Investigational therapy in rheumatoid arthritis: A critical review

Investigational

Therapy in Rheumatoid A Critical Review ByMuhammad

R

HEUMATOID ARTHRITIS (RA) is a chronic disease that is frequently progressive and destructive causing significant disability. Currently approved therapy for RA includes a number of nonsteroidal antiinflammatory drugs and several disease modifying agents, including hydroxychloroquine, parenteral and oral gold, penicillamine, and azathioprine. While systemic corticosteroids have marked antiinflammatory effect, they probably do not favorably change the course of arthritis. Despite the availability of a considerable number of drugs for the treatment of RA, a significant number of patients remain resistant to such treatment with continued disease activity and disability. Therefore, it is not surprising that efforts are continued towards helping these suffering individuals. This report will critically assess the efficacy of, and the possible rationale for, several treatment modalities for RA that are under study and not currently approved by the Food and Drug Administration (investigational). Some of these modalities will only be briefly mentioned at the end, either because of the limited scope of this article, or because insufficient data are available. Further, newer nonsteroidal antiinflammatory drugs will not be described, since their effects are generally similar to those currently available in the United States. The forms of therapy, including drugs, that will be discussed in some detail are: 1. Cytotoxic drugs Methotrexate Cyclophosphamide 2. Sulfasalazine 3. Thoracic duct drainage 4. Apheresis (plasmapheresis, lymphopheresis and lymphoplasmapheresis) 5. Total lymphoid irradiation 6. Pulse methylprednisolone A brief review of the pathogenesis of RA’ will be useful in understanding the possible rationale for use of the above-mentioned treatment modalities. Probable pathogenetic mechanisms in RA involve two pathways, ie, immune complex formation within the joints resulting in inflammatory changes, and activation of T cells and Seminarsin Arthritisand Rheumatism,

Arthritis:

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macrophages with formation of lymphokines and monokines and resultant inflammation, degradation of cartilage, and bone erosion. An unknown antigenic stimulus probably alters the normal configuration of IgG with formation of anti-IgG or rheumatoid factors. IgG-anti-IgG immune complexes then activate the complement pathway with resultant increased vascular permeability, chemotaxis, phagocytosis, and release by polymorphonuclear leucocytes of lysosomal enzymes, oxygen radicals, and arachidonic acid metabolites, all of which cause tissue damage. In the lymphokine and monokine (interleukin) pathway, the macrophages process and present the antigen to T cells which are activated by interleukin- 1 (IL-l), producing several soluble factors (lymphokines) that recruit and further activate other T lymphocytes and macrophages (monocytes). Additional soluble factors are manufactured by these cells that stimulate chondrocytes, fibroblasts, and osteoclasts.2 Macrophages, chondrocytes, and fibroblasts all release destructive enzymes and chemicals including collagenase and PGE2, whereas the stimulated osteoclasts induce bone resorption. Prostaglandins (which are also produced by synovial cells) play an additional role in bone resorption, whereas collagenase contributes to connective tissue destruction. It is quite likely that byproducts of the inflammation or altered constituents of the articular tissues, eg, fibrinogen, DNA, partially digested IgG, collagen, or cartilage provide further antigenic stimulus for immune complex formation, causing a vicious cycle and perpetuating chronic articular damage. It may be recalled that while the majority of cells in the synovial fluid are polymorphonuclear

From The Department of Medicine. Division of Rheumatology, University of Illinois College of Medicine at Peoria. Muhammad B. Yunus, MD: Associate Professor of Medicine, Division of Rheumatology, University of Illinois College of Medicine at Peoria. Address reprint requests to Dr h4.B. Yunus, Department of Medicine, UKOM-P, PO Box 1649. Peoria, IL 61656. o 1988 by Grune % Stratton, Inc. 0049-0172/88/l 703-0006$5.00/O

Vol 17, No 3 (February), 1988: pp 163- 184

163

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leucocytes, lymphocytes (mostly T cells) dominate the rheumatoid synovium. The overall picture in the synovium is one of cellular hypersensitivity. The relative importance of the two pathways mentioned above is not definitely known, but the presence of interleukins in cultured synovial tissue and synovial fluid, the dramatic response following thoracic duct drainage and total lymphoid irradiation in some patients, an RA-like disease in agammaglobulinemia, and a general lack of correlation between rheumatoid factor titer and disease activity suggest that the cellular immune mechanism is probably more important than antibody and immune complex formation. CYTOTOXIC DRUGS

The only cytotoxic drug approved by FDA for the treatment of RA is azathioprine, which has been found to be effective in this disease. Several other cytotoxic drugs have been studied in RA, of which methotrexate and cyclophosphamide will be discussed here. The rationale for using cytotoxic drugs in RA is that they are also immunosuppressive and possess such properties as elimination of sensitized and immunologically committed lymphoid cells, suppression of functional capabilities of lymphoid cells, and elimination of nonsensitized lymphoid cells or nonlymphoid cells engaged in nonspecific aberrant immunologic and inflammatory reactions.3 However, therapeutic doses of these drugs also suppress the normal host defense mechanisms, increasing the risk of infection or neoplasm.

Methotrexate Methotrexate (MTX) is a folic acid antagonist that inhibits DNA synthesis and cellular proliferation. MTX suppresses both primary and secondary antibody response in humans,4.5 but has little effect on delayed cutaneous hypersensitivity.’ Absorption of MTX is variable, but generally greater with a low dose (~12 to 30 mg/m2) than a higher dose.6s7 Pharmacokinetics of MTX at low doses for nonmalignant diseases have not been well studied and appear to be complicated.’ Bioavailability of this drug may be influenced by food. A study in children with acute lymphoblastic leukemia has shown that milk decreases absorption of MTX.9 MTX may also be administered parenterally. Approximately 50% of the

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drug is bound to plasma proteins, and MTX may be displaced by such drugs as salicylates. sulfonamides, and tetracycline. Probenecid and, to a lesser extent, salicylates can significantly decrease renal clearance of MTX, and nephrotoxic drugs can also decrease renal elimination of MTX, increasing its potential for greater toxicity.” However, such drug interactions appear to be clinically important only if high doses of MTX are used, eg, SO to 1.50 mg/wk. Most of the drug is excreted by the kidney.“,” MTX was first reported to be beneficial in RA in I95 I .I’ In recent years, several uncontrolled studies have supported the initial impression of efficacy.‘3-‘9 This drug has also been found to be useful in psoriatic arthritis.” In 1985, several double-blind, controlled short-term studies demonstrated the efficacy of MTX in the treatment of RA.2’-23 The trials by Weinblatt et al” and Williams et aI” both used oral MTX at a dose of 7.5 to 15 mg/wk. administered in three doses, I:! hours apart, or a placebo. In both studies, the entry criteria included a lack of response to nonsteroidal antiinflammatory drug (NSAID) and withdrawal of gold. penicillamine, or hydroxychloroquine for the preceding 2 months, if patients were taking such drugs. Lack of response to parenteral gold and penicillamine was a pre-requirement in two controlled stud22.23 while this was not clarified in the other.” ies, The study by Anderson et al involved a small number of patients (n = 12) who were given MTX by weekly intramuscular (IM) injections at doses of 10 to 25 mg/wk, or normal saline injections as placebo; entry criteria included inefficacy or unacceptable side effects of a NSAID, gold compounds, and penicillamine.23 Summary results of these three studies are shown in Table 1. Statistically significant improvement in subjective and objective parameters, including morning stiffness, swollen joints, and tender joints, was demonstrated in all the three doubleblind studies over a period of 12 to 18 weeks. Grip strength showed improvement in one study after 18 weeksz2 and in another one after 24 weeks.2’ Fifty-foot walking time (not shown in Table 1) improved in all of them.2’-23 ESR significantly decreased in two studies22*23 and rheumatoid factor titer in one22; the other study did show an improvement in ESR at 24 weeks.2’ Cellular immunity was not suppressed in the two studies

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THERAPY IN RA

Table 1. Results of Recent Double-Blind Controlled Studies of MTX in AA

Investigator Weinblatt”t

Difference* in AM Stiffness fmin)

Differencein No. of Swol!%nJoints

Differencein No. of TenderJoints

Diffsrencain Grip Strength

fmmHe)

Differencein ESR knm/hl

(n = 28)

MTX

134 2 58

P valuet

<.Ol -36

Placebo

14 + 2

f 32

P value

26 + 4

<.05 5+2

NS

-2l+

4*4

NS

7

17 * 7

NS

<.Ol -4

* 3 NS

NS

NS -4

+ 5 NS

Williamsz2t (n = 110) 117 + 418

MTX P value

<.05

Placebo

88 f 402

P value Andersor?§

11 f

7+9 c.001 -1

12

<.OOl

*s

329

-32

& 41

<.OOl -2

+ 28

24 <.OOl 1

NS

NS

NS

NS

NS

(P < .OOZ)ll

(P < .002)ll

(P < .OOl)ll

NST

(P < .OOl)ll

(n = 12)

MTX Placebo

NOTE: Clinical variables as shown in this table were analyzed after 12 weeks, 18 weeks, and 13 weeks in the studies of Weinblatt et al, Williams et al, and Anderson et al, respectively. Data, when shown, represent mean f SE” or mean + SD”: difference in ESR shown in the studY of Williams et al represents the median difference. Abbreviation: NS, not significant. *Difference in various clinical parameters indicates the difference between baseline values and values at assessment after MTX therapy; negative values of difference indicate that the values at assessment of therapy are greater than baseline values. TAnalyses and P values are based on difference between baseline and time of assessment in references 2 1 and 22. SAlI significant P values are related to improvement following MTX therapy. $ln the studY of Anderson et al,*’ data were presented as final figures after placebo and MTX therapy, and P values reflect the differences between placebo and MTX figures; significant differences indicate favorable response of MTX. TSignificant compared with placebo.

in which this was assessed.2’*23Interestingly, a significantly increased frequency of HLA-DR2 was present or observed in the eight patients with most impressive improvement in the study of Weinblatt et al.*’ Long-term effects of low dose MTX in RA have been reviewed by Kremer.24 The results described by various investigators are based on uncontrolled, open, and sometimes, retrospective reports without critical assessment of disease parameters, and should be interpreted with caution. Hoffmeister followed 78 patients for a period of up to 15 years (mean or median not reported).‘* From the data presented, 52 patients (67%) had received therapy for 5 years. MTX was initially administered by IM route; most patients were then switched to oral therapy after marked improvement that occurred in 45 (58%). Complete remission was recorded in 15 (19%). MTX therapy was stopped in 14 (18%) because of inadequate response and in 7 (9%) because of toxicity. Of the 67 RA patients followed by Willkens and Watson for 3 months to 10 years, “approximately 75% had an improved global response with a significant decrease in active

joints and ESR,” although no statistics comparing the baseline values were provided.25 Treatment was discontinued in 11 (16%) for inefficacy and in 16 (24%) for adverse reactions; two patients died of neoplasm. Zeiders reported the outcome of 183 RA patients not responding to other disease modifying drugs, who were followed for .5 to 77 months (mean and median period not known).26 Weekly dosage ranged from 2.5 to 25 mg (mean, 8.9 mg). Response was “excellent” in 15%, “good” in 35%, “fair” in 25%, and “absent” in 26%. Thirty-six percent developed one or more side effects, one third of which were asymptomatic abnormal laboratory values. Adverse reactions, including bleeding ulcers in two, leukopenia in two, and hepatitis in one, required cessation of MTX therapy in seven (4%). Weinstein et al reported the results of low-dose MTX therapy in 21 RA patients who had received this drug for up to 5 years.” Fifteen patients (71%) continued the drug with benefit for a mean of 42 months. Three patients (14%) had complete remission and another nine (43%) had excellent response. Liver toxicity, assessed

166

by biopsy in 17 patients after a mean of 1.9 g total dose, showed mild fibrosis in six, and no cirrhosis. Common adverse reactions of oral MTX therapy seen in the two controlled studies combined (n = 128, including crossed-over patients in the study of Weinblatt et al”) were as follows: elevated liver enzymes (20%), gastrointestinal (GI) side effects (16%), stomatitis (6%), and bone marrow suppression (3%).“,‘* In the 18week study by Williams et al,** nearly one third of the patients were withdrawn from the study because of side effects, mostly elevated liver enzymes, but such abnormal liver enzyme level was managed by temporarily withholding the drug for 1 to 3 weeks in the study of Weinblatt et al.” In the other controlled study where IM MTX was employed (n = 12), transient stomatitis, pruritic rash, and 1 + proteinuria were seen in one patient each. 23 An additional p atient developed significant bone marrow suppression; this patient was receiving MTX at a dose of 20 mg/wk by IM route, and had elevated serum creatinine of 1.9 mg/dL. The investigators state that, in retrospect, this patient was mistakenly entered in the study without measurement of creatinine clearance. Serious side effects were rare in these short-term studies. Serious pulmonary toxicity has been reported in ten RA patients treated with low-dose MTX*‘31 and another case was suspected to have this toxicity. 3’ The manifestations among these patients were acute dyspnea, fever, cough, diffuse alveolar and interstitial infiltrates on chest x-ray, and hypoxemia, presumably due to a drug hypersensitivity reaction. Two of these reported cases died,29,3’ but one of them had an associated extensive chronic interstitial fibrosis with bronchiectasis, most likely related to RA.3’ The duration of MTX therapy among these patients with pulmonary complications varied between 12 and 54 weeks before respiratory symptoms developed. Canon et al have described such acute inflammatory lung disease among five of 127 RA patients treated with MTX suggesting a prevalence of 4% for this side effect that should be carefully monitored by appropriate warning to the patients and history taking.30 The frequency of this pulmonary complication was estimated to be 3.1% (three of 95) in the Duke series.29 Similar pulmonary complications have been

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reported among non-RA patients treated with MTX, as reviewed by Weinblatt.32 No predictive risk factor has been identified for pulmonary toxicity. Serious hepatotoxicity has so far not been reported with low-dose MTX treatment in RA. Several reports of liver biopsy findings are available,‘“.19,33-35 Only the study by Mackenzie34 had included a controlled group of RA patients, and ten of the 34 patients reported by Hoffmeister’* and 15 of the 30 reported by Lanse et al-” had a baseline liver biopsy for comparison. Mackenzie performed liver biopsies in 60 RA patients who had received a mean weekly dose of 8.6 mg MTX (mean cumulative dose of 1,837 mg per patient) for a mean period of 4 years (range, 2 to 8 years). and in 25 equally severe RA patients who did not receive MTX. Types of medications besides MTX were comparable in both groups; these included aspirin. nonsteroidal antiinflammatory agents, and antimalarial compounds. Fatty intiltration and portal inflammation occurred with almost equal frequency among the RA patients receiving MTX and those not receiving such therapy (about 50%~ for fatty infiltration and 20% for portal inflammation). Grade 2 portal fibrosis (according to the grading of Roenick36) was seen in only one of the 60 patients in the former group. Cirrhosis of liver has not yet been reported among MTX treated RA patients, but remains a possibility. Review of other liver biopsy reports indicate that mild inflammatory changes and fatty infiltration are common among RA patients not receiving MTX, and this drug does not seem to cause significant liver damage over a relatively short period of time as reported in the above mentioned studies.‘8.‘9,33.3” Whether these liver changes are due to RA itself or various drugs used besides MTX is not known. Long-term effects of low-dose MTX on liver function among RA patients remain unknown. There is no correlation between elevated liver enzymes and cirrhosis,33V37,38although persistent elevation of liver enzymes was reported to have a correlation with abnormal liver histology in one study that did not report baseline biopsies or other controls.33 Therefore, the changes are not all necessarily due to MTX.33 In this study of 29 patients, Tolman reports that both hypoalbuminemia and persistent serial elevations of aminotransferase and/or alkaline phosphatase levels

INVESTIGATIONAL

THERAPY IN RA

are “specific indicators” of the development of “liver disease” (defined as abnormal liver histology).33 Seven of the eight patients who had developed hypoalbuminemia during study developed liver disease, with grade 3 changes (according to grading of Roenigk36) in five (63%) of the eight.33 Also in this study, 12 (92%) of the 13 patients who had serial elevations of liver enzymes had liver disease, with grade 3 changes in six (46%); in contrast, six (75%) of the eight patients who had an isolated elevation of an enzyme had liver disease, with grade 3 in three (38%).33 Based on these observations, the investigators conclude that hypoalbuminemia is the best predictor of grade 3 liver disease. Paulus reported the data from Lederle Laboratories on hepatotoxicity and findings of liver biopsies, as presented to the FDA Arthritis Advisory Committee meeting in May, 1986.” Transient elevations of liver enzymes following MTX ingestion are common and not associated with permanent hepatic injury. Among 98 liver biopsy specimens obtained 28 to 40 months after MTX therapy (cumulative dose, 750 to 2,250 mg), 13 had mild fibrosis and two had moderate to severe fibrosis; no fibrosis was demonstrated among an additional 16 patients who had received more than 2,250 mg (total dose). Interestingly, 54% of those with mild fibrosis and both the patients with moderate to severe fibrosis had an abnormally low albumin value sometime during the MTX therapy, as compared with 25% who had hypoalbuminemia but no fibrosis. However, no other liver function tests correlated with hepatic fibrosis. Nevertheless, persistent elevations in transaminase levels and low albumin level in a RA patient whose disease is generally well controlled with MTX are considered indications for a liver biopsy.3* It may be noted that albumin levels may be low in a patient with active RA before MTX therapy. However, hypoalbuminemia gradually improves as the disease is controlled with therapy. Mackenzie suggests that liver biopsy need not be done more frequently than every fourth or fifth year in the RA patients receiving low-dose MTX (5 to 12.5 mg/wk), except in those with alcohol abuse, significant folate deficiency, and sustained elevation of hepatic enzymes.34 On the basis of recent evidence, one may add that development of hypoalbuminemia and persistently elevated liver enzymes of significant degree dur

167

ing MTX therapy are indications for liver biopA baseline liver biopsy may be carried out, sy. 33*38 but there is no general agreement as to its necessity.34 The question of malignancy in long-term use of MTX cannot be definitely answered,“’ but a large controlled study in psoriatic arthritis showed no increased malignancy.3g However, the potential for malignancy is present with this drug.3” Willkens and Watson reported two deaths from malignancy among the 67 RA patients who were treated with low-dose MTX for 3 months to 10 years.25 Embryotoxicity of MTX is well established with abortion and multiple birth defects if this drug is administered early in pregnancy.38*40*4’ Women of child bearing potential should not receive MTX unless reliable contraceptive measures are used.32*38 Weinblatt reviewed toxicity of low-dose MTX among a total of 587 patients from the literature.32 The most common side effects were GI (lo%), followed by stomatitis (6%), hematologic (3%), alopecia (l%), and headaches or dizziness (.5%). Toxicity was severe in 15 patients (2.6%), resulting in withdrawal of therapy. A higher frequency of toxicity, both minor (in 63.8%) and major (in 9.7%) has recently been reported by Gispen et al from a retrospective series of 72 RA patients who were treated with low-dose MTX.3’ The mean follow-up period was 1 year. A careful review of this report suggests that not all major side effects (including infection, respiratory failure, seizures, and GI bleeding) were definitely related to MTX, and at least one of the two deaths reported cannot be directly attributed to MTX.3’ Moreover, it appears that the severity of RA was unusually great, with an average disease duration of 13.6 years in this university tertiary care center. The mode of action of MTX in RA is not known. As mentioned earlier, MTX had no effect on cellular immunity during two clinical trials.*‘.*’ Although it has been suggested that MTX may have an inhibitory effect on proliferative synovial lining cells or mononuclear cells involved in the inflammatory process, data are lacking to support this hypothesis!* Interestingly, a recent study in mice demonstrated that low-dose MTX inhibits leukotrien B, (LTB4) and C5a induced neutrophil chemotaxis.43 Such inhibition of neutrophil chemotaxis may also

168

occur among RA patients treated with MTX and explain, at least in part, the relatively rapid onset of antiinflammatory effect of this drug observed in clinical practice and trials. Several studies have demonstrated the neutrophil chemotactic property of LTB444 and C5a,45 which are both elevated in RA synovial fluid.46*47It is of interest that a decrease in neutrophil chemotaxis has been demonstrated in psoriatic arthritis patients who were treated with MTX.48 In conclusion, limited, but well-controlled recent studies suggest that MTX is effective in RA with an acceptable risk/benefit ratio. However, further well-conducted long-term studies are required before MTX therapy can be generally recommended. Absolute contraindications for the use of this drug are known renal and hepatic disease, and other risk factors for toxicity are excess alcohol intake, diabetes mellitus, and during MTX therobesity. 36 Hypoalbuminemia apy has been identified to be a risk factor for hepatic fibrosis.33,38 Such hypoalbuminemia, as well as persistent and significant elevation of hepatic enzymes, are indications for liver biopsy during MTX therapy.38 For monitoring of toxicity, all patients receiving MTX should have complete blood count and platelet estimation every 4 weeks, and a chemistry profile should be requested every 8 weeks, with special attention to the results of serum albumin, BUN, creatinine, and hepatic enzymes. Patients with macrocytosis or suspected malnutrition should also have serum folic acid levels checked and treated appropriately if levels are low. MTX should be temporarily discontinued if the white cell count is below 3,OOO/pL, platelet count is
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outlined is essential. Women of childbearing potential should undertake reliable contraceptive measures during MTX therapy.“.38 Cyclophosphamide

Cyclophosphamide is a potent alkylating agent that is well absorbed orally and can also be administered intravenously (IV). The plasma half-life is six to seven hours, which may be significantly prolonged by allopurinol. Sixty percent of the drug is excreted through the kidney in the form of active metabolites; therefore, renal failure may increase its immunosuppressive properties, as well as toxic effects. Cyclophosphamide can affect virtually all components of humoral as well as cellular immunity, with more marked effect on B cells and inhibition of antibody production.’ When chronically administered, cyclophosphamide consistently produces lymphopenia involving both B and T cells. Several clinical trials of cyclophosphamide in RA49-57 including controlled ones,5’-57 have been published. These studies suggest that cyclophosphamide is effective in RA, with reduction in bone erosions in some patients, when used at a high dose level, eg, 150 mg/d (Table 2). However, this dose causes significant side effects including infections, alopecia, stomatitis, hemorrhagic cystitis, bone marrow suppression. GI side effects, and sterility. Decker compared the toxic effects of azathioprine, MTX, and cyclophosphamide, and found cyclophosphamide more toxic than the other two.58.59 The potential for induction of certain types of neoplasia (eg, carcinoma of bladder and skin) in chronic use of cyclophosphamide, is clearly higher than azathioprine.58 Testicular and ovarian functions are commonly affected by cyclophosphamide. Azoospermia Table

2.

Therapeutic

Effect

Cyclophosphamide Median Swollen Jomts

DO%

in RA Median Tender Jams

Entry

32 wk

Change*

Entry

32ti

Change

15(22j5’

14

18

tl

28

21

* 1.5

75(34)-

17

14

-5

22

18

5

(mg/dV(n)

150

(36)”

20

12

-7

27

13

11

150

(28)”

22

12

-8

28

7

10

*The of

of Increasing

Dose

values

ranking

necessarily median ment.

the

indicate changes

equivalent

values:

+

median

changes

in the to the

indicates

that represent

individual

difference worsening,

patients between ~

the results and

initial

indicates

are and

not final

improve-

INVESTIGATIONAL

THERAPY IN RA

occurred in all six tested patients receiving cyclophosphamide in one tria1.54 Cyclophosphamide has been used in rheumatoid vasculitis with apparent success.6062 Controlled studies employing nonimmunosuppressive drugs are not available, nor do they appear justified given the potentially serious nature of RA vasculitis. However, considering the fact that a high morbidity and mortality rate was reported in rheumatoid vasculitis in the early 1960~,~~ cyclophosphamide therapy in this serious complication of RA, as described in the recent reports,“62 is probably beneficial. In an open study, Scott and Bacon treated 21 systemic rheumatoid vasculitis patients with high-dose methylprednisolone and cyclophosphamide, both by IV infusion, and 24 similar patients with other treatments including oral azathioprine, 20 to 60 mg/d of oral prednisolone and o-penicillamine.62 The cyclophosphamide plus methylprednisolone (C + M) group had more severe disease initially, but overall showed a greater response, including an impressive improvement of mononeuritis in the three who had this complication. Mortality rate was 24% in the C + M group, as compared with 29% in the other treatment group. In another study, high serum immune complex levels in RA vasculitis decreased following treatment with cyclophosphamide, along with clinical improvement.60 In conclusion, cyclophosphamide is useful in RA synovitis, but the effective dose causes bothersome side effects, including infection, testicular and ovarian dysfunction, and cystitis; neoplasm in long-term use is a clear concern.” However, the drug may be beneficially used in the treatment of systemic rheumatoid vasculitis, which frequently causes significant morbidity and mortality. SULFASALAZINE

Sulfasalazine (SSZ) was synthesized by Nanna Svartz by combining sulfonamide and salicylate.63 Svartz was the first to treat RA with this compound and found a 63% success rate.64 The rationale for use of SSZ in RA at that time was based on the belief that RA is an infectious disease that should respond to a drug that combines both the antimicrobial and analgesic effect. However, following a report by Sinclair and Duthie in 1948 when the drug was unfavorably

169

compared with gold, interest in SSZ waned.65 However, SSZ was only administered for an average period of 2 months in that trial. About 30% of sulfasalazine is absorbed in the small intestine and most of it is subjected to the action of bacterial flora in the large intestine where the azo bond is split with release of 5-aminosalicylic acid and sulfapyridine. Sulfapyridine is then mostly absorbed, whereas 5aminosalicylic acid is mostly excreted unchanged in the feces.66 The work by Pullar suggests that sulfapyridine is the more active component of SSZ in RA,67 whereas the therapeutic effect in inflammatory bowel disease is exerted by the salicylate component.66*68 Recent interest in SSZ as a treatment agent for RA began with an open trial by McConkey et al 69 followed by several other similar publications showing efficacy of this drug in RA at a dose of 2 g/d.70-72Three double-blind controlled studies, two from the United Kingdom73*74and the other from the United States,75 have confirmed the efficacy of SSZ in RA with acceptable risks. One study compared SSZ with penicillamine,73 one with placebo and sodium aurothiomalate,74 and the other with placebo only.75 The maximum daily dose of SSZ used in these studies was either 2 g or 3 g. Summary of the results of these three studies is shown in Table 3.66-68In the study of Pinals et al, 50 patients were enrolled in the SSZ group, but 31 completed the 15 weeks of study; among the withdrawal patients, 15 were due to either inefficacy or adverse reactions from SSZ.75 Significant improvement in various disease parameters, including joint swelling in the study of Pinals et al, was noted in these studies when compared with baseline.75 All the study groups were generally well-matched at baseline in the three studies. Joint swelling was not measured in the two British studies. ESR was significantly improved in these two studies in the SSZ group when compared with the baseline values73*74;such improvement was not noted in the United States trial when compared with either the baseline or placebo values, although the difference between SSZ and placebo changes approached statistical significance (P < .07).75 Long-term effects of SSZ were assessed over 24 to 42 months in an open trial by Bax and Amos, where 59 RA patients on SSZ were

170

MUHAMMAD

Table

3.

Results

Study Investigator

in RA

Joint Tenderness

ImmHgl

Score

? 4

After I+ 37

*

Baseline 95

5

i

5

<.Ol 54

*

5

P Pulla?

of Sufasalazine

Grip Strength

P PNC

Studies

Visual Analogue

66

SSZ

In = 63)

Controlled

Pain Score (mm) Baseline

Medications

Neuman73

of Double-Blind

34

After It 125

t

BaselIne 28

9

*

5

109

+

10

121

<.Ol

ESR (mm/h)

After ii

+ 3

18

c.01

+ 3

BsS.&le

After I(

Wlth&awal*

53

32

3

26%

6

38%(120/o)

+ 4

17

25

i

3

17

t

I

NS

i

(6%)

~ .Ol

. .Ol r

El. YUNUS

3

54

*

8

38

r

~ .Ol

.05

ssz

P

(n = 90)

NS

,005

,001

,005

37%

(6%)

. .OOl

,005

40%

(6%)

SAT

P

c.005

NS

Placebo

NS

50%

(43%)

ssz

56

i

24

33

? 26

101

f

49

120

r 58

37

L 20

23

k

17

64.2

48.0

30%

(2%)

Placebo

48

+ 23

44

? 29

109

+ 65

112

+ 61

36

i

33

t

24

48.7

41.6

11%

(8%)

P Pinals”

NS

NS

NS

(n = 62) 22

P (SSZ ”

NOTE: Pullar,

et al. Data which

Analysis

of clinical

et al, and after are shown

is shown

Abbreviations: *Withdrawal

SSZ,

variables

15 weeks as mean

as mean

I

1.005

placebo)

value

were

of Pinals,

+ SE in the study

done

after

et al. Actual

of Neuman,

16 weeks

. ,005

in the study

data at baselme

et al; the study

of Neuman

and after

of Pinals.

NS

et al.. after

therapy

were

et al, shows

24

weeks

not shown

all data

In the study

in the study

as mean

of

of Pullar,

? SD besides

ES8

only.

sulfasalazine;

due to inefficacy

as shown

in the study

.05

PNC,

or adverse

penicillamine; reactions;

SAT, figures

sodium

aurothiomalate;

m parentheses

compared with 84 on sodium aurothiomalate (SAT).72 Thirty-two percent in SSZ and 44% in the SAT group were judged to have a highly satisfactory response, whereas another 19% and 12% had partial success, respectively. Further, 25% in the SSZ group and 35% in the gold group satisfied the American Rheumatism Association criteria for complete remission.76 However, SSZ was safer than SAT; adverse reactions requiring withdrawal occurred in 10% in the former and 37% in the latter group.72 Side effects from SSZ causing withdrawal from study in the combined population of the three above-mentioned double-blind controlled 50 initially studies73-75 (n = 11 1, including enrolled in the study of Pinals et al)75 were as follows: nausea or vomiting, 14%; skin rash or pruritus, 4%; mildly elevated liver enzymes, 3%; fever, 2%; and mouth ulcers and neutropenia, 0.9% each. The most frequent side effect of SSZ is dyspepsia, nausea, or vomiting, which may be reduced by using an enteric-coated preparation and gradually increasing the dose.” Amos et al reviewed the charts of 774 RA patients treated with SSZ over a period of 1 to 11 years.” Two hundred five (27%) patients had stopped SSZ permanently because of an adverse reaction. The

indicate

Ii,

therapy:

withdrawal

NS,

not signiftcant.

due to IneffIcacy.

number of patients who continued treatment for 1.2, and 3 years was 397 (5 l%), 175 (23%), and 84 (1 I%), respectively. Symptoms of nausea. vomiting, dizziness, and abdominal pain frequently occurred together and accounted for 125 or 61% of all withdrawals. Among the 774 patients, adverse reactions leading to withdrawal were: GI symptoms and dizziness (19%), mucocutaneous lesions (5%), leucopenia (I%), megaloblastic anemia (0. I %), and miscellaneous others (2%). The investigators comment that 66%) of the relatively serious side effects occurred within 3 months and suggest special precautions during this period. It has been suggested by Pullar et al that GI side effects may be related to slow since five of the six acetylator phenotype. patients who had stopped taking SSZ in their study because of GI side effects were slow acetylators, whereas two patients who had withdrawn from the study because of lack of effect were fast acetylators.74 In a subsequent study, Pullar et al confirmed the relationship between Cl side effects and slow acetylation of SSZ.” However. no relationship exists between acetylator phenotype and more serious toxic events or efficacy of ssz.78.79 Neutropenia occurred in one of 74 patients of

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McConkey et al” and one of the 30 patients studied by Pullar, Hunter, and Cape11.74In the large series of 774 patients by Amos et al,” neutropenia occurred in eight (1%) leading to withdrawal, and another three had a transient neutropenia. Severe neutropenia was reported by Farr et al in two patients 1 month after starting SSZ.80 Megaloblastic anemia due to folate deficiency was found in five of the 74 (7%) patients during the open trial by McConkey et al.” Two of the 15 patients of Bird et al also developed high mean corpuscular volume, but were not further studied.” Megaloblastic anemia was described in one other case report during treatment of ulcerative colitis.” A rare occurrence of reversible male infertility has been described in patients treated with SSZ for inflammatory bowel disease. 66 Extensive e xperience with SSZ in treating inflammatory bowel disease has shown that rare but serious reactions may occur, including exfoliative dermatitis, drug fever, fibrosing alveolitis and other pulmonary complications, hepatitis, and lupus-like syndrome.66 Desensitization to SSZ has been successfully undertaken in those with rash and fever.82-84 Overall, limited experience with SSZ in RA suggests that serious side effects of SSZ are fewer than gold72-74and penicillamine.73 The mechanisms of action of SSZ are unknown, but are likely immunologic. It is a slow-acting drug that takes 2 to 5 months to become effective. The related drug dapsone has been shown to have immunosuppressive properties,” and SSZ modifies adjuvant arthritis.86,87 However, studies in inflammatory bowel disease suggest that SSZ does not have any effect on suppressor T cell activity, nor does it alter immunoglobulin production by peripheral mononuclear cells.88~89 Inhibition of synthesis of neutrophil lipoxygenase,” as well as platelet thromboxane synthetase:’ by SSZ has been reported. Since SSZ can impair folic acid absorption and metabolism, it is possible that SSZ and MTX share a common mechanism of action, among other mechanisms.66 The antibacterial effect of SSZ may also alter the gut flora, which might provide the antigenic stimulus for the immunopathogenesis of RA.92 In conclusion, SSZ is effective in RA and probably a safer alternative to gold and penicillamine. However, further long-term studies should

be carried out to have a better understanding of its true efficacy, adverse reactions, mode of action, and potentials for remission induction and retardation of bone erosions. GI side effects account for most withdrawls. Hematologic sideeffects seem to be uncommon, but should be monitored from time to time to detect neutropenia and folate deficiency. The report by Amos et al suggests that white cell count should be obtained every 4 weeks during the first 3 months and less frequently in subsequent months, depending on individual cases.” All patients should be warned of neutropenia-related symptoms, which should be promptly reported to the physician. THORACIC DUCT DRAINAGE

Since lymphocytes are implicated in the pathogenesis of RA, thoracic duct drainage (TDD) as a means of producing lymphopenia has been employed as a treatment modality in this disease.93-97In the inital studies of small numbers of patients, TDD was performed over a brief period of time (three to eight days).93*94Although impressive clinical improvement was seen in these short-term studies, effects of long-term drainage were not known until the laborious and detailed study of Paulus et al was published.95*96 Paulus et al studied nine hospitalized patients with severe RA where TDD was successfully carried out for a mean of 53 + 11 days (range, 19 to 105), during which period a mean of 46 + 12 x 10” lymphocytes were removed?5 Technical problems prevented the establishment of a fistula in four patients with equally severe RA who acted as controls. Considerable lymphocyte depletion occurred in peripheral blood and lymph which stabilized at 4 weeks, and it took approximately 15 weeks for the lymphocyte count to return to baseline after discontinuation of TDD. Statistically significant and impressive clinical improvement of RA, including joint count, ring size, morning stiffness, and grip strength occurred by the second or third week among the nine patients who had their thoracic duct drained, whereas none of the four controls demonstrated such improvement. Disease activity recurred 2 to 12 weeks following completion of TDD. IV reinfusion of autologous lymphocytes was accomplished in four patients (unlabeled in one, and “Cr-labeled in three), with exacerba-

172

tion of disease in one patient with unlabeled live cells and two of the three patients with labeled live cells. Intraarticular injection of live lymphyocytes caused flare up in one patient, but killed cells had no such effect in another patient. Following infusion of “Cr-labeled live lymphocytes, surface gamma counts over the liver and spleen increased tenfold, while the increase in the inflamed knees was much smaller. Cell-mediated immunity in general and some humoral antibody responses were suppressed following TDD, but inflammatory response to chemical or mechanical methods was unaffected. More recently, Vaughan et al treated five RA patients with severe disease who had not responded to remittive agents with TDD for 1 to 2 months in an open tria1.97 Two of the five were judged to have shown “major clinical improvement” that lasted as long as 9 months; two other patients also demonstrated some improvement. However, the methods of clinical assessment and presentation of clinical data were unsatisfactory, and no statistical data were provided. The number of swollen joints was not assessed. Moreover, Imuran was continued in all patients during and after the period of TDD. TDD produced a consistent decrease in the mitogen-induced proliferative responses of blood lymphocytes, as well as a change in the 0KT4 to OKTS ratio, with a higher proportion of 0KT8. In this study, in vivo complement activation was assessed with rocket immunoelectrophoresis, and indicated by the C4d to C4 ratio in plasma. There was an inverse relationship between responsiveness to TDD and the degree of in vivo disease-induced complement activation, suggesting that a subset of RA patients with a low C4d to C4 ratio is more likely to respond to TDD. However, no firm conclusions can be made because of the small number of patients studied. Complications of TDD in the study by Paulus et al included septicemia in three patients, including an infected wound at draining site in one patient.95 In the study of Vaughan et al, one patient died of massive GI hemorrhage from a peptic ulcer 2 weeks after TDD; the relationship of this patient’s hemorrhage of TDD is unclear.97 Although TDD appears effective in RA, the complicated and difficult technique of continuous drainage, combined with enormous cost and transient clinical benefit, makes this procedure

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an impractical and unjustified treatment modality for RA, particularly because easier methods of producing lymphopenia (eg, by cytotoxic drugs or lymphapheresis), is available. However, the most valuable contribution of these laborious studies is the understanding that lymphocytes play an important role in the pathogenesis of RA. APHERESIS

Apheresis means removal of a component of the blood from intravascular circulation. Thoracic duct drainage, as mentioned earlier. is also a form of apheresis. Plasmapheresis means removal of plasma without significant removal of cellular components. This procedure nonselectively removes immune complexes, cryoproteins. complement, antibodies, coagulation factors (including fibrinogen), immunoglobulins, cytotoxins, vasoactive peptides. as well as sex and adrenocorticosteroid hormones and minerals. Cytapheresis is selective removal of cells, eg, lymphocytes (lymphapheresis), platelets. and red cells. Plasmapheresis, lymphapheresis, and lymphoplasmapheresis have been carried out in the treatment of RA on the surmise that removal of pathogenetic immune complexes and lymphocytes will ameliorate the aberrant immunemediated reactions and inflammatory process.9R-‘oR Plasmapheresis is truly a plasma exchange where plasma volume is replaced by a combination of albumin and normal saline with or without other fluids such as acid citrate dextrose. Usually, 40 mL of plasma/kg body weight (a maximum of 3 L) is removed twice a week for 3 weeks,“* although a total of 20 exchanges over a period of 11 weeks has been employed.99 Various protocols have been used for lymphapheresis. In one study,“’ cells were removed by continuous flow cell separators via venous access two to three times a week for 13 to 16 procedures over 5 weeks, with removal of a mean of 13.7 x IO”’ lymphocytes per patient during the study and resulting in a mean decrease of lymphocyte count to 0.9 x 103/pL from 2.1 x I 03/pL. A number of clinical trials,98-‘07 including controlled ones in plasmapheresis,‘02~‘os leuka(lympha)pheresis,“’ and lymphoplasmapheresis’W.‘06 have been performed in recent years. Most studies have included severe RA patients who have not responded to at least one remittive agent. The

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results of these studies can be summarized by saying that apheresis is either minimally effective or effective in a subset of patients in whom the benefits last for a brief period of time (several weeks) following completion of the procedures. Plasmapheresis alone was found ineffective in both controlled tria1s.‘02-‘05 The controlled study of lymphapheresis by Karsh et al employed a small number of patients (n = 6) in each group of actual and control procedures, and the trial was designed to study immediate effects following 5 to 7 weeks of treatment.‘03 There was no significant improvement in subjective pain, morning stiffness, grip strength, or tender joints by objective examination, but the number of active and swollen joints were significantly (P < .05) improved as compared with the control group. The overall improvement is less than that observed by the same investigators in their earlier open trial.“’ It has been claimed that patients with anergy to skin-test antigens are more likely to improve by leukapheresis.“’ However, the numbers studied are small, and further studies are warranted to confirm these interesting results. Of the two double-blind, controlled studies of lymphoplasmapheresis,‘“~‘06 onelM demonstrated improvement after nine treatments, whereas the otherlo showed no benefit as compared with the control group. Significant reduction in ESR, C-reactive proteins, and IgG level were noted in the lymphoplasmapheresis group, but these parameters returned to baseline level 5 weeks later. The study by Wallace”“’ has been criticizedio6 because of the brief follow-up period, small number (n = 7 in each of true and sham apheresis groups), and the fact that RA activity was greater in the lymphoplasmapheresis group, with higher potential of postive changes in this group when compared with the baseline activity. It has been suggested that concurrent administration of remittive agents, eg, gold, penicillamine, or cytotoxic drugs, are necessary to prevent a rebound effect of plasmapheresis, ‘04but this has been refuted.‘063’08~‘09 Experience with various methods of apheresis has shown that while immune complexes and rheumatoid factors do decrease and lymphopenia does occur following appropriate apheresis, the degree of clinical improvement achieved in some patients simply does not correlate with the level of immune complex or the number of lymphocytes removed. This may be explained by the fact

173

that plasmapheresis involves a global depletion of many substances, including hormones and other factors of regulatory importance in the pathogenesis of RA. The simplistic rationale for apheresis as mentioned at the onset does not appear true in reality, and other unknown mechanisms may be operative. It is possible that beneficial effect results from the procedure itself, eg, intermittent anticoagulation by heparin or surface contact of tubing that may have unidentified biologic effect on cells involved in immune response as suggested by Klippel.“’ Surface contact with tubing has been mentioned to activate complement and platelets.“’ Another mechanism of beneficial effect by lymphoplasmapheresis may involve unblocking of immune complex clearance abnormalities of the reticuloendothelial system.“* The present uncertain status of apheresis in the treatment of rheumatic diseases has been well summarized by Klippel.“’ A subset of RA patients may respond to lymphapheresis or lymphoplasmapheresis, but overall the benefit is rather temporary. Certainly more data are needed for better characterization of these possible subsets. The cost-benefit ratio is quite high, and apheresis cannot be generally recommended for the treatment of rheumatoid joint activity at this time. Since rheumatoid vasculitis is likely to be immune complex mediated, the rationale for plasmapheresis is somewhat stronger in the case of this complication. Several uncontrolled reports suggest benefit,“3-“7 but concomitant use of cyclophosphamide makes true judgement difficult since cyclophosphamide alone may be beneficia1.60-62 However, plasmapheresis may be effective in life-threatening hyperviscosity syndrome complicating RA.“* Adverse reactions from apheresis are infrequent if proper care is taken, but may include anemia, bleeding diathesis, thrombosis, fluid and electrolyte imbalance, hypervolemia, hypotension, infection at access sites, and rarely hepatitis.“’ TOTAL LYMPHOID IRRADIATION

Total lymphoid irradiation (TLI) has been used in treating Hodgkin’s disease and nonHodgkin’s lymphomas for the past three decades.‘20 Prolonged suppression of cellmediated immunity has been observed among

174

Hodgkin’s disease patients treated with TLI,“’ and similar immunosuppression has been demonstrated in animals with induction of allograft tolerance,122 prolonged survival of bone marrow transplants,123 and suppression of adjuvant arthritis,124 as well as arthritis induced by collagen.12’These observations, as well as the fact that new neoplasms as a complication of TLI have rarely been observed in long-term follow-up among more than 3,000 patients with Hodgkin’s disease,120~12a prompted investigators at Stanford School of Medicine and Harvard Medical School to study the immunological and clinical effects of TLI in intractable RA. Beginning with subdiaphragmatic irradiation in four RA patients in a pilot study,‘27 two open studies employing TLI were independently conducted and simultaneously published in 1981 .128*129 The Harvard study included ten patients,“’ whereas 11 patients took part in the Stanford tria1.129 Both the Harvard and the Stanford groups used irradiation to the “mantle field” (cervical, axillary, mediastinal and hilar lymph nodes, and the thymus), the inverted “Y” field (subdiaphragmatic nodes including para-aortic, iliac, and inguinal-femoral nodes), and the spleen.128*129 The Harvard investigators used a total of 3,000 rad over a period of 13 to 15 weeks, including 2-week rest periods, whereas the Stanford group used 2,000 rad given more continuously (four to five days a week) over a total period of 5 to 6 weeks. Both groups included severe, erosive, progressive, and active RA patients who did not respond to conventional therapy, including gold and penicillamine; prednisone dose of 110 mg/d was allowed in both studies. Results were similar in both trials with statistically significant clinical improvement in such parameters as swollen joints, joint tenderness, and morning stiffness. Significant benefit was noted in 80% of patients after 6 months, lasting for about 1 year in the majority of patients; follow-up period was up to 21 months. Similar clinical improvement was noted in subsequently published trials,13s136including two double-blind, randomized ones,132*134 that compared 2,000 rad v 200 rad, and 2,000 rad v 750 rad, respectively. In the Standford study by Strober et al, statistically significant improvement over baseline was noted in the high dose (2,000 rad) group in various disease param-

eters, eg, morning stiffness, “global composite scores” (based on zero to four measurement scales of 11 subjective variables, plus grip strengths and overall physician assessment), as well as joint tenderness scores.132Such improvement was absent in the low-dose (200 rad) group. Although improvement in mean joint swelling score (percent change from pretreatment value) was almost double in the high-dose as compared with the low-dose group (- 47% v - 26%), the difference between the two groups was not statistically significant. Absolute joint swelling score at baseline and after 6 months in the high-dose group was 31.2 (mean) f SE 3.5 and 18.0 f 2.7, respectively (P < .Ol), whereas the corresponding figure for the low-dose group was 31.3 + 3.9 and 24.2 + 4.1, respectively (P > .05). Evaluation at 3 months showed a similar pattern, although data were not presented. Overall, 2,000 rad of irradiation was effective, but 200 rad was not. Significant immunologic changes (see below) were also observed in the high-dose group, but not among the low-dose patients. Adverse reactions of TLI are considerable (described below), and it is disconcerting that some of these occurred even in the 200-rad group, including fatigue or malaise in all and herpes zoster in three. Hanly et a1134from Dublin, Ireland, compared the effect of 750 rad and 2,000 rad in 20 severe RA patients (ten in each group) in a doubleblind, randomized study. Patients in both groups were well-matched with regards to disease severity and previous treatment. Both groups showed similar statistically significant differences after a mean of 10 months as compared with baseline in the following parameters: morning stiffness, joint tenderness, and hand proximal interphalangeal (PIP) joint circumference; significant improvement in grip strength was noted in the 750 rad group (P -c .05), whereas pain significantly decreased (P < .02) in the 2,000 rad group. No significant change in PIP joint circumference was noted after 6 months in the 2,000 rad, but, rather unexpectedly, the difference was significant (P < .05 by Wilcoxon signed rank test) in the 750 rad group (Table 4). No patient was judged to be in remission at mean follow-up of 10 months. Side effects, including fatigue, dry mouth, and bone marrow suppression did occur among the 750 rad group, but less

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Table 4. Clinical Effect of TLI in Two Double-Blind Randomized Trials at 6 Months in Severe RA AM

TLIDose Investigator

Strober’32 (n = 26)

Stiffness*

Baseline

bad)

After 9t

2,000

6.7 + 1.3

2.3 f 1.0

P§ 200

4.7 f 1.2

4.7 + 1.4

91 + 15

52 + 13

165 f 35

46 f 21

18.0 f 2.7

37.3

+ 3.9

24.2

70.9

f 1.6

68.3

71.7

* 1.9

P

<.05

Baseline

f 4.1

23.1 f 3.9

45.9 f 5.6

49.3 + 11.8

25.0 f 3.0

14.0 f 2.0

28.0 f 3.0

17.0 f 3.0

co5 NS

NS f 1.8

<.05

NS 69 + 1.9

After F$

42.0 f 7.2

<.Ol

<.05

P 750

f 3.5

NS

2,000

Joint Tendemess$

After F$

31.2

<.05

P Hanly’” (n = 20)

Joint Swellingt Baseline

<.05

<.Ol

NOTE: All values given are mean f SE. Abbreviation: &, therapy. *Shown as hours by Strober et al, and minutes by Hanly et al. TJoint swelling was measured as swelling score by Strober et al, and proximal interphalangeal joint circumference (mm) by Henley et al. &loint tenderness score (O-4 scale) was used by Strober et al, and Ritchie index (which uses a O-3 scale) was used by Hanly et al. §P relate to the differences between baseline and post-TLI values and are based on Students’ 2-tailed

t test

in the study of Strober et al,

and Wilcoxon signed rank test in the study of Hanly et al.

frequently. Although bone marrow suppression was noted in one of ten patients in the 750 rad group (compared with four in the 2,000 rad group), no infections occurred in the smaller dose group (compared with four patients in the larger 2,000 rad group). Changes in clinical parameters, as demonstrated in two double-blind randomized trials, are shown in the Table 4.‘32V’34 The open trial from the Federal Republic of Germany employing 11 patients also showed significant clinical improvement after 6 months. But, as in other studies, severe adverse reactions were common, including mortality among four patients at a follow-up period of 2 years.‘33*‘3’ Long-term effects of TLI are difficult to assess with certainty, since only a small number of patients have been reported for follow-up. Overall, significant clinical effects of TLI last for about 12 months in most patients, and some patients maintain such improvement for even a longer period. Ten Harvard patients were reevaluated after a mean + SE of 30 f 2 months.13’ Significant improvement was retained at this period of follow-up in number of swollen and painful joints, overall degree of synovitis, morning stiffness, and 50-feet walking time when compared with pre-TLI values. However, morbidity and mortality among the 12 Harvard patients treated with TLI were considerable, with four deaths among these 12 patients.“’ Two follow-up reports from Stanford University have been published, one with the results of a mean follow-up period of 21 months,‘30 and the other

for a period of up to 48 months.‘36 The latter report describes follow-up of 32 RA patients who had received TLI; however, only 14, 13, and six patients were reevaluated after 2,3, and 4 years, respectively. After 1 year, 30 patients were available for reevaluation and these patients showed a mean f SEM improvement of 50 f 7.8% in joint swelling and 45 f 9.5% in joint tenderness, as compared with the baseline. At 2 years, the corresponding values for the 14 patients assessed were 41 * 16% and 41 f 17%, respectively. The level of improvement was similar at 3 years. However, at 4 years, three of the five patients evaluated were receiving disease modifying drugs because of a worsening of their condition. Considering that a 50% improvement in such indices as joint swelling and tenderness represents “important improvement” of clinical significance in RA,13’ it would appear that such improvement is lacking after 1 year of TLI treatment. The immunologic and laboratory effects on parameters such as ESR and rheumatoid factor were remarkably similar in all studies.‘28-‘34*138 Profound and sustained lymphopenia, predominant depletion of T helper cells with a decrease in T helper/T suppressor ratio (as in acquired immunodeficiency syndrome), and decreased proliferative response of mononuclear cells to phytohemagglutinin and concanavalin A were consistently observed. Generally, no change in rheumatoid factor titer, immune complex levels, antinuclear antibody titer, immunoglobulins,

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and ESR was noted. Synovial fluid (SF) changes were assessed in one study’34 showing a significant decrease in polymorphonuclear leucocytes (P < .05), but none in lymphocytes or their subpopulations. Further, SF levels of total IgM, IgA, and IgG decreased significantly (P < .Ol), but SF IgM rheumatoid factor levels remained unchanged. No studies evaluated cellular changes in synovium or changes in radiologic bony erosions. Adverse reactions of TLI are common and frequently serious. Fatigue, anorexia and other GI symptoms, malaise, and dry mouth are almost universal, and bacterial sepsis as well as herpes zoster infections are common. Various side effects of TLI from the combined published series (n = 57) are shown in Table 5. Mortality rate is disconcertingly high. The patients reported by Herbst et a1’35 seem to be the same ones reported by Niisslein et a1’33 and were not included in analysis. Also, the earlier Harvard’28 and Stanford’*’ patients were included in subsequent follow-up reports from these centers,‘3’.‘30 and, therefore, were not counted among the 57 patients. Ten of the 57 (18%) patients died, although death was probably not causally related in one patient following hip surgery. Causes of death among these ten patients were sepsis in three, renal failure due to amyloidosis in two, Table

5.

Percent

Frequency

due

Fatigue,

malaise,

to TLI

of Adverse

Used

Reactions

in RA

100

GI symptoms

Xerostomia

77

Alopecia

57

(21)

30

133)

Significant

weight

loss

Leucopenia/bone

marrow

25

suppression

18

Deatht Bacterial

18

infections

Herpes

zoster

18

infection

Cardiopulmonary

failure/myocardial

9

infarction

33

Other$ NOTE:

A

received

total

either

inclusive

the

study

population

2,000

of those

*Figures whom

(22)’

or

causing

of rad.

57

patients,

Adverse

who

had

reactions

are

death.

in parentheses frequency

3,000

are the

of

the

total

particular

numbers adverse

of patients

in

reactions

were

includes

loss of

specified. tSee

text for causes

SOther, teeth

in

as mentioned three

amyloidosis one of nine,“’

of

with

of death. by various

12,13’

renal failure

and esophageal

investigators,

hypothyroidism in two

in

three

of 1 1 ,13’ Keposi’s

candidiasis

of

12,13’

sarcoma

in one of ten.‘34

in

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myocardial infarction in two, cardiopulmonary arrest in two, and pulmonary embolism (following hip surgery) in one. It seems probable that cardiovascular deaths are causally related to TLI, in view of recent evidence that TLI may accelerate coronary artery disease.‘39’40 The mean interval following TLI at which death occurred was 14.6 months (range, 2 to 29 months) among the eight patients in whom this information was provided. Constitutional symptoms, including fatigue, malaise, and anorexia usually lasted for K 10 weeks. However, xerostomia can be prolonged and may lead to loss of teeth despite maintenance of vigorous oral hygiene.13’ Leukopenia is not usually permanent but often associated with infections. Infections and septicemia are a common cause of morbidity and mortality. The reasons for increased adverse reactions from TLI in RA as compared with Hodgkin’s disease are not known, but older age, previous treatment with immunosuppressive/ immune modifying drugs, and perhaps RA itself may be responsible. Although doses smaller than 2,000 rad may be effective with fewer and less serious side effects,‘34 the effect of such low dose on stem-cell DNA is not known. It is possible that lower doses will cause damage to the stem cell without killing it, thus encouraging leukemic growth. Among Hodgkins disease patients treated with TLI, an increased occurrence of both acute leukemia and solid tumors has recently been reported.‘4’,‘42 Thus, the most serious side effects of TLI may occur months or years later among the RA patients, and, therefore, continued close surveillance of these patients must be carried out.‘43 Adverse reactions of TLI and immunosuppressive drugs were compared in a recent report describing 34 patients treated with TLI and 32 with various immunosuppressive agents that included azathioprine in 18, MTX in eight, cyclophosphamide in five, and chlorambucil in one.‘44 Mean follow-up period was 2.7 years in the former group and 5.9 years in the latter. The most impressive finding was a significantly higher frequency of infections requiring hospitalization among the TLI group. Besides infections, major side effects (leukopenia, thrombocytopenia, aplastic anemia) occurred in 18% in the TLI group and 9% in the immunosuppressive therapy group. However, minor side effects (eg, GI,

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stomatitis, rash) requiring cessation of therapy were more frequently present in the latter group of patients. Four deaths occurred in each group, but two were most likely related to TLI, compared with one caused by an immunosuppressive agent. Thus, serious side effects were more frequently encountered in the TLI group. In conclusion, TLI appears effective in RA, although no true double-blind sham-controlled studies are available, and the numbers of patients studied in all the trials have been small. TLI causes rather prolonged and marked lymphopenia, and clinical improvement is maintained for approximately 12 months in a majority of patients, following a peak effect at about 6 months. It is clear that the beneficial effects of TLI are not permanent and most patients require additional immunosuppressive therapy within a few years. Side effects are common, and frequent serious adverse reactions are generally unacceptable. The mortality rate is disturbingly high, and one center has discontinued using TLI as a form of therapy in RA.14’ Using lower doses may decrease such side effects, but may also increase the potential for malignancies. However, recent studies of TLI in RA have been of great help in better understanding of RA pathogenesis. It appears that cell mediated immunity plays an important role in RA, and future therapeutic efforts should be directed to modify T cell dysfunction. The important role of T cells in RA was earlier demonstrated in the detailed and laborious study of thoracic duct drainage.g’ PULSE METHYLPREDNISOLONE

Use of pulse methylprednisolone (MP) in RA was stimulated by reported beneficial effects of this therapy in such rheumatic conditions as lupus nephritis,‘4”‘48 severe ankylosing spondylitis,14’and polyarteritis nodosa.“’ In 1978, Fan et al treated six RA patients with 1 g MP as a single dose and another six patients with a total of 3 g MP (1 g/d for three consecutive days), with clinical improvement in three of six in the first group and five of six in the latter group.15’ Maximum response, often dramatic, occurred on day 4, and six patients still felt better at 4 weeks (four patients in 3-g dose and two in l-g dose groups). Moverover, one patient in each group “entered a complete remission” that lasted for more than 16 weeks.

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Results of the first double-blind, placebo controlled study including ten RA patients who received either 1 g of MP every month for 6 months, or placebo, were encouraging, showing improvement in clinical parameters as well as levels of serum immune complexes.“* However, in this cross-over study the numbers were too small, and drop out or switch over ratio was high. Therefore, the results should be interpreted with caution, as acknowledged by the investigators. Forster et al treated 14 hospitalized patients not responding to gold, penicillamine, or sulfasalazine in an open trial with 27 courses of pulse MP, each consisting of three IV infusions on alternate days. ‘53“Clinical improvement” as well as significant decrease in acute phase reactants, eg, ESR, C-reactive protein, C3, and C4, occurred within seven days. Improvement lasted for a mean period of 7 weeks. Uncontrolled nature of the study, effect of hospitalization, and a lack of objective measurements, eg, joint swelling and articular index, make the assessment of the results of this trial difficult. Williams et al reported the results of a doubleblind placebo controlled trial of 1 g IV MP followed by single-blind assessment.‘54 Only two of the 20 patients had been previously treated with systemic corticosteroids or a disease modifying drug. Statistically significant improvement was observed after 6 weeks in various clinical parameters, eg, articular index, morning stiffness, grip strength, and subjective pain. The benefit lasted for 6 weeks in all patients. Williams subsequently reported the results of pulse 1 to 3 g MP, given at variable intervals, in 123 patients that were monitored in an open tria1.‘55 In contrast to their earlier trial,‘54 the latter with a larger number of patients155 demonstrated that only half the patients showed improvement for 6 weeks, and the overall progress of the disease also remained relatively unaffected. The investigator attributes this difference to a larger sample in the latter report, representing a wider spectrum of disease activity and more chronic disease. Serious side effects of pulse MP are rare, and overall, this form of therapy appears relatively safe, at least in short-term use.‘47,155s156 Common side effects are a bitter taste during the infusion (which is assuaged by sucking a hard candy), transient headache, facial flushing, psychological effects (jitteriness, insomnia, euphoria),

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tachycardia, GI intolerance, hypertension, and hyperglycemia, all of which are usually transient and occur within 48 hours postinfusion. Serious, but less common, adverse reactions include hypotension, arrhythmia, avascular necrosis, glaucoma, and seizures. Prolonged adrenal suppression has not been observed.‘s5~‘57 Intractable hiccups were reported in four patients, one with RA.“* Presence of infection is an absolute contraindication to pulse MP therapy,‘55 and MP should be administered diluted (eg, in 50 to 100 mL of 0.9% sodium chloride) and slowly over 30 to 45 minutes.“’ Repeated bolus injections would appear to predispose to serious side-effects, eg, avascular necrosis.“’ Patients should also be screened for cardiac diseases, and special care is needed in elderly patients. The mode of action of pulse MP is uncertain. When infused over a period of 20 minutes, MP attains peak plasma levels within the first hour, decreasing to very low concentrations in six to seven hours.“’ The minute plasma levels still present after three to four days are insufficient to explain the prolonged effect in RA and other diseases. Changes in rheumatoid factor titer have not been noted, although serum immune complexes decreased in one study.15* Lymphopenia with selective T cell suppression was noted two hours after each infusion with maximal effect at six hours, but recovering completely after 24 hours; delayed hypersensitivity, as measured by skin testing by recall antigens (such as PPD and histoplasmin), as well as antibody response to tetanus and typhoid, were maintained normally?’ A more recent study confirmed lymphopenia, affecting both 0KT4 and OKT8 cells, four hours post infusion of pulse MP.‘59 In SF, there was a significant decrease in numbers of polymorphonuclear leucocytes, lymphocytes, immune complexes, and C-reactive protein with a disproportionate decrease in the percentage of SF lymphocytes expressing HLA-DR antigens. Results of this study suggest that pulse MP causes rapid but transient changes in inflammatory activities and directly modulates T cell activation within the joints in RA.‘59 In conclusion, pulse MP has not been shown to have a long-lasting beneficial effect in RA, nor does it seem to have any effect on the progression of disease. The indications for use of pulse MP are not clear, but this form of therapy may be

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beneficial in some patients during an acute flare. or for active disabling disease at the initiation of disease-modifying drug treatment. Pulse MP under these circumstances may produce fewer significant side effects than daily corticosteroids in a moderately high dose. Overall, pulse MP has few serious side effects, but frequent administration should be avoided, particularly in elderly individuals. As mentioned earlier (see the section on cyclophosphamide), pulse MP has been used along with IV cyclophosphamide in serious rheumatoid vasculitis.62 OTHER DRUGS

Levamisole is a three-ringed antihelmenthic drug that augments helper, amplifier, suppressor, and cytotoxic functions of T cells.‘60 This drug also enhances chemotactic and phagocytic functions of polymorphonuclear leucocytes and monocytes when these functions are impaired.“’ and may indirectly stimulate antibody production.16’ Levamisole has been used in various autoimmune diseases with varied and sometimes contradictory results, which are perhaps expected in view of multiple actions of this drug. Several trials of levamisole in RA indicate varying degrees of efficacy, but unacceptable adverse reactions occur with effective dose schedules.“‘‘66 Limiting side effects of levamisole include agranulocytosis, mucocutaneous lesions, fever, nausea and vomiting, fatigue, and drowsiness. It has been aptly concluded that “because effective doses are poorly tolerated, and tolerable lower doses are relatively ineffective, levamisole cannot be recommended as standard treatment of rheumatoid arthritis.“‘6h Cyclosporin A (CyA) is a 1,200-dalton fungal metabolite having a weak antifungal action, but marked effects on the immune response. The drug has recently been used successfully as an immunosuppressive agent for organ transplantation,16’ as well as bone marrow transplantation,‘68 with significant impairment of T cell mediated graft-v-host disease, without having much effect on the rapidly dividing transplanted stem cells. The drug has a low degree of bone marrow toxicity, but produces marked inhibitory effect on T cell functions, particularly those dependent on helper/inducer activity. CyA preferentially acts on proliferating T lymphocytes,‘68.‘69 probably by inhibiting the production

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of receptors for IL- 1.“O In addition to its selective effect on helper T-lymphocyte function, CyA has also been shown to have selective direct effects of either inhibition or enhancement on certain subsets of B cells,“’ with increase in IgG levels.‘67 Various adverse reactions, including nephrotoxicity, are a limiting factor for use of CyA. Lymphomas have also been reported, probably from immunosuppression.167 Results of limited trials of CyA in a dose of 5 to 10 mg/kg/d in RA, both open172~173 and double-blind,174have recently been published. Only a small number of patients was studied in these trials, but significant improvement in various clinical parameters, including joint swelling and tenderness, was evident. However, considerable side-effects with patient withdrawal from the study were frequent.172S174 Most common adverse reactions were a rise in serum creatinine, hypertension, and GI symptoms. Other reactions included hypertrichosis, gingival hyperplasia, paresthesia, tremor, and elevated hepatic enzymes. Limited data are available on the effect of y interferon,17’~176dietary fish oil,“’ fish-oil fatty acid supplementation,178,179 clotrimazole,‘80*181 and venoms’82 in RA. Preliminary data show some beneficial effects of these therapeutic modalities among RA patients, but further studies are clearly necessary. A recent double-blind, placebo-controlled, cross over study of fish-oil fatty acids demonstrating beneficial effect in RA179 is particularly interesting. In this study, statistically significant improvement occurred in ARA functional class and tender joints after 7 weeks, and in morning fatigue, ARA class, physician global assessment, tender joints, and swollen joints in 14 weeks. Neutrophil leukotrien B4 production also decreased significantly and correlated with decrease in number of tender joints (P < .05). 179It is known that fish-oil fatty acids (eicosapentaenoic acid and docosahexaenoic acid) competitively inhibit the production of leukotriens183 and prostaglandins.184 Fish-oil fatty acids were generally well-tolerated in the study of Kremer et al, although transient stomach upset and loose stools were reported by several patients.179 Two recent articles have nicely reviewed several nontraditional forms of therapy in RA.185*‘86 Monoclonal antibodies directed against spe-

cific cell populations and the use of various antibiotics in RA are currently under study in several centers. Results of these studies are awaited with interest. CONCLUSION

Therapeutic efficacy and possible mechanisms of action of several investigational therapies in RA have been reviewed. MTX and sulfasalazine are most promising as disease modifying agents with a favorable benefit to risk ratio. Long-term eIIicacy and adverse reactions of these drugs are unknown. Total lymphoid irradiation is also effective, but serious adverse reactions are prohibitive. Both cyclophosphamide and plasmapheresis may be used in life-threatening rheumatoid vasculitis; the latter should further be employed in serious RA complications of hyperviscosity syndrome and cryoglobulinemia. Pulse methylprednisolone is useful in some patients, but its effects are not long lasting and repeated infusions may cause unwanted adverse reactions; this form of therapy may be used in acute flare-ups of RA or while effects of a slow acting drug are awaited in active, disabling disease. Various other forms of therapy, including use of CyA, y interferon, antibiotics, dietary fatty acids, and monoclonal antibodies against specific cell populations, are under study. CyA appears effective, but adverse reactions are considerable; other cyclosporins with fewer side effects may be available for clinical trial in the future. It is hoped that continued efforts to find newer forms of therapy, along with better understanding of the pathogenetic mechanism in RA, will allow for more satisfactory management of this disabling condition in the future. ACKNOWLEDGMENT The author wishes to thank Drs Alfonse T. Masi and David E. Trentham for their helpful critique of the manuscript, Barbara Lundeen for her valuable technical help, and the Word Processing Center for fine typing. REFERENCES 1. Yunus MB: Auranotin in the treatment of rheumatoid arthritis. Continuing Ed Fam Phys 21:37-47, 1986 2. Decker JL, Malone DG, Haraoui B, et al: Rheumatoid arthritis: Evolving concepts of pathogenesis and treatment. Ann Intern Med 101:810-824, 1984 3. Fauci AS: Cytotoxic and other immunoregulatory drugs, in Kelly WN, Harris ED, et al (eds): Textbook of Rheumatology. Philadelphia, Saunders, 1985, pp 833-857

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leucotrien B, and complement C5a. J Rheumatol 14:9-l 1, 1987 44. Ford-Hutchison AW, Bray MA, Doig MV, et al: Leukotrien B,, a potent chemokinetic and aggregating substance released from polymorphonuclear leucocytes. Nature 286:264-265, 1980 45. Hughli TE, Miiler-Eberhard HJ: Anaphylatoxins: C3a and C5a. Adv Immunol26:1-28,1978 46. Ward PA, Zvaifler NJ: Complement-derived leukotactic factors in inflammatory synovial fluids of humans. J Clin Invest 50:606-6 16, 197 1 47. Klickstein LB, Shapleigh C, Goetzl EJ: Lipoxygenation of arachidonic acid as a source of polymorphonuclear leucocyte chemotactic factors in synovial fluid and tissue in rheumatoid arthritis and spondylarthritis. J Clin Invest 66:1166-1170, 1980 48. Walsdorfer V, Christophers E, Shroder JM, et al: Methotrexate inhibitis polymorphonuclear leuckocyte chemotaxis in psoriasis. Br J Dermatol 108:451-456, 1983 49. Fosdick WM, Parsons JL, Hill DF: Long-term cyclophosphamide therapy in rheumatoid arthritis. Arthritis Rheum 11:151-161, 1968 50. Fosdick WM. Parsons JL, Hill DF: Long-term cyclophosphamide therapy in rheumatoid arthritis: A progress report, six years’ experience. Arthritis Rheum 12:663, 1969 (abstr) 51. Cooperating Clinics Committee of the American Rheumatism Association: A controlled trial of cyclophosphamide in rheumatoid arthritis. N Engl J Med 283:883-889, 1970 52. Lidsky M, Sharp JT, Billings S: Double-blind study of cyclophosphamide in rheumatoid arthritis. Arthritis Rheum 16:148-153, 1973 53. Curlis JE, Sharp JT, Lidsky MD, et al: Immune response of patients with rheumatoid arthritis during cyclophosphamide treatment. Arthritis Rheum 13:754-760, 1970 54. Currey HLF, Harris J, Mason RM, et al: Comparison of azathioprine, cyclophosphamide, and gold in treatment of rheumatoid arthritis. Br Med J 3:763-766, 1974 55. Smyth CJ, Bartholomew BA, Mills DM, et al: Cyclophosphamide therapy for rheumatoid arthritis. Arch Intern Med 135:789-793, 1975 56. Townes AS, Sowa JM, Shulman LE: Controlled trial of cyclophosphamide in rheumatoid arthritis. Arthritis Rheum 19:563-573, 1976 57. Williams HJ, Reading JC, Ward JR, et al: Comparison of high and low dose cyclophosphamide therapy in rheumatoid arthritis. Arthritis Rheum 23:521-527, 1980 58. Decker JL: Toxicity of immunosuppressive drugs in man. Arthritis Rheum 16:89-91, 1973 59. Decker JL: Azathioprine and cyclophosphamide as slow-actings for rheumatoid arthritis. Am J Med 75:74-78, 1983 60. Abel T, Andrews BS, Cunningham PH, et al: Rheumatoid vasculitis: Effect of cyclophophamide on the clinical course and levels of circulating immune complexes. Ann Intern Med 93:407-413, 1980 61. Scott DGI, Bacon PA, Allen C, et al: IgG rheumatoid factor, complement and immune complexes in rheumatoid synovitis and vasculitis: Comparative and serial studies during cytotoxic therapy. Clin Exp Immunol43:54-63, 1981

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