M Cesarotti treatment in patients with hypogamma- immunoglobulin (Endobulin, Immuno SpA, F Spinozzi have also Pisa, Italy) was infused slowly. Subsequently, R Gerli globulinaemia.1 More recently, they been shown to be effective as immuno- 400 mg/kg of IVIg was administered once a Institute ofPediatrics was A Bertotto modulating therapy in a wide variety of chronic month for 12 months. diseases restricted to a constant dose of prednisone Division ofNuclear autoimmune including juvenile Medicine, rheumatoid arthritis (RA).2 3 However, the role (maximum 10 mg/day) or non-steroidal anti- Perugia General of IVIg therapy in adult RA is unclear, as only inflammatory (NSAIDs) (naproxen Hospital, a few short term studies have been carried out 500-1000 mg/day or piroxicam 20 mg/day), or Perugia, Italy G Fiorucci on small numbers of patients, and most were both, to obtain pain relief and slow reduction for the 30 days preceding the study Correspondence to: receiving concomitant treatment with Dr Roberto Gerli, acting antirheumatic drugs (SAARDs).i-6 and during the 15 months of the trial. Institute of a and Oncological Sciences, The present study evaluated the effects of University of Perugia, one year treatment with high dose IVIg not Policlinico di Monteluce, associated with SAARDs on the clinical and CLINICAL AND LABORATORY ASSESSMENT I-06100 Perugia, Italy. in adult with Clinical evaluation, performed in each patient Accepted for publication laboratory parameters patients 9 December 1994 active RA. In addition, serum concentrations every month, is described in the table. Intravenous immunoglobulins in rheumatoid arthritis 383

Clinical and laboratory features ofthe 10 RA patients before IVIg treatment* IL-6 (Genzyme, Cambridge, MA), IFN-y (Byk Gulden Italia, Milan, Italy), sIL-2R (T Cell Patient Moming Patient 's Grip ESR CRP score stiffness pain global strength (mm/lst h) (mg/dl) Diagnostics, Cambridge MA) and TNFa Ann Rheum Dis: first published as 10.1136/ard.54.5.382 on 1 May 1995. Downloaded from (min) assessment§ assessment§ (mm Hg) (Genzyme). 1 7 240 45 50 240 76 5-75 2 28 180 75 83 200 44 2-46 3 16 60 95 75 100 84 5-24 4 23 360 50 50 140 38 5-53 STATISTICAL ANALYSIS 5 10 150 47 50 170 45 4-13 Variations in clinical and laboratory par- 6 18 180 80 72 95 46 2-7 7 21 120 63 86 110 53 3 16 ameters were evaluated by analysis of variance 8 22 150 70 77 100 42 4-23 for repeated measures, testing both parametric 9 30 240 60 40 130 20 6-5 10 13 180 50 60 110 55 4-26 and non-parametric methods. Contrast analysis was used to evaluate, within subjects, *Active disease was defined by the presence of six or more tender , and two of the following conditions: nine or more swollen joints, morning stiffness lasting more than 45 minutes or the effect of treatment over time. Values of Westergren erythrocyte sedimentation rate (ESR) > 28 mm/lst h. p - 0 05 were considered significant. tObtained by summing the score of the single tender joints (1 = mild, 2 = intermediate, and 3 = severe pain). §Patient's pain and physician's Qverall assessments were evaluated using a visual analogue pain scale (0 mm = absence of pain/disease activity; 100 mm = the maximum pain/disease activity). Results Only eight patients completed the trial as two Laboratory analysis included evaluation of ery- (Nos 7 and 8) suffered minor side effects (mild throcyte sedimentation rate (ESR), C reactive hypotension, lumbar pain, nausea, and protein (CRP), full count, RF (latex hyperemesis) immediately after starting the agglutination assay), IgG, IgA, IgM (nephel- IVIg infusion. Although the adverse effects ometry) and ANA (indirect immuno- reversed spontaneously after IVIg was stopped, fluorescence on HEp-2 cells). Hand, feet and the patients refused to continue therapy. The any other involved joints were radiographed in other eight patients did not suffer from any each patient at the start and end ofthe trial and adverse effects or illness, related either directly scored according to Sharp's criteria.10 All films to IVIg or to during the were evaluated blind by the same observer. course of the study. Figure 1 shows the mean changes in some clinical parameters and ESR values in the eight LYMPHOKINE DETERMINATION patients who completed the trial. Although an Serum samples were obtained from each increase in both ESR (fig 1) and CRP (data not patient every three months, and from 40 shown) was documented in all patients after healthy volunteers to evaluate the normal the first month of IVIg infusion, a gradual range. Commercially available enzyme linked subjective and objective improvement of immunosorbent assay kits were used for clinically assessed disease activity was observed

assaying serum IL-Ic (Immunotech SA, from the second month oftreatment. However, http://ard.bmj.com/ Marseille, France), IL-1, (Immunotech SA), a statistically significant improvement was

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-C 0 - fL- .IIII II I~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~0- -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 1415 -1 0 1 2 3 4 5 6 7 8 9 10 1112 13 1415 Months Months Figure 1 Average ofjoint score, morning stiffness, physician's global assessment values and ESR in eight RA patients treated with IVIg. *p < 0-03forjoint score and morning stiffness and p < 0-05forphysician global assessment, compared with baseline. 384 Muscat, Bertotto, Ercolani, et al

obtained only after six months of therapy, and study (data not shown). Although IL-l, con- was maintained throughout the treatment centrations were higher in all and IL-6 concen-

phase, in joint score (p < 003), duration of trations greater in five patients with respect to Ann Rheum Dis: first published as 10.1136/ard.54.5.382 on 1 May 1995. Downloaded from morning stiffness (p < 003) and physician's normal values, the changes in these two global assessment (p < 0 05). Improvements in cytokines were not significant during the trial patient pain assessment and grip strength did (fig 2). not reach statistical significance (data not shown). In contrast ESR, CRP concentrations and other laboratory variables studied (haemo- Discussion globin, RF, ANA, IgG, IgA, IgM or comple- The results ofthe present investigation support ment components C3 and C4) were not a positive effect of IVIg in the treatment of affected by treatment (data not shown). adult RA. However, in contrast with previous According to previously described criteria for studies which reported that IVIg adminis- assessing individual response to treatment,8 six tration exerted a rapid influence on clinical and out of the eight patients (75%) could be laboratory inflammation indexes,3 4 we found considered responders. clinical improvement only after six months of As shown in figure 1, disease relapse was therapy. In addition, despite the fact that the clinically evident in most patients about one clinical benefit was maintained throughout the month after stopping IVIg. trial, it was not associated with improvement There were no significant radiological in values of laboratory variables which, on the changes, as assessed by the Sharp's score, after contrary, underwent a transitory worsening at 12 months of therapy (data not shown). the beginning of the treatment, perhaps Large concentrations of soluble TNFct were because of IVIg overload. detected in the serum of five of the eight As it is well known that RA is a hetero- patients (mean 166 (SD 58) pg/ml) but, geneous disorder in which clinical course, interestingly, could not be detected in any prognosis, and response to therapy can differ patient after three months of therapy or between subjects,' these conflicting results during the treatment phase (p < OOO1) may be explained, at least in part, by differ- (fig 2). The abnormally high levels of sIL-2R ences in selection of patients, different levels of (924 (326) IU/ml), detected in six of the disease activity, and different doses of IVIg. eight patients, decreased significantly from the Furthermore, the fact that IVIg preparations, ninth month of treatment (486 (65) IU/ml; although similar in Ig composition, are not p < 005). Interestingly, pathological levels of identical but vary in purity, activity, both TNFa and sIL-2R were revealed after and content of other immunomodulatory IVIg was stopped. IL-lot and IFNy serum proteins,'2 may account for the discrepancies concentrations in all patients were within the between our results and those from other normal range both at baseline and during the trials. http://ard.bmj.com/

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0 3 6 9 12 15 0 3 6 9 12 15 Months Months Figure 2 Average of TNFa, sIL-2R, IL-1,B and IL-6 serum concentrations in eight RA patients treated with IVIg. Broken horizontal line indicates upper limit of range ofnormal values. *p < 0-001 for TNFa andp < 005 for sIL-2R compared with baseline. Intravenous immunoglobulins in rheumatoid arthritis 385

In the majority of patients in whom IVIg has development of RA synovitis," we do not have been of benefit, it is uncertain whether its enough data to support the hypothesis that T

immunomodulatory effects were the results of cells have been the main target of IVIg Ann Rheum Dis: first published as 10.1136/ard.54.5.382 on 1 May 1995. Downloaded from alterations in T or function, or immunomodulation in determining long modulation of -presenting cell activity.2 lasting remission in our RA patients. Moreover IVIg may, in certain clinical In conclusion, our data indicate that IVIg situations, directly reduce the inflammatory can ameliorate symptoms and improve response without exerting any immuno- functional capability of RA patients. Although modulatory effect.2 it had an effect on some immunological Accumulating evidence indicates that a parameters, complete remission was not number of cytokines are crucial in the patho- obtained. The lack of effect on aspecific genesis of RA synovitis and joint damage.9 inflammation indexes, which is consistent with Cytokines such as IL-lot and -113, TNFot and the effect of other new drugs used in the IL-6, expressed as a result of macrophage treatment of RA, ' may have implications in activation, have been demonstrated in the evolution of joint disease. However, the rheumatoid synovium, and increased concen- improvement in quality of life induced by IVIg trations of these monokines have been found may predict a long term gain in morbidity. Two in the synovial fluid and serum of RA patients withdrew from the trial early because subjects;" increased concentrations of sIL-2R, of minor side effects, but tolerance was considered a marker of T cell activation, have otherwise optimal throughout the 12 months of also been detected in this disorder.9 Despite the treatment. Although the present trial was fact that serum concentrations of IL-1 ot and uncontrolled and the results may therefore be IFN-y in our patients were within normal too limited to permit definitive conclusions, values, all had abnormally high serum these observations suggest that, despite its high concentrations of IL- 113 and six had increased cost, IVIg may be a valid, tolerable, alternative concentrations of sIL-2R, TNFot, or IL-6, or combination drug for maintenance therapy both. None displayed simultaneously normal in RA. values of these immune active proteins, which The authors would like to thank Dr Alfonso Iorio for assistance have been associated with disease severity in in the statistical analysis. RA patients.9 1 In the present study, IVIg administration 1 Roifman C M, Levison H, Gelfand E. High-dose versus low-dose intravenous gammaglobulin in hypogamma- had a partial influence on the synthesis of globulinemia and chronic lung disease. Lancet 1987; i: macrophage derived cytokines, as there was a 1075-80. 2 Dwyer J M. Manipulating the with immune dramatic and rapid decrease in TNFoL, while globulin. NEnglJMed 1992; 326: 107-16. IL-6 and IL-1 serum concentrations remained 3 Silverman E D, Laxer R M, Greenwald M, et al. Intravenous gammaglobulin therapy in systemic juvenile rheumatoid unaffected. The -macrophage system arthritis. Arthritis Rheum 1990; 33: 1015-22. is one of the potential targets of IVIg therapy.2 4 Tumiati B, Casoli P, Veneziani M, Rinaldi G. High-dose as an immunomodulatory http://ard.bmj.com/ IVIg may decrease or block reticuloendothelial treatment of rheumatoid arthritis. Arthritis Rheum 1992; system function by occupying, downregulating 35: 1126-33. 5 Combe B, Cosso B, Clot J, Bonneau M, Sany J. Human or decreasing the affinity of the Fc receptors, placenta-eluated gammaglobulin in immunomodulating thereby interfering with the binding of immune treatment of rheumatoid arthritis. Am . Med 1985; 78: 920-8. complexes.2 Our findings agree with the recent 6 Emery P, Spath P, Affentranger P, Schwarz M A, Gough A. demonstration of a downregulation of TNFot A placebo controlled double-blind study of high-dose secretion following IVIg treatment in experi- intravenous immunoglobulin therapy in patients with early rheumatoid arthritis [abstract]. Arthritis Rheum on September 25, 2021 by guest. Protected copyright. mental models ofT cell mediated autoimmune 1993; 36: 57. 7 Arnett F C, Edworthy S M, Bloch D A, et al. The American disease. 3 Moreover, a partial inhibition of Rheumatism Association 1987 revised criteria for the monokine synthesis by SAARD treatment has classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 315-24. recently been described in RA patients: Danis 8 Paulus H E, Egger M J, Ward J R, Williams H J. Analysis and colleagues noted that clinically successful of improvement in individual rheumatoid arthritis patients treated with disease-modifying antirheumatic treatment with sulphasalazine was associated drugs, based on the findings in patients treated with with reduction in serum concentrations of IL-I placebo. Arthritis Rheum 1990; 33: 477-84. 9 Barrera P, Boerbooms A M, Jannsen E M, et al. Circulating and TNFot, but not IL-6. 4 The different soluble receptors, interleukin-2 in vitro effects of sulphasalazine on monokine receptors, tumor necrosis factor a, and interleukin-6 levels in rheumatoid arthritis. Arthritis Rheum 1993; 36: production observed by these investigators 1070-9. may mean that high concentrations ofthis drug 10 Sharp J T, Young D Y, Bluhm G B, et al. How many joints in the hands and wrist should be included in a score of are needed to inhibit IL-6 synthesis than those radiologic abnormalities used to assess rheumatoid required to block IL-1 and TNFao production. arthritis? Arthritis Rheum 1985; 28: 1326-35. In consequence, although the different effects 11 Harris E D Jr. Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med 1990; 322: on these cytokines are not completely clear, the 1277-89. 12 Lam L, Whinset C F, McNicholl J M, Hodge T W, possibility cannot be excluded that the IVIg Hooper J. Immunologically active proteins in intravenous doses we adopted were too small to inhibit IL- 1 immunoglobulin. Lancet 1993; 342: 678. 13 Achiron A, Margalit R, Hershkoviz R, et al. Intravenous and IL-6 synthesis completely. immunoglobulin treatment of experimental T cell- A significant reduction in sIL-2R serum mediated . Upregulation of T cell proliferation and downregulation of tumor necrosis factor concentrations was reached late in the course a secretion. J Clin Invest 1994; 93: 600-5. of treatment, when a significant clinical 14 Danis V A, Franic G M, Rathjen D A, Laurent R M, Brooks P M. Circulating cytokine levels in patients with improvement was also obtained. This suggests rheumatoid arthritis: results of a double blind trial with that changes in sIL-2R serum values reflect the sulphasalazine. Ann Rheum Dis 1992; 51: 946-50. 15 Tugwell P, Bombardier C, Gent M, et at. Low-dose effect of IVIg on disease activity. However, cyclosporin versus placebo in patients with rheumatoid although T lymphocytes play a key role in the arthritis. Lancet 1990; 335: 1051-5.